Sample records for abnormal substantia nigra

  1. Illicit Stimulant Use Is Associated with Abnormal Substantia Nigra Morphology in Humans

    PubMed Central

    Todd, Gabrielle; Noyes, Carolyn; Flavel, Stanley C.; Della Vedova, Chris B.; Spyropoulos, Peter; Chatterton, Barry; Berg, Daniela; White, Jason M.

    2013-01-01

    Use of illicit stimulants such as methamphetamine, cocaine, and ecstasy is an increasing health problem. Chronic use can cause neurotoxicity in animals and humans but the long-term consequences are not well understood. The aim of the current study was to investigate the long-term effect of stimulant use on the morphology of the human substantia nigra. We hypothesised that history of illicit stimulant use is associated with an abnormally bright and enlarged substantia nigra (termed ‘hyperechogenicity’) when viewed with transcranial sonography. Substantia nigra morphology was assessed in abstinent stimulant users (n = 36; 31±9 yrs) and in two groups of control subjects: non-drug users (n = 29; 24±5 yrs) and cannabis users (n = 12; 25±7 yrs). Substantia nigra morphology was viewed with transcranial sonography and the area of echogenicity at the anatomical site of the substantia nigra was measured at its greatest extent. The area of substantia nigra echogenicity was significantly larger in the stimulant group (0.273±0.078 cm2) than in the control (0.201±0.054 cm2; P<0.001) and cannabis (0.202±0.045 cm2; P<0.007) groups. 53% of stimulant users exhibited echogenicity that exceeded the 90th percentile for the control group. The results of the current study suggest that individuals with a history of illicit stimulant use exhibit abnormal substantia nigra morphology. Substantia nigra hyperechogenicity is a strong risk factor for developing Parkinson's disease later in life and further research is required to determine if the observed abnormality in stimulant users is associated with a functional deficit of the nigro-striatal system. PMID:23418568

  2. Adults with a history of illicit amphetamine use exhibit abnormal substantia nigra morphology and parkinsonism.

    PubMed

    Todd, Gabrielle; Pearson-Dennett, Verity; Wilcox, Robert A; Chau, Minh T; Thoirs, Kerry; Thewlis, Dominic; Vogel, Adam P; White, Jason M

    2016-04-01

    The sonographic appearance of the substantia nigra is abnormally bright and enlarged (hyperechogenic) in young adults with a history of illicit stimulant use. The abnormality is a risk factor for Parkinson's disease. The aim of the current study was to identify the type of illicit stimulant drug associated with substantia nigra hyperechogenicity and to determine if individuals with a history of illicit stimulant use exhibit clinical signs of parkinsonism. We hypothesised that use of amphetamines (primarily methamphetamine) is associated with substantia nigra hyperechogenicity and clinical signs of parkinsonism. The area of echogenic signal in the substantia nigra was measured in abstinent human amphetamine users (n = 27; 33 ± 8 years) and in three control groups comprising a) 'ecstasy' users (n = 19; 23 ± 3 years), b) cannabis users (n = 30; 26 ± 8 years), and c) non-drug users (n = 37; 25 ± 7 years). A subset of subjects (n = 55) also underwent a neurological examination comprising the third and fifth part of the Unified Parkinson's Disease Rating Scale. Area of substantia nigra echogenicity was significantly larger in the amphetamine group (0.276 ± 0.080 cm(2)) than in the control groups (0.200 ± 0.075, 0.190 ± 0.049, 0.191 ± 0.055 cm(2), respectively; P < 0.002). The score on the clinical rating scale was also significantly higher in the amphetamine group (8.4 ± 8.1) than in pooled controls (3.3 ± 2.8; P = 0.002). Illicit use of amphetamines is associated with abnormal substantia nigra morphology and subtle clinical signs of parkinsonism. The results support epidemiological findings linking use of amphetamines, particularly methamphetamine, with increased risk of developing Parkinson's disease later in life. Copyright © 2016 Elsevier Ltd. All rights reserved.

  3. Substantia Nigra Free Water Increases Longitudinally in Parkinson Disease.

    PubMed

    Guttuso, T; Bergsland, N; Hagemeier, J; Lichter, D G; Pasternak, O; Zivadinov, R

    2018-02-01

    Free water in the posterior substantia nigra obtained from a bi-tensor diffusion MR imaging model has been shown to significantly increase over 1- and 4-year periods in patients with early-stage idiopathic Parkinson disease compared with healthy controls, which suggests that posterior substantia nigra free water may be an idiopathic Parkinson disease progression biomarker. Due to the known temporal posterior-to-anterior substantia nigra degeneration in idiopathic Parkinson disease, we assessed longitudinal changes in free water in both the posterior and anterior substantia nigra in patients with later-stage idiopathic Parkinson disease and age-matched healthy controls for comparison. Nineteen subjects with idiopathic Parkinson disease and 19 age-matched healthy control subjects were assessed on the same 3T MR imaging scanner at baseline and after approximately 3 years. Baseline mean idiopathic Parkinson disease duration was 7.1 years. Both anterior and posterior substantia nigra free water showed significant intergroup differences at baseline ( P < .001 and P = .014, respectively, idiopathic Parkinson disease versus healthy controls); however, only anterior substantia nigra free water showed significant longitudinal group × time interaction increases ( P = .021, idiopathic Parkinson disease versus healthy controls). There were no significant longitudinal group × time interaction differences found for conventional diffusion tensor imaging or free water-corrected DTI assessments in either the anterior or posterior substantia nigra. Results from this study provide further evidence supporting substantia nigra free water as a promising disease-progression biomarker in idiopathic Parkinson disease that may help to identify disease-modifying therapies if used in future clinical trials. Our novel finding of longitudinal increases in anterior but not posterior substantia nigra free water is potentially a result of the much longer disease duration of our cohort compared

  4. [Morphochemical changes in the substantia nigra cellular structures in Parkinson's disease].

    PubMed

    Salkov, V N; Khudoerkov, R M; Voronkov, D N; Sobolev, V B; Kutukova, K A

    to clarify the features of morphochemical changes in the substantia nigra cellular structures in Parkinson's disease. The structural characteristics of the substantia nigra were studied microscopically and quantified using computer morphometric methods at brain autopsies of individuals with Parkinson's disease who had died from intercurrent diseases and those who had no evidence of neurological disorders in their history (a control group). This investigation could clarify the features of morphochemical changes in both the neural network structures and the glial populations of the substantia nigra in Parkinson's disease. The number of neurons containing tyrosine hydroxylase (a marker of dopamine neurons) in the compact part of the substantia nigra (a ventral region) was smaller and the density distribution of Lewy bodies was higher in the patients with Parkinson's disease than in the control group. The accumulation of iron (II) compounds in the cellular elements and neuropile and the increased expression of glial fibrillary acidic protein in Parkinson's disease were more pronounced than those in the controls. Postmortem diagnosis in Parkinson's disease should be based on a full description of a set of neuronal and glial morphochemical and structural changes in the substantia nigra rather than on the identification of cellular markers for the neurodegenerative process.

  5. Dopamine D2 receptor levels in striatum, thalamus, substantia nigra, limbic regions, and cortex in schizophrenic subjects.

    PubMed

    Kessler, Robert M; Woodward, Neil D; Riccardi, Patrizia; Li, Rui; Ansari, M Sib; Anderson, Sharlett; Dawant, Benoit; Zald, David; Meltzer, Herbert Y

    2009-06-15

    Studies in schizophrenic patients have reported dopaminergic abnormalities in striatum, substantia nigra, thalamus, anterior cingulate, hippocampus, and cortex that have been related to positive symptoms and cognitive impairments. [(18)F]fallypride positron emission tomography studies were performed in off-medication or never-medicated schizophrenic subjects (n = 11, 6 men, 5 women; mean age of 30.5 +/- 8.0 [SD] years; 4 drug-naive) and age-matched healthy subjects (n = 11, 5 men, 6 women, mean age of 31.6 +/- 9.2 [SD]) to examine dopamine D(2) receptor (DA D(2)r) levels in the caudate, putamen, ventral striatum, medial thalamus, posterior thalamus, substantia nigra, amygdala, temporal cortex, anterior cingulate, and hippocampus. In schizophrenic subjects, increased DA D(2)r levels were seen in the substantia nigra bilaterally; decreased levels were seen in the left medial thalamus. Correlations of symptoms with ROI data demonstrated a significant correlation of disorganized thinking/nonparanoid delusions with the right temporal cortex ROI (r = .94, p = .0001), which remained significant after correction for multiple comparisons (p < .03). Correlations of symptoms with parametric images of DA D(2)r levels revealed no significant clusters of correlations with negative symptoms but significant clusters of positive correlations of total positive symptoms, delusions and bizarre behavior with the lateral and anterior temporal cortex, and hallucinations with the left ventral striatum. The results of this study demonstrate abnormal DA D(2)r-mediated neurotransmission in the substantia nigra consistent with nigral dysfunction in schizophrenia and suggest that both temporal cortical and ventral striatal DA D(2)r mediate positive symptoms.

  6. Substantia nigra neuromelanin: structure, synthesis, and molecular behaviour

    PubMed Central

    Zecca, L; Tampellini, D; Gerlach, M; Riederer, P; Fariello, R G; Sulzer, D

    2001-01-01

    The pigmented neurones of the substantia nigra are typically lost in Parkinson's disease; however, the possible relation between neuronal vulnerability and the presence of neuromelanin has not been elucidated. Early histological studies revealed the presence of increasing amounts of neuromelanin in the substantia nigra with aging in higher mammals, showed that the neuromelanin granules are surrounded by a membrane, and comparatively evaluated the pigmentation of the substantia nigra in different animal species. Histochemical studies showed the association of neuromelanin with lipofuscins. However, systematic investigations of the structure, synthesis, and molecular interactions of neuromelanin have been undertaken only during the past decade. In these later studies, neuromelanin was identified as a genuine melanin with a strong chelating ability for iron and an affinity for compounds such as lipids, pesticides, and MPP+. The affinity of neuromelanin for a variety of inorganic and organic toxins is consistent with a postulated protective function for neuromelanin. Moreover, the neuronal accumulation of neuromelanin during aging and the link between its synthesis and a high cytosolic concentration of catechols suggest a protective role. However, its putative neuroprotective effects could be quenched in conditions of toxin overload. PMID:11724917

  7. Dopamine D2 Receptor Levels in Striatum, Thalamus, Substantia Nigra, Limbic Regions, and Cortex in Schizophrenic Subjects

    PubMed Central

    Kessler, Robert M; Woodward, Neil D; Riccardi, Patrizia; Li, Rui; Ansari, M Sib; Anderson, Sharlett; Dawant, Benoit; Zald, David; Meltzer, Herbert Y

    2009-01-01

    Background Studies in schizophrenics have reported dopaminergic abnormalities in striatum, substantia nigra, thalamus, anterior cingulate, hippocampus and cortex which have been related to positive symptoms and cognitive impairments. Methods [18F]fallypride PET studies were performed in off medication or never medicated schizophrenic subjects [N = 11, 6 M, 5 F; mean age of 30.5 ± 8.0 (S.D.); 4 drug naive] and age matched healthy subjects [N = 11, 5M, 6F, mean age of 31.6 ± 9.2 (S.D.)] to examine dopamine D2 receptor (DA D2r) levels in the caudate, putamen, ventral striatum, medial thalamus, posterior thalamus, substantia nigra, amygdala, temporal cortex, anterior cingulate, and hippocampus. Results In schizophrenic subjects increased DA D2r levels were seen in the substantia nigra bilaterally; decreased levels were seen in the left medial thalamus. Correlations of symptoms with region of interest data demonstrated a significant correlation of disorganized thinking/nonparanoid delusions with the right temporal cortex region of interest (r = 0.94, P = 0.0001) which remained significant after correction for multiple comparisons (P<0.03). Correlations of symptoms with parametric images of DA D2r levels revealed no significant clusters of correlations with negative symptoms, but significant clusters of positive correlations of total positive symptoms, delusions and bizarre behavior with the lateral and anterior temporal cortex, and hallucinations with the left ventral striatum. Conclusions The results of this study demonstrate abnormal DA D2r mediated neurotransmission in the substantia nigra consistent with nigral dysfunction in schizophrenia and suggest that both temporal cortical and ventral striatal DA D2r mediate positive symptoms. PMID:19251247

  8. Bidirectional Modulation of Substantia Nigra Activity by Motivational State

    PubMed Central

    Rossi, Mark A.; Fan, David; Barter, Joseph W.; Yin, Henry H.

    2013-01-01

    A major output nucleus of the basal ganglia is the substantia nigra pars reticulata, which sends GABAergic projections to brainstem and thalamic nuclei. The GABAergic (GABA) neurons are reciprocally connected with nearby dopaminergic neurons, which project mainly to the basal ganglia, a set of subcortical nuclei critical for goal-directed behaviors. Here we examined the impact of motivational states on the activity of GABA neurons in the substantia nigra pars reticulata and the neighboring dopaminergic (DA) neurons in the pars compacta. Both types of neurons show short-latency bursts to a cue predicting a food reward. As mice became sated by repeated consumption of food pellets, one class of neurons reduced cue-elicited firing, whereas another class of neurons progressively increased firing. Extinction or pre-feeding just before the test session dramatically reduced the phasic responses and their motivational modulation. These results suggest that signals related to the current motivational state bidirectionally modulate behavior and the magnitude of phasic response of both DA and GABA neurons in the substantia nigra. PMID:23936522

  9. Effects of mild running on substantia nigra during early neurodegeneration.

    PubMed

    Almeida, Michael F; Silva, Carolliny M; Chaves, Rodrigo S; Lima, Nathan C R; Almeida, Renato S; Melo, Karla P; Demasi, Marilene; Fernandes, Tiago; Oliveira, Edilamar M; Netto, Luis E S; Cardoso, Sandra M; Ferrari, Merari F R

    2018-06-01

    Moderate physical exercise acts at molecular and behavioural levels, such as interfering in neuroplasticity, cell death, neurogenesis, cognition and motor functions. Therefore, the aim of this study is to analyse the cellular effects of moderate treadmill running upon substantia nigra during early neurodegeneration. Aged male Lewis rats (9-month-old) were exposed to rotenone 1mg/kg/day (8 weeks) and 6 weeks of moderate treadmill running, beginning 4 weeks after rotenone exposure. Substantia nigra was extracted and submitted to proteasome and antioxidant enzymes activities, hydrogen peroxide levels and Western blot to evaluate tyrosine hydroxylase (TH), alpha-synuclein, Tom-20, PINK1, TrkB, SLP1, CRMP-2, Rab-27b, LC3II and Beclin-1 level. It was demonstrated that moderate treadmill running, practiced during early neurodegeneration, prevented the increase of alpha-synuclein and maintained the levels of TH unaltered in substantia nigra of aged rats. Physical exercise also stimulated autophagy and prevented impairment of mitophagy, but decreased proteasome activity in rotenone-exposed aged rats. Physical activity also prevented H 2 O 2 increase during early neurodegeneration, although the involved mechanism remains to be elucidated. TrkB levels and its anterograde trafficking seem not to be influenced by moderate treadmill running. In conclusion, moderate physical training could prevent early neurodegeneration in substantia nigra through the improvement of autophagy and mitophagy.

  10. Infusion of opiates into substantia nigra protects against maximal electroshock seizures in rats.

    PubMed

    Garant, D S; Gale, K

    1985-07-01

    Microinfusion of morphine sulfate (50 nmol), [d-Ala2]-Met-enkephalin (35 nmol) or dynorphin A 1-13 (1 nmol) bilaterally into the substantia nigra significantly attenuated seizures induced by maximal electroshock in rats. This action was accompanied by stereotyped behavioral hyperactivity. These anticonvulsant and behavioral effects were antagonized by systemic naloxone administration; neither effect was observed after intranigral microinjection of dynorphin A 1-17 amide (1 nmol). These results are consistent with a mu opiate receptor-mediated inhibition of substantia nigra efferent neurons, and with the proposal that bilateral inhibition of nigral efferents attenuates seizure propagation. However, intranigral morphine failed to alter the severity of i.v. bicuculline seizures, indicating that opiate-mediated inhibition in substantia nigra is distinct from that produced by gamma-aminobutyric acid.

  11. Increased expression of glutamic acid decarboxylase mRNA in rat substantia nigra after an ibotenic acid lesion in the caudate-putamen.

    PubMed

    Lindefors, N; Brené, S; Persson, H

    1990-04-01

    In situ hybridization histochemistry and RNA blots were used to study expression of glutamic acid decarboxylase (GAD) mRNA in rat caudate-nucleus and substantia nigra. In situ hybridization combined with computerized image analysis revealed that in the intact substantia nigra reticulata the cross-section area of GAD mRNA positive neurons were 25% larger in the dorsolateral part as compared with the ventromedial part. A unilateral ibotenic acid injection in caudate-putamen lesioned neurons, some of which project to the ipsilateral substantia nigra. An increased level of GAD mRNA was observed in substantia nigra ipsilateral to the lesion. Computerized image analysis of sections from in situ hybridization revealed an increase in the number of silver grains over GAD mRNA positive neurons in the dorsolateral substantia nigra reticulata ipsilateral to the lesion. However, no change was observed in the ventromedial part suggesting that GAD mRNA expression in this part of the nigra is less sensitive to inhibition by caudate-putamen afferents. In agreement with in situ experiments, RNA blots showed a 2-fold increased level of GAD mRNA in substantia nigra ipsilateral to the lesion. The increased GAD mRNA expression in the deafferented substantia nigra suggests a disinhibition of nigral GABA neurons, resulting in an increased utilization of GABA in these substantia nigra neurons.

  12. Striatal infarction in the rat causes a transient reduction of tyrosine hydroxylase immunoreactivity in the ipsilateral substantia nigra.

    PubMed

    Soriano, M A; Justicia, C; Ferrer, I; Rodríguez-Farré, E; Planas, A M

    1997-01-01

    Dopaminergic neurons of the substantia nigra pars compacta were examined in the rat brain following striatal infarction subsequent to transient focal cerebral ischemia. Rats had the middle cerebral artery occluded for 2 h or were sham-operated, and tyrosine hydroxylase immunoreactivity was evaluated by Western blot and immunohistochemistry at different times ranging from 1 to 60 days after ischemia. The number of tyrosine hydroxylase-immunoreactive cells in the substantia nigra pars compacta was counted under the light microscope and compared to that in the contralateral side and controls. No changes of tyrosine hydroxylase immunoreactivity were detected in the ipsilateral versus the contralateral substantia nigra of sham-operated rats or 1 day after ischemia. However, a statistically significant reduction of tyrosine hydroxylase-immunoreactive cells became apparent in the ipsilateral compared with the contralateral substantia nigra at 7 and 14 days after ischemia. This reduction showed a clear recovery at 30 days after ischemia, and no signs of difference between the ipsilateral and the contralateral side were apparent by 60 days. Therefore, the reduction of tyrosine hydroxylase immunoreactivity in the ipsilateral substantia nigra was only transiently seen from 1 to 2 weeks following ischemia. The observed loss of tyrosine hydroxylase was not accompanied by signs of cell death or gliosis in the ipsilateral pars compacta. The present results show a transitory reduction of tyrosine hydroxylase immunoreactivity in the ipsilateral substantia nigra pars compacta after focal ischemia and suggest that striatal infarction causes a transient deficit of dopaminergic function.

  13. Lateral Asymmetry and Spatial Difference of Iron Deposition in the Substantia Nigra of Patients with Parkinson Disease Measured with Quantitative Susceptibility Mapping.

    PubMed

    Azuma, M; Hirai, T; Yamada, K; Yamashita, S; Ando, Y; Tateishi, M; Iryo, Y; Yoneda, T; Kitajima, M; Wang, Y; Yamashita, Y

    2016-05-01

    Quantitative susceptibility mapping is useful for assessing iron deposition in the substantia nigra of patients with Parkinson disease. We aimed to determine whether quantitative susceptibility mapping is useful for assessing the lateral asymmetry and spatial difference in iron deposits in the substantia nigra of patients with Parkinson disease. Our study population comprised 24 patients with Parkinson disease and 24 age- and sex-matched healthy controls. They underwent 3T MR imaging by using a 3D multiecho gradient-echo sequence. On reconstructed quantitative susceptibility mapping, we measured the susceptibility values in the anterior, middle, and posterior parts of the substantia nigra, the whole substantia nigra, and other deep gray matter structures in both hemibrains. To identify the more and less affected hemibrains in patients with Parkinson disease, we assessed the severity of movement symptoms for each hemibrain by using the Unified Parkinson's Disease Rating Scale. In the posterior substantia nigra of patients with Parkinson disease, the mean susceptibility value was significantly higher in the more than the less affected hemibrain substantia nigra (P < .05). This value was significantly higher in both the more and less affected hemibrains of patients with Parkinson disease than in controls (P < .05). Asymmetry of the mean susceptibility values was significantly greater for patients than controls (P < .05). Receiver operating characteristic analysis showed that quantitative susceptibility mapping of the posterior substantia nigra in the more affected hemibrain provided the highest power for discriminating patients with Parkinson disease from the controls. Quantitative susceptibility mapping is useful for assessing the lateral asymmetry and spatial difference of iron deposition in the substantia nigra of patients with Parkinson disease. © 2016 by American Journal of Neuroradiology.

  14. Near-Infrared Confocal Laser Reflectance Cytoarchitectural Imaging of the Substantia Nigra and Cerebellum in the Fresh Human Cadaver.

    PubMed

    Cheyuo, Cletus; Grand, Walter; Balos, Lucia L

    2017-01-01

    Cytoarchitectural neuroimaging remains critical for diagnosis of many brain diseases. Fluorescent dye-enhanced, near-infrared confocal in situ cellular imaging of the brain has been reported. However, impermeability of the blood-brain barrier to most fluorescent dyes limits clinical utility of this modality. The differential degree of reflectance from brain tissue with unenhanced near-infrared imaging may represent an alternative technique for in situ cytoarchitectural neuroimaging. We assessed the utility of unenhanced near-infrared confocal laser reflectance imaging of the cytoarchitecture of the cerebellum and substantia nigra in 2 fresh human cadaver brains using a confocal near-infrared laser probe. Cellular images based on near-infrared differential reflectance were captured at depths of 20-180 μm from the brain surface. Parts of the cerebellum and substantia nigra imaged using the probe were subsequently excised and stained with hematoxylin and eosin for histologic correlation. Near-infrared reflectance imaging revealed the 3-layered cytoarchitecture of the cerebellum, with Purkinje cells appearing hyperreflectant. In the substantia nigra, neurons appeared hyporeflectant with hyperreflectant neuromelanin cytoplasmic inclusions. Cytoarchitecture of the cerebellum and substantia nigra revealed on near-infrared imaging closely correlated with the histology on hematoxylin-eosin staining. We showed that unenhanced near-infrared reflectance imaging of fresh human cadaver brain can reliably identify and distinguish neurons and detailed cytoarchitecture of the cerebellum and substantia nigra. Copyright © 2016 Elsevier Inc. All rights reserved.

  15. Ventral Tegmental Area and Substantia Nigra Neural Correlates of Spatial Learning

    ERIC Educational Resources Information Center

    Martig, Adria K.; Mizumori, Sheri J. Y.

    2011-01-01

    The ventral tegmental area (VTA) and substantia nigra pars compacta (SNc) may provide modulatory signals that, respectively, influence hippocampal (HPC)- and striatal-dependent memory. Electrophysiological studies investigating neural correlates of learning and memory of dopamine (DA) neurons during classical conditioning tasks have found DA…

  16. Glutamate neurons in the substantia nigra compacta and retrorubral field

    PubMed Central

    Yamaguchi, Tsuyoshi; Wang, Hui-Ling; Morales, Marisela

    2013-01-01

    Dopaminergic neurons of the substantia nigra compacta (SNC), ventral tegmental area (VTA) and retrorubral field (RRF) play a role in reward, motivation, learning, memory, and movement. These neurons are intermingled with GABAergic neurons. Recent evidence shows that the VTA contains glutamatergic neurons expressing vesicular glutamate transporter type 2 (VGluT2); some of them co-express tyrosine hydroxylase (TH). Here, we used a combination of radioactive in situ hybridization and immunohistochemistry to explore whether any of the vesicular glutamate transporters [vesicular glutamate transporter type 1 (VGluT1), VGluT2, or vesicular glutamate transporter type 3 (VGluT3)] were encoded by neurons in the SNC or RRF. We found expression of VGluT2 mRNA, but not of VGluT1 or VGluT3, in the SNC and RRF. These VGluT2 neurons rarely showed TH immunoreactivity. Within the SNC, the VGluT2 neurons were infrequently found at the rostral level, but were often seen at the medial and caudal levels intercalated in the mediolateral portion of the dorsal tier, at a ratio of one VGluT2 neuron per 4.4 TH neurons. At this level, VGluT2 neurons were also found in the adjacent substantia nigra reticulata and substantia nigra pars lateralis. Within the RRF, the VGluT2 neurons showed an increasing rostrocaudal gradient of distribution. The RRF proportion of VGluT2 neurons in relation to TH neurons was constant throughout the rostrocaudal levels, showing an average ratio of one VGluT2 neuron per 1.7 TH neurons. In summary, we provide evidence indicating that the SNC and RRF, which are traditionally considered to be dopaminergic areas, have neurons with the ability to participate in glutamate signaling. PMID:24102658

  17. Glutamate neurons in the substantia nigra compacta and retrorubral field.

    PubMed

    Yamaguchi, Tsuyoshi; Wang, Hui-Ling; Morales, Marisela

    2013-12-01

    Dopaminergic neurons of the substantia nigra compacta (SNC), ventral tegmental area (VTA) and retrorubral field (RRF) play a role in reward, motivation, learning, memory, and movement. These neurons are intermingled with GABAergic neurons. Recent evidence shows that the VTA contains glutamatergic neurons expressing vesicular glutamate transporter type 2 (VGluT2); some of them co-express tyrosine hydroxylase (TH). Here, we used a combination of radioactive in situ hybridisation and immunohistochemistry to explore whether any of the vesicular glutamate transporters [vesicular glutamate transporter type 1 (VGluT1), VGluT2, or vesicular glutamate transporter type 3 (VGluT3)] were encoded by neurons in the SNC or RRF. We found expression of VGluT2 mRNA, but not of VGluT1 or VGluT3, in the SNC and RRF. These VGluT2 neurons rarely showed TH immunoreactivity. Within the SNC, the VGluT2 neurons were infrequently found at the rostral level, but were often seen at the medial and caudal levels intercalated in the mediolateral portion of the dorsal tier, at a ratio of one VGluT2 neuron per 4.4 TH neurons. At this level, VGluT2 neurons were also found in the adjacent substantia nigra reticulata and substantia nigra pars lateralis. Within the RRF, the VGluT2 neurons showed an increasing rostrocaudal gradient of distribution. The RRF proportion of VGluT2 neurons in relation to TH neurons was constant throughout the rostrocaudal levels, showing an average ratio of one VGluT2 neuron per 1.7 TH neurons. In summary, we provide evidence indicating that the SNC and RRF, which are traditionally considered to be dopaminergic areas, have neurons with the ability to participate in glutamate signaling. © 2013 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

  18. Chronic Nicotine Treatment Increases nAChRs and Microglial Expression in Monkey Substantia Nigra after Nigrostriatal Damage

    PubMed Central

    Campos, Carla; Parameswaran, Neeraja; William Langston, J.; Michael McIntosh, J.; Yeluashvili, Michael

    2010-01-01

    Our previous work had shown that long-term nicotine administration improved dopaminergic markers and nicotinic receptors (nAChRs) in the striatum of monkeys with nigrostriatal damage. The present experiments were done to determine whether nicotine treatment also led to changes in the substantia nigra, the region containing dopaminergic cell bodies. Monkeys were chronically treated with nicotine in the drinking water for 6 months after which they were injected with low dose MPTP for a further 6-month period. Nicotine was administered until the monkeys were euthanized 2 months after the last MPTP injection. Nicotine treatment did not affect the dopamine transporter or the number of tyrosine hydroxylase positive cells in the substantia nigra of lesioned monkeys. However, nicotine administration did lead to a greater increase in α3/α6β2* and α4β2* nAChRs in lesioned monkeys compared to controls. Nicotine also significantly elevated microglia and reduced the number of extracellular neuromelanin deposits in the substantia nigra of MPTP-lesioned monkeys. These findings indicate that long-term nicotine treatment modulates expression of several molecular measures in monkey substantia nigra that may result in an improvement in nigral integrity and/or function. These observations may have therapeutic implications for Parkinson’s disease. PMID:19685015

  19. Encephalitis Lethargica With Isolated Substantia Nigra Lesions Followed by a Second Encephalitis in a Child With Humoral Immunodeficiency.

    PubMed

    Yang, Lu; Jia, Guijuan; Li, Baomin; Lei, Gefei; Sun, Ruopeng

    2015-12-01

    Encephalitis lethargica is an encephalitic illness with multiple nervous system symptoms. Lesions only involving substantia nigra on magnetic resonance imaging are uncommon, especially in children. A second encephalitis illness after encephalitis lethargica has never been reported before. We describe a 7-year-old boy with humoral immunity deficiency who developed encephalitis lethargica associated with bilateral substantia nigra lesions on magnetic resonance imaging. After a nearly complete recovery, he developed encephalitis once again. He was diagnosed with encephalitis lethargica with somnolence, akinetic mutism, and ophthalmoplegia after intermittent fever. Cerebrospinal fluid pleocytosis and positive oligoclonal bands were documented. Symmetrical substantia nigra lesions on high-intensity magnetic resonance imaging gradually evolved into a liquid signal. He had almost recovered when he developed fatigue and hypersomnia and was diagnosed with encephalitis again, supported by mild pleocytosis in cerebrospinal fluid and subcortical white matter lesions in the frontal lobes. His symptoms resolved following administration of corticosteroids and immunoglobulins. This is the first report of an immune-deficient child to develop encephalitis lethargica with isolated substantia nigra lesions on magnetic resonance imaging and a second encephalitis illness after recovery from encephalitis lethargica. Copyright © 2015. Published by Elsevier Inc.

  20. Comparison of 3T and 7T susceptibility-weighted angiography of the substantia nigra in diagnosing Parkinson disease.

    PubMed

    Cosottini, M; Frosini, D; Pesaresi, I; Donatelli, G; Cecchi, P; Costagli, M; Biagi, L; Ceravolo, R; Bonuccelli, U; Tosetti, M

    2015-03-01

    Standard neuroimaging fails in defining the anatomy of the substantia nigra and has a marginal role in the diagnosis of Parkinson disease. Recently 7T MR target imaging of the substantia nigra has been useful in diagnosing Parkinson disease. We performed a comparative study to evaluate whether susceptibility-weighted angiography can diagnose Parkinson disease with a 3T scanner. Fourteen patients with Parkinson disease and 13 healthy subjects underwent MR imaging examination at 3T and 7T by using susceptibility-weighted angiography. Two expert blinded observers and 1 neuroradiology fellow evaluated the 3T and 7T images of the sample to identify substantia nigra abnormalities indicative of Parkinson disease. Diagnostic accuracy and intra- and interobserver agreement were calculated separately for 3T and 7T acquisitions. Susceptibility-weighted angiography 7T MR imaging can diagnose Parkinson disease with a mean sensitivity of 93%, specificity of 100%, and diagnostic accuracy of 96%. 3T MR imaging diagnosed Parkinson disease with a mean sensitivity of 79%, specificity of 94%, and diagnostic accuracy of 86%. Intraobserver and interobserver agreement was excellent at 7T. At 3T, intraobserver agreement was excellent for experts, and interobserver agreement ranged between good and excellent. The less expert reader obtained a diagnostic accuracy of 89% at 3T. Susceptibility-weighted angiography images obtained at 3T and 7T differentiate controls from patients with Parkinson disease with a higher diagnostic accuracy at 7T. The capability of 3T in diagnosing Parkinson disease might encourage its use in clinical practice. The use of the more accurate 7T should be supported by a dedicated cost-effectiveness study. © 2015 by American Journal of Neuroradiology.

  1. Internal pallidum and substantia nigra control different parts of the mesopontine reticular formation in primate.

    PubMed

    Rolland, Anne-Sophie; Karachi, Carine; Muriel, Marie-Paule; Hirsch, Etienne C; François, Chantal

    2011-08-01

    The locomotor area has recently emerged as a target for deep brain stimulation to lessen gait disturbances in advanced parkinsonian patients. An important step in choosing this target is to define anatomical limits of its 2 components, the pedunculopontine nucleus and the cuneiform nucleus, their connections with the basal ganglia, and their output descending pathway. Based on the hypothesis that pedunculopontine nucleus controls locomotion whereas cuneiform nucleus controls axial posture, we analyzed whether both nuclei receive inputs from the internal pallidum and substantia nigra using anterograde and retrograde tract tracing in monkeys. We also examined whether these nuclei convey descending projections to the reticulospinal pathway. Pallidal terminals were densely distributed and restricted to the pedunculopontine nucleus, whereas nigral terminals were diffusely observed in the whole extent of both the pedunculopontine nucleus and the cuneiform nucleus. Moreover, nigral terminals formed symmetric synapses with pedunculopontine nucleus and cuneiform nucleus dendrites. Retrograde tracing experiments confirmed these results because labeled cell bodies were observed in both the internal pallidum and substantia nigra after pedunculopontine nucleus injection, but only in the substantia nigra after cuneiform nucleus injection. Furthermore, anterograde tracing experiments revealed that the pedunculopontine nucleus and cuneiform nucleus project to large portions of the pontomedullary reticular formation. This is the first anatomical evidence that the internal pallidum and the substantia nigra control different parts of the brain stem and can modulate the descending reticulospinal pathway in primates. These findings support the functional hypothesis that the nigro-cuneiform nucleus pathway could control axial posture whereas the pallido-pedunculopontine nucleus pathway could modulate locomotion. Copyright © 2011 Movement Disorder Society.

  2. Proteome analysis of human substantia nigra in Parkinson's disease

    PubMed Central

    Werner, Cornelius J; Heyny-von Haussen, Roland; Mall, Gerhard; Wolf, Sabine

    2008-01-01

    Background Parkinson's disease (PD) is the most common neurodegenerative disorder involving the motor system. Although not being the only region involved in PD, affection of the substantia nigra and its projections is responsible for some of the most debilitating features of the disease. To further advance a comprehensive understanding of nigral pathology, we conducted a tissue based comparative proteome study of healthy and diseased human substantia nigra. Results The gross number of differentially regulated proteins in PD was 221. In total, we identified 37 proteins, of which 16 were differentially expressed. Identified differential proteins comprised elements of iron metabolism (H-ferritin) and glutathione-related redox metabolism (GST M3, GST P1, GST O1), including novel redox proteins (SH3BGRL). Additionally, many glial or related proteins were found to be differentially regulated in PD (GFAP, GMFB, galectin-1, sorcin), as well as proteins belonging to metabolic pathways sparsely described in PD, such as adenosyl homocysteinase (methylation), aldehyde dehydrogenase 1 and cellular retinol-binding protein 1 (aldehyde metabolism). Further differentially regulated proteins included annexin V, beta-tubulin cofactor A, coactosin-like protein and V-type ATPase subunit 1. Proteins that were similarly expressed in healthy or diseased substantia nigra comprised housekeeping proteins such as COX5A, Rho GDI alpha, actin gamma 1, creatin-kinase B, lactate dehydrogenase B, disulfide isomerase ER-60, Rab GDI beta, methyl glyoxalase 1 (AGE metabolism) and glutamine synthetase. Interestingly, also DJ-1 and UCH-L1 were expressed similarly. Furthermore, proteins believed to serve as internal standards were found to be expressed in a constant manner, such as 14-3-3 epsilon and hCRMP-2, thus lending further validity to our results. Conclusion Using an approach encompassing high sensitivity and high resolution, we show that alterations of SN in PD include many more proteins than

  3. Degradation of substance P by membrane peptidases in the rat substantia nigra: effect of selective inhibitors.

    PubMed

    Oblin, A; Danse, M J; Zivkovic, B

    1988-01-11

    The hydrolysis of substance P by membrane peptidases prepared from the rat substantia nigra was studied in the presence of selective inhibitors. Substance P degradation by synaptic and mitochondrial membranes was completely inhibited by 1,10-phenanthroline (1 mM), a non-specific metallopeptidase inhibitor. Captopril and bestatine, selective inhibitors of angiotensin converting enzyme and aminopeptidases respectively, were without effects. However, phosphoramidon (1 microM), a putative 'enkephalinase' inhibitor, selectively inhibited substance P degradation by synaptic membranes. These results suggest that a phosphoramidon-sensitive endopeptidase may be the principal enzyme responsible for substance P degradation in substantia nigra.

  4. Apelin-13 ameliorates cognitive impairments in 6-hydroxydopamine-induced substantia nigra lesion in rats.

    PubMed

    Haghparast, Elham; Esmaeili-Mahani, Saeed; Abbasnejad, Mehdi; Sheibani, Vahid

    2018-04-01

    Although Parkinson's disease (PD) is well known with its motor deficits, the patients often suffer from cognitive dysfunction. Apelin, as the endogenous ligand of the APJ receptor, is found in several brain regions such as substantia nigra and mesolimbic pathway. However, the role of apelin in cognition and cognitive disorders has not been fully clarified. In this study the effects of apelin-13 were investigated on cognitive disorders in rat Parkinsonism experimental model. 6-hydroxydopamine (6-OHDA) was administrated into the substantia nigra. Apelin-13 (1, 2 and 3μg/rat) was administered into the substantia nigra one week after the 6-OHDA injection. Morris water maze (MWM), object location and novel object recognition tests were performed one month after the apelin injection. 6-OHDA-treated animals showed a significant impairment in cognitive functions which was revealed by the increased in the escape latency and traveled distance in MWM test and decreased in the exploration index in novel object recognition and object location tasks. Apelin-13 (3μg/rat) significantly attenuates the mentioned cognitive impairments in 6-OHDA-treated animals. In conclusion, the data support the pro-cognitive property of apelin-13 in 6-OHDA-induced cognitive deficit and provided a new pharmacological aspect of the neuropeptide apelin. Copyright © 2018 Elsevier Ltd. All rights reserved.

  5. Acute Neuroinflammatory Response in the Substantia Nigra Pars Compacta of Rats after a Local Injection of Lipopolysaccharide.

    PubMed

    Flores-Martinez, Yazmin M; Fernandez-Parrilla, Manuel A; Ayala-Davila, Jose; Reyes-Corona, David; Blanco-Alvarez, Victor M; Soto-Rojas, Luis O; Luna-Herrera, Claudia; Gonzalez-Barrios, Juan A; Leon-Chavez, Bertha A; Gutierrez-Castillo, Maria E; Martínez-Dávila, Irma A; Martinez-Fong, Daniel

    2018-01-01

    Models of Parkinson's disease with neurotoxins have shown that microglial activation does not evoke a typical inflammatory response in the substantia nigra, questioning whether neuroinflammation leads to neurodegeneration. To address this issue, the archetypal inflammatory stimulus, lipopolysaccharide (LPS), was injected into the rat substantia nigra. LPS induced fever, sickness behavior, and microglial activation (OX42 immunoreactivity), followed by astrocyte activation and leukocyte infiltration (GFAP and CD45 immunoreactivities). During the acute phase of neuroinflammation, pro- and anti-inflammatory cytokines (TNF- α , IL-1 β , IL-6, IL-4, and IL-10) responded differentially at mRNA and protein level. Increased NO production and lipid peroxidation occurred at 168 h after LPS injection. At this time, evidence of neurodegeneration could be seen, entailing decreased tyrosine hydroxylase (TH) immunoreactivity, irregular body contour, and prolongation discontinuity of TH + cells, as well as apparent phagocytosis of TH + cells by OX42 + cells. Altogether, these results show that LPS evokes a typical inflammatory response in the substantia nigra that is followed by dopaminergic neurodegeneration.

  6. Acute Neuroinflammatory Response in the Substantia Nigra Pars Compacta of Rats after a Local Injection of Lipopolysaccharide

    PubMed Central

    Gonzalez-Barrios, Juan A.; Gutierrez-Castillo, Maria E.

    2018-01-01

    Models of Parkinson's disease with neurotoxins have shown that microglial activation does not evoke a typical inflammatory response in the substantia nigra, questioning whether neuroinflammation leads to neurodegeneration. To address this issue, the archetypal inflammatory stimulus, lipopolysaccharide (LPS), was injected into the rat substantia nigra. LPS induced fever, sickness behavior, and microglial activation (OX42 immunoreactivity), followed by astrocyte activation and leukocyte infiltration (GFAP and CD45 immunoreactivities). During the acute phase of neuroinflammation, pro- and anti-inflammatory cytokines (TNF-α, IL-1β, IL-6, IL-4, and IL-10) responded differentially at mRNA and protein level. Increased NO production and lipid peroxidation occurred at 168 h after LPS injection. At this time, evidence of neurodegeneration could be seen, entailing decreased tyrosine hydroxylase (TH) immunoreactivity, irregular body contour, and prolongation discontinuity of TH+ cells, as well as apparent phagocytosis of TH+ cells by OX42+ cells. Altogether, these results show that LPS evokes a typical inflammatory response in the substantia nigra that is followed by dopaminergic neurodegeneration. PMID:29854828

  7. Oxidative stress-dependent changes in immune responses and cell death in the substantia nigra after ozone exposure in rat.

    PubMed

    Rivas-Arancibia, Selva; Zimbrón, Luis Fernando Hernández; Rodríguez-Martínez, Erika; Maldonado, Perla D; Borgonio Pérez, Gabino; Sepúlveda-Parada, María

    2015-01-01

    Parkinson's disease has been associated with the selective loss of neurons in the substantia nigra pars compacta. Increasing evidence suggests that oxidative stress plays a major role. The resulting increase in reactive oxygen species triggers a sequence of events that leads to cell damage, activation of microglia cells and neuroinflammatory responses. Our objective was to study whether chronic exposure to low doses of ozone, which produces oxidative stress itself, induces progressive cell death in conjunction with glial alterations in the substantia nigra. Animals were exposed to an ozone-free air stream (control) or to low doses of ozone for 7, 15, 30, 60, or 90 days. Each group underwent (1) spectrophotometric analysis for protein oxidation; (2) western blot testing for microglia reactivity and nuclear factor kappa B expression levels; and (3) immunohistochemistry for cytochrome c, GFAP, Iba-1, NFkB, and COX-2. Our results indicate that ozone induces an increase in protein oxidation levels, changes in activated astrocytes and microglia, and cell death. NFkB and cytochrome c showed an increase until 30 days of exposure, while cyclooxygenase 2 in the substantia nigra increased from 7 days up to 90 days of repetitive ozone exposure. These results suggest that oxidative stress caused by ozone exposure induces changes in inflammatory responses and progressive cell death in the substantia nigra in rats, which could also be occurring in Parkinson's disease.

  8. Oxidative stress-dependent changes in immune responses and cell death in the substantia nigra after ozone exposure in rat

    PubMed Central

    Rivas-Arancibia, Selva; Zimbrón, Luis Fernando Hernández; Rodríguez-Martínez, Erika; Maldonado, Perla D.; Borgonio Pérez, Gabino; Sepúlveda-Parada, María

    2015-01-01

    Parkinson's disease has been associated with the selective loss of neurons in the substantia nigra pars compacta. Increasing evidence suggests that oxidative stress plays a major role. The resulting increase in reactive oxygen species triggers a sequence of events that leads to cell damage, activation of microglia cells and neuroinflammatory responses. Our objective was to study whether chronic exposure to low doses of ozone, which produces oxidative stress itself, induces progressive cell death in conjunction with glial alterations in the substantia nigra. Animals were exposed to an ozone-free air stream (control) or to low doses of ozone for 7, 15, 30, 60, or 90 days. Each group underwent (1) spectrophotometric analysis for protein oxidation; (2) western blot testing for microglia reactivity and nuclear factor kappa B expression levels; and (3) immunohistochemistry for cytochrome c, GFAP, Iba-1, NFkB, and COX-2. Our results indicate that ozone induces an increase in protein oxidation levels, changes in activated astrocytes and microglia, and cell death. NFkB and cytochrome c showed an increase until 30 days of exposure, while cyclooxygenase 2 in the substantia nigra increased from 7 days up to 90 days of repetitive ozone exposure. These results suggest that oxidative stress caused by ozone exposure induces changes in inflammatory responses and progressive cell death in the substantia nigra in rats, which could also be occurring in Parkinson's disease. PMID:25999851

  9. Sequence analysis of 497 mouse brain ESTs expressed in the substantia nigra

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Stewart, G.J.; Savioz, A.; Davies, R.W.

    1997-01-15

    The use of subtracted, region-specific cDNA libraries combined with single-pass cDNA sequencing allows the discovery of novel genes and facilitates molecular description of the tissue or region involved. We report the sequence of 497 mouse expressed sequence tags (ESTs) from two subtracted libraries enriched for cDNAs expressed in the substantia nigra, a brain region with important roles in movement control and Parkinson disease. Of these, 238 ESTs give no database matches and therefore derive from novel genes. A further 115 ESTs show sequence similarity to ESTs from other organisms, which themselves do not yield any significant database matches to genesmore » of known function. Fifty-six ESTs show sequence similarity to previously identified genes whose mouse homologues have not been reported. The total number of ESTs reported that are new for the mouse is 407, which, together with the 90 ESTs corresponding to known mouse genes or cDNAs, contributes to the molecular description of the substantia nigra. 21 refs., 4 tabs.« less

  10. Convection-enhanced delivery of MANF--volume of distribution analysis in porcine putamen and substantia nigra.

    PubMed

    Barua, N U; Bienemann, A S; Woolley, M; Wyatt, M J; Johnson, D; Lewis, O; Irving, C; Pritchard, G; Gill, S

    2015-10-15

    Mesencephalic astrocyte-derived neurotrophic factor (MANF) is a 20kDa human protein which has both neuroprotective and neurorestorative activity on dopaminergic neurons and therefore may have application for the treatment of Parkinson's Disease. The aims of this study were to determine the translational potential of convection-enhanced delivery (CED) of MANF for the treatment of PD by studying its distribution in porcine putamen and substantia nigra and to correlate histological distribution with co-infused gadolinium-DTPA using real-time magnetic resonance imaging. We describe the distribution of MANF in porcine putamen and substantia nigra using an implantable CED catheter system using co-infused gadolinium-DTPA to allow real-time MRI tracking of infusate distribution. The distribution of gadolinium-DTPA on MRI correlated well with immunohistochemical analysis of MANF distribution. Volumetric analysis of MANF IHC staining indicated a volume of infusion (Vi) to volume of distribution (Vd) ratio of 3 in putamen and 2 in substantia nigra. This study confirms the translational potential of CED of MANF as a novel treatment strategy in PD and also supports the co-infusion of gadolinium as a proxy measure of MANF distribution in future clinical studies. Further study is required to determine the optimum infusion regime, flow rate and frequency of infusions in human trials. Copyright © 2015 Elsevier B.V. All rights reserved.

  11. Increased protein oxidation in human substantia nigra pars compacta in comparison with basal ganglia and prefrontal cortex measured with an improved dinitrophenylhydrazine assay.

    PubMed

    Floor, E; Wetzel, M G

    1998-01-01

    The dopaminergic phenotype of neurons in human substantia nigra deteriorates during normal aging, and loss of these neurons is prominent in Parkinson's disease. These degenerative processes are hypothesized to involve oxidative stress. To compare oxidative stress in the nigra and related regions, we measured carbonyl modifications of soluble proteins in postmortem samples of substantia nigra, basal ganglia, and prefrontal cortex from neurologically normal subjects, using an improved 2,4-dinitrophenylhydrazine assay. The protein carbonyl content was found to be about twofold higher in substantia nigra pars compacta than in the other regions. To further analyze this oxidative damage, the distribution of carbonyl groups on soluble proteins was determined by western immunoblot analysis. This method revealed that carbonyl content of the major proteins in each region was linearly dependent on molecular weight. This distribution raises the possibility that protein carbonyl content is controlled by a size-dependent mechanism in vivo. Our results suggest that oxidative stress is elevated in human substantia nigra pars compacta in comparison with other regions and that oxidative damage is higher within the dopaminergic neurons. Elevated oxidative damage may contribute to the degeneration of nigral dopaminergic neurons in aging and in Parkinson's disease.

  12. Systemic administration of the propargylamine CGP 3466B prevents behavioural and morphological deficits in rats with 6-hydroxydopamine-induced lesions in the substantia nigra.

    PubMed

    Andringa, G; van Oosten, R V; Unger, W; Hafmans, T G; Veening, J; Stoof, J C; Cools, A R

    2000-08-01

    The ability of CGP 3466B to attenuate the behavioural and morphological consequences of experimentally induced cell death was investigated in a recently updated animal model of Parkinson's disease. 6-Hydroxydopamine was infused bilaterally into the substantia nigra pars compacta of rats that were pretreated with desimipramine. Treatment with CGP 3466B (0.0014-1.4 mg/kg, injected subcutaneously) or its solvent was begun 2 h after the 6-OHDA injection, and maintained twice daily for 14 days. After a washout period of 14 days, changes in motor behaviour were evaluated, using the open field test (analysis of normal and abnormal stepping, e.g.) and the paw test (analysis of retraction time of limbs). Changes in learning and memory were evaluated with the help of the Morris water maze task. Following immunocytochemical staining of tyrosine hydroxylase, the extent of the lesion was quantified using a computerized system. CGP 3466B prevented all deficits produced by 6-hydroxydopamine (6-OHDA), though at different doses. It prevented: abnormal stepping (0.0014-0.014 mg/kg); increased forelimb and hindlimb retraction time (0.014-0.14 mg/kg and 0.0014-0.14 mg/kg, respectively); delayed learning (1.4 mg/kg); and reduced tyrosine hydroxylase immunoreactivity in the substantia nigra (0.0014-0.014 mg/kg). CGP 3466B (0.0014-0.14 mg/kg) induced no deficits in sham-treated rats. CGP 3466B (1.4 mg/kg), however, did not show any benefit on motor deficits in 6-OHDA-lesioned rats, and induced abnormal movements and decreased the tyrosine hydroxylase immunoreactivity in the substantia nigra pars compacta and the ventral tegmental area of sham-lesioned animals. It is concluded that CGP 3466B prevents all 6-OHDA-induced behavioural and immunocytochemical deficits, though at different doses. CGP 3466B is suggested to be a valuable agent for inhibiting the dopaminergic degeneration in patients with Parkinson's disease.

  13. Functional recovery of supersensitive dopamine receptors after intrastriatal grafts of fetal substantia nigra

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Dawson, T.M.; Dawson, V.L.; Gage, F.H.

    1991-03-01

    Interruption of the ascending dopamine neurons of the nigrostriatal pathway, by 6-hydroxydopamine (6-OHDA) lesion in rats, produced a significant loss of the dopamine transport complexes labeled with the phencyclidine derivative (3H)BTCP. This loss of dopamine innervation in the striatum was present at least 12 to 14 months after lesioning and was functionally manifested by ipsilateral rotation of the animals in response to amphetamine. In these same animals, in comparison to controls, there was a significant increase in the number (Bmax) of (3H)SCH 23390-labeled D-1 receptors in the striatum (36.7%) and the substantia nigra (35.1%) and a 54.4% increase in themore » number (Bmax) of (3H)sulpiride-labeled striatal D-2 receptors without an apparent change in affinity (Kd). Ten to twelve months after the transplantation of homologous fetal substantia nigra into the denervated striatum, there was a significant decrease in amphetamine-induced turning behavior. In these animals, there was an ingrowth of dopamine nerve terminals in the striatum as demonstrated by a return of (3H)BTCP binding. Accompanying this reinnervation was the normalization of D-1 and D-2 receptors to control values in the striatum as well as the return of D-1 receptors to prelesion densities in the substantia nigra. In a subgroup of transplanted rats, amphetamine continued to induce ipsilateral turning. In these animals both D-1 and D-2 receptors remained supersensitive. These results support the hypothesis that the functional recovery of transplanted animals is due, in part, to reinnervation of the striatum. In addition, long-term alterations in receptor density may be related to the behavioral deficits that are associated with the 6-OHDA-lesioned rat.« less

  14. Increased Frequency of α-Synuclein in the Substantia Nigra in HIV Infection

    PubMed Central

    Khanlou, Negar; Moore, David J.; Chana, Gursharan; Cherner, Mariana; Lazzaretto, Deborah; Dawes, Sharron; Grant, Igor; Masliah, Eliezer; Everall, Ian P.

    2014-01-01

    The frequency of neurodegenerative markers among long surviving HIV infected individuals is unknown, therefore, the present study investigated the frequency of α-synuclein, β-amyloid and HIV-associated brain pathology in the brains of older HIV infected individuals. We examined the substantia nigra of 73 clinically well-characterized HIV infected individuals aged 50 to 76 years from the National NeuroAIDS Tissue Consortium. We also examined the frontal and temporal cortical regions of a subset of 36 individuals. The brain regions were examined for the presence of α-synuclein, β-amyloid and HIV-associated brain pathology. Neuritic α-synuclein expression was found in 16% (12/73) of the substantia nigra of the HIV+ cases and none of the older control cases (0/18). β-amyloid deposits were prevalent and found in nearly all of the HIV+ cases (35/36). Despite these increases of degenerative pathology, HIV-associated brain pathology was present in only 10% of cases. Among older HIV+ adults HIV-associated brain pathology does not appear elevated; however, the frequency of both α-synuclein and β-amyloid is higher than that found in older healthy persons. The increased prevalence of α-synuclein and β-amyloid in the brains of older HIV-infected individuals may predict an increased risk of developing neurodegenerative disease. PMID:19115126

  15. Navigation-supported diagnosis of the substantia nigra by matching midbrain sonography and MRI

    NASA Astrophysics Data System (ADS)

    Salah, Zein; Weise, David; Preim, Bernhard; Classen, Joseph; Rose, Georg

    2012-03-01

    Transcranial sonography (TCS) is a well-established neuroimaging technique that allows for visualizing several brainstem structures, including the substantia nigra, and helps for the diagnosis and differential diagnosis of various movement disorders, especially in Parkinsonian syndromes. However, proximate brainstem anatomy can hardly be recognized due to the limited image quality of B-scans. In this paper, a visualization system for the diagnosis of the substantia nigra is presented, which utilizes neuronavigated TCS to reconstruct tomographical slices from registered MRI datasets and visualizes them simultaneously with corresponding TCS planes in realtime. To generate MRI tomographical slices, the tracking data of the calibrated ultrasound probe are passed to an optimized slicing algorithm, which computes cross sections at arbitrary positions and orientations from the registered MRI dataset. The extracted MRI cross sections are finally fused with the region of interest from the ultrasound image. The system allows for the computation and visualization of slices at a near real-time rate. Primary tests of the system show an added value to the pure sonographic imaging. The system also allows for reconstructing volumetric (3D) ultrasonic data of the region of interest, and thus contributes to enhancing the diagnostic yield of midbrain sonography.

  16. Microstimulation of the Human Substantia Nigra Alters Reinforcement Learning

    PubMed Central

    Ramayya, Ashwin G.; Misra, Amrit

    2014-01-01

    Animal studies have shown that substantia nigra (SN) dopaminergic (DA) neurons strengthen action–reward associations during reinforcement learning, but their role in human learning is not known. Here, we applied microstimulation in the SN of 11 patients undergoing deep brain stimulation surgery for the treatment of Parkinson's disease as they performed a two-alternative probability learning task in which rewards were contingent on stimuli, rather than actions. Subjects demonstrated decreased learning from reward trials that were accompanied by phasic SN microstimulation compared with reward trials without stimulation. Subjects who showed large decreases in learning also showed an increased bias toward repeating actions after stimulation trials; therefore, stimulation may have decreased learning by strengthening action–reward associations rather than stimulus–reward associations. Our findings build on previous studies implicating SN DA neurons in preferentially strengthening action–reward associations during reinforcement learning. PMID:24828643

  17. Picrotoxin antagonism of γ aminobutyric acid inhibitory responses and synaptic inhibition in the rat substantia nigra

    PubMed Central

    Crossman, A. R.; Walker, R. J.; Woodruff, G. N.

    1973-01-01

    Neurones in the substantia nigra of the rat, anaesthetized with urethane, are inhibited both by electrical stimulation of the ipsilateral caudate nucleus and by iontophoretically applied γ-aminobutyric acid (GABA). Iontophoretically applied picrotoxin reversibly blocks both of these inhibitory responses. These results are consistent with the hypothesis that GABA is the transmitter released by the inhibitory striato-nigral pathway. PMID:4362811

  18. Microstimulation of the human substantia nigra alters reinforcement learning.

    PubMed

    Ramayya, Ashwin G; Misra, Amrit; Baltuch, Gordon H; Kahana, Michael J

    2014-05-14

    Animal studies have shown that substantia nigra (SN) dopaminergic (DA) neurons strengthen action-reward associations during reinforcement learning, but their role in human learning is not known. Here, we applied microstimulation in the SN of 11 patients undergoing deep brain stimulation surgery for the treatment of Parkinson's disease as they performed a two-alternative probability learning task in which rewards were contingent on stimuli, rather than actions. Subjects demonstrated decreased learning from reward trials that were accompanied by phasic SN microstimulation compared with reward trials without stimulation. Subjects who showed large decreases in learning also showed an increased bias toward repeating actions after stimulation trials; therefore, stimulation may have decreased learning by strengthening action-reward associations rather than stimulus-reward associations. Our findings build on previous studies implicating SN DA neurons in preferentially strengthening action-reward associations during reinforcement learning. Copyright © 2014 the authors 0270-6474/14/346887-09$15.00/0.

  19. Protection of the aged substantia nigra of the rat against oxidative damage by (-)-deprenyl.

    PubMed Central

    de la Cruz, C. P.; Revilla, E.; Steffen, V.; Rodríguez-Gómez, J. A.; Cano, J.; Machado, A.

    1996-01-01

    1. We have studied the effect of (-)-deprenyl on the oxidative damage that the rat substantia nigra suffers during aging. 2. (-)-Deprenyl (2 mg kg-1, three times a week) administered for two months, beginning at 22 months of age, produced a significant increase in tyrosine hydroxylase (TH) activity (2.67 +/- 0.40 and 3.64 +/- 0.38 nmol mg-1 protein h-1 in untreated aged rats and treated aged rats respectively, P < 0.05) and in TH amount (0.072 +/- 0.012 and 0.128 +/- 0.38 absorbance 405 nm in untreated aged and treated aged rats respectively, P < 0.05). 3. The proteins of aged rat substantia nigra showed a significant decrease of carbonyl groups in treated animals compared with saline-injected control rats (136.2 +/- 21.8 and 71.5 +/- 13.2 c.p.m. microgram-1 protein in untreated aged and treated aged rats respectively, P < 0.05). 4. The carbonyl groups measured in TH enzyme showed a statistically significant decrease (42.3%) after (-)-deprenyl treatment (471.4 +/- 73.0 and 271.9 +/- 50.00 c.p.m. in untreated aged and treated aged rats respectively, P < 0.001). 5. All these results suggest that oxidative damage produced during aging is prevented by (-)-deprenyl treatment and could explain the effect of this drug in Parkinson's disease (PD) and other degenerative diseases such as Alzheimer's disease. PMID:8732287

  20. [Effect of activation and blockade of the GABA-ergic system of the substantia nigra in the midbrain on the realization of conditioned food reflexes in dogs].

    PubMed

    Iakimovskiĭ, A F

    1988-01-01

    Bilateral injection of 45 mcg of GABA into substantia nigra pars compacta produced in dogs a manifested improvement of parameters of the conditioned differentiation inhibition but failed to influence the positive Pavlovian alimentary conditioned reflex. Injection of GABA synaptic antagonist--picrotoxin impaired conditioned alimentary behaviour. Numerous injections of the GABAergic pharmacological agents resulted in motor disturbance--rotatory movements--and skin trophic deviations. The data obtained and literature references give ground for discussion of the role of striato-nigral and internal GABAergic substantia nigra systems in the positive modulation of adaptive alimentary behaviour and conditioned stimuli differentiation.

  1. Dopamine-dependent neurotoxicity of lipopolysaccharide in substantia nigra.

    PubMed

    De Pablos, Rocío M; Herrera, Antonio J; Villarán, Ruth F; Cano, Josefina; Machado, Alberto

    2005-03-01

    Intranigral injection of lipopolysaccharide (LPS), a potent inductor of inflammation, induces degeneration of dopaminergic neurons, along with an inflammatory process that features activation of microglial cells and loss of astrocytes. To test the involvement of dopamine (DA) in this degeneration induced by LPS, we treated albino Wistar rats with different concentrations of alpha-methyl-p-tyrosine (alpha-MPT), an inhibitor of tyrosine hydroxylase (TH) activity. Results showed that alpha-MPT prevented LPS-induced loss of TH immunostaining and expression of mRNA for TH and DA transporter; it also prevented substantial activation of microglial cells. Loss of the astroglial population, a marker of damage in our model, was also prevented. This protective effect resulted from inhibition of TH and the consequent decrease in DA concentration, because treatment with L-DOPA/benserazide, which bypasses TH inhibition induced by alpha-MPT, reversed the protective effect produced by this drug. These results point out the important contribution of DA to the vulnerability and degeneration of dopaminergic neurons of the substantia nigra. Knowledge about the involvement of DA in this process may lead to the possibility of new protection strategies against this important degenerative process.

  2. Stimulation of the substantia nigra influences the specification of memory-guided saccades

    PubMed Central

    Mahamed, Safraaz; Garrison, Tiffany J.; Shires, Joel

    2013-01-01

    In the absence of sensory information, we rely on past experience or memories to guide our actions. Because previous experimental and clinical reports implicate basal ganglia nuclei in the generation of movement in the absence of sensory stimuli, we ask here whether one output nucleus of the basal ganglia, the substantia nigra pars reticulata (nigra), influences the specification of an eye movement in the absence of sensory information to guide the movement. We manipulated the level of activity of neurons in the nigra by introducing electrical stimulation to the nigra at different time intervals while monkeys made saccades to different locations in two conditions: one in which the target location remained visible and a second in which the target location appeared only briefly, requiring information stored in memory to specify the movement. Electrical manipulation of the nigra occurring during the delay period of the task, when information about the target was maintained in memory, altered the direction and the occurrence of subsequent saccades. Stimulation during other intervals of the memory task or during the delay period of the visually guided saccade task had less effect on eye movements. On stimulated trials, and only when the visual stimulus was absent, monkeys occasionally (∼20% of the time) failed to make saccades. When monkeys made saccades in the absence of a visual stimulus, stimulation of the nigra resulted in a rotation of the endpoints ipsilaterally (∼2°) and increased the reaction time of contralaterally directed saccades. When the visual stimulus was present, stimulation of the nigra resulted in no significant rotation and decreased the reaction time of contralaterally directed saccades slightly. Based on these measurements, stimulation during the delay period of the memory-guided saccade task influenced the metrics of saccades much more than did stimulation during the same period of the visually guided saccade task. Because these effects

  3. Abnormal Echogenicity of the Substantia Nigra, Raphe Nuclei, and Third-Ventricle Width as Markers of Cognitive Impairment in Parkinsonian Disorders: A Cross-Sectional Study

    PubMed Central

    Bouwmans, Angela E. P.; Leentjens, Albert F. G.; Mess, Werner H.; Weber, Wim E. J.

    2016-01-01

    Background. Patients with Parkinson's disease (PD) have a high risk of cognitive problems. Objective. This study assesses whether abnormal echogenicity of the substantia nigra (SN) and raphe nuclei (RN) and the diameter of third ventricle are markers of cognitive impairment in patients with PD and other forms of parkinsonism. Methods. 126 outpatients with early signs of parkinsonism underwent transcranial sonography (TCS). The scales for the outcome of Parkinson's disease cognition (SCOPA-COG) were used as cognitive measure. Definite neurological diagnosis was established after two-year follow-up. Results. One-third of the patients with PD and half of those with APS had signs of cognitive impairment. The echogenicity of the SN was not related to cognitive impairment. The diameter of the third ventricle was significantly larger in PD patients with cognitive impairment compared to those without. In patients with APS we found a significantly higher frequency of hypoechogenic RN in patients with cognitive problems. Conclusions. Cognitive impairment is already present in a substantial proportion of patients with PD and APS at first referral. In patients with APS the frequency of hypoechogenic RN points to the direction of other pathophysiology with more emphasis on deficits in the serotonergic neurotransmitter system. The larger diameter of the third ventricle in PD patients with cognitive impairment may reflect Alzheimer like brain atrophy, as has been reported in earlier studies. PMID:26881179

  4. Regulation of dopaminergic neuron firing by heterogeneous dopamine autoreceptors in the substantia nigra pars compacta.

    PubMed

    Jang, Jin Young; Jang, Miae; Kim, Shin Hye; Um, Ki Bum; Kang, Yun Kyung; Kim, Hyun Jin; Chung, Sungkwon; Park, Myoung Kyu

    2011-03-01

    Dopamine (DA) receptors generate many cellular signals and play various roles in locomotion, motivation, hormone production, and drug abuse. According to the location and expression types of the receptors in the brain, DA signals act in either stimulatory or inhibitory manners. Although DA autoreceptors in the substantia nigra pars compacta are known to regulate firing activity, the exact expression patterns and roles of DA autoreceptor types on the firing activity are highly debated. Therefore, we performed individual correlation studies between firing activity and receptor expression patterns using acutely isolated rat substantia nigra pars compacta DA neurons. When we performed single-cell RT-PCR experiments, D(1), D(2)S, D(2)L, D(3), and D(5) receptor mRNA were heterogeneously expressed in the order of D(2)L > D(2)S > D(3) > D(5) > D(1). Stimulation of D(2) receptors with quinpirole suppressed spontaneous firing similarly among all neurons expressing mRNA solely for D(2)S, D(2)L, or D(3) receptors. However, quinpirole most strongly suppressed spontaneous firing in the neurons expressing mRNA for both D(2) and D(3) receptors. These data suggest that D(2) S, D(2)L, and D(3) receptors are able to equally suppress firing activity, but that D(2) and D(3) receptors synergistically suppress firing. This diversity in DA autoreceptors could explain the various actions of DA in the brain. © 2011 The Authors. Journal of Neurochemistry © 2011 International Society for Neurochemistry.

  5. Constructing a new nigrostriatal pathway in the Parkinsonian model with bridged neural transplantation in substantia nigra.

    PubMed

    Zhou, F C; Chiang, Y H; Wang, Y

    1996-11-01

    The physical repair and restoration of a completely damaged pathway in the brain has not been achieved previously. In a previous study, using excitatory amino acid bridging and fetal neural transplantation, we demonstrated that a bridged mesencephalic transplant in the substantia nigra generated an artificial nerve pathway that reinnervated the striatum of 6-hydroxydopamine (6-OHDA)-lesioned rats. In the current study, we report that a bridged mesencephalic transplant can anatomically, neurochemically, and functionally reinstate the 6-OHDA-eradicated nigro-striatal pathway. An excitatory amino acid, kainic acid, laid down in a track during the transplant generated a trophic environment that effectively guided the robust growth of transplanted neuronal fibers in a bundle to innervate the distal striatum. Growth occurred at the remarkable speed of approximately 200 microm/d. Two separate and distinct types of dopamine (DA) innervation from the transplant have been achieved for the first time: (1) DA innervation of the striatum, and (2) DA innervation of the pars reticularis of the substantia nigra. In addition, neuronal tracing revealed that reciprocal connections were achieved. The grafted DA neurons in the SNr innervated the host's striatum, whereas the host's striatal neurons, in turn, innervated the graft within 3-8 weeks. Electrochemical volt- ammetry recording revealed the restoration of DA release and clearance in a broad striatal area associated with the DA reinnervation. Furthermore, the amphetamine-induced rotation was attenuated, which indicates that the artificial pathways were motor functional. This study provides additional evidences that our bridged transplantation technique is a potential means for the repair of a completely damaged neuronal pathway.

  6. Protective Effects of Vitamin E Consumption against 3MT Electromagnetic Field Effects on Oxidative Parameters in Substantia Nigra in Rats

    PubMed Central

    Ghanbari, Ahmad Ali; Shabani, Kobra; Mohammad Nejad, Daryoush

    2016-01-01

    Introduction: Electromagnetic fields (EMFs) can influence the biological system by the formation of free radicals in cells. The EMFs are able to deteriorate defense system against free radicals that leads to oxidative stress (OS). Lipid peroxidation process (LPO) is an index of oxidative stress, and the Malandialdehyde (MDA) is the final product of LPO. Vitamin E is the most important antioxidant which inhibits the LPO process. The aim of this study was to evaluate the effects of 3MT EMF exposure on oxidative stress parameters in substantia nigra and the role of vitamin E in reducing oxidative stress and preventing of LPO process. Methods: 40 male Wistar rats were randomly divided into 4 groups: 1) Control group: received standard food without exposure to EMF and without consumption of vitamin E, 2) Experimental group 1: was exposed to EMF (3MT) 4 h/day for 50 days, 3) The experimental group 2: received 200 mg/kg vitamin E with gavage every day and also was exposed to EMF (3MT) 4 h/day for 50 days, 4) Sham group: received water with gavage for 50 days. Results: A significant increase in MDA levels and Glutation peroxidase (GSH-Px) activity of the substantia nigra following 50 days exposure to EMF was detected, but the superoxide dismutase (SOD) activity was decreased. Exposure did not change total antioxidant capacity (TAC) levels in plasma. Vitamin E treatment significantly prevented the increase of the MDA levels and GSHPx activity and also prevented the decrease of SOD activity in tissue but did not alter TAC levels. The GSH-Px activity increased because the duration and intensity of exposure were not enough to decrease it. Conclusion: We demonstrated two important findings; that 50 days exposure to 3 MT electromagnetic field caused oxidative stress by increasing the levels of MDA, and decreasing SOD activity in the substantia nigra; and that treatment with the vitamin E significantly prevented the oxidative stress and lipid peroxidation. PMID:27872692

  7. Protective Effects of Vitamin E Consumption against 3MT Electromagnetic Field Effects on Oxidative Parameters in Substantia Nigra in Rats.

    PubMed

    Ghanbari, Ahmad Ali; Shabani, Kobra; Mohammad Nejad, Daryoush

    2016-10-01

    Electromagnetic fields (EMFs) can influence the biological system by the formation of free radicals in cells. The EMFs are able to deteriorate defense system against free radicals that leads to oxidative stress (OS). Lipid peroxidation process (LPO) is an index of oxidative stress, and the Malandialdehyde (MDA) is the final product of LPO. Vitamin E is the most important antioxidant which inhibits the LPO process. The aim of this study was to evaluate the effects of 3MT EMF exposure on oxidative stress parameters in substantia nigra and the role of vitamin E in reducing oxidative stress and preventing of LPO process. 40 male Wistar rats were randomly divided into 4 groups: 1) Control group: received standard food without exposure to EMF and without consumption of vitamin E, 2) Experimental group 1: was exposed to EMF (3MT) 4 h/day for 50 days, 3) The experimental group 2: received 200 mg/kg vitamin E with gavage every day and also was exposed to EMF (3MT) 4 h/day for 50 days, 4) Sham group: received water with gavage for 50 days. A significant increase in MDA levels and Glutation peroxidase (GSH-Px) activity of the substantia nigra following 50 days exposure to EMF was detected, but the superoxide dismutase (SOD) activity was decreased. Exposure did not change total antioxidant capacity (TAC) levels in plasma. Vitamin E treatment significantly prevented the increase of the MDA levels and GSHPx activity and also prevented the decrease of SOD activity in tissue but did not alter TAC levels. The GSH-Px activity increased because the duration and intensity of exposure were not enough to decrease it. We demonstrated two important findings; that 50 days exposure to 3 MT electromagnetic field caused oxidative stress by increasing the levels of MDA, and decreasing SOD activity in the substantia nigra; and that treatment with the vitamin E significantly prevented the oxidative stress and lipid peroxidation.

  8. [The role of the opiate mechanisms of the hippocampus and substantia nigra in the behavioral and convulsive disorders in picrotoxin-induced kindling].

    PubMed

    Kryzhanovskiĭ, G N; Shandra, A A; Godlevskiĭ, L S; Mazarati, A M; Nguyen, T T

    1991-03-01

    It was shown in the experiments on rats that the repeated picrotoxin administration resulted in the kindling of generalized seizures. Generalized convulsions were followed by the development of either postictal depression or explosiveness. The injection of mu-opiate agonist met-enkephalin into hippocampus of kindled rats resulted in the increase in the severity of seizure reactions which were induced by picrotoxin and also in the increase in the number of animals with postictal explosiveness. The injection of dynorphin-A-1-13 (kappa-opiate agonist) into substantia nigra reticulata induced the locomotor depression which was like one in postictal period and resulted in the decrease of picrotoxin-induced seizures severity. It was concluded that mu-opiate system of hippocampus took part in the formation of generator of pathologically enhanced excitation in the structure during kindling and the development of seizure syndrome, providing also the postictal explosiveness. Kappa-opiate system of substantia nigra plays an important role in the activation of the antiepileptic system, limitation of seizures and the development of postictal depression.

  9. Anatomical and functional organization of the human substantia nigra and its connections

    PubMed Central

    Zhang, Yu; Larcher, Kevin Michel-Herve; Misic, Bratislav

    2017-01-01

    We investigated the anatomical and functional organization of the human substantia nigra (SN) using diffusion and functional MRI data from the Human Connectome Project. We identified a tripartite connectivity-based parcellation of SN with a limbic, cognitive, motor arrangement. The medial SN connects with limbic striatal and cortical regions and encodes value (greater response to monetary wins than losses during fMRI), while the ventral SN connects with associative regions of cortex and striatum and encodes salience (equal response to wins and losses). The lateral SN connects with somatomotor regions of striatum and cortex and also encodes salience. Behavioral measures from delay discounting and flanker tasks supported a role for the value-coding medial SN network in decisional impulsivity, while the salience-coding ventral SN network was associated with motor impulsivity. In sum, there is anatomical and functional heterogeneity of human SN, which underpins value versus salience coding, and impulsive choice versus impulsive action. PMID:28826495

  10. Topographic and functional neuroanatomical study of GABAergic disinhibitory striatum-nigral inputs and inhibitory nigrocollicular pathways: neural hodology recruiting the substantia nigra, pars reticulata, for the modulation of the neural activity in the inferior colliculus involved with panic-like emotions.

    PubMed

    Castellan-Baldan, Lissandra; da Costa Kawasaki, Mateus; Ribeiro, Sandro José; Calvo, Fabrício; Corrêa, Vani Maria Alves; Coimbra, Norberto Cysne

    2006-08-01

    Considering the influence of the substantia nigra on mesencephalic neurons involved with fear-induced reactions organized in rostral aspects of the dorsal midbrain, the present work investigated the topographical and functional neuroanatomy of similar influence on caudal division of the corpora quadrigemina, addressing: (a) the neural hodology connecting the neostriatum, the substantia nigra, periaqueductal gray matter and inferior colliculus (IC) neural networks; (b) the influence of the inhibitory neostriatonigral-nigrocollicular GABAergic links on the control of the defensive behavior organized in the IC. The effects of the increase or decrease of activity of nigrocollicular inputs on defensive responses elicited by either electrical or chemical stimulation of the IC were also determined. Electrolytic or chemical lesions of the substantia nigra, pars reticulata (SNpr), decreased the freezing and escape behaviors thresholds elicited by electrical stimulation of the IC, and increased the behavioral responses evoked by the GABAA blockade in the same sites of the mesencephalic tectum (MT) electrically stimulated. These findings were corroborated by similar effects caused by microinjections of the GABAA-receptor agonist muscimol in the SNpr, followed by electrical and chemical stimulations of the IC. The GABAA blockade in the SNpr caused a significant increase in the defensive behavior thresholds elicited by electrical stimulation of the IC and a decrease in the mean incidence of panic-like responses induced by microinjections of bicuculline in the mesencephalic tectum (inferior colliculus). These findings suggest that the substantia nigra receives GABAergic inputs that modulate local and also inhibitory GABAergic outputs toward the IC. In fact, neurotracing experiments with fast blue and iontophoretic microinjections of biotinylated dextran amine either into the inferior colliculus or in the reticular division of the substantia nigra demonstrated a neural link

  11. Superparamagnetic iron oxide nanoparticles modified with dimyristoylphosphatidylcholine and their distribution in the brain after injection in the rat substantia nigra.

    PubMed

    Su, Lichao; Zhang, Baolin; Huang, Yinping; Zhang, Hao; Xu, Qin; Tan, Jie

    2017-12-01

    The subcellular distributions of nanoparticles in the brain are important for their biological application. We synthesized and characterized the superparamagnetic iron oxide nanoparticles (SPIONs) modified with poly (ethylene glycol) (PEG) and polyethylenimine (PEI) (PEG/PEI-SPIONs), and with dimyristoylphosphatidylcholine (DMPC) (DMPC-SPIONs). The nanoparticles were unilaterally injected into the left substantia nigra of rat brains. The distributions of the nanoparticles in the left brains of the rats were examined by ICP-OES (inductively coupled plasma optical emission spectrometer) and TEM (transmission electron microscopy) at 24h after the injection. Iron was found in the olfactory bulb, temporal lobe, frontal cortex, thalamus and brain stem at 24h after the injection of DMPC-SPIONs and PEG/PEI-SPIONs. In the rat substantia nigra, most DMPC-SPIONs were distributed in and on the myelin sheath around axons or on cell membranes, some were in cells. As a comparison, less iron was found in the rat brains at 24h after the injection of PEG/PEI-SPIONs. Our experiments suggest DMPC modification on SPIONs be a safe and effective method for increasing SPIONs distribution on the cell membranes. This work is encouraging for further study on using DMPC-SPIONs for efficient drug delivery or for deep brain stimulation of neurons in a magnetic field. Copyright © 2017 Elsevier B.V. All rights reserved.

  12. Major Alterations of Phosphatidylcholine and Lysophosphotidylcholine Lipids in the Substantia Nigra Using an Early Stage Model of Parkinson’s Disease

    PubMed Central

    Farmer, Kyle; Smith, Catherine A.; Hayley, Shawn; Smith, Jeffrey

    2015-01-01

    Parkinson’s disease (PD) is a progressive neurodegenerative disease affecting the nigrostriatal pathway, where patients do not manifest motor symptoms until >50% of neurons are lost. Thus, it is of great importance to determine early neuronal changes that may contribute to disease progression. Recent attention has focused on lipids and their role in pro- and anti-apoptotic processes. However, information regarding the lipid alterations in animal models of PD is lacking. In this study, we utilized high performance liquid chromatography electrospray ionization tandem mass spectrometry (HPLC-ESI-MS/MS) and novel HPLC solvent methodology to profile phosphatidylcholines and sphingolipids within the substantia nigra. The ipsilateral substantia nigra pars compacta was collected from rats 21 days after an infusion of 6-hydroxydopamine (6-OHDA), or vehicle into the anterior dorsal striatum. We identified 115 lipid species from their mass/charge ratio using the LMAPS Lipid MS Predict Database. Of these, 19 lipid species (from phosphatidylcholine and lysophosphotidylcholine lipid classes) were significantly altered by 6-OHDA, with most being down-regulated. The two lipid species that were up-regulated were LPC (16:0) and LPC (18:1), which are important for neuroinflammatory signalling. These findings provide a first step in the characterization of lipid changes in early stages of PD-like pathology and could provide novel targets for early interventions in PD. PMID:26274953

  13. Substantia nigra depigmentation and exposure to encephalitis lethargica.

    PubMed

    Hack, Nawaz; Jicha, Gregory A; Abell, Annalisa; Dean, Dawson; Vitek, Jerrold L; Berger, Joseph R

    2012-12-01

    Parkinsonism has occasionally been reported as a consequence of infectious diseases. The present study examines the clinical and pathological correlates of parkinsonism across birth cohorts in relation to critical exposure to the encephalitis lethargica epidemic in the early 1900s. The study population consisted of 678 participants in the Nun Study, of whom 432 died and came to autopsy. Qualitative indices of substantia nigra (SN) depigmentation were verified in a subset of 40 randomly selected subjects using quantitative stereological techniques. SN depigmentation, detected neuropathologically, was correlated with clinical parameters of Parkinson disease, age, and birth cohort. SN depigmentation was detected in 57 (13.2%) of the cohort. Although qualitative SN depigmentation correlated modestly with age (p = 0.02), it correlated best with birth cohort (p = 0.009) for women born in the years 1895-1899. Quantitative measures of SN depigmentation were increased in this birth cohort compared to age matched subjects from flanking birth cohorts 1890-1894 and 1900-1904 (p < 0.001). SN depigmentation correlated with speed of 6- and 50-foot walk (p < 0.0001), up and go test (p < 0.0001), and hand coordination (p < 0.0001). Subjects in the birth cohort 1895-1899 would have been in their late teens and 20s at the onset and during the peak of the encephalitis lethargica epidemic. These were precisely the age ranges of persons who were most often affected by the illness. These data suggest the possibility that the coexistence of parkinsonism and SN depigmentation in this birth cohort may have resulted from the yet undetermined infectious agent responsible for encephalitis lethargica. Copyright © 2012 American Neurological Association.

  14. Cell type analysis of functional fetal dopamine cell suspension transplants in the striatum and substantia nigra of patients with Parkinson’s disease

    PubMed Central

    Mendez, Ivar; Sanchez-Pernaute, Rosario; Cooper, Oliver; Viñuela, Angel; Ferrari, Daniela; Björklund, Lars; Dagher, Alain; Isacson, Ole

    2008-01-01

    We report the first post-mortem analysis of two patients with Parkinson’s disease who received fetal midbrain transplants as a cell suspension in the striatum, and in one case also in the substantia nigra. These patients had a favourable clinical evolution and positive 18F-fluorodopa PET scans and did not develop motor complications. The surviving transplanted dopamine neurons were positively identified with phenotypic markers of normal control human substantia nigra (n = 3), such as tyrosine hydroxylase, G-protein-coupled inward rectifying current potassium channel type 2 (Girk2) and calbindin. The grafts restored the cell type that provides specific dopaminergic innervation to the most affected striatal regions in the parkinsonian brain. Such transplants were able to densely reinnervate the host putamen with new dopamine fibres. The patients received only 6 months of standard immune suppression, yet by post-mortem analysis 3–4 years after surgery the transplants appeared only mildly immunogenic to the host brain, by analysis of microglial CD45 and CD68 markers. This study demonstrates that, using these methods, dopamine neuronal replacement cell therapy can be beneficial for patients with advanced disease, and that changing technical approaches could have a favourable impact on efficacy and adverse events following neural transplantation. PMID:15872020

  15. Parcellation of the human substantia nigra based on anatomical connectivity to the striatum☆

    PubMed Central

    Chowdhury, Rumana; Lambert, Christian; Dolan, Raymond J.; Düzel, Emrah

    2013-01-01

    Substantia nigra/ventral tegmental area (SN/VTA) subregions, defined by dopaminergic projections to the striatum, are differentially affected by health (e.g. normal aging) and disease (e.g. Parkinson's disease). This may have an impact on reward processing which relies on dopaminergic regions and circuits. We acquired diffusion tensor imaging (DTI) with probabilistic tractography in 30 healthy older adults to determine whether subregions of the SN/VTA could be delineated based on anatomical connectivity to the striatum. We found that a dorsomedial region of the SN/VTA preferentially connected to the ventral striatum whereas a more ventrolateral region connected to the dorsal striatum. These SN/VTA subregions could be characterised by differences in quantitative structural imaging parameters, suggesting different underlying tissue properties. We also observed that these connectivity patterns differentially mapped onto reward dependence personality trait. We show that tractography can be used to parcellate the SN/VTA into anatomically plausible and behaviourally meaningful compartments, an approach that may help future studies to provide a more fine-grained synopsis of pathological changes in the dopaminergic midbrain and their functional impact. PMID:23684858

  16. Midlife milk consumption and substantia nigra neuron density at death.

    PubMed

    Abbott, Robert D; Ross, G Webster; Petrovitch, Helen; Masaki, Kamal H; Launer, Lenore J; Nelson, James S; White, Lon R; Tanner, Caroline M

    2016-02-09

    To examine the relationship between midlife milk intake and Parkinson disease (PD) incidence through associations with substantia nigra (SN) neuron density and organochlorine pesticide exposure in decedent brains from the Honolulu-Asia Aging Study. Milk intake data were collected from 1965 to 1968 in 449 men aged 45-68 years with postmortem examinations from 1992 to 2004. Neuron density (count/mm(2)) was measured in quadrants from a transverse section of the SN. Additional measures included brain residues of heptachlor epoxide, an organochlorine pesticide found at excessively high levels in the milk supply in Hawaii in the early 1980s. Neuron density was lowest in nonsmoking decedents who consumed high amounts of milk (>16 oz/d). After removing cases of PD and dementia with Lewy bodies, adjusted neuron density in all but the dorsomedial quadrant was 41.5% lower for milk intake >16 oz/d vs intake that was less (95% confidence interval 22.7%-55.7%, p < 0.001). Among those who drank the most milk, residues of heptachlor epoxide were found in 9 of 10 brains as compared to 63.4% (26/41) for those who consumed no milk (p = 0.017). For those who were ever smokers, an association between milk intake and neuron density was absent. Milk intake is associated with SN neuron loss in decedent brains unaffected by PD. Whether contamination of milk with organochlorine pesticides has a role in SN neurodegeneration warrants further study. © 2015 American Academy of Neurology.

  17. Unitary synaptic connections among substantia nigra pars reticulata neurons

    PubMed Central

    Wilson, Charles J.

    2016-01-01

    Neurons in substantia nigra pars reticulata (SNr) are synaptically coupled by local axon collaterals, providing a potential mechanism for local signal processing. Because SNr neurons fire spontaneously, these synapses are constantly active. To investigate their properties, we recorded spontaneous inhibitory postsynaptic currents (sIPSCs) from SNr neurons in brain slices, in which afferents from upstream nuclei are severed, and the cells fire rhythmically. The sIPSC trains contained a mixture of periodic and aperiodic events. Autocorrelation analysis of sIPSC trains showed that a majority of cells had one to four active unitary inputs. The properties of the unitary IPSCs (uIPSCs) were analyzed for cells with one unitary input, using a model of periodic presynaptic firing and stochastic synaptic transmission. The inferred presynaptic firing rates and coefficient of variation of interspike intervals (ISIs) corresponded well with direct measurements of spiking in SNr neurons. Methods were developed to estimate the success probability, amplitude distributions, and kinetics of the uIPSCs, while removing the contribution from aperiodic sIPSCs. The sIPSC amplitudes were not increased upon release from halorhodopsin silencing, suggesting that most synapses were not depressed at the spontaneous firing rate. Gramicidin perforated-patch recordings indicated that the average reversal potential of spontaneous inhibitory postsynaptic potentials was −64 mV. Because of the change in driving force across the ISI, the unitary inputs are predicted to have a larger postsynaptic impact when they arrive late in the ISI. Simulations of network activity suggest that this very sparse inhibitory coupling may act to desynchronize the activity of SNr neurons while having only a small effect on firing rate. PMID:26961101

  18. Cav1.3 channels control D2-autoreceptor responses via NCS-1 in substantia nigra dopamine neurons

    PubMed Central

    Dragicevic, Elena; Poetschke, Christina; Duda, Johanna; Schlaudraff, Falk; Lammel, Stephan; Schiemann, Julia; Fauler, Michael; Hetzel, Andrea; Watanabe, Masahiko; Lujan, Rafael; Malenka, Robert C.; Striessnig, Joerg

    2014-01-01

    Dopamine midbrain neurons within the substantia nigra are particularly prone to degeneration in Parkinson’s disease. Their selective loss causes the major motor symptoms of Parkinson’s disease, but the causes for the high vulnerability of SN DA neurons, compared to neighbouring, more resistant ventral tegmental area dopamine neurons, are still unclear. Consequently, there is still no cure available for Parkinson’s disease. Current therapies compensate the progressive loss of dopamine by administering its precursor l-DOPA and/or dopamine D2-receptor agonists. D2-autoreceptors and Cav1.3-containing L-type Ca2+ channels both contribute to Parkinson’s disease pathology. L-type Ca2+ channel blockers protect SN DA neurons from degeneration in Parkinson’s disease and its mouse models, and they are in clinical trials for neuroprotective Parkinson’s disease therapy. However, their physiological functions in SN DA neurons remain unclear. D2-autoreceptors tune firing rates and dopamine release of SN DA neurons in a negative feedback loop through activation of G-protein coupled potassium channels (GIRK2, or KCNJ6). Mature SN DA neurons display prominent, non-desensitizing somatodendritic D2-autoreceptor responses that show pronounced desensitization in PARK-gene Parkinson’s disease mouse models. We analysed surviving human SN DA neurons from patients with Parkinson’s disease and from controls, and detected elevated messenger RNA levels of D2-autoreceptors and GIRK2 in Parkinson’s disease. By electrophysiological analysis of postnatal juvenile and adult mouse SN DA neurons in in vitro brain-slices, we observed that D2-autoreceptor desensitization is reduced with postnatal maturation. Furthermore, a transient high-dopamine state in vivo, caused by one injection of either l-DOPA or cocaine, induced adult-like, non-desensitizing D2-autoreceptor responses, selectively in juvenile SN DA neurons, but not ventral tegmental area dopamine neurons. With pharmacological

  19. Cav1.3 channels control D2-autoreceptor responses via NCS-1 in substantia nigra dopamine neurons.

    PubMed

    Dragicevic, Elena; Poetschke, Christina; Duda, Johanna; Schlaudraff, Falk; Lammel, Stephan; Schiemann, Julia; Fauler, Michael; Hetzel, Andrea; Watanabe, Masahiko; Lujan, Rafael; Malenka, Robert C; Striessnig, Joerg; Liss, Birgit

    2014-08-01

    Dopamine midbrain neurons within the substantia nigra are particularly prone to degeneration in Parkinson's disease. Their selective loss causes the major motor symptoms of Parkinson's disease, but the causes for the high vulnerability of SN DA neurons, compared to neighbouring, more resistant ventral tegmental area dopamine neurons, are still unclear. Consequently, there is still no cure available for Parkinson's disease. Current therapies compensate the progressive loss of dopamine by administering its precursor l-DOPA and/or dopamine D2-receptor agonists. D2-autoreceptors and Cav1.3-containing L-type Ca(2+) channels both contribute to Parkinson's disease pathology. L-type Ca(2+) channel blockers protect SN DA neurons from degeneration in Parkinson's disease and its mouse models, and they are in clinical trials for neuroprotective Parkinson's disease therapy. However, their physiological functions in SN DA neurons remain unclear. D2-autoreceptors tune firing rates and dopamine release of SN DA neurons in a negative feedback loop through activation of G-protein coupled potassium channels (GIRK2, or KCNJ6). Mature SN DA neurons display prominent, non-desensitizing somatodendritic D2-autoreceptor responses that show pronounced desensitization in PARK-gene Parkinson's disease mouse models. We analysed surviving human SN DA neurons from patients with Parkinson's disease and from controls, and detected elevated messenger RNA levels of D2-autoreceptors and GIRK2 in Parkinson's disease. By electrophysiological analysis of postnatal juvenile and adult mouse SN DA neurons in in vitro brain-slices, we observed that D2-autoreceptor desensitization is reduced with postnatal maturation. Furthermore, a transient high-dopamine state in vivo, caused by one injection of either l-DOPA or cocaine, induced adult-like, non-desensitizing D2-autoreceptor responses, selectively in juvenile SN DA neurons, but not ventral tegmental area dopamine neurons. With pharmacological and genetic

  20. Magnetic Transfer Contrast Accurately Localizes Substantia Nigra Confirmed by Histology

    PubMed Central

    Bolding, Mark S.; Reid, Meredith A.; Avsar, Kathy B.; Roberts, Rosalinda C.; Gamlin, Paul D.; Gawne, Timothy J.; White, David M.; den Hollander, Jan A.; Lahti, Adrienne C.

    2012-01-01

    Background Magnetic Resonance Imaging (MRI) has multiple contrast mechanisms. Like various staining techniques in histology, each contrast type reveals different information about the structure of the brain. However, it is not always clear how structures visible in MRI correspond to structures previously identified by histology. The purpose of this study was to determine if magnetic transfer contrast (MTC) or T2 contrast MRI was better at delineating the substantia nigra. Methods MRI scans were acquired in-vivo from two non-human primates (NHPs). The NHPs were subsequently euthanized, perfused, and their brains sectioned for histological analyses. Each slice was photographed prior to sectioning. Each brain was sectioned into approximately 500, 40-micron sections, encompassing most of the cortex, midbrain, and dorsal parts of the hindbrain. Levels corresponding to anatomical MRI images were selected. From these, adjacent sections were stained using Kluver Barrera (myelin and cell bodies) or tyrosine hydroxylase (TH) (dopaminergic neurons) immunohistochemistry. The resulting images were coregistered to the block-face images using a moving least squares algorithm with similarity transformations. MR images were similarly coregistered to the block-face images, allowing the structures in the MRI to be identified with structures in the histological images. Results We found that hyperintense (light) areas in MTC images were coextensive with the SN as delineated histologically. The hypointense (dark) areas in T2-weighted images were not coextensive with the SN, but extended partially into the SN and partially into the cerebral peduncles. Conclusions MTC is a more accurate contrast mechanism than T2-weighting for localizing the SN in vivo. PMID:22981657

  1. Microstructural changes in the substantia nigra of asymptomatic agricultural workers.

    PubMed

    Du, Guangwei; Lewis, Mechelle M; Sterling, Nicholas W; Kong, Lan; Chen, Honglei; Mailman, Richard B; Huang, Xuemei

    2014-01-01

    Parkinson's disease (PD) is marked by the loss of dopamine neurons in the substantia nigra (SN). Although the exact etiology is unknown, sporadic PD is hypothesized to be a result of genetic susceptibility interacting with environmental insult. Epidemiological studies suggest that pesticide exposure is linked to higher PD risk, but there are no studies demonstrating SN changes with chronic pesticide exposure in human subjects. Thus, high resolution T2-weighted magnetic resonance imaging (MRI) and diffusion tensor (DTI) images were obtained from 12 agricultural workers with chronic pesticide exposure, 12 controls, and 12 PD subjects. Neither controls nor pesticide-exposed subjects, had any parkinsonian symptoms. Exposure history to pesticides was assessed by a structured questionnaire. DTI measures in the SN, including fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD), were obtained for all subjects and compared among groups. Compared to controls, PD patients showed the expected significant changes in all DTI measurements in the SN. The pesticide-exposed subjects, compared to controls, had significantly lower FA values (p=0.022, after multiple comparisons correction), but no significant differences in RD, MD, or AD measures. The study is the first to demonstrate microstructural changes in the SN of human subjects with chronic pesticide exposure. The changes detected by MRI may mark "one of the hits" leading to PD, and underlie the increased risk of PD in pesticide users found in epidemiological studies. Further human studies assisted by these imaging markers may be useful in understanding the etiology of PD. Copyright © 2013 Elsevier Inc. All rights reserved.

  2. Molecular and functional differences in voltage-activated sodium currents between GABA projection neurons and dopamine neurons in the substantia nigra

    PubMed Central

    Ding, Shengyuan; Wei, Wei

    2011-01-01

    GABA projection neurons (GABA neurons) in the substantia nigra pars reticulata (SNr) and dopamine projection neurons (DA neurons) in substantia nigra pars compacta (SNc) have strikingly different firing properties. SNc DA neurons fire low-frequency, long-duration spikes, whereas SNr GABA neurons fire high-frequency, short-duration spikes. Since voltage-activated sodium (NaV) channels are critical to spike generation, the different firing properties raise the possibility that, compared with DA neurons, NaV channels in SNr GABA neurons have higher density, faster kinetics, and less cumulative inactivation. Our quantitative RT-PCR analysis on immunohistochemically identified nigral neurons indicated that mRNAs for pore-forming NaV1.1 and NaV1.6 subunits and regulatory NaVβ1 and Navβ4 subunits are more abundant in SNr GABA neurons than SNc DA neurons. These α-subunits and β-subunits are key subunits for forming NaV channels conducting the transient NaV current (INaT), persistent Na current (INaP), and resurgent Na current (INaR). Nucleated patch-clamp recordings showed that INaT had a higher density, a steeper voltage-dependent activation, and a faster deactivation in SNr GABA neurons than in SNc DA neurons. INaT also recovered more quickly from inactivation and had less cumulative inactivation in SNr GABA neurons than in SNc DA neurons. Furthermore, compared with nigral DA neurons, SNr GABA neurons had a larger INaR and INaP. Blockade of INaP induced a larger hyperpolarization in SNr GABA neurons than in SNc DA neurons. Taken together, these results indicate that NaV channels expressed in fast-spiking SNr GABA neurons and slow-spiking SNc DA neurons are tailored to support their different spiking capabilities. PMID:21880943

  3. Marinesco bodies and substantia nigra neuron density in Parkinson's disease.

    PubMed

    Abbott, R D; Nelson, J S; Ross, G W; Uyehara-Lock, J H; Tanner, C M; Masaki, K H; Launer, L J; White, L R; Petrovitch, H

    2017-12-01

    Marinesco bodies (MB) are intranuclear inclusions in pigmented neurons of the substantia nigra (SN). While rare in children, frequency increases with normal ageing and is high in Alzheimer's disease, dementia with Lewy bodies and other neurodegenerative disorders. Coinciding with the age-related rise in MB frequency is initiation of cell death among SN neurons. Whether MB have a role in this process is unknown. Our aim is to examine the association of MB with SN neuron density in Parkinson's disease (PD) in the Honolulu-Asia Aging Study. Data on MB and neuron density were measured in SN transverse sections in 131 autopsied men aged 73-99 years at the time of death from 1992 to 2007. Marinesco body frequency was low in the presence vs. absence of PD (2.3% vs. 6.6%, P < 0.001). After PD onset, MB frequency declined as duration of PD increased (P = 0.006). Similar patterns were observed for SN neuron density. When MB frequency was low, neuron density was noticeably reduced in the SN ventrolateral quadrant, the region most vulnerable to PD neurodegeneration. Low MB frequency was unique to PD as its high frequency in non-PD cases was unrelated to parkinsonian signs and incidental Lewy bodies. Frequency was high in the presence of Alzheimer's disease and apolipoprotein ε4 alleles. While findings confirm that MB frequency is low in PD, declines in MB frequency continue with PD duration. The extent to which MB have a distinct relationship with PD warrants clarification. Further studies of MB could be important in understanding PD processes. © 2017 British Neuropathological Society.

  4. Ketogenic diet prevents neuronal firing increase within the substantia nigra during pentylenetetrazole-induced seizure in rats.

    PubMed

    Viggiano, Andrea; Stoddard, Madison; Pisano, Simone; Operto, Francesca Felicia; Iovane, Valentina; Monda, Marcellino; Coppola, Giangennaro

    2016-07-01

    The mechanism responsible for the anti-seizure effect of ketogenic diets is poorly understood. Because the substantia nigra pars reticulata (SNr) is a "gate" center for seizures, the aim of the present experiment was to evaluate if a ketogenic diet modifies the neuronal response of this nucleus when a seizure-inducing drug is administered in rats. Two groups of rats were given a standard diet (group 1) or a ketogenic diet (group 2) for four weeks, then the threshold for seizure induction and the firing rate of putative GABAergic neurons within the SNr were evaluated with progressive infusion of pentylenetetrazole under general anesthesia. The results demonstrated that the ketogenic diet abolished the correlation between the firing rate response of SNr-neurons and the seizure-threshold. This result suggests that the anti-seizure effect of ketogenic diets can be due to a decrease in reactivity of GABAergic SNr-neurons. Copyright © 2016 Elsevier Inc. All rights reserved.

  5. The inhibitory microcircuit of the substantia nigra provides feedback gain control of the basal ganglia output

    PubMed Central

    Brown, Jennifer; Pan, Wei-Xing; Dudman, Joshua Tate

    2014-01-01

    Dysfunction of the basal ganglia produces severe deficits in the timing, initiation, and vigor of movement. These diverse impairments suggest a control system gone awry. In engineered systems, feedback is critical for control. By contrast, models of the basal ganglia highlight feedforward circuitry and ignore intrinsic feedback circuits. In this study, we show that feedback via axon collaterals of substantia nigra projection neurons control the gain of the basal ganglia output. Through a combination of physiology, optogenetics, anatomy, and circuit mapping, we elaborate a general circuit mechanism for gain control in a microcircuit lacking interneurons. Our data suggest that diverse tonic firing rates, weak unitary connections and a spatially diffuse collateral circuit with distinct topography and kinetics from feedforward input is sufficient to implement divisive feedback inhibition. The importance of feedback for engineered systems implies that the intranigral microcircuit, despite its absence from canonical models, could be essential to basal ganglia function. DOI: http://dx.doi.org/10.7554/eLife.02397.001 PMID:24849626

  6. Distinct Contributions of Ventromedial and Dorsolateral Subregions of the Human Substantia Nigra to Appetitive and Aversive Learning

    PubMed Central

    Larsen, Tobias; Collette, Sven; Tyszka, Julian M.; Seymour, Ben; O'Doherty, John P.

    2015-01-01

    The role of neurons in the substantia nigra (SN) and ventral tegmental area (VTA) of the midbrain in contributing to the elicitation of reward prediction errors during appetitive learning has been well established. Less is known about the differential contribution of these midbrain regions to appetitive versus aversive learning, especially in humans. Here we scanned human participants with high-resolution fMRI focused on the SN and VTA while they participated in a sequential Pavlovian conditioning paradigm involving an appetitive outcome (a pleasant juice), as well as an aversive outcome (an unpleasant bitter and salty flavor). We found a degree of regional specialization within the SN: Whereas a region of ventromedial SN correlated with a temporal difference reward prediction error during appetitive Pavlovian learning, a dorsolateral area correlated instead with an aversive expected value signal in response to the most distal cue, and to a reward prediction error in response to the most proximal cue to the aversive outcome. Furthermore, participants' affective reactions to both the appetitive and aversive conditioned stimuli more than 1 year after the fMRI experiment was conducted correlated with activation in the ventromedial and dorsolateral SN obtained during the experiment, respectively. These findings suggest that, whereas the human ventromedial SN contributes to long-term learning about rewards, the dorsolateral SN may be particularly important for long-term learning in aversive contexts. SIGNIFICANCE STATEMENT The role of the substantia nigra (SN) and ventral tegmental area (VTA) in appetitive learning is well established, but less is known about their contribution to aversive compared with appetitive learning, especially in humans. We used high-resolution fMRI to measure activity in the SN and VTA while participants underwent higher-order Pavlovian learning. We found a regional specialization within the SN: a ventromedial area was selectively engaged

  7. Coexistence of glutamatergic spine synapses and shaft synapses in substantia nigra dopamine neurons

    PubMed Central

    Jang, Miae; Bum Um, Ki; Jang, Jinyoung; Jin Kim, Hyun; Cho, Hana; Chung, Sungkwon; Kyu Park, Myoung

    2015-01-01

    Dopamine neurons of the substantia nigra have long been believed to have multiple aspiny dendrites which receive many glutamatergic synaptic inputs from several regions of the brain. But, here, using high-resolution two-photon confocal microscopy in the mouse brain slices, we found a substantial number of common dendritic spines in the nigral dopamine neurons including thin, mushroom, and stubby types of spines. However, the number of dendritic spines of the dopamine neurons was approximately five times lower than that of CA1 pyramidal neurons. Immunostaining and morphological analysis revealed that glutamatergic shaft synapses were present two times more than spine synapses. Using local two-photon glutamate uncaging techniques, we confirmed that shaft synapses and spine synapses had both AMPA and NMDA receptors, but the AMPA/NMDA current ratios differed. The evoked postsynaptic potentials of spine synapses showed lower amplitudes but longer half-widths than those of shaft synapses. Therefore, we provide the first evidence that the midbrain dopamine neurons have two morphologically and functionally distinct types of glutamatergic synapses, spine synapses and shaft synapses, on the same dendrite. This peculiar organization could be a new basis for unraveling many physiological and pathological functions of the midbrain dopamine neurons. PMID:26435058

  8. Presynaptic transmitters and depolarizing influences regulate development of the substantia nigra in culture.

    PubMed

    Friedman, W J; Dreyfus, C F; McEwen, B; Black, I B

    1988-10-01

    Recent evidence suggests that extracellular signals regulate neurotransmitter traits in brain catecholaminergic (CA) neurons as in the periphery. Development of the dopaminergic phenotype in the mouse substantia nigra (SN) was studied by monitoring tyrosine hydroxylase (TH), the rate-limiting enzyme in CA biosynthesis in vivo and in culture. Explants of SN were dissected from embryonic day 15 embryos and grown in culture for a week. To define the influence of depolarizing signals on central dopaminergic neurons, cultures were grown with the pharmacologic depolarizing agent veratridine. This treatment elicited a significant increase in TH enzyme activity, accompanied by elevated levels of enzyme protein. The increase in activity was prevented by TTX, suggesting that transmembrane Na+ influx was necessary for the rise in TH. A physiologic presynaptic agonist, substance P, also evoked a significant increase in TH activity; however, the coproduced tachykinin peptide, substance K (SK, neurokinin A) elicited a more dramatic rise. The SK effect was blocked by TTX, suggesting that the physiologic agonist was acting through the same mechanism as the pharmacologic agent veratridine. Immunoblot analysis revealed that SK elicited a parallel increase in TH enzyme protein. Our observations suggest that the novel peptide, SK, serves a physiological role in the regulation of TH in the striatonigral pathway.

  9. Novelty-Sensitive Dopaminergic Neurons in the Human Substantia Nigra Predict Success of Declarative Memory Formation.

    PubMed

    Kamiński, Jan; Mamelak, Adam N; Birch, Kurtis; Mosher, Clayton P; Tagliati, Michele; Rutishauser, Ueli

    2018-05-07

    The encoding of information into long-term declarative memory is facilitated by dopamine. This process depends on hippocampal novelty signals, but it remains unknown how midbrain dopaminergic neurons are modulated by declarative-memory-based information. We recorded individual substantia nigra (SN) neurons and cortical field potentials in human patients performing a recognition memory task. We found that 25% of SN neurons were modulated by stimulus novelty. Extracellular waveform shape and anatomical location indicated that these memory-selective neurons were putatively dopaminergic. The responses of memory-selective neurons appeared 527 ms after stimulus onset, changed after a single trial, and were indicative of recognition accuracy. SN neurons phase locked to frontal cortical theta-frequency oscillations, and the extent of this coordination predicted successful memory formation. These data reveal that dopaminergic neurons in the human SN are modulated by memory signals and demonstrate a progression of information flow in the hippocampal-basal ganglia-frontal cortex loop for memory encoding. Copyright © 2018 The Author(s). Published by Elsevier Ltd.. All rights reserved.

  10. Modality distribution of sensory neurons in the feline caudate nucleus and the substantia nigra.

    PubMed

    Márkus, Zita; Eördegh, Gabriella; Paróczy, Zsuzsanna; Benedek, G; Nagy, A

    2008-09-01

    Despite extensive analysis of the motor functions of the basal ganglia and the fact that multisensory information processing appears critical for the execution of their behavioral action, little is known concerning the sensory functions of the caudate nucleus (CN) and the substantia nigra (SN). In the present study, we set out to describe the sensory modality distribution and to determine the proportions of multisensory units within the CN and the SN. The separate single sensory modality tests demonstrated that a majority of the neurons responded to only one modality, so that they seemed to be unimodal. In contrast with these findings, a large proportion of these neurons exhibited significant multisensory cross-modal interactions. Thus, these neurons should also be classified as multisensory. Our results suggest that a surprisingly high proportion of sensory neurons in the basal ganglia are multisensory, and demonstrate that an analysis without a consideration of multisensory cross-modal interactions may strongly underrepresent the number of multisensory units. We conclude that a majority of the sensory neurons in the CN and SN process multisensory information and only a minority of these units are clearly unimodal.

  11. [Simultaneous micro-transplantation of fetal mesencephalic cells to the striate and substantia nigra pars reticulata in hemi-parkinsonian rats. A study of behavior].

    PubMed

    Blanco, L; Pavón, N; Macías, R; Castillo, L; Díaz, C; García, A; Alvarez, P

    Microtransplantation of fetal dopaminergic cells has been used over the past ten years with good results in models of Parkinson's disease. To evaluate the effect of microtransplantation of fetal dopaminergic cells 'seeded' in the substantia nigra pars reticulata (SNpr) and striate (St) simultaneously. The animals received a transplant or microtransplant of cells into the St and SNpr ipsilateral to the lesion in the substantia nigra pars compacta or to both regions. Depending on the site and technique used the following experimental groups were considered: I. Macrotransplantation to the St (n = 20); II. Microtransplant to the St (n = 20); III. Microtransplant to St + SNpr (n = 20); IV. Microtransplant to St + SNpr (n = 20); V. Macrotransplantation to SNpr (n = 20); VI. Microtransplantation to SNpr (n = 20); and VII. Control (lesion only) (n = 20). The rotations induced by D-amphetamine (5 mg/kg i.p.) and by apomorphine were studied 1, 2, 3 and 6 months and 3 and 6 months respectively after transplantation. Three months after transplantation we studied the motor asymmetry shown by the animals by means of the ladder test. The rotations were reduced in the groups with intrastriate transplantation. Comparison between the surgical techniques showed nonsignificant differences between them. The ladder test showed significant differences in use of the limbs in all experimental groups. Use of the left limb was significantly reduced in all groups. Modification of the rotations seems more sensitive to the site of transplant than to the technique used. It seems that the skills studied using the ladder test are not altered by the microtransplant technique.

  12. [Effect of stimulation of GABA-ergic structures of the substantia nigra and caudate nucleus on food-getting behavior in the cat].

    PubMed

    Shugalev, N P

    1983-01-01

    A study was made of the functional significance of GABA-ergic structures of the substantia nigra (SN) and the caudate nucleus (CN) and their role in food-procuring behaviour of cats. Analysis was made of behavioral and EEG-effects of local GABA and the GABA antagonist, picrotoxin, microinjections into the studied brain structures. Stimulation of the GABA-ergic structures of the SN produced a sedative effect and depression of the cat food-procuring behaviour. Effects of stimulation of the CN GABA-ergic structures were to a great degree reverse. The conclusion has been made that GABA-ergic structures of the SN and the CN play different roles in controlling the CN inhibitory influence upon food-procuring behaviour.

  13. Mitochondrial uncoupling agents antagonize rotenone actions in rat substantia nigra dopamine neurons.

    PubMed

    Wu, Yan-Na; Munhall, Adam C; Johnson, Steven W

    2011-06-13

    Mild uncoupling of oxidative phosphorylation has been reported to reduce generation of reactive oxygen species (ROS) and therefore may be neuroprotective. We reported previously that the mitochondrial poison rotenone enhanced currents evoked by N-methyl-D-aspartate (NMDA) by a ROS-dependent mechanism in rat midbrain dopamine neurons. Thus, rotenone, which produces a model of Parkinson's disease in rodents, may increase the risk of dopamine neuron excitotoxicity. The purpose of this study was to test the hypothesis that oxidative phosphorylation uncoupling agents would antagonize the effect of rotenone on NMDA current. We used patch pipettes to record whole-cell currents under voltage-clamp (-60 mV) in substantia nigra dopamine neurons in slices of rat brain. Rotenone, NMDA and uncoupling agents were added to the brain slice superfusate. Inward currents evoked by NMDA (30 μM) more than doubled in amplitude after slices were superfused for 30 min with 100 nM rotenone. Continuous superfusion with the uncoupling agent carbonyl cyanide-p-trifluoromethoxy-phenylhydrazone (1-3 nM) or 2,4-dinitrophenol (100 nM) significantly antagonized and delayed the ability of rotenone to potentiate NMDA currents. Coenzyme Q₁₀ (1-10 nM), which has been reported to facilitate uncoupling protein activity, also antagonized this action of rotenone. These results suggest that mild uncoupling of oxidative phosphorylation may protect dopamine neurons against injury from mitochondrial poisons such as rotenone. Published by Elsevier B.V.

  14. The inhibitory microcircuit of the substantia nigra provides feedback gain control of the basal ganglia output.

    PubMed

    Brown, Jennifer; Pan, Wei-Xing; Dudman, Joshua Tate

    2014-05-21

    Dysfunction of the basal ganglia produces severe deficits in the timing, initiation, and vigor of movement. These diverse impairments suggest a control system gone awry. In engineered systems, feedback is critical for control. By contrast, models of the basal ganglia highlight feedforward circuitry and ignore intrinsic feedback circuits. In this study, we show that feedback via axon collaterals of substantia nigra projection neurons control the gain of the basal ganglia output. Through a combination of physiology, optogenetics, anatomy, and circuit mapping, we elaborate a general circuit mechanism for gain control in a microcircuit lacking interneurons. Our data suggest that diverse tonic firing rates, weak unitary connections and a spatially diffuse collateral circuit with distinct topography and kinetics from feedforward input is sufficient to implement divisive feedback inhibition. The importance of feedback for engineered systems implies that the intranigral microcircuit, despite its absence from canonical models, could be essential to basal ganglia function. DOI: http://dx.doi.org/10.7554/eLife.02397.001. Copyright © 2014, Brown et al.

  15. Substantia nigra activity level predicts trial-to-trial adjustments in cognitive control

    PubMed Central

    Boehler, C.N.; Bunzeck, N.; Krebs, R.M.; Noesselt, T.; Schoenfeld, M.A.; Heinze, H.-J.; Münte, T.F.; Woldorff, M.G.; Hopf, J.-M.

    2011-01-01

    Effective adaptation to the demands of a changing environment requires flexible cognitive control. The medial and lateral frontal cortices are involved in such control processes, putatively in close interplay with the basal ganglia. In particular, dopaminergic projections from the midbrain (i.e., from the substantia nigra (SN) and the ventral tegmental area (VTA)) have been proposed to play a pivotal role in modulating the activity in these areas for cognitive control purposes. In that dopaminergic involvement has been strongly implicated in reinforcement learning, these ideas suggest functional links between reinforcement learning, where the outcome of actions shapes behavior over time, and cognitive control in a more general context, where no direct reward is involved. Here, we provide evidence from functional MRI in humans that activity in the SN predicts systematic subsequent trial-to-trial response time (RT) prolongations that are thought to reflect cognitive control in a Stop-signal paradigm. In particular, variations in the activity level of the SN in one trial predicted the degree of RT prolongation on the subsequent trial, consistent with a modulating output signal from the SN being involved in enhancing cognitive control. This link between SN activity and subsequent behavioral adjustments lends support to theoretical accounts that propose dopaminergic control signals that shape behavior both in the presence and absence of direct reward. This SN-based modulatory mechanism is presumably mediated via a wider network that determines response speed in this task, including frontal and parietal control regions, along with the basal ganglia and the associated subthalamic nucleus. PMID:20465358

  16. Silibinin attenuates MPP⁺-induced neurotoxicity in the substantia nigra in vivo.

    PubMed

    Jung, Un Ju; Jeon, Min-Tae; Choi, Myung-Sook; Kim, Sang Ryong

    2014-05-01

    Parkinson's disease (PD) is characterized by degeneration of the nigrostriatal dopaminergic (DA) pathway. The cause of neuronal death in PD is largely unknown, but it is becoming clear that inflammation plays a significant role in the pathophysiology of PD. Silibinin is a major flavonoid in milk thistle which has an anti-inflammatory activity. We investigated whether silibinin could have neuroprotective effects on DA neurons in the 1-methyl-4-phenylpyridinium ion (MPP(+))-treated animal model of PD in vivo. To address this question, animals received intraperitoneal (i.p.) injections 10, 50, or 100 mg/kg of silibinin, starting 1 day before MPP(+) injection and continued daily until 6 days post-lesion for tyrosine hydroxylase (TH) staining, or until 1 hour prior to the MPP(+) injection to examine the expression levels of inflammatory proteins. Finally, their brains were harvested at the indicated time points for the analyses. Silibinin treatment with 10 mg/kg had no significantly neuroprotective effects in the substantia nigra (SN). However, 50 and 100 mg/kg of silibinin ameliorated the MPP(+)-induced neurotoxicity in the SN in a dose-dependent manner, and the increased levels of inflammatory molecules such as tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β) and inducible nitric oxide synthase (iNOS) by MPP(+) treatment were attenuated by treatment with 100 mg/kg of silibinin. These results indicate that silibinin could be a useful and beneficial natural product offering promise for the prevention of DA neuronal degeneration involved in PD.

  17. Protein Markers of Neurotransmitter Synthesis and Release in Postmortem Schizophrenia Substantia Nigra.

    PubMed

    Schoonover, Kirsten E; McCollum, Lesley A; Roberts, Rosalinda C

    2017-01-01

    The substantia nigra (SN) provides the largest dopaminergic input to the brain, projects to the striatum (the primary locus of action for antipsychotic medication), and receives GABAergic and glutamatergic inputs. This study used western blot analysis to compare protein levels of tyrosine hydroxylase (TH), glutamate decarboxylase (GAD67), and vesicular glutamate transporters (vGLUT1 and vGLUT2) in postmortem human SN in schizophrenia subjects (n=13) and matched controls (n=12). As a preliminary analysis, the schizophrenia group was subdivided by (1) treatment status: off medication (n=4) or on medication (n=9); or (2) treatment response: treatment resistant (n=5) or treatment responsive (n=4). The combined schizophrenia group had higher TH and GAD67 protein levels than controls (an increase of 69.6%, P=0.01 and 19.5%, P=0.004, respectively). When subdivided by medication status, these increases were found in the on-medication subjects (TH 88.3%, P=0.008; GAD67 40.6%, P=0.003). In contrast, unmedicated schizophrenia subjects had higher vGLUT2 levels than controls (an increase of 28.7%, P=0.041), but vGLUT2 levels were similar between medicated schizophrenia subjects and controls. Treatment-resistant subjects had significantly higher TH and GAD67 levels than controls (an increase of 121.0%, P=0.0003 and 58.7%, P=0.004, respectively). These data suggest increases in dopamine and GABA transmission in the SN in schizophrenia, with a potential relation to treatment and response.

  18. Intrinsic and integrative properties of substantia nigra pars reticulata neurons

    PubMed Central

    Zhou, Fu-Ming; Lee, Christian R.

    2011-01-01

    The GABA projection neurons of the substantia nigra pars reticulata (SNr) are output neurons for the basal ganglia and thus critical for movement control. Their most striking neurophysiological feature is sustained, spontaneous high frequency spike firing. A fundamental question is: what are the key ion channels supporting the remarkable firing capability in these neurons? Recent studies indicate that these neurons express tonically active TRPC3 channels that conduct a Na-dependent inward current even at hyperpolarized membrane potentials. When the membrane potential reaches −60 mV, a voltage-gated persistent sodium current (INaP) starts to activate, further depolarizing the membrane potential. At or slightly below −50 mV, the large transient voltage-activated sodium current (INaT) starts to activate and eventually triggers the rapid rising phase of action potentials. SNr GABA neurons have a higher density of (INaT), contributing to the faster rise and larger amplitude of action potentials, compared with the slow-spiking dopamine neurons. INaT also recovers from inactivation more quickly in SNr GABA neurons than in nigral dopamine neurons. In SNr GABA neurons, the rising phase of the action potential triggers the activation of high-threshold, inactivation-resistant Kv3-like channels that can rapidly repolarize the membrane. These intrinsic ion channels provide SNr GABA neurons with the ability to fire spontaneous and sustained high frequency spikes. Additionally, robust GABA inputs from direct pathway medium spiny neurons in the striatum and GABA neurons in the globus pallidus may inhibit and silence SNr GABA neurons, whereas glutamate synaptic input from the subthalamic nucleus may induce burst firing in SNr GABA neurons. Thus, afferent GABA and glutamate synaptic inputs sculpt the tonic high frequency firing of SNr GABA neurons and the consequent inhibition of their targets into an integrated motor control signal that is further fine-tuned by neuromodulators

  19. Substantia nigra hyperechogenicity is related to decline in verbal memory in healthy elderly adults.

    PubMed

    Yilmaz, R; Behnke, S; Liepelt-Scarfone, I; Roeben, B; Pausch, C; Runkel, A; Heinzel, S; Niebler, R; Suenkel, U; Eschweiler, G W; Maetzler, W; Berg, D

    2016-05-01

    Deficits in cognition have been reported in Parkinson's disease (PD) already in the early and even in the pre-motor stages. Whilst substantia nigra hyperechogenicity measured by transcranial B-mode sonography (TCS) represents a strong PD marker and is associated with an increased risk for PD in still healthy individuals, its association with cognitive performance in prodromal PD stages is not well established. Two different cohorts of healthy elderly individuals were assessed by TCS and two different neuropsychological test batteries covering executive functions, verbal memory, language, visuo-constructional function and attention. Cognitive performance was compared between individuals with hyperechogenicity (SN+) and without hyperechogenicity (SN-). In both cohorts, SN+ individuals performed significantly worse than the SN- group in tests assessing verbal memory (word list delayed recall P = 0.05, logical memory II P < 0.017). Significant differences in Mini-Mental State Examination score (cohort 1, P = 0.02) and executive function tests (cohort 2, Stroop Color-Word Reading, P = 0.004) could only be shown in one of the two cohorts. No between-group effects were found in other cognitive tests and domains. These results indicate that individuals with the PD risk marker SN+ perform worse in verbal memory compared to SN- independent of the assessment battery. Memory performance should be assessed in detail in individuals at risk for PD. © 2016 EAN.

  20. Transient glutathione depletion in the substantia nigra compacta is associated with neuroinflammation in rats.

    PubMed

    Díaz-Hung, Mei-Li; Yglesias-Rivera, Arianna; Hernández-Zimbrón, Luis Fernando; Orozco-Suárez, Sandra; Ruiz-Fuentes, Jenny Laura; Díaz-García, Alexis; León-Martínez, Rilda; Blanco-Lezcano, Lisette; Pavón-Fuentes, Nancy; Lorigados-Pedre, Lourdes

    2016-10-29

    Glutathione (GSH) deficiency has been identified as an early event in the progression of Parkinson's disease. However, the role of GSH in the etiology and pathogenesis of this neurodegenerative disorder is not well established. The aim of this study is to assess the effect of transient GSH depletion in the substantia nigra pars compacta (SNpc) on neuroinflammation after the injection of a single dose of l-buthionine sulfoximine (BSO) into the SNpc of male Sprague-Dawley rats. The results showed that BSO treatment stimulates microglia (p<0.01) and astroglial response (p<0.01), c-Jun N-terminal kinase and inducible nitric oxide synthase (iNOS) (p<0.001) in the SNpc, accompanied by dopaminergic dysfunction. In addition, high levels of tumor necrosis factor α (p<0.01), interleukins IL-1β p<0.01), IL-6 p<0.001) and nitric oxide p<0.01) were found in the treated animals compared to control groups, while no significant differences were found in IL-10 levels. These results suggest that transient GSH depletion can increase the susceptibility of SNpc to degeneration by promoting an inflammatory response and nitrosative stress, reinforcing the possible role of GSH unbalance, oxygen/nitrogen reactive species and neuroinflammation as causal factors on the degeneration of the SNpc. Copyright © 2016 IBRO. Published by Elsevier Ltd. All rights reserved.

  1. Substantia Nigra Volume Loss Before Basal Forebrain Degeneration in Early Parkinson Disease

    PubMed Central

    Ziegler, David A.; Wonderlick, Julien S.; Ashourian, Paymon; Hansen, Leslie A.; Young, Jeremy C.; Murphy, Alex J.; Koppuzha, Cecily K.; Growdon, John H.; Corkin, Suzanne

    2017-01-01

    Objective To test the hypothesis that degeneration of the substantia nigra pars compacta (SNc) precedes that of the cholinergic basal forebrain (BF) in Parkinson disease (PD) using new multispectral structural magnetic resonance (MR) imaging tools to measure the volumes of the SNc and BF. Design Matched case-control study. Setting The Athinoula A. Martinos Imaging Center at the McGovern Institute for Brain Research, Massachusetts Institute of Technology (MIT), and the Massachusetts General Hospital/MIT Morris Udall Center of Excellence in Parkinson Disease Research. Patients Participants included 29 patients with PD (Hoehn and Yahr [H&Y] stages 1–3) and 27 matched healthy control subjects. Main Outcome Measures We acquired multiecho T1-weighted, multiecho proton density, T2-weighted, and T2-weighted fluid-attenuated inversion recovery (FLAIR) sequences from each participant. For the SNc, we created a weighted mean of the multiple echoes, yielding a single volume with a high ratio of contrast to noise. We visualized the BF using T2-weighted FLAIR images. For each participant, we manually labeled the 2 structures and calculated their volumes. Results Relative to the controls, 13 patients with H&Y stage 1 PD had significantly decreased SNc volumes. Sixteen patients with H&Y stage 2 or 3 PD showed little additional volume loss. In contrast, the BF volume loss occurred later in the disease, with a significant decrease apparent in patients having H&Y stage 2 or 3 PD compared with the controls and the patients having H&Y stage 1 PD. The latter group did not differ significantly from the controls. Conclusion Our results support the proposed neuropathological trajectory in PD and establish novel multispectral methods as MR imaging biomarkers for tracking the degeneration of the SNc and BF. PMID:23183921

  2. Calpain inhibition reduces NMDA receptor rundown in rat substantia nigra dopamine neurons.

    PubMed

    Zhao, Jerry; Baudry, Michel; Jones, Susan

    2018-05-04

    Repeated activation of N-Methyl-d-aspartate receptors (NMDARs) causes a Ca 2+ -dependent reduction in NMDAR-mediated current in dopamine (DA) neurons of the substantia nigra pars compacta (SNc) in one week old rats; however, a Ca 2+ -dependent regulatory protein has not been identified. The role of the Ca 2+ -dependent cysteine protease, calpain, in mediating NMDAR current rundown was investigated. In brain slices from rats aged postnatal day 7-9 ('P7'), bath application of either of the membrane permeable calpain inhibitors, N-Acetyl-L-leucyl-L-leucyl-L-norleucinal (ALLN, 20 μM) or MDL-28170 (30 μM) significantly reduced whole-cell NMDAR current rundown. To investigate the role of the calpain-2 isoform, the membrane permeable calpain-2 inhibitor, Z-Leu-Abu-CONH-CH2-C6H3 (3, 5-(OMe)2 (C2I, 200 nM), was applied; C2I application significantly reduced whole cell NMDAR current rundown. Interestingly, ALLN but not C2I significantly reduced rundown of NMDA-EPSCs. These results suggest the calpain-2 isoform mediates Ca 2+ -dependent regulation of extrasynaptic NMDAR current in the first postnatal week, while calpain-1 might mediate rundown of synaptic NMDAR currents. One week later in postnatal development, at P12-P16 ('P14'), there was significantly less rundown in SNc-DA neurons, and no significant effect on rundown of either Ca 2+ chelation or treatment with the calpain inhibitor, ALLN, suggesting that the rundown observed in SNc-DA neurons from two week-old rats might be Ca 2+ -independent. In conclusion, Ca 2+ -dependent rundown of extrasynaptic NMDAR currents in SNc DA neurons involves calpain-2 activation, but Ca 2+ - and calpain-2-dependent NMDAR current rundown is developmentally regulated. Copyright © 2018 Elsevier Ltd. All rights reserved.

  3. Human substantia nigra and ventral tegmental area involvement in computing social error signals during the ultimatum game

    PubMed Central

    Hétu, Sébastien; Luo, Yi; D’Ardenne, Kimberlee; Lohrenz, Terry

    2017-01-01

    Abstract As models of shared expectations, social norms play an essential role in our societies. Since our social environment is changing constantly, our internal models of it also need to change. In humans, there is mounting evidence that neural structures such as the insula and the ventral striatum are involved in detecting norm violation and updating internal models. However, because of methodological challenges, little is known about the possible involvement of midbrain structures in detecting norm violation and updating internal models of our norms. Here, we used high-resolution cardiac-gated functional magnetic resonance imaging and a norm adaptation paradigm in healthy adults to investigate the role of the substantia nigra/ventral tegmental area (SN/VTA) complex in tracking signals related to norm violation that can be used to update internal norms. We show that the SN/VTA codes for the norm’s variance prediction error (PE) and norm PE with spatially distinct regions coding for negative and positive norm PE. These results point to a common role played by the SN/VTA complex in supporting both simple reward-based and social decision making. PMID:28981876

  4. Edaravone protects neurons in the rat substantia nigra against 6-hydroxydopamine-induced oxidative stress damage.

    PubMed

    Liu, Xiqi; Shao, Rushing; Li, Meng; Yang, Guofeng

    2014-11-01

    To investigate the mechanism of the neuroprotective effect of edaravone in substantia nigra (SN) of the 6-OHDA-induced rat model of Parkinson's disease. Animal model of Parkinson's disease was induced in male Sprague-Dawley rats by injecting 6-OHDA into the left medial forebrain bundle. Subsequently, rats were intraperitoneally injected with 0.3, 1, or 3 mg/kg of edaravone for 14 days or with 3 mg/kg edaravone for 14 days followed by 14 days of no treatment. We evaluated the effect of edaravone on the rotational and normal behavior of the rats, and on the number of tyrosine hydroxylase (TH)-positive cells, the amount of Nissl bodies, and the levels of glutathione (GSH), and malondialdehyde (MDA) in the SN. Edaravone treatment at 3 mg/kg significantly reduced apomorphine-induced rotational behavior (P < 0.01), improved the spontaneous behavior, prevented the decrease in the levels of TH-positive cells, Nissl bodies and GSH, and inhibited the increase in the levels of MDA (P < 0.05) in SN of rats with 6-OHDA-induced PD. Edaravone exerted a long-term neuroprotective effects in 6-OHDA-induced PD animal model by attenuating changes in the levels of GSH and MDA in SN, caused by oxidative stress. Edaravone prevented 6-OHDA-induced behavioral changes and de-pigmentation of SN that results from the loss of dopaminergic neurons.

  5. p62 Pathology Model in the Rat Substantia Nigra with Filamentous Inclusions and Progressive Neurodegeneration

    PubMed Central

    Jackson, Kasey L.; Lin, Wen-Lang; Miriyala, Sumitra; Dayton, Robert D.; Panchatcharam, Manikandan; McCarthy, Kevin J.; Castanedes-Casey, Monica; Dickson, Dennis W.; Klein, Ronald L.

    2017-01-01

    One of the proteins most frequently found in neuropathological lesions is the ubiquitin binding protein p62 (sequestosome 1). Post-mortem analysis of p62 is a defining diagnostic marker in several neurodegenerative diseases including amyotrophic lateral sclerosis and inclusion body myositis. Since p62 functions in protein degradation pathways including autophagy, the build-up of p62-positive inclusions suggests defects in protein clearance. p62 was expressed unilaterally in the rat substantia nigra with an adeno-associated virus vector (AAV9) in order to study p62 neuropathology. Inclusions formed within neurons from several days to several weeks after gene transfer. By electron microscopy, the inclusions were found to contain packed 10 nm thick filaments, and mitochondria cristae structure was disrupted, resulting in the formation of empty spaces. In corollary cell culture transfections, p62 clearly impaired mitochondrial function. To probe for potential effects on macroautophagy, we co-expressed p62 with a double fluorescent tagged reporter for the autophagosome protein LC3 in the rat. p62 induced a dramatic and specific dissociation of the two tags. By 12 weeks, a rotational behavior phenotype manifested, consistent with a significant loss of dopaminergic neurons analyzed post-mortem. p62 overexpression resulted in a progressive and robust pathology model with neuronal inclusions and neurodegeneration. p62 gene transfer could be a novel methodological probe to disrupt mitochondrial function or autophagy in the brain and other tissues in vivo. PMID:28076378

  6. p62 Pathology Model in the Rat Substantia Nigra with Filamentous Inclusions and Progressive Neurodegeneration.

    PubMed

    Jackson, Kasey L; Lin, Wen-Lang; Miriyala, Sumitra; Dayton, Robert D; Panchatcharam, Manikandan; McCarthy, Kevin J; Castanedes-Casey, Monica; Dickson, Dennis W; Klein, Ronald L

    2017-01-01

    One of the proteins most frequently found in neuropathological lesions is the ubiquitin binding protein p62 (sequestosome 1). Post-mortem analysis of p62 is a defining diagnostic marker in several neurodegenerative diseases including amyotrophic lateral sclerosis and inclusion body myositis. Since p62 functions in protein degradation pathways including autophagy, the build-up of p62-positive inclusions suggests defects in protein clearance. p62 was expressed unilaterally in the rat substantia nigra with an adeno-associated virus vector (AAV9) in order to study p62 neuropathology. Inclusions formed within neurons from several days to several weeks after gene transfer. By electron microscopy, the inclusions were found to contain packed 10 nm thick filaments, and mitochondria cristae structure was disrupted, resulting in the formation of empty spaces. In corollary cell culture transfections, p62 clearly impaired mitochondrial function. To probe for potential effects on macroautophagy, we co-expressed p62 with a double fluorescent tagged reporter for the autophagosome protein LC3 in the rat. p62 induced a dramatic and specific dissociation of the two tags. By 12 weeks, a rotational behavior phenotype manifested, consistent with a significant loss of dopaminergic neurons analyzed post-mortem. p62 overexpression resulted in a progressive and robust pathology model with neuronal inclusions and neurodegeneration. p62 gene transfer could be a novel methodological probe to disrupt mitochondrial function or autophagy in the brain and other tissues in vivo.

  7. Specificity and sensitivity of transcranial sonography of the substantia nigra in the diagnosis of Parkinson's disease: prospective cohort study in 196 patients

    PubMed Central

    Bouwmans, Angela E P; Vlaar, Annemarie M M; Mess, Werner H; Kessels, Alfons; Weber, Wim E J

    2013-01-01

    Objective Numerous ultrasound studies have suggested that a typical enlarged area of echogenicity in the substantia nigra (SN+) can help diagnose idiopathic Parkinson's disease (IPD). Almost all these studies were retrospective and involved patients with well-established diagnoses and long-disease duration. In this study the diagnostic accuracy of transcranial sonography (TCS) of the substantia nigra in the patient with an undiagnosed parkinsonian syndrome of recent onset has been evaluated. Design Prospective cohort study for diagnostic accuracy. Setting Neurology outpatient clinics of two teaching hospitals in the Netherlands. Patients 196 consecutive patients, who were referred to two neurology outpatient clinics for analysis of clinically unclear parkinsonism. Within 2 weeks of inclusion all patients also underwent a TCS and a 123I-ioflupane Single Photon Emission CT (FP-CIT SPECT) scan of the brain (n=176). Outcome measures After 2 years, patients were re-examined by two movement disorder specialist neurologists for a final clinical diagnosis, that served as a surrogate gold standard for our study. Results Temporal acoustic windows were insufficient in 45 of 241 patients (18.67%). The final clinical diagnosis was IPD in 102 (52.0%) patients. Twenty-four (12.3%) patients were diagnosed with atypical parkinsonisms (APS) of which 8 (4.0%) multisystem atrophy (MSA), 6 (3.1%) progressive supranuclear palsy (PSP), 6 (3.1%) Lewy body dementia and 4 (2%) corticobasal degeneration. Twenty-one (10.7%) patients had a diagnosis of vascular parkinsonism, 20 (10.2%) essential tremor, 7 (3.6%) drug-induced parkinsonism and 22 (11.2%) patients had no parkinsonism but an alternative diagnosis. The sensitivity of a SN+ for the diagnosis IPD was 0.40 (CI 0.30 to 0.50) and the specificity 0.61 (CI 0.52 to 0.70). Hereby the positive predictive value (PPV) was 0.53 and the negative predictive value (NPV) 0.48. The sensitivity and specificity of FP-CIT SPECT scans for diagnosing

  8. Dissociation between iron accumulation and ferritin upregulation in the aged substantia nigra: attenuation by dietary restriction

    PubMed Central

    Walker, Thomas; Michaelides, Christos; Ekonomou, Antigoni; Geraki, Kalotina; Parkes, Harold G; Suessmilch, Maria; Herlihy, Amy H; Crum, William R; So, Po-Wah

    2016-01-01

    Despite regulation, brain iron increases with aging and may enhance aging processes including neuroinflammation. Increases in magnetic resonance imaging transverse relaxation rates, R2 and R2*, in the brain have been observed during aging. We show R2 and R2* correlate well with iron content via direct correlation to semi-quantitative synchrotron-based X-ray fluorescence iron mapping, with age-associated R2 and R2* increases reflecting iron accumulation. Iron accumulation was concomitant with increased ferritin immunoreactivity in basal ganglia regions except in the substantia nigra (SN). The unexpected dissociation of iron accumulation from ferritin-upregulation in the SN suggests iron dyshomeostasis in the SN. Occurring alongside microgliosis and astrogliosis, iron dyshomeotasis may contribute to the particular vulnerability of the SN. Dietary restriction (DR) has long been touted to ameliorate brain aging and we show DR attenuated agerelated in vivo R2 increases in the SN over ages 7 – 19 months, concomitant with normal iron-induction of ferritin expression and decreased microgliosis. Iron is known to induce microgliosis and conversely, microgliosis can induce iron accumulation, which of these may be the initial pathological aging event warrants further investigation. We suggest iron chelation therapies and anti-inflammatory treatments may be putative ‘antibrain aging’ therapies and combining these strategies may be synergistic. PMID:27743512

  9. Rotenone induces oxidative stress and dopaminergic neuron damage in organotypic substantia nigra cultures.

    PubMed

    Testa, Claudia M; Sherer, Todd B; Greenamyre, J Timothy

    2005-03-24

    Rotenone, a pesticide and complex I inhibitor, causes nigrostriatal degeneration similar to Parkinson disease pathology in a chronic, systemic, in vivo rodent model [M. Alam, W.J. Schmidt, Rotenone destroys dopaminergic neurons and induces parkinsonian symptoms in rats, Behav. Brain Res. 136 (2002) 317-324; R. Betarbet, T.B. Sherer, G. MacKenzie, M. Garcia-Osuna, A.V. Panov, J.T. Greenamyre, Chronic systemic pesticide exposure reproduces features of Parkinson's disease, Nat. Neurosci. 3 (2000) 1301-1306; S.M. Fleming, C. Zhu, P.O. Fernagut, A. Mehta, C.D. DiCarlo, R.L. Seaman, M.F. Chesselet, Behavioral and immunohistochemical effects of chronic intravenous and subcutaneous infusions of varying doses of rotenone, Exp. Neurol. 187 (2004) 418-429; T.B. Sherer, J.H. Kim, R. Betarbet, J.T. Greenamyre, Subcutaneous rotenone exposure causes highly selective dopaminergic degeneration and alpha-synuclein aggregation, Exp. Neurol. 179 (2003) 9-16.]. To better investigate the role of mitochondria and complex I inhibition in chronic, progressive neurodegenerative disease, we developed methods for long-term culture of rodent postnatal midbrain organotypic slices. Chronic complex I inhibition over weeks by low dose (10-50 nM) rotenone in this system lead to dose- and time-dependent destruction of substantia nigra pars compacta neuron processes, morphologic changes, some neuronal loss, and decreased tyrosine hydroxylase (TH) protein levels. Chronic complex I inhibition also caused oxidative damage to proteins, measured by protein carbonyl levels. This oxidative damage was blocked by the antioxidant alpha-tocopherol (vitamin E). At the same time, alpha-tocopherol also blocked rotenone-induced reductions in TH protein and TH immunohistochemical changes. Thus, oxidative damage is a primary mechanism of mitochondrial toxicity in intact dopaminergic neurons. The organotypic culture system allows close study of this and other interacting mechanisms over a prolonged time period in

  10. Autophagy Protects Against Aminochrome-Induced Cell Death in Substantia Nigra-Derived Cell Line

    PubMed Central

    Paris, Irmgard; Muñoz, Patricia; Huenchuguala, Sandro; Couve, Eduardo; Sanders, Laurie H.; Greenamyre, John Timothy; Caviedes, Pablo; Segura-Aguilar, Juan

    2011-01-01

    Aminochrome, the precursor of neuromelanin, has been proposed to be involved in the neurodegeneration neuromelanin-containing dopaminergic neurons in Parkinson’s disease. We aimed to study the mechanism of aminochrome-dependent cell death in a cell line derived from rat substantia nigra. We found that aminochrome (50μM), in the presence of NAD(P)H-quinone oxidoreductase, EC 1.6.99.2 (DT)-diaphorase inhibitor dicoumarol (DIC) (100μM), induces significant cell death (62 ± 3%; p < 0.01), increase in caspase-3 activation (p < 0.001), release of cytochrome C, disruption of mitochondrial membrane potential (p < 0.01), damage of mitochondrial DNA, damage of mitochondria determined with transmission electron microscopy, a dramatic morphological change characterized as cell shrinkage, and significant increase in number of autophagic vacuoles. To determine the role of autophagy on aminochrome-induced cell death, we incubated the cells in the presence of vinblastine and rapamycin. Interestingly, 10μM vinblastine induces a 5.9-fold (p < 0.001) and twofold (p < 0.01) significant increase in cell death when the cells were incubated with 30μM aminochrome in the absence and presence of DIC, respectively, whereas 10μM rapamycin preincubated 24 h before addition of 50μM aminochrome in the absence and the presence of 100μM DIC induces a significant decrease (p < 0.001) in cell death. In conclusion, autophagy seems to be an important protective mechanism against two different aminochrome-induced cell deaths that initially showed apoptotic features. The cell death induced by aminochrome when DT-diaphorase is inhibited requires activation of mitochondrial pathway, whereas the cell death induced by aminochrome alone requires inhibition of autophagy-dependent degrading of damaged organelles and recycling through lysosomes. PMID:21427056

  11. Differential Regulation of Action Potential Shape and Burst-Frequency Firing by BK and Kv2 Channels in Substantia Nigra Dopaminergic Neurons

    PubMed Central

    Kimm, Tilia; Khaliq, Zayd M.

    2015-01-01

    Little is known about the voltage-dependent potassium currents underlying spike repolarization in midbrain dopaminergic neurons. Studying mouse substantia nigra pars compacta dopaminergic neurons both in brain slice and after acute dissociation, we found that BK calcium-activated potassium channels and Kv2 channels both make major contributions to the depolarization-activated potassium current. Inhibiting Kv2 or BK channels had very different effects on spike shape and evoked firing. Inhibiting Kv2 channels increased spike width and decreased the afterhyperpolarization, as expected for loss of an action potential-activated potassium conductance. BK inhibition also increased spike width but paradoxically increased the afterhyperpolarization. Kv2 channel inhibition steeply increased the slope of the frequency–current (f–I) relationship, whereas BK channel inhibition had little effect on the f–I slope or decreased it, sometimes resulting in slowed firing. Action potential clamp experiments showed that both BK and Kv2 current flow during spike repolarization but with very different kinetics, with Kv2 current activating later and deactivating more slowly. Further experiments revealed that inhibiting either BK or Kv2 alone leads to recruitment of additional current through the other channel type during the action potential as a consequence of changes in spike shape. Enhancement of slowly deactivating Kv2 current can account for the increased afterhyperpolarization produced by BK inhibition and likely underlies the very different effects on the f–I relationship. The cross-regulation of BK and Kv2 activation illustrates that the functional role of a channel cannot be defined in isolation but depends critically on the context of the other conductances in the cell. SIGNIFICANCE STATEMENT This work shows that BK calcium-activated potassium channels and Kv2 voltage-activated potassium channels both regulate action potentials in dopamine neurons of the substantia nigra

  12. Differential Regulation of Action Potential Shape and Burst-Frequency Firing by BK and Kv2 Channels in Substantia Nigra Dopaminergic Neurons.

    PubMed

    Kimm, Tilia; Khaliq, Zayd M; Bean, Bruce P

    2015-12-16

    Little is known about the voltage-dependent potassium currents underlying spike repolarization in midbrain dopaminergic neurons. Studying mouse substantia nigra pars compacta dopaminergic neurons both in brain slice and after acute dissociation, we found that BK calcium-activated potassium channels and Kv2 channels both make major contributions to the depolarization-activated potassium current. Inhibiting Kv2 or BK channels had very different effects on spike shape and evoked firing. Inhibiting Kv2 channels increased spike width and decreased the afterhyperpolarization, as expected for loss of an action potential-activated potassium conductance. BK inhibition also increased spike width but paradoxically increased the afterhyperpolarization. Kv2 channel inhibition steeply increased the slope of the frequency-current (f-I) relationship, whereas BK channel inhibition had little effect on the f-I slope or decreased it, sometimes resulting in slowed firing. Action potential clamp experiments showed that both BK and Kv2 current flow during spike repolarization but with very different kinetics, with Kv2 current activating later and deactivating more slowly. Further experiments revealed that inhibiting either BK or Kv2 alone leads to recruitment of additional current through the other channel type during the action potential as a consequence of changes in spike shape. Enhancement of slowly deactivating Kv2 current can account for the increased afterhyperpolarization produced by BK inhibition and likely underlies the very different effects on the f-I relationship. The cross-regulation of BK and Kv2 activation illustrates that the functional role of a channel cannot be defined in isolation but depends critically on the context of the other conductances in the cell. This work shows that BK calcium-activated potassium channels and Kv2 voltage-activated potassium channels both regulate action potentials in dopamine neurons of the substantia nigra pars compacta. Although both

  13. Functional territories in primate substantia nigra pars reticulata separately signaling stable and flexible values

    PubMed Central

    Hikosaka, Okihide

    2014-01-01

    Gaze is strongly attracted to visual objects that have been associated with rewards. Key to this function is a basal ganglia circuit originating from the caudate nucleus (CD), mediated by the substantia nigra pars reticulata (SNr), and aiming at the superior colliculus (SC). Notably, subregions of CD encode values of visual objects differently: stably by CD tail [CD(T)] vs. flexibly by CD head [CD(H)]. Are the stable and flexible value signals processed separately throughout the CD-SNr-SC circuit? To answer this question, we identified SNr neurons by their inputs from CD and outputs to SC and examined their sensitivity to object values. The direct input from CD was identified by SNr neuron's inhibitory response to electrical stimulation of CD. We found that SNr neurons were separated into two groups: 1) neurons inhibited by CD(T) stimulation, located in the caudal-dorsal-lateral SNr (cdlSNr), and 2) neurons inhibited by CD(H) stimulation, located in the rostral-ventral-medial SNr (rvmSNr). Most of CD(T)-recipient SNr neurons encoded stable values, whereas CD(H)-recipient SNr neurons tended to encode flexible values. The output to SC was identified by SNr neuron's antidromic response to SC stimulation. Among the antidromically activated neurons, many encoded only stable values, while some encoded only flexible values. These results suggest that CD(T)-cdlSNr-SC circuit and CD(H)-rvmSNr-SC circuit transmit stable and flexible value signals, largely separately, to SC. The speed of signal transmission was faster through CD(T)-cdlSNr-SC circuit than through CD(H)-rvmSNr-SC circuit, which may reflect automatic and controlled gaze orienting guided by these circuits. PMID:25540224

  14. Neuroprotective Effect of Exogenous Melatonin on Dopaminergic Neurons of the Substantia Nigra in Ovariectomized Rats

    PubMed Central

    Mehraein, Fereshteh; Talebi, Reza; Jameie, Behnamedin; Joghataie, Mohammad Taghi; Madjd, Zahra

    2011-01-01

    Background: Melatonin has receptors in substantia nigra pars compacta (SNc) and regulates development of dopaminergic (DA) neurons. This study was undertaken to determine ability of melatonin to protect SNc dopaminergic neuron loss induced by estrogen deficiency in ovariectomized rats. Methods: Female rats were randomized into four groups of seven each: control, ethanol sham, ovariectomy (ovx) and ovx with melatonin (ovx + m). In ovx, ovaries were removed. Ovx + m group was intraperitoneally injected with melatonin for 10 days, while the ethanol sham group received only ethanol. All rats were perfused with 4% paraformaldehyde, midbrains removed, fixed and paraffin embedded, then processed for Nissl and tyrosine hydroxylase staining (IHC). Ten sections of SNc in Nissl and IHC staining were analyzed in each animal, Nissl stained and tyrosine hydroxylase (TH) immunoreactive cells were counted in five experimental groups randomly. Data was analyzed using SPSS by ANOVA and t-test. Differences were considered significant for P<0.05. Results: There was less cell number in ovx compared to control and ethanol sham groups significantly (P<0.001). The ovx + m group had more cells than the ovx group in the SNc significantly (P<0.001). Furthermore, there was significant decrease of TH positive cell number in the ovx group compared to control and ethanol sham groups (P<0.05). The number of TH immunoreactive cells was higher in ovx + m compared to the ovx group (P<0.05). Conclusion: These findings can be compared with human and used in clinical application for prevention of DA neuron death of SNc after ovariectomy. PMID:21725499

  15. Age- and sex-related characteristics of tonic GABA currents in the rat substantia nigra pars reticulata.

    PubMed

    Chudomel, O; Hasson, H; Bojar, M; Moshé, S L; Galanopoulou, A S

    2015-04-01

    Previous studies have shown that the pharmacologic effects of GABAergic drugs and the postsynaptic phasic GABAAergic inhibitory responses in the anterior part of the rat substantia nigra pars reticulata (SNRA) are age- and sex-specific. Here, we investigate whether there are age- and sex-related differences in the expression of the δ GABAA receptor (GABAAR) subunit and GABAAR mediated tonic currents. We have used δ-specific immunochemistry and whole cell patch clamp to study GABAAR mediated tonic currents in the SNRA of male and female postnatal day (PN) PN5-9, PN11-16, and PN25-32 rats. We observed age-related decline, but no sex-specific changes, in bicuculline (BIM) sensitive GABAAR tonic current density, which correlated with the decline in δ subunit in the SNRA between PN15 and 30. Furthermore, we show that the GABAAR tonic currents can be modified by muscimol (GABAAR agonist; partial GABACR agonist), THIP (4,5,6,7-tetrahydroisoxazolo (5,4-c)pyridin-3-ol: α4β3δ GABAARs agonist and GABACR antagonist), and zolpidem (α1-subunit selective GABAAR agonist) in age- and sex-dependent manner specific for each drug. We propose that the emergence of the GABAAR-sensitive anticonvulsant effects of the rat SNRA during development may depend upon the developmental decline in tonic GABAergic inhibition of the activity of rat SNRA neurons, although other sex-specific factors are also involved.

  16. Escalating Methamphetamine Regimen Induces Compensatory Mechanisms, Mitochondrial Biogenesis, and GDNF Expression, in Substantia Nigra.

    PubMed

    Valian, Neda; Ahmadiani, Abolhassan; Dargahi, Leila

    2017-06-01

    Methamphetamine (MA) produces long-lasting deficits in dopaminergic neurons in the long-term use via several neurotoxic mechanisms. The effects of MA on mitochondrial biogenesis is less studied currently. So, we evaluated the effects of repeated escalating MA regimen on transcriptional factors involved in mitochondrial biogenesis and glial-derived neurotrophic factor (GDNF) expression in substantia nigra (SN) and striatum of rat. In male Wistar rats, increasing doses of MA (1-14 mg/kg) were administrated twice a day for 14 days. At the 1st, 14th, 28th, and 60th days after MA discontinuation, we measured the PGC1α, TFAM and NRF1 mRNA levels, indicator of mitochondrial biogenesis, and GDNF expression in SN and striatum. Furthermore, we evaluated the glial fibrillary acidic protein (GFAP) and Iba1 mRNA levels, and the levels of tyrosine hydroxylase (TH) and α-synuclein (α-syn) using immunohistochemistry and real-time polymerase chain reaction (PCR). We detected increments in PGC1α and TFAM mRNA levels in SN, but not striatum, and elevations in GDNF levels in SN immediately after MA discontinuation. We also observed increases in GFAP and Iba1 mRNA levels in SN on day 1 and increases in Iba1 mRNA on days 1 and 14 in striatum. Data analysis revealed that the number of TH + cells in the SN did not reduce in any time points, though TH mRNA levels was increased on day 1 after MA discontinuation in SN. These data show that repeated escalating MA induces several compensatory mechanisms, such as mitochondrial biogenesis and elevation in GDNF in SN. These mechanisms can reverse MA-induced neuroinflammation and prevent TH-immunoreactivity reduction in nigrostriatal pathway. J. Cell. Biochem. 118: 1369-1378, 2017. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  17. Correlation of dopaminergic terminal dysfunction and microstructural abnormalities of the basal ganglia and the olfactory tract in Parkinson's disease.

    PubMed

    Scherfler, Christoph; Esterhammer, Regina; Nocker, Michael; Mahlknecht, Philipp; Stockner, Heike; Warwitz, Boris; Spielberger, Sabine; Pinter, Bernadette; Donnemiller, Eveline; Decristoforo, Clemens; Virgolini, Irene; Schocke, Michael; Poewe, Werner; Seppi, Klaus

    2013-10-01

    Signal abnormalities of the substantia nigra and the olfactory tract detected either by diffusion tensor imaging, including measurements of mean diffusivity, a parameter of brain tissue integrity, and fractional anisotropy, a parameter of neuronal fibre integrity, or transcranial sonography, were recently reported in the early stages of Parkinson's disease. In this study, changes in the nigral and olfactory diffusion tensor signal, as well as nigral echogenicity, were correlated with clinical scales of motor disability, odour function and putaminal dopamine storage capacity measured with 6-[(18)F] fluorolevodopa positron emission tomography in early and advanced stages of Parkinson's disease. Diffusion tensor imaging, transcranial sonography and positron emission tomography were performed on 16 patients with Parkinson's disease (mean disease duration 3.7 ± 3.7 years, Hoehn and Yahr stage 1 to 4) and 14 age-matched healthy control subjects. Odour function was measured by the standardized Sniffin' Sticks Test. Mean putaminal 6-[(18)F] fluorolevodopa influx constant, mean nigral echogenicity, mean diffusivity and fractional anisotropy values of the substantia nigra and the olfactory tract were identified by region of interest analysis. When compared with the healthy control group, the Parkinson's disease group showed significant signal changes in the caudate and putamen by 6-[(18)F] fluorolevodopa positron emission tomography, in the substantia nigra by transcranial sonography, mean diffusivity and fractional anisotropy (P < 0.001, P < 0.01, P < 0.05, respectively) and in the olfactory tract by mean diffusivity (P < 0.05). Regional mean diffusivity values of the substantia nigra and the olfactory tract correlated significantly with putaminal 6-[(18)F] fluorolevodopa uptake (r = -0.52, P < 0.05 and r = -0.71, P < 0.01). Significant correlations were also found between nigral mean diffusivity values and the Unified Parkinson's Disease Rating Scale motor score (r = -0

  18. 6-OHDA induced calcium influx through N-type calcium channel alters membrane properties via PKA pathway in substantia nigra pars compacta dopaminergic neurons.

    PubMed

    Qu, Liang; Wang, Yuan; Zhang, Hai-Tao; Li, Nan; Wang, Qiang; Yang, Qian; Gao, Guo-Dong; Wang, Xue-Lian

    2014-07-11

    Voltage gated calcium channels (VGCC) are sensitive to oxidative stress, and their activation or inactivation can impact cell death. Although these channels have been extensively studied in expression systems, their role in the brain, particularly in the substantia nigra pars compacta (SNc), remain controversial. In this study, we assessed 6-hydroxydopamine (6-OHDA) induced transformation of firing pattern and functional changes of calcium channels in SNc dopaminergic neurons. Application of 6-OHDA (0.5-2mM) evoked a dose-dependent, desensitizing inward current and intracellular free calcium concentration ([Ca(2+)]i) rise. In voltage clamp, ω-conotoxin-sensitive Ca(2+) current modulation mediated by 6-OHDA reflected an altered sensitivity. Furthermore, we found that 6-OHDA modulated Ca(2+) currents through PKA pathway. These results provided evidence for the potential role of VGCCs and PKA involved in oxidative stress in degeneration of SNc neurons in Parkinson's disease (PD). Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  19. Environment- and activity-dependent dopamine neurotransmitter plasticity in the adult substantia nigra.

    PubMed

    Aumann, Tim D

    2016-04-01

    The ability of neurons to change the amount or type of neurotransmitter they use, or 'neurotransmitter plasticity', is an emerging new form of adult brain plasticity. For example, it has recently been shown that neurons in the adult rat hypothalamus up- or down-regulate dopamine (DA) neurotransmission in response to the amount of light the animal receives (photoperiod), and that this in turn affects anxiety- and depressive-like behaviors (Dulcis et al., 2013). In this Chapter I consolidate recent evidence from my laboratory suggesting neurons in the adult mouse substantia nigra pars compacta (SNc) also undergo DA neurotransmitter plasticity in response to persistent changes in their electrical activity, including that driven by the mouse's environment or behavior. Specifically, we have shown that the amounts of tyrosine hydroxylase (TH, the rate-limiting enzyme in DA synthesis) gene promoter activity, TH mRNA and TH protein in SNc neurons increases or decreases after ∼20h of altered electrical activity. Also, infusion of ion-channel agonists or antagonists into the midbrain for 2 weeks results in ∼10% (∼500 neurons) more or fewer TH immunoreactive (TH+) SNc neurons, with no change in the total number of SNc neurons (TH+ and TH-). Targeting ion-channels mediating cell-autonomous pacemaker activity in, or synaptic input and afferent pathways to, SNc neurons are equally effective in this regard. In addition, exposing mice to different environments (sex pairing or environment enrichment) for 1-2 weeks induces ∼10% more or fewer TH+ SNc (and ventral tegmental area or VTA) neurons and this is abolished by concurrent blockade of synaptic transmission in midbrain. Although further research is required to establish SNc (and VTA) DA neurotransmitter plasticity, and to determine whether it alters brain function and behavior, it is an exciting prospect because: (1) It may play important roles in movement, motor learning, reward, motivation, memory and cognition; and (2

  20. Diagnostic value of combined assessment of olfaction and sustantia nigra hyperechogenicity for Parkinson's disease.

    PubMed

    López Hernández, N; García Escrivá, A; Shalabi Benavent, M

    2015-10-01

    Hyposmia and substantia nigra hyperechogenicity (SN+) are characteristic markers of Parkinson's disease (PD), although their diagnostic value in isolation may be limited. We evaluated the combined prevalence of both disorders in patients diagnosed with PD and assessed their diagnostic yield compared to a sample with essential tremor (ET) and another group of healthy subjects. Patients diagnosed with PD and ET and treated in our outpatient clinic were enrolled. Olfaction was assessed using the "Sniffin' Sticks" odour identification test (SS-12) and hyperechogenicity of the substantia nigra (SN+) was assessed by transcranial duplex ultrasound. A total of 98 subjects were analysed, comprising 30 with PD, 21 with ET, and 47 controls. The respective prevalence rates of hyposmia (SS-12 < 8) and SN+ (area > .24cm(2)) were 70% and 83.3% in PD, 33.3% and 9.5% in ET, and 17% and 10.6% in controls. Both markers were present in 63% of patients with PD, none of the patients with ET, and only 2 of the controls. Combined use of substantia nigra sonography and olfactory testing with SS-12, two rapid, safe, and accessible tests, was more specific than each isolated marker for distinguishing patients with PD from patients with ET and control subjects. Since both markers have been described in very early phases of PD, combined use may be helpful in providing early diagnosis of PD. Copyright © 2013 Sociedad Española de Neurología. Published by Elsevier España, S.L.U. All rights reserved.

  1. State-dependent spike and local field synchronization between motor cortex and substantia nigra in hemiparkinsonian rats.

    PubMed

    Brazhnik, Elena; Cruz, Ana V; Avila, Irene; Wahba, Marian I; Novikov, Nikolay; Ilieva, Neda M; McCoy, Alex J; Gerber, Colin; Walters, Judith R

    2012-06-06

    Excessive beta frequency oscillatory and synchronized activity has been reported in the basal ganglia of parkinsonian patients and animal models of the disease. To gain insight into processes underlying this activity, this study explores relationships between oscillatory activity in motor cortex and basal ganglia output in behaving rats after dopamine cell lesion. During inattentive rest, 7 d after lesion, increases in motor cortex-substantia nigra pars reticulata (SNpr) coherence emerged in the 8-25 Hz range, with significant increases in local field potential (LFP) power in SNpr but not motor cortex. In contrast, during treadmill walking, marked increases in both motor cortex and SNpr LFP power, as well as coherence, emerged in the 25-40 Hz band with a peak frequency at 30-35 Hz. Spike-triggered waveform averages showed that 77% of SNpr neurons, 77% of putative cortical interneurons, and 44% of putative pyramidal neurons were significantly phase-locked to the increased cortical LFP activity in the 25-40 Hz range. Although the mean lag between cortical and SNpr LFPs fluctuated around zero, SNpr neurons phase-locked to cortical LFP oscillations fired, on average, 17 ms after synchronized spiking in motor cortex. High coherence between LFP oscillations in cortex and SNpr supports the view that cortical activity facilitates entrainment and synchronization of activity in basal ganglia after loss of dopamine. However, the dramatic increases in cortical power and relative timing of phase-locked spiking in these areas suggest that additional processes help shape the frequency-specific tuning of the basal ganglia-thalamocortical network during ongoing motor activity.

  2. Adulthood Exposure to Lipopolysaccharide Exacerbates the Neurotoxic and Inflammatory Effects of Rotenone in the Substantia Nigra

    PubMed Central

    Huang, Chun; Zhu, Li; Li, Huan; Shi, Fu-Guo; Wang, Guo-Qing; Wei, Yi-Zheng; Liu, Jie; Zhang, Feng

    2017-01-01

    Parkinson’s disease (PD) is the second most neurodegenerative disorder with a regional decrease of dopamine (DA) neurons in the substantia nigra (SN). Despite intense exploration, the etiology of PD progressive process remains unclear. This study was to investigate the synergistic effects of systemic inflammation of lipopolysaccharide (LPS) and neurotoxicity of rotenone (ROT) on exacerbating DA neuron lesion. Male SD adulthood rats received a single intraperitoneal injection of LPS. Seven months later, rats were subcutaneously given ROT five times a week for consecutive 4 weeks. Rat behavior changes were assessed via rotarod and open-field tests. Brain SN was immunostained to evaluate DA neuronal loss and microglia activation. Striatum DA and its metabolites levels were determined by high performance liquid chromatography (HPLC) coupled with electrochemistry. The protein levels of α-synuclein (α-Syn), inflammatory factors and mitogen-activated protein kinase (MAPK) pathway activation were detected by western blotting analysis. Results indicated that no significant difference between the control and LPS alone groups was shown. Compared with ROT alone group, LPS combined with ROT significantly reduced motor activity and induced SN DA neurons loss accompanied by the decreased contents of striatum DA and its metabolites. Furthermore, LPS together with ROT enhanced microglia activation and the increased expressions of α-Syn and inflammatory factors and also MAPK signaling pathway activation. However, LPS alone had no significant effects on the above parameters. These findings suggest that adulthood exposure to LPS exacerbates the neurotoxic and inflammatory effects of ROT in the SN. PMID:28533741

  3. Metabolism Regulates the Spontaneous Firing of Substantia Nigra Pars Reticulata Neurons via KATP and Nonselective Cation Channels

    PubMed Central

    Lutas, Andrew; Birnbaumer, Lutz

    2014-01-01

    Neurons use glucose to fuel glycolysis and provide substrates for mitochondrial respiration, but neurons can also use alternative fuels that bypass glycolysis and feed directly into mitochondria. To determine whether neuronal pacemaking depends on active glucose metabolism, we switched the metabolic fuel from glucose to alternative fuels, lactate or β-hydroxybutyrate, while monitoring the spontaneous firing of GABAergic neurons in mouse substantia nigra pars reticulata (SNr) brain slices. We found that alternative fuels, in the absence of glucose, sustained SNr spontaneous firing at basal rates, but glycolysis may still be supported by glycogen in the absence of glucose. To prevent any glycogen-fueled glycolysis, we directly inhibited glycolysis using either 2-deoxyglucose or iodoacetic acid. Inhibiting glycolysis in the presence of alternative fuels lowered SNr firing to a slower sustained firing rate. Surprisingly, we found that the decrease in SNr firing was not mediated by ATP-sensitive potassium (KATP) channel activity, but if we lowered the perfusion flow rate or omitted the alternative fuel, KATP channels were activated and could silence SNr firing. The KATP-independent slowing of SNr firing that occurred with glycolytic inhibition in the presence of alternative fuels was consistent with a decrease in a nonselective cationic conductance. Although mitochondrial metabolism alone can prevent severe energy deprivation and KATP channel activation in SNr neurons, active glucose metabolism appears important for keeping open a class of ion channels that is crucial for the high spontaneous firing rate of SNr neurons. PMID:25471572

  4. Memantine block depends on agonist presentation at the NMDA receptor in substantia nigra pars compacta dopamine neurones

    PubMed Central

    Wild, A.R.; Akyol, E.; Brothwell, S.L.C.; Kimkool, P.; Skepper, J.N.; Gibb, A.J.; Jones, S.

    2015-01-01

    NMDA glutamate receptors (NMDARs) have critical functional roles in the nervous system but NMDAR over-activity can contribute to neuronal damage. The open channel NMDAR blocker, memantine is used to treat certain neurodegenerative diseases, including Parkinson’s disease (PD) and is well tolerated clinically. We have investigated memantine block of NMDARs in substantia nigra pars compacta (SNc) dopamine neurones, which show severe pathology in PD. Memantine (10 μM) caused robust inhibition of whole-cell (synaptic and extrasynaptic) NMDARs activated by NMDA at a high concentration or a long duration, low concentration. Less memantine block of NMDAR-EPSCs was seen in response to low frequency synaptic stimulation, while responses to high frequency synaptic stimulation were robustly inhibited by memantine; thus memantine inhibition of NMDAR-EPSCs showed frequency-dependence. By contrast, MK-801 (10 μM) inhibition of NMDAR-EPSCs was not significantly different at low versus high frequencies of synaptic stimulation. Using immunohistochemistry, confocal imaging and stereological analysis, NMDA was found to reduce the density of cells expressing tyrosine hydroxylase, a marker of viable dopamine neurones; memantine prevented the NMDA-evoked decrease. In conclusion, memantine blocked NMDAR populations in different subcellular locations in SNc dopamine neurones but the degree of block depended on the intensity of agonist presentation at the NMDAR. This profile may contribute to the beneficial effects of memantine in PD, as glutamatergic activity is reported to increase, and memantine could preferentially reduce over-activity while leaving some physiological signalling intact. PMID:23727219

  5. Acute Depletion of D2 Receptors from the Rat Substantia Nigra Alters Dopamine Kinetics in the Dorsal Striatum and Drug Responsivity

    PubMed Central

    Budygin, Evgeny A.; Oleson, Erik B.; Lee, Yun Beom; Blume, Lawrence C.; Bruno, Michael J.; Howlett, Allyn C.; Thompson, Alexis C.; Bass, Caroline E.

    2017-01-01

    Recent studies have used conditional knockout mice to selectively delete the D2 autoreceptor; however, these approaches result in global deletion of D2 autoreceptors early in development. The present study takes a different approach using RNA interference (RNAi) to knockdown the expression of the D2 receptors (D2R) in the substantia nigra (SN), including dopaminergic neurons, which project primarily to the dorsal striatum (dStr) in adult rats. This approach restricts the knockdown primarily to nigrostriatal pathways, leaving mesolimbic D2 autoreceptors intact. Analyses of dopamine (DA) kinetics in the dStr reveal a decrease in DA transporter (DAT) function in the knockdown rats, an effect not observed in D2 autoreceptor knockout mouse models. SN D2 knockdown rats exhibit a behavioral phenotype characterized by persistent enhancement of locomotor activity in a familiar open field, reduced locomotor responsiveness to high doses of cocaine and the ability to overcome haloperidol-induced immobility on the bar test. Together these results demonstrate that presynaptic D2R can be depleted from specific neuronal populations and implicates nigrostriatal D2R in different behavioral responses to psychotropic drugs. PMID:28154530

  6. GABAB-receptor activation alters the firing pattern of dopamine neurons in the rat substantia nigra.

    PubMed

    Engberg, G; Kling-Petersen, T; Nissbrandt, H

    1993-11-01

    Previous electrophysiological experiments have emphasized the importance of the firing pattern for the functioning of midbrain dopamine (DA) neurons. In this regard, excitatory amino acid receptors appear to constitute an important modulatory control mechanism. In the present study, extracellular recording techniques were used to investigate the significance of GABAB-receptor activation for the firing properties of DA neurons in the substantia nigra (SN) in the rat. Intravenous administration of the GABAB-receptor agonist baclofen (1-16 mg/kg) was associated with a dose-dependent regularization of the firing pattern, concomitant with a reduction in burst firing. At higher doses (16-32 mg/kg), the firing rate of the DA neurons was dose-dependently decreased. Also, microiontophoretic application of baclofen regularized the firing pattern of nigral DA neurons, including a reduction of burst firing. Both the regularization of the firing pattern and inhibition of firing rate produced by systemic baclofen administration was antagonized by the GABAB-receptor antagonist CGP 35348 (200 mg/kg, i.v.). The GABAA-receptor agonist muscimol produced effects on the firing properties of DA neurons that were opposite to those observed following baclofen, i.e., an increase in firing rate accompanied by a decreased regularity. The NMDA receptor antagonist MK 801 (0.4-3.2 mg/kg, i.v.) produced a moderate, dose-dependent increase in the firing rate of the nigral DA neurons as well as a slightly regularized firing pattern. Pretreatment with MK 801 (3.2 mg/kg, i.v., 3-10 min) did neither promote nor prevent the regularization of the firing pattern or inhibition of firing rate on the nigral DA neurons produced by baclofen. The present results clearly show that GABAB-receptors can alter the firing pattern of nigral DA neurons, hereby counterbalancing the previously described ability of glutamate to induce burst firing activity on these neurons.

  7. Overexpression of VMAT-2 and DT-diaphorase protects substantia nigra-derived cells against aminochrome neurotoxicity

    PubMed Central

    Muñoz, Patricia; Paris, Irmgard; Sanders, Laurie H.; Greenamyre, J. Timothy; Segura-Aguilar, Juan

    2013-01-01

    We tested the hypothesis that both VMAT-2 and DT-diaphorase are an important cellular defense against aminochrome-dependent neurotoxicity during dopamine oxidation. A cell line with VMAT-2 and DT-diaphorase over-expressed was created. The transfection of RCSN-3 cells with a bicistronic plasmid coding for VMAT-2 fused with GFP-IRES-DT-diaphorase cDNA induced a significant increase in protein expression of VMAT-2 (7-fold; P<0.001) and DT-diaphorase (9-fold; P<0.001), accompanied by a 4- and 5.5-fold significant increase in transport and enzyme activity, respectively. Studies with synaptic vesicles from rat substantia nigra revealed that VMAT-2 uptake of 3H-aminochrome 6.3 ± 0.4nmol/min/mg was similar to dopamine uptake 6.2 ± 0.3 nmol/min/mg that which were dependent on ATP. Interestingly, aminochrome uptake was inhibited by 2 μM lobeline but not reserpine (1 and 10 μM). Incubation of cells overexpressing VMAT-2 and DT-diaphorase with 20 μM aminochrome resulted in (i) a significant decrease in cell death (6-fold, P<0.001); (ii) normal ultra structure determined by transmission electron microscopy contrasting with a significant increase of autophagosome and a dramatic remodeling of the mitochondrial inner membrane in wild type cells; (iii) normal level of ATP (256 ± 11 μM) contrasting with a significant decrease in wild type cells (121 ± 11 μM, P<0.001); and (iv) a significant decrease in DNA laddering (21 ± 8 pixels, P<0.001) cells in comparison with wild type cells treated with 20 μM aminochrome (269 ± 9). These results support our hypothesis that VMAT-2 and DT-diaphorase are an important defense system against aminochrome formed during dopamine oxidation. PMID:22483869

  8. State-Dependent Spike and Local Field Synchronization between Motor Cortex and Substantia Nigra in Hemiparkinsonian Rats

    PubMed Central

    Brazhnik, Elena; Cruz, Ana V.; Avila, Irene; Wahba, Marian I.; Novikov, Nikolay; Ilieva, Neda M.; McCoy, Alex J.; Gerber, Colin; Walters, Judith. R.

    2012-01-01

    Excessive beta frequency oscillatory and synchronized activity has been reported in the basal ganglia of Parkinsonian patients and animal models of the disease. To gain insight into processes underlying this activity, this study explores relationships between oscillatory activity in motor cortex and basal ganglia output in behaving rats after dopamine cell lesion. During inattentive rest, seven days after lesion, increases in motor cortex-substantia nigra pars reticulata (SNpr) coherence emerged in the 8–25 Hz range, with significant increases in local field potential (LFP) power in SNpr but not motor cortex. In contrast, during treadmill walking, marked increases in both motor cortex and SNpr LFP power, as well as coherence, emerged in the 25–40 Hz band with a peak frequency at 30–35 Hz. Spike-triggered waveform averages showed that 77% of SNpr neurons, 77% of putative cortical interneurons and 44% of putative pyramidal neurons were significantly phase-locked to the increased cortical LFP activity in the 25–40 Hz range. Although the mean lag between cortical and SNpr LFPs fluctuated around zero, SNpr neurons phase-locked to cortical LFP oscillations fired, on average, 17 ms after synchronized spiking in motor cortex. High coherence between LFP oscillations in cortex and SNpr supports the view that cortical activity facilitates entrainment and synchronization of activity in basal ganglia after loss of dopamine. However, the dramatic increases in cortical power and relative timing of phase-locked spiking in these areas suggest that additional processes help shape the frequency-specific tuning of the basal ganglia-thalamocortical network during ongoing motor activity. PMID:22674263

  9. Characterization of dopamine release in the substantia nigra by in vivo microdialysis in freely moving rats.

    PubMed

    Robertson, G S; Damsma, G; Fibiger, H C

    1991-07-01

    Dopamine (DA) is released not only from the terminals of the nigrostriatal projection, but also from the dendrites of these neurons, which arborize in the substantia nigra pars reticulata (SNR). Although striatal DA release has been extensively studied by in vivo microdialysis, dendritic DA release in the SNR has not been characterized by this technique. Extracellular DA was monitored simultaneously in the ipsilateral striatum and SNR. The nigral probe was implanted at a 50 degree angle, permitting 2.5 mm of SNR to be dialyzed. Delivery of the tracer Fluoro-Gold into the striatal probe retrogradely labeled tyrosine hydroxylase-positive cell bodies and dendrites in the vicinity of the nigral probe. Hence, it could be demonstrated that dopaminergic neurons near the nigral probe projected to the vicinity of the striatal probe. Addition of 50 mM KCl to the SNR perfusion solution produced a 3.5-fold increase in DA and a 50% reduction in dihydroxyphenylacetic acid (DOPAC) in the SNR; in contrast, this manipulation in the SNR caused DA release in the striatum to be decreased by 20%, while striatal DOPAC was increased by 50%. Local administration of nomifensine (10 microM) in the SNR produced a sevenfold increase in SNR DA but had no effect on striatal DA. Systemic injection of d-amphetamine (2 mg/kg, s.c.) elevated DA in the SNR and striatum five- to sevenfold, while DOPAC was decreased in both structures by at least 40%. To determine the effect of tetrodotoxin (TTX), basal concentrations of DA in the SNR were first elevated threefold by including nomifensine (1 microM) in the nigral perfusion solution.(ABSTRACT TRUNCATED AT 250 WORDS)

  10. The role of the substantia nigra pars compacta in regulating sleep patterns in rats.

    PubMed

    Lima, Marcelo M S; Andersen, Monica L; Reksidler, Angela B; Vital, Maria A B F; Tufik, Sergio

    2007-06-06

    As of late, dopaminergic neurotransmission has been recognized to be involved in the generation of sleep disturbances. Increasing evidence shows that sleep disturbances in Parkinson's disease (PD) patients are mostly related to the disease itself, rather than being a secondary phenomenon. Evidence contained in the literature lends support to the hypothesis that the dopaminergic nigrostriatal pathway is closely involved in the regulation of sleep patterns. To test this hypothesis we examined the electrophysiological activity along the sleep-wake cycle of rats submitted to a surgically induced lesion of the SNpc by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). We demonstrated that a 50% lesion of the substantia nigra pars compacta (SNpc) suffices to produce disruptions of several parameters in the sleep-wake pattern of rats. A robust and constant decrease in the latency to the onset of slow wave sleep (SWS) was detected throughout the five days of recording in both light [F((22.16)) = 72.46, p<0.0001] and dark [F((22.16)) = 75.0, p<0.0001] periods. Also found was a pronounced increase in the percentage of sleep efficiency during the first four days of recording [F((21.15)) = 21.48, p<0.0001], in comparison to the sham group. Additionally, the reduction in the SNpc dopaminergic neurons provoked an ablation in the percentage of rapid eye movement sleep (REM) during three days of the sleep-wake recording period with a strong correlation (r = 0.91; p<0.0001) between the number of dopaminergic neurons lost and the percentage decrease of REM sleep on the first day of recording. On day 4, the percentage of REM sleep during the light and dark periods was increased, [F((22.16)) = 2.46, p<0.0007], a phenomenon consistent with REM rebound. We propose that dopaminergic neurons present in the SNpc possess a fundamental function in the regulation of sleep processes, particularly in promoting REM sleep.

  11. Metabolism regulates the spontaneous firing of substantia nigra pars reticulata neurons via KATP and nonselective cation channels.

    PubMed

    Lutas, Andrew; Birnbaumer, Lutz; Yellen, Gary

    2014-12-03

    Neurons use glucose to fuel glycolysis and provide substrates for mitochondrial respiration, but neurons can also use alternative fuels that bypass glycolysis and feed directly into mitochondria. To determine whether neuronal pacemaking depends on active glucose metabolism, we switched the metabolic fuel from glucose to alternative fuels, lactate or β-hydroxybutyrate, while monitoring the spontaneous firing of GABAergic neurons in mouse substantia nigra pars reticulata (SNr) brain slices. We found that alternative fuels, in the absence of glucose, sustained SNr spontaneous firing at basal rates, but glycolysis may still be supported by glycogen in the absence of glucose. To prevent any glycogen-fueled glycolysis, we directly inhibited glycolysis using either 2-deoxyglucose or iodoacetic acid. Inhibiting glycolysis in the presence of alternative fuels lowered SNr firing to a slower sustained firing rate. Surprisingly, we found that the decrease in SNr firing was not mediated by ATP-sensitive potassium (KATP) channel activity, but if we lowered the perfusion flow rate or omitted the alternative fuel, KATP channels were activated and could silence SNr firing. The KATP-independent slowing of SNr firing that occurred with glycolytic inhibition in the presence of alternative fuels was consistent with a decrease in a nonselective cationic conductance. Although mitochondrial metabolism alone can prevent severe energy deprivation and KATP channel activation in SNr neurons, active glucose metabolism appears important for keeping open a class of ion channels that is crucial for the high spontaneous firing rate of SNr neurons. Copyright © 2014 the authors 0270-6474/14/3416336-12$15.00/0.

  12. Calcium mobilization elicited by two types of nicotinic acetylcholine receptors in mouse substantia nigra pars compacta.

    PubMed

    Tsuneki, H; Klink, R; Léna, C; Korn, H; Changeux, J P

    2000-07-01

    Nicotinic acetylcholine receptors (nAChRs) are expressed in the midbrain ascending dopaminergic system, a target of many addictive drugs. Here we assessed the intracellular Ca2+ level by imaging fura-2-loaded cells in substantia nigra pars compacta in mouse brain slices, and we examined the influence on this level of prolonged exposures to nicotine using mice lacking the nAChR beta2-subunit. In control cells, superfusion with nicotine (10-100 microM) caused a long-lasting rise of intracellular Ca2+ level which depended on extracellular Ca2+. This nicotinic response was almost completely absent in beta2-/- mutant mice, leaving a small residual response to a high concentration (100 microM) of nicotine which was inhibited by the alpha7-subunit-selective antagonist, methyllycaconitine. Conversely, the alpha7-subunit-selective agonist choline (10 mM) caused a methyllycaconitine-sensitive increase in intracellular Ca2+ level both in wild-type and beta2-/- mutant mice. Nicotine-elicited Ca2+ mobilization was reduced by the Na+ channel blocker tetrodotoxin (TTX) and by T-type Ca2+ channel blocking agents, whereas the choline-elicited Ca2+ increase was insensitive to TTX. Neither nicotine nor choline produced Ca2+ increase following inhibition of the release of Ca2+ from intracellular stores by dantrolene. These results demonstrate that in nigral dopaminergic neurons, nicotine can elicit Ca2+ mobilization via activation of two distinct nAChR subtypes: that of beta2-subunit-containing nAChR followed by activation of Na+ channel and T-type Ca2+ channels, and/or activation of alpha7-subunit-containing nAChR. The Ca2+ influx due to nAChR activation is subsequently amplified by the recruitment of intracellular Ca2+ stores. This Ca2+ mobilization may possibly contribute to the long-term effects of nicotine on the dopaminergic system.

  13. Fibroblast growth factor (FGF)-2 and FGF receptor 3 are required for the development of the substantia nigra, and FGF-2 plays a crucial role for the rescue of dopaminergic neurons after 6-hydroxydopamine lesion.

    PubMed

    Timmer, Marco; Cesnulevicius, Konstantin; Winkler, Christian; Kolb, Julia; Lipokatic-Takacs, Esther; Jungnickel, Julia; Grothe, Claudia

    2007-01-17

    Basic fibroblast growth factor (FGF-2) is involved in the development and maintenance of the nervous system. Exogenous administration of FGF-2 increased dopaminergic (DA) graft survival in different animal models of Parkinson's disease. To study the physiological function of the endogenous FGF-2 system, we analyzed the nigrostriatal system of mice lacking FGF-2, mice overexpressing FGF-2, and FGF-receptor-3 (FGFR3)-deficient mice both after development and after 6-hydroxydopamine lesion. FGFR3-deficient mice (+/-) displayed a reduced number of DA neurons compared with the respective wild type. Whereas absence of FGF-2 led to significantly increased numbers of DA neurons, enhanced amount of the growth factor in mice overexpressing FGF-2 resulted in less tyrosine hydroxylase expression and a reduced DA cell density. The volumes of the substantia nigra were enlarged in both FGF-2(-/-) and in FGF-2 transgenic mice, suggesting an important role of FGF-2 for the establishment of the proper number of DA neurons and a normal sized substantia nigra during development. In a second set of experiments, the putative relevance of endogenous FGF-2 after neurotoxin application was investigated regarding the number of rescued DA neurons after partial 6-OHDA lesion. Interestingly, the results after lesion were directly opposed to the results after development: significantly less DA neurons survived in FGF-2(-/-) mice compared with wild-type mice. Together, the results indicate that FGFR3 is crucially involved in regulating the number of DA neurons. The lack of FGF-2 seems to be (over)compensated during development, but, after lesion, compensation mechanisms fail. The transgenic mice showed that endogenous FGF-2 protects DA neurons from 6-OHDA neurotoxicity.

  14. In vivo gene transfer to dopamine neurons of rat substantia nigra via the high-affinity neurotensin receptor.

    PubMed Central

    Alvarez-Maya, I.; Navarro-Quiroga, I.; Meraz-Ríos, M. A.; Aceves, J.; Martinez-Fong, D.

    2001-01-01

    BACKGROUND: Recently, we synthesized a nonviral gene vector capable of transfecting cell lines taking advantage of neurotensin (NT) internalization. The vector is NT cross-linked with poly-L-lysine, to which a plasmid DNA was bound to form a complex (NT-polyplex). Nigral dopamine neurons are able to internalize NT, thus representing a target for gene transfer via NT-polyplex. This hypothesis was tested here using reporter genes encoding green fluorescent protein or chloramphenicol acetyl transferase. MATERIALS AND METHODS: NT-polyplex was injected into the substantia nigra. Double immunofluorescence labeling was used to reveal the cell type involved in the propidium iodide-labeled polyplex internalization and reporter gene expression. RESULTS: Polyplex internalization was observed within dopamine neurons but not within glial cells, and was prevented by both hypertonic sucrose solution and SR-48692, a selective nonpeptide antagonist of NT receptors. Reporter gene expression was observed in dopamine neurons from 48 hr up to 15 days after NT-polyplex injection, and was prevented by SR-48692. However, no expression was seen when the NT-polyplex was injected into the ansiform lobule of the cerebellum, which contains low- but not high-affinity NT receptors. Neither internalization nor expression was observed in cultured glial cells, despite the NT-polyplex binding to those cells that was prevented by levocabastine, a low-affinity NT receptor antagonist. CONCLUSIONS: These results suggest that high-affinity NT receptors mediate the uptake of NT-polyplex with the subsequent reporter gene expression in vivo. NT polyfection may be used to transfer genes of physiologic interest to nigrostriatal dopamine neurons, and to produce transgenic animal models of dopamine-related diseases. PMID:11471555

  15. Selective loss of dopaminergic neurons in the substantia nigra pars compacta after systemic administration of MPTP facilitates extinction learning.

    PubMed

    Kinoshita, Ken-ichi; Tada, Yayoi; Muroi, Yoshikage; Unno, Toshihiro; Ishii, Toshiaki

    2015-09-15

    Parkinson's disease (PD) is a neurodegenerative disorder characterized by progressive loss of dopaminergic (DAergic) neurons in the substantia nigra pars compacta (SNpc). In PD, thinking and retrieval deficits often arise from cognitive impairments. However, the mechanism of cognitive disorders in PD remains unknown. Therefore, we investigated cognitive function in PD model mice produced by intraperitoneal administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), which specifically destroys the DAergic neurons in the SNpc. We evaluated the cognitive function of MPTP-treated mice (PD mice) using the contextual fear conditioning test. In the test, each experiment consists of three phases: training, re-exposure, and testing. Mice were trained with a foot shock (a weak unconditioned stimulus: 1mA/2s duration, once, or an intense unconditioned stimulus: 2mA/2s duration, twice), and 24h later, mice were re-exposed to the training context for 3min to determine reconsolidation or 30min to determine extinction. The percentage of time spent freezing was measured during the test session as indexes of memory consolidation, reconsolidation, and extinction. Reconsolidation of PD mice occurred normally but memory extinction was facilitated in PD mice compared to control mice. Moreover, memory retention in PD mice was attenuated earlier than in controls following repeated conditioned stimuli every day. PD mice with selective loss of DAergic neurons in the SNpc showed attenuated memory retention, probably via facilitated extinction learning. Copyright © 2015 Elsevier Inc. All rights reserved.

  16. Sonographic detection of basal ganglia abnormalities in spasmodic dysphonia.

    PubMed

    Walter, U; Blitzer, A; Benecke, R; Grossmann, A; Dressler, D

    2014-02-01

    Abnormalities of the lenticular nucleus (LN) on transcranial sonography (TCS) are a characteristic finding in idiopathic segmental and generalized dystonia. Our intention was to study whether TCS detects basal ganglia abnormalities also in spasmodic dysphonia, an extremely focal form of dystonia. Transcranial sonography of basal ganglia, substantia nigra and ventricles was performed in 14 patients with spasmodic dysphonia (10 women, four men; disease duration 16.5 ± 6.1 years) and 14 age- and sex-matched healthy controls in an investigator-blinded setting. Lenticular nucleus hyperechogenicity was found in 12 spasmodic dysphonia patients but only in one healthy individual (Fisher's exact test, P < 0.001) whilst other TCS findings did not differ. The area of LN hyperechogenic lesions quantified on digitized image analysis correlated with spasmodic dysphonia severity (Spearman test, r = 0.82, P < 0.001). Our findings link the underlying pathology of spasmodic dysphonia to that of more widespread forms of dystonia. © 2013 The Author(s) European Journal of Neurology © 2013 EFNS.

  17. The behavioural effects of a novel substance P analogue following infusion into the ventral tegmental area or substantia nigra of rat brain.

    PubMed

    Eison, A S; Eison, M S; Iversen, S D

    1982-04-22

    The behavioural response following infusion of a novel, stable substance P (SP) analogue, DiMe-C7, into the ventral tegmental area (VTA) of rats was characterized and contrasted with the response to an equal dose of the parent compound SP. DiMe-C7 produced a longer-lasting behavioural stimulation than SP as evidenced in several behaviours, including locomotor activity, wet dog shakes, rearing and grooming. DiMe-C7-induced locomotor activity and rearing were potentiated by concurrent peripheral administration of D-amphetamine and blocked by pretreatment with haloperidol. Such responses to DiMe-C7 may thus be dependent upon dopaminergic activity. When given immediately following VTA infusion of DiMe-C7, morphine decreased, while naloxone had no effect upon most behavioural measures. The effect of methysergide on DiMe-C7 or SP into the substantia nigra reticulata produced a pattern of responses similar to nature to those produced by VTA infusion but different with respect to time course. These findings suggest that DiMe-C7 is a metabolically stable analogue of substance P which manifests prolonged actions on behaviour when centrally administered. Further, a role for central dopaminergic mechanisms is implicated in DiMe-C7-induced behavioural action.

  18. Iron concentrations and distributions in the parkinsonian substantia nigra of aged and young primate models

    NASA Astrophysics Data System (ADS)

    Ren, M. Q.; Xie, J. P.; Wang, X. S.; Ong, W. Y.; Leong, S. K.; Watt, F.

    2001-07-01

    Parkinson's disease (PD) is a progressive neuronal degenerative brain disease of the elderly, and is caused by the selective degeneration of neurons in the substantia nigra (SN) region of the brain, resulting in a reduced production of the neurotransmitter dopamine. Iron has been linked to dopaminergic cell death in Parkinson's disease because of its potential to promote free radicals, leading to oxidative stress. The present study is aimed at using the techniques of nuclear microscopy to elucidate the iron concentrations and distributions in the SN of both young and old monkeys following unilateral 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioning. A group of three old monkeys (older than 7 years) and a group of three young monkeys (younger than 7 years) were unilaterally MPTP-lesioned (right side) to induce parkinsonism and sacrificed after 35 days. The left side SN was used as a control. This time interval was chosen to correspond to an average 50% loss of dopamine producing cells in the lesioned right side SN. We have observed a significant difference in iron concentrations between the SNs of the young and old monkeys (increasing from an average of 233 to 1092 parts per million dry weight). When comparing the lesioned and non-lesioned SNs of the same animal, we found no significant difference in iron levels for each young monkey. However we have found a slight increase in iron (approximately 10%) between the lesioned SN and control SN for old monkeys. We have also observed that in the SN of younger primates, there is a weak anti-correlation in the SN iron levels with the neuron distribution. In the older monkeys, however, we have observed a proliferation of iron-rich granules, which appear to be more strongly anti-correlated with the distribution of neurons. The iron-cell anti-correlation occurs both in the control as well as the lesioned SN. Our results suggest that iron, particularly in the form of iron-rich deposits, accumulates in specific sites

  19. The role of iron and copper molecules in the neuronal vulnerability of locus coeruleus and substantia nigra during aging

    PubMed Central

    Zecca, Luigi; Stroppolo, Antonella; Gatti, Alberto; Tampellini, Davide; Toscani, Marco; Gallorini, Mario; Giaveri, Giuseppe; Arosio, Paolo; Santambrogio, Paolo; Fariello, Ruggero G.; Karatekin, Erdem; Kleinman, Mark H.; Turro, Nicholas; Hornykiewicz, Oleh; Zucca, Fabio A.

    2004-01-01

    In this study, a comparative analysis of metal-related neuronal vulnerability was performed in two brainstem nuclei, the locus coeruleus (LC) and substantia nigra (SN), known targets of the etiological noxae in Parkinson's disease and related disorders. LC and SN pars compacta neurons both degenerate in Parkinson's disease and other Parkinsonisms; however, LC neurons are comparatively less affected and with a variable degree of involvement. In this study, iron, copper, and their major molecular forms like ferritins, ceruloplasmin, neuromelanin (NM), manganese-superoxide dismutase (SOD), and copper/zinc-SOD were measured in LC and SN of normal subjects at different ages. Iron content in LC was much lower than that in SN, and the ratio heavy-chain ferritin/iron in LC was higher than in the SN. The NM concentration was similar in LC and SN, but the iron content in NM of LC was much lower than SN. In both regions, heavy- and light-chain ferritins were present only in glia and were not detectable in neurons. These data suggest that in LC neurons, the iron mobilization and toxicity is lower than that in SN and is efficiently buffered by NM. The bigger damage occurring in SN could be related to the higher content of iron. Ferritins accomplish the same function of buffering iron in glial cells. Ceruloplasmin levels were similar in LC and SN, but copper was higher in LC. However, the copper content in NM of LC was higher than that of SN, indicating a higher copper mobilization in LC neurons. Manganese-SOD and copper/zinc-SOD had similar age trend in LC and SN. These results may explain at least one of the reasons underlying lower vulnerability of LC compared to SN in Parkinsonian syndromes. PMID:15210960

  20. Substance P enhances microglial density in the substantia nigra through neurokinin-1 receptor/NADPH oxidase-mediated chemotaxis in mice.

    PubMed

    Wang, Qingshan; Oyarzabal, Esteban; Wilson, Belinda; Qian, Li; Hong, Jau-Shyong

    2015-10-01

    The distribution of microglia varies greatly throughout the brain. The substantia nigra (SN) contains the highest density of microglia among different brain regions. However, the mechanism underlying this uneven distribution remains unclear. Substance P (SP) is a potent proinflammatory neuropeptide with high concentrations in the SN. We recently demonstrated that SP can regulate nigral microglial activity. In the present study, we further investigated the involvement of SP in modulating nigral microglial density in postnatal developing mice. Nigral microglial density was quantified in wild-type (WT) and SP-deficient mice from postnatal day 1 (P1) to P30. SP was detected at high levels in the SN as early as P1 and microglial density did not peak until around P30 in WT mice. SP-deficient mice (TAC1(-/-)) had a significant reduction in nigral microglial density. No differences in the ability of microglia to proliferate were observed between TAC1(-/-) and WT mice, suggesting that SP may alter microglial density through chemotaxic recruitment. SP was confirmed to dose-dependently attract microglia using a trans-well culture system. Mechanistic studies revealed that both the SP receptor neurokinin-1 receptor (NK1R) and the superoxide-producing enzyme NADPH oxidase (NOX2) were necessary for SP-mediated chemotaxis in microglia. Furthermore, genetic ablation and pharmacological inhibition of NK1R or NOX2 attenuated SP-induced microglial migration. Finally, protein kinase Cδ (PKCδ) was recognized to couple SP/NK1R-mediated NOX2 activation. Altogether, we found that SP partly accounts for the increased density of microglia in the SN through chemotaxic recruitment via a novel NK1R-NOX2 axis-mediated pathway. © 2015 Authors; published by Portland Press Limited.

  1. Clinical features and dysfunctions of iron metabolism in Parkinson disease patients with hyper echogenicity in substantia nigra: a cross-sectional study.

    PubMed

    Yu, Shu-Yang; Cao, Chen-Jie; Zuo, Li-Jun; Chen, Ze-Jie; Lian, Teng-Hong; Wang, Fang; Hu, Yang; Piao, Ying-Shan; Li, Li-Xia; Guo, Peng; Liu, Li; Yu, Qiu-Jin; Wang, Rui-Dan; Chan, Piu; Chen, Sheng-di; Wang, Xiao-Min; Zhang, Wei

    2018-01-17

    Transcranial ultrasound is a useful tool for providing the evidences for the early diagnosis and differential diagnosis of Parkinson disease (PD). However, the relationship between hyper echogenicity in substantia nigra (SN) and clinical symptoms of PD patients remains unknown, and the role of dysfunction of iron metabolism on the pathogenesis of SN hyper echogenicity is unclear. PD patients was detected by transcranial sonography and divided into with no hyper echogenicity (PDSN-) group and with hyper echogenicity (PDSN+) group. Motor symptoms (MS) and non-motor symptoms (NMS) were evaluated, and the levels of iron and related proteins in serum and cerebrospinal fluid (CSF) were detected for PD patients. Data comparison between the two groups and correlation analyses were performed. PDSN+ group was significantly older, and had significantly older age of onset, more advanced Hohen-Yahr stage, higher SCOPA-AUT score and lower MoCA score than PDSN- group (P < 0.05). Compared with PDSN- group, the levels of transferrin and light-ferritin in serum and iron level in CSF were significantly elevated (P < 0.05), but ferroportin level in CSF was significantly decreased in PDSN+ group (P < 0.05). PD patients with hyper echogenicity in SN are older, at more advanced disease stage, have severer motor symptoms, and non-motor symptoms of cognitive impairment and autonomic dysfunction. Hyper echogenicity of SN in PD patients is related to dysfunction of iron metabolism, involving increased iron transport from peripheral system to central nervous system, reduction of intracellular iron release and excessive iron deposition in brain.

  2. Dopaminergic Presynaptic Modulation of Nigral Afferents: Its Role in the Generation of Recurrent Bursting in Substantia Nigra Pars Reticulata Neurons

    PubMed Central

    de Jesús Aceves, José; Rueda-Orozco, Pavel E.; Hernández, Ricardo; Plata, Víctor; Ibañez-Sandoval, Osvaldo; Galarraga, Elvira; Bargas, José

    2011-01-01

    Previous work has shown the functions associated with activation of dopamine presynaptic receptors in some substantia nigra pars reticulata (SNr) afferents: (i) striatonigral terminals (direct pathway) posses presynaptic dopamine D1-class receptors whose action is to enhance inhibitory postsynaptic currents (IPSCs) and GABA transmission. (ii) Subthalamonigral terminals posses D1- and D2-class receptors where D1-class receptor activation enhances and D2-class receptor activation decreases excitatory postsynaptic currents. Here we report that pallidonigral afferents posses D2-class receptors (D3 and D4 types) that decrease inhibitory synaptic transmission via presynaptic modulation. No action of D1-class agonists was found on pallidonigral synapses. In contrast, administration of D1-receptor antagonists greatly decreased striatonigral IPSCs in the same preparation, suggesting that tonic dopamine levels help in maintaining the function of the striatonigral (direct) pathway. When both D3 and D4 type receptors were blocked, pallidonigral IPSCs increased in amplitude while striatonigral connections had no significant change, suggesting that tonic dopamine levels are repressing a powerful inhibition conveyed by pallidonigral synapses (a branch of the indirect pathway). We then blocked both D1- and D2-class receptors to acutely decrease direct pathway (striatonigral) and enhance indirect pathways (subthalamonigral and pallidonigral) synaptic force. The result was that most SNr projection neurons entered a recurrent bursting firing mode similar to that observed during Parkinsonism in both patients and animal models. These results raise the question as to whether the lack of dopamine in basal ganglia output nuclei is enough to generate some pathological signs of Parkinsonism. PMID:21347219

  3. Nuclear microscopic investigations into the elemental changes in the substantia nigra of unilaterally MPTP-lesioned Parkinsonian monkeys

    NASA Astrophysics Data System (ADS)

    Thong, P. S. P.; He, Y.; Lee, T.; Watt, F.

    1997-07-01

    Various transition metals, particularly iron, have been implicated in the aetiology of the neurodegenerative disease, Parkinson's disease, in which there is a characteristic loss of cells in the substantia nigra (SN) region of the brain. In this study, monkeys were unilaterally lesioned with the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydro-pyridine (MPTP) to obtain primate models of parkinsonism, with the non-lesioned side of the brain serving as controls. The monkeys were sacrificed at one day, one week, two weeks, one month and one year after lesioning to investigate the time dependent elemental changes in the parkinsonian SN. Sections of the brain encompassing both the lesioned and non-lesioned SNs were analysed using the National University of Singapore nuclear microscope. Adjacent sections were tyrosine hydroxylase (TH) immunohistochemically stained to provide complementary information on dopaminergic cell loss and to facilitate definition of the SN boundaries during data analysis. In one-day and one-week monkeys (representing early stages of the disease), there were no changes in elemental concentrations within experimental errors and the adjacent TH-stained sections did not show apparent cell loss in the SN. At two weeks, cell loss was seen in the lesioned SN compared to the control SN. Although there was no bulk increase in SN iron, localised accumulation of iron in granules containing up to 15% by weight iron was observed in the lesioned SN of one of the two-week monkeys. An average 15% increase in nigral iron, significant at the 90% confidence level ( p < 0.1), was seen in the one-month monkeys. TH-stained sections for the one-month monkeys showed cell loss in the lesioned SN. In one-year samples (representing the advanced stage of the disease) there was a significant ( p < 0.05) 56% increase in iron, 14% increase in phosphorous and a 20% decrease in copper. Here an almost complete loss of cells in the lesioned SN was apparent from the adjacent TH

  4. Intracranial dialysis measurement of oxytocin, monoamine and uric acid release from the olfactory bulb and substantia nigra of sheep during parturition, suckling, separation from lambs and eating.

    PubMed

    Kendrick, K M; Keverne, E B; Chapman, C; Baldwin, B A

    1988-01-26

    Intracranial dialysis was used to measure the release of oxytocin (OXY), monoamines and their metabolites and uric acid (UA) from the substantia nigra (SN) and olfactory bulb (OB) of sheep during parturition, suckling, separation from lambs and eating. Results showed that OXY concentrations increased significantly during parturition, suckling and eating in the SN and during parturition and suckling in the OB. Concentrations of dopamine (DA) increased significantly in the SN during suckling and eating and in the OB during parturition and suckling. The dopamine metabolite, homovanillic acid, also increased significantly in the SN during parturition. Concentrations of the noradrenaline metabolite, 4-hydroxy-3-methoxyphenylethan-1,2-diol (MHPG) and the purine metabolite, UA, were significantly raised during parturition, suckling and separation from the lambs in the SN and increased UA levels were also found during eating. In a separate experiment it was confirmed that OXY was detectable in homogenates of both the SN and the OB. These results show that, in the sheep, OXY and DA release in the SN is associated with maternal and ingestive behaviour whereas similar release in the OB may only be related to maternal behaviour. Release of MHPG in the SN may be associated with maternal behaviour and/or stress.

  5. Intranasal insulin protects against substantia nigra dopaminergic neuronal loss and alleviates motor deficits induced by 6-OHDA in rats.

    PubMed

    Pang, Y; Lin, S; Wright, C; Shen, J; Carter, K; Bhatt, A; Fan, L-W

    2016-03-24

    Protection of substantia nigra (SN) dopaminergic (DA) neurons by neurotrophic factors (NTFs) is one of the promising strategies in Parkinson's disease (PD) therapy. A major clinical challenge for NTF-based therapy is that NTFs need to be delivered into the brain via invasive means, which often shows limited delivery efficiency. The nose to brain pathway is a non-invasive brain drug delivery approach developed in recent years. Of particular interest is the finding that intranasal insulin improves cognitive functions in Alzheimer's patients. In vitro, insulin has been shown to protect neurons against various insults. Therefore, the current study was designed to test whether intranasal insulin could afford neuroprotection in the 6-hydroxydopamine (6-OHDA)-based rat PD model. 6-OHDA was injected into the right side of striatum to induce a progressive DA neuronal lesion in the ipsilateral SN pars compact (SNc). Recombinant human insulin was applied intranasally to rats starting from 24h post lesion, once per day, for 2 weeks. A battery of motor behavioral tests was conducted on day 8 and 15. The number of DA neurons in the SNc was estimated by stereological counting. Our results showed that 6-OHDA injection led to significant motor deficits and 53% of DA neuron loss in the ipsilateral side of injection. Treatment with insulin significantly ameliorated 6-OHDA-induced motor impairments, as shown by improved locomotor activity, tapered/ledged beam-walking performance, vibrissa-elicited forelimb-placing, initial steps, as well as methamphetamine-induced rotational behavior. Consistent with behavioral improvements, insulin treatment provided a potent protection of DA neurons in the SNc against 6-OHDA neurotoxicity, as shown by a 74.8% increase in tyrosine hydroxylase (TH)-positive neurons compared to the vehicle group. Intranasal insulin treatment did not affect body weight and blood glucose levels. In conclusion, our study showed that intranasal insulin provided strong

  6. The GABA uptake inhibitor beta-alanine reduces pilocarpine-induced tremor and increases extracellular GABA in substantia nigra pars reticulata as measured by microdialysis.

    PubMed

    Ishiwari, Keita; Mingote, Susana; Correa, Merce; Trevitt, Jennifer T; Carlson, Brian B; Salamone, John D

    2004-12-30

    Substantia nigra pars reticulata (SNr) is a major output nucleus of the basal ganglia that receives GABAergic projections from neostriatum and globus pallidus. Previous research has shown that local pharmacological manipulations of GABA in SNr can influence tremulous jaw movements in rats. Tremulous jaw movements are defined as rapid vertical deflections of the lower jaw that resemble chewing but are not directed at a particular stimulus, and evidence indicates that these movements share many characteristics with parkinsonian tremor in humans. In order to investigate the role of GABA in motor functions related to tremor, the present study tested the GABA uptake blocker beta-alanine for its ability to reduce pilocarpine-induced tremulous jaw movements. In a parallel experiment, the effect of an active dose of beta-alanine on dialysate levels of GABA in SNr was assessed using microdialysis methods. GABA levels in dialysis samples were measured using high performance liquid chromatography with electrochemical detection. beta-Alanine (250-500 mg/kg) significantly reduced tremulous jaw movements induced by pilocarpine (4.0 mg/kg). Moreover, systemic administration of beta-alanine at a dose that reduced tremulous jaw movements (500 mg/kg) resulted in a substantial increase in extracellular levels of GABA in SNr compared to the pre-injection baseline. Thus, the present results are consistent with the hypothesis that GABAergic tone in SNr plays a role in the regulation of tremulous jaw movements. This research may lead to a better understanding of how parkinsonian symptoms are modulated by SNr GABA mechanisms.

  7. In Vivo Electrochemical Evidence for Simultaneous 5-HT and Histamine Release in the Rat Substantia Nigra pars Reticulata Following Medial Forebrain Bundle Stimulation

    PubMed Central

    Hashemi, Parastoo; Dankoski, Elyse C.; Wood, Kevin M.; Ambrose, R. Ellen; Wightman, R. Mark

    2011-01-01

    Exploring the mechanisms of serotonin (5-hydoxytryptophan (5-HT)) in the brain requires an in vivo method that combines fast temporal resolution with chemical selectivity. Fast-scan cyclic voltammetry (FSCV) is a technique with sufficient temporal and chemical resolution for probing dynamic 5-HT neurotransmission events; however, traditionally it has not been possible to probe in vivo 5-HT mechanisms. Recently, we optimized FSCV for measuring 5-HT release and uptake in vivo in the substantia nigra pars reticulata (SNR) with electrical stimulation of the dorsal raphe nucleus (DRN) in the rat brain. Here, we address technical challenges associated with rat DRN surgery by electrically stimulating 5-HT projections in the medial forebrain bundle (MFB), a more accessible anatomical location. MFB stimulation elicits 5-HT in the SNR; furthermore, we find simultaneous release of an additional species. We use electrochemical and pharmacological methods and describe physiological, anatomical and independent chemical analyses to identify this species as histamine. We also show pharmacologically that increasing the lifetime of extracellular histamine significantly decreases 5-HT release, most likely due to increased activation of histamine H-3 receptors that inhibit 5-HT release. Despite this, under physiological conditions, we find by kinetic comparisons of DRN and MFB stimulations that the simultaneous release of histamine does not interfere with the quantitative 5-HT concentration profile. We therefore present a novel and robust electrical stimulation of the MFB that is technically less challenging than DRN stimulation to study 5-HT and histamine release in the SNR. PMID:21682723

  8. [The effects of lesions in the compact part of the substantia nigra on glutamate and GABA release in the pedunculopontine nucleus].

    PubMed

    Blanco-Lezcano, L; Rocha-Arrieta, L L; Alvarez-González, L; Martínez-Martí, L; Pavón-Fuentes, N; González-Fraguela, M E; Bauzá-Calderín, Y; Coro-Grave de Peralta, Y

    The pedunculopontine nucleus (PPN), co-localized with the mesencephalic locomotor region, has been proposed as a key structure in the physiopathology of Parkinson's disease. The goal of the present study was to assess if the aminoacid neurotransmitter release in the PPN is modified by the degeneration of dopaminergic cells, from substantia nigra pars compacta in 6-hydroxidopamine (6-OHDA)-lesioned rats. In addition, it was studied the aminoacid neurotransmitter release in the PPN of rats with lesion of the subthalamic nucleus by quinolinic acid (QUIN) (100 nmol) intracerebral injection. Rats were assigned to five groups: untreated rats (I) (n = 13), 6-OHDA lesion (II) (n = 11), 6-OHDA + QUIN lesion (III) (n = 9), sham-operated (IV) (n = 10), QUIN, STN (V) lesioned (n = 9). The extracellular concentrations of glutamic acid (GLU) and gamma-aminobutyric acid (GABA) were determined by brain microdialysis and high performance liquid chromatography (HPLC). RESULTS. GLU released in PPN from 6-OHDA lesioned rats (group II), was significantly increased in comparison with the others groups (F(4, 47) = 18.21, p < 0.001). GABA released shows significant differences between experimental groups (F(4, 45) = 12.75, p < 0.001). It was detected a higher valour (p < 0.05) in-group II. The groups III and IV exhibited intermeddle valour (p < 0.001) and groups I and IV (p < 0.001) showed the lower GABA extracellular concentrations. The infusion of artificial cerebrospinal fluid with higher potassium (100 mmol) induced an increase in the GLU and GABA released in all groups, which confirm the neuronal origin of the extracellular content. These results are in agreement with the current model of basal ganglia functioning and suggest the role of STN-PPN projection in the physiopathology of Parkinson's disease.

  9. A Physiological Neural Network for Saccadic Eye Movement Control

    DTIC Science & Technology

    1994-04-01

    cerebellum, substantia nigra, nucleus reticularis tegmenti pontis, the thalamus, the deep layers of the superior colliculus and the oculomotor plant...and pause cells), the vestibular nucleus , abducens nucleus , oculomotor nucleus , cerebellum, substantia nigra, nucleus reticularis tegmenti pontis, the...vestibular nucleus , abducens nucleus , oculomotor nucleus , cerebellum, substantia nigra, nucleus reticularis tegmenti pontis (NRTP), the thalamus, the

  10. Differential vulnerability of substantia nigra and corpus striatum to oxidative insult induced by reduced dietary levels of essential fatty acids

    PubMed Central

    Cardoso, Henriqueta D.; Passos, Priscila P.; Lagranha, Claudia J.; Ferraz, Anete C.; Santos Júnior, Eraldo F.; Oliveira, Rafael S.; Oliveira, Pablo E. L.; Santos, Rita de C. F.; Santana, David F.; Borba, Juliana M. C.; Rocha-de-Melo, Ana P.; Guedes, Rubem C. A.; Navarro, Daniela M. A. F.; Santos, Geanne K. N.; Borner, Roseane; Picanço-Diniz, Cristovam W.; Beltrão, Eduardo I.; Silva, Janilson F.; Rodrigues, Marcelo C. A.; Andrade da Costa, Belmira L. S.

    2012-01-01

    Oxidative stress (OS) has been implicated in the etiology of certain neurodegenerative disorders. Some of these disorders have been associated with unbalanced levels of essential fatty acids (EFA). The response of certain brain regions to OS, however, is not uniform and a selective vulnerability or resilience can occur. In our previous study on rat brains, we observed that a two-generation EFA dietary restriction reduced the number and size of dopaminergic neurons in the substantia nigra (SN) rostro-dorso-medial. To understand whether OS contributes to this effect, we assessed the status of lipid peroxidation (LP) and anti-oxidant markers in both SN and corpus striatum (CS) of rats submitted to this dietary treatment for one (F1) or two (F2) generations. Wistar rats were raised from conception on control or experimental diets containing adequate or reduced levels of linoleic and α-linolenic fatty acids, respectively. LP was measured using the thiobarbituric acid reaction method (TBARS) and the total superoxide dismutase (t-SOD) and catalase (CAT) enzymatic activities were assessed. The experimental diet significantly reduced the docosahexaenoic acid (DHA) levels of SN phospholipids in the F1 (~28%) and F2 (~50%) groups. In F1 adult animals of the experimental group there was no LP in both SN and CS. Consistently, there was a significant increase in the t-SOD activity (p < 0.01) in both regions. In EF2 young animals, degeneration in dopaminergic and non-dopaminergic neurons and a significant increase in LP (p < 0.01) and decrease in the CAT activity (p < 0.001) were detected in the SN, while no inter-group difference was found for these parameters in the CS. Conversely, a significant increase in t-SOD activity (p < 0.05) was detected in the CS of the experimental group compared to the control. The results show that unbalanced EFA dietary levels reduce the redox balance in the SN and reveal mechanisms of resilience in the CS under this stressful condition. PMID

  11. Altered machinery of protein synthesis is region- and stage-dependent and is associated with α-synuclein oligomers in Parkinson's disease.

    PubMed

    Garcia-Esparcia, Paula; Hernández-Ortega, Karina; Koneti, Anusha; Gil, Laura; Delgado-Morales, Raul; Castaño, Ester; Carmona, Margarita; Ferrer, Isidre

    2015-12-01

    Parkinson's disease (PD) is characterized by the accumulation of abnormal α-synuclein in selected regions of the brain following a gradient of severity with disease progression. Whether this is accompanied by globally altered protein synthesis is poorly documented. The present study was carried out in PD stages 1-6 of Braak and middle-aged (MA) individuals without alterations in brain in the substantia nigra, frontal cortex area 8, angular gyrus, precuneus and putamen. Reduced mRNA expression of nucleolar proteins nucleolin (NCL), nucleophosmin (NPM1), nucleoplasmin 3 (NPM3) and upstream binding transcription factor (UBF), decreased NPM1 but not NPM3 nucleolar protein immunostaining in remaining neurons; diminished 18S rRNA, 28S rRNA; reduced expression of several mRNAs encoding ribosomal protein (RP) subunits; and altered protein levels of initiation factor eIF3 and elongation factor eEF2 of protein synthesis was found in the substantia nigra in PD along with disease progression. Although many of these changes can be related to neuron loss in the substantia nigra, selective alteration of certain factors indicates variable degree of vulnerability of mRNAs, rRNAs and proteins in degenerating sustantia nigra. NPM1 mRNA and 18S rRNA was increased in the frontal cortex area 8 at stage 5-6; modifications were less marked and region-dependent in the angular gyrus and precuneus. Several RPs were abnormally regulated in the frontal cortex area 8 and precuneus, but only one RP in the angular gyrus, in PD. Altered levels of eIF3 and eIF1, and decrease eEF1A and eEF2 protein levels were observed in the frontal cortex in PD. No modifications were found in the putamen at any time of the study except transient modifications in 28S rRNA and only one RP mRNA at stages 5-6. These observations further indicate marked region-dependent and stage-dependent alterations in the cerebral cortex in PD. Altered solubility and α-synuclein oligomer formation, assessed in total homogenate

  12. Radiosurgery performed with the aid of a 3-mm collimator in the subthalamic nucleus and substantia nigra of the vervet monkey.

    PubMed

    De Salles, A A; Melega, W P; Laćan, G; Steele, L J; Solberg, T D

    2001-12-01

    Radiosurgery for functional neurosurgery performed using a linear accelerator (LINAC) has not been extensively characterized in preclinical studies. In the present study, the properties of a newly designed 3-mm-diameter collimator were evaluated in a dedicated LINAC, which produced lesions in the basal ganglia of vervet monkeys. Lesion formation was determined in vivo in three animals by examining magnetic resonance (MR) images to show the dose-delivery precision of targeting and the geometry and extent of the lesions. Postmortem immunohistochemical studies were conducted to determine the extent of lesion-induced radiobiological effects. In three male vervet monkeys, the subthalamic nucleus (STN; one animal) and the pars compacta of the lateral substantia nigra (SN; two animals) were targeted by a Novalis Shaped Beam Surgery System that included a 3-mm collimator and delivered a maximum dose of 150 Gy. Magnetic resonance images obtained 4, 5, and 9 months posttreatment were reviewed, and the animals were killed so that immunohistological characterizations could be made. The generation of precise radiosurgical lesions by a 3-mm collimator was validated in studies that targeted the basal ganglia of the vervet monkey. The extent of the lesions created in all animals remained restricted in diameter (< 3 mm) throughout the duration of the studies, as assessed by reviewing MR images. Histological studies showed that the lesions were contained within the STN and SN target areas and that there were persistent increases in glial fibrillary acidic protein immunoreactivity. Increases in immunoreactivity for tyrosine hydroxylase, the serotonin transporter, and the GluR1 subunit of the alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate glutamate receptor in penumbral regions of the lesion were suggestive of compensatory neuronal adaptations. This radiosurgical approach may be of particular interest for the induction of lesions of the STN and SN in studies of experimental

  13. Paraquat induces oxidative stress, neuronal loss in substantia nigra region and parkinsonism in adult rats: neuroprotection and amelioration of symptoms by water-soluble formulation of coenzyme Q10.

    PubMed

    Somayajulu-Niţu, Mallika; Sandhu, Jagdeep K; Cohen, Jerome; Sikorska, Marianna; Sridhar, T S; Matei, Anca; Borowy-Borowski, Henryk; Pandey, Siyaram

    2009-07-27

    Parkinson's disease, for which currently there is no cure, develops as a result of progressive loss of dopamine neurons in the brain; thus, identification of any potential therapeutic intervention for disease management is of a great importance. Here we report that prophylactic application of water-soluble formulation of coenzyme Q10 could effectively offset the effects of environmental neurotoxin paraquat, believed to be a contributing factor in the development of familial PD. In this study we utilized a model of paraquat-induced dopaminergic neurodegeneration in adult rats that received three weekly intra-peritoneal injections of the herbicide paraquat. Histological and biochemical analyses of rat brains revealed increased levels of oxidative stress markers and a loss of approximately 65% of dopamine neurons in the substantia nigra region. The paraquat-exposed rats also displayed impaired balancing skills on a slowly rotating drum (rotorod) evidenced by their reduced spontaneity in gait performance. In contrast, paraquat exposed rats receiving a water-soluble formulation of coenzyme Q10 in their drinking water prior to and during the paraquat treatment neither developed neurodegeneration nor reduced rotorod performance and were indistinguishable from the control paraquat-untreated rats. Our data confirmed that paraquat-induced neurotoxicity represents a convenient rat model of parkinsonian neurodegeneration suitable for mechanistic and neuroprotective studies. This is the first preclinical evaluation of a water-soluble coenzyme Q10 formulation showing the evidence of prophylactic neuroprotection at clinically relevant doses.

  14. Paraquat induces oxidative stress, neuronal loss in substantia nigra region and Parkinsonism in adult rats: Neuroprotection and amelioration of symptoms by water-soluble formulation of Coenzyme Q10

    PubMed Central

    Somayajulu-Niţu, Mallika; Sandhu, Jagdeep K; Cohen, Jerome; Sikorska, Marianna; Sridhar, TS; Matei, Anca; Borowy-Borowski, Henryk; Pandey, Siyaram

    2009-01-01

    Background Parkinson's disease, for which currently there is no cure, develops as a result of progressive loss of dopamine neurons in the brain; thus, identification of any potential therapeutic intervention for disease management is of a great importance. Results Here we report that prophylactic application of water-soluble formulation of coenzyme Q10 could effectively offset the effects of environmental neurotoxin paraquat, believed to be a contributing factor in the development of familial PD. In this study we utilized a model of paraquat-induced dopaminergic neurodegeneration in adult rats that received three weekly intra-peritoneal injections of the herbicide paraquat. Histological and biochemical analyses of rat brains revealed increased levels of oxidative stress markers and a loss of approximately 65% of dopamine neurons in the substantia nigra region. The paraquat-exposed rats also displayed impaired balancing skills on a slowly rotating drum (rotorod) evidenced by their reduced spontaneity in gait performance. In contrast, paraquat exposed rats receiving a water-soluble formulation of coenzyme Q10 in their drinking water prior to and during the paraquat treatment neither developed neurodegeneration nor reduced rotorod performance and were indistinguishable from the control paraquat-untreated rats. Conclusion Our data confirmed that paraquat-induced neurotoxicity represents a convenient rat model of Parkinsonian neurodegeneration suitable for mechanistic and neuroprotective studies. This is the first preclinical evaluation of a water-soluble coenzyme Q10 formulation showing the evidence of prophylactic neuroprotection at clinically relevant doses. PMID:19635141

  15. Nigral stimulation for resistant axial motor impairment in Parkinson’s disease? A randomized controlled trial

    PubMed Central

    Walach, Margarete; Meisner, Christoph; Fritz, Melanie; Scholten, Marlieke; Breit, Sorin; Plewnia, Christian; Bender, Benjamin; Gharabaghi, Alireza; Wächter, Tobias

    2013-01-01

    Gait and balance disturbances typically emerge in advanced Parkinson’s disease with generally limited response to dopaminergic medication and subthalamic nucleus deep brain stimulation. Therefore, advanced programming with interleaved pulses was put forward to introduce concomittant nigral stimulation on caudal contacts of a subthalamic lead. Here, we hypothesized that the combined stimulation of subthalamic nucleus and substantia nigra pars reticulata improves axial symptoms compared with standard subthalamic nucleus stimulation. Twelve patients were enrolled in this 2 × 2 cross-over double-blind randomized controlled clinical trial and both the safety and efficacy of combined subthalamic nucleus and substantia nigra pars reticulata stimulation were evaluated compared with standard subthalamic nucleus stimulation. The primary outcome measure was the change of a broad-scaled cumulative axial Unified Parkinson’s Disease Rating Scale score (Scale II items 13–15, Scale III items 27–31) at ‘3-week follow-up’. Secondary outcome measures specifically addressed freezing of gait, balance, quality of life, non-motor symptoms and neuropsychiatric symptoms. For the primary outcome measure no statistically significant improvement was observed for combined subthalamic nucleus and substantia nigra pars reticulata stimulation at the ‘3-week follow-up’. The secondary endpoints, however, revealed that the combined stimulation of subthalamic nucleus and substantia nigra pars reticulata might specifically improve freezing of gait, whereas balance impairment remained unchanged. The combined stimulation of subthalamic nucleus and substantia nigra pars reticulata was safe, and of note, no clinically relevant neuropsychiatric adverse effect was observed. Patients treated with subthalamic nucleus and substantia nigra pars reticulata stimulation revealed no ‘global’ effect on axial motor domains. However, this study opens the perspective that concomittant stimulation

  16. Nigral stimulation for resistant axial motor impairment in Parkinson's disease? A randomized controlled trial.

    PubMed

    Weiss, Daniel; Walach, Margarete; Meisner, Christoph; Fritz, Melanie; Scholten, Marlieke; Breit, Sorin; Plewnia, Christian; Bender, Benjamin; Gharabaghi, Alireza; Wächter, Tobias; Krüger, Rejko

    2013-07-01

    Gait and balance disturbances typically emerge in advanced Parkinson's disease with generally limited response to dopaminergic medication and subthalamic nucleus deep brain stimulation. Therefore, advanced programming with interleaved pulses was put forward to introduce concomittant nigral stimulation on caudal contacts of a subthalamic lead. Here, we hypothesized that the combined stimulation of subthalamic nucleus and substantia nigra pars reticulata improves axial symptoms compared with standard subthalamic nucleus stimulation. Twelve patients were enrolled in this 2 × 2 cross-over double-blind randomized controlled clinical trial and both the safety and efficacy of combined subthalamic nucleus and substantia nigra pars reticulata stimulation were evaluated compared with standard subthalamic nucleus stimulation. The primary outcome measure was the change of a broad-scaled cumulative axial Unified Parkinson's Disease Rating Scale score (Scale II items 13-15, Scale III items 27-31) at '3-week follow-up'. Secondary outcome measures specifically addressed freezing of gait, balance, quality of life, non-motor symptoms and neuropsychiatric symptoms. For the primary outcome measure no statistically significant improvement was observed for combined subthalamic nucleus and substantia nigra pars reticulata stimulation at the '3-week follow-up'. The secondary endpoints, however, revealed that the combined stimulation of subthalamic nucleus and substantia nigra pars reticulata might specifically improve freezing of gait, whereas balance impairment remained unchanged. The combined stimulation of subthalamic nucleus and substantia nigra pars reticulata was safe, and of note, no clinically relevant neuropsychiatric adverse effect was observed. Patients treated with subthalamic nucleus and substantia nigra pars reticulata stimulation revealed no 'global' effect on axial motor domains. However, this study opens the perspective that concomittant stimulation of the substantia

  17. Effects of treadmill exercise on behavioral recovery and neural changes in the substantia nigra and striatum of the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned mouse

    PubMed Central

    Goldberg, Natalie R.S.; Meshul, Charles K.

    2011-01-01

    Our goal was to extend our understanding of the neural changes behind motor recovery with treadmill exercise in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned mouse. We determined the extent of dopamine (DA) terminal changes using western immunoblotting [striatal dopamine transporter (DAT) and tyrosine hydroxylase (TH)] and alterations in the mean number of DA cells/section by immunohistochemistry and Nissl staining [TH-labeled cells and thionin-stained cells in the substantia nigra pars compacta (SN-PC)]. We measured recovery of gait performance and amount of spontaneous physical activity using the parallel rod activity chamber (PRAC). We hypothesized that the decrease in TH-labeled neurons in the SN-PC due to MPTP will be partially reversed by treadmill exercise, leading to recovery of motor behavior as measured by the PRAC. Following MPTP or vehicle administration, mice ran on the treadmill for 1 hour per day at 18 cm/s, 5 days per week. Results showed that treadmill exercise improves gait performance and increases physical activity while promoting increased protein expression of striatal DAT and TH. Exercise was effective for all mice, however effects of early treadmill-based intervention appear to have an additional and unique benefit in mice who received MPTP. We are the first to show that, even following a nearly 50% decrease in the mean number of TH-labeled neurons/section in the SN-PC following MPTP, treadmill exercise leads to an increase of neurons in the SN-PC and improved motor behavior. PMID:21315689

  18. Compensatory T-type Ca2+ channel activity alters D2-autoreceptor responses of Substantia nigra dopamine neurons from Cav1.3 L-type Ca2+ channel KO mice.

    PubMed

    Poetschke, Christina; Dragicevic, Elena; Duda, Johanna; Benkert, Julia; Dougalis, Antonios; DeZio, Roberta; Snutch, Terrance P; Striessnig, Joerg; Liss, Birgit

    2015-09-18

    The preferential degeneration of Substantia nigra dopamine midbrain neurons (SN DA) causes the motor-symptoms of Parkinson's disease (PD). Voltage-gated L-type calcium channels (LTCCs), especially the Cav1.3-subtype, generate an activity-related oscillatory Ca(2+) burden in SN DA neurons, contributing to their degeneration and PD. While LTCC-blockers are already in clinical trials as PD-therapy, age-dependent functional roles of Cav1.3 LTCCs in SN DA neurons remain unclear. Thus, we analysed juvenile and adult Cav1.3-deficient mice with electrophysiological and molecular techniques. To unmask compensatory effects, we compared Cav1.3 KO mice with pharmacological LTCC-inhibition. LTCC-function was not necessary for SN DA pacemaker-activity at either age, but rather contributed to their pacemaker-precision. Moreover, juvenile Cav1.3 KO but not WT mice displayed adult wildtype-like, sensitised inhibitory dopamine-D2-autoreceptor (D2-AR) responses that depended upon both, interaction of the neuronal calcium sensor NCS-1 with D2-ARs, and on voltage-gated T-type calcium channel (TTCC) activity. This functional KO-phenotype was accompanied by cell-specific up-regulation of NCS-1 and Cav3.1-TTCC mRNA. Furthermore, in wildtype we identified an age-dependent switch of TTCC-function from contributing to SN DA pacemaker-precision in juveniles to pacemaker-frequency in adults. This novel interplay of Cav1.3 L-type and Cav3.1 T-type channels, and their modulation of SN DA activity-pattern and D2-AR-sensitisation, provide new insights into flexible age- and calcium-dependent activity-control of SN DA neurons and its pharmacological modulation.

  19. Dietary administration of paraquat for 13 weeks does not result in a loss of dopaminergic neurons in the substantia nigra of C57BL/6J mice.

    PubMed

    Minnema, Daniel J; Travis, Kim Z; Breckenridge, Charles B; Sturgess, Nicholas C; Butt, Mark; Wolf, Jeffrey C; Zadory, Dan; Beck, Melissa J; Mathews, James M; Tisdel, Merrill O; Cook, Andrew R; Botham, Philip A; Smith, Lewis L

    2014-03-01

    Several investigations have reported that mice administered paraquat dichloride (PQ·Cl2) by intraperitoneal injection exhibit a loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc). In this study, male and female C57BL/6J mice were administered PQ·Cl2 in the diet at concentrations of 0 (control), 10, and 50ppm for a duration of 13weeks. A separate group of mice were administered 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) during week 12 as positive controls to produce a loss of dopaminergic neurons in the SNpc. The comparative effects of PQ and MPTP on the SNpc and/or striatum were assessed using neurochemical, neuropathological, and stereological endpoints. Morphological and stereological assessments were performed by investigators 'blinded' to the origin of the tissue. Neither dose of PQ·Cl2 (10 or 50 ppm in the diet) caused a loss of striatal dopamine or dopamine metabolite concentrations in the brains of mice. Pathological assessments of the SNpc and striatum showed no evidence of neuronal degeneration or astrocytic/microglial activation. Furthermore, the number of tyrosine hydroxylase-positive (TH(+)) neurons in the SNpc was not reduced in PQ-treated mice. In contrast, MPTP caused a decrease in striatal dopamine concentration, a reduction in TH(+) neurons in the SNpc, and significant pathological changes including astrocytic and microglial activation in the striatum and SNpc. The MPTP-induced effects were greater in males than in females. It is concluded that 13weeks of continuous dietary exposure of C57BL/6J mice to 50ppm PQ·Cl2 (equivalent to 10.2 and 15.6mg PQ ion/kg body weight/day for males and females, respectively) does not result in the loss of, or damage to, dopaminergic neurons in the SNpc. Copyright © 2013 The Authors. Published by Elsevier Inc. All rights reserved.

  20. Assessment of the Effects of MPTP and Paraquat on Dopaminergic Neurons and Microglia in the Substantia Nigra Pars Compacta of C57BL/6 Mice.

    PubMed

    Smeyne, Richard Jay; Breckenridge, Charles B; Beck, Melissa; Jiao, Yun; Butt, Mark T; Wolf, Jeffrey C; Zadory, Dan; Minnema, Daniel J; Sturgess, Nicholas C; Travis, Kim Z; Cook, Andrew R; Smith, Lewis L; Botham, Philip A

    2016-01-01

    The neurotoxicity of paraquat dichloride (PQ) was assessed in two inbred strains of 9- or 16-week old male C57BL/6 mice housed in two different laboratories and compared to the effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). PQ was administered by intraperitoneal injections; either once (20 mg/kg) or twice (10 mg/kg) weekly for 3 weeks, while MPTP-HCl was injected 4 times on a single day (20 mg/kg/dose). Brains were collected 8, 16, 24, 48, 96 or 168 hours after the last PQ treatment, and 48 or 168 hours after MPTP treatment. Dopamine neurons in the substantia nigra pars compacta (SNpc) were identified by antibodies to tyrosine hydroxylase (TH+) and microglia were identified using Iba-1 immunoreactivity. The total number of TH+ neurons and the number of resting and activated microglia in the SNpc at 168 hours after the last dose were estimated using model- or design-based stereology, with investigators blinded to treatment. In a further analysis, a pathologist, also blinded to treatment, evaluated the SNpc and/or striatum for loss of TH+ neurons (SNpc) or terminals (striatum), cell death (as indicated by amino cupric silver uptake, TUNEL and/or caspase 3 staining) and neuroinflammation (as indicated by Iba-1 and/or GFAP staining). PQ, administered either once or twice weekly to 9- or 16-week old mice from two suppliers, had no effect on the number of TH+ neurons or microglia in the SNpc, as assessed by two groups, each blinded to treatment, using different stereological methods. PQ did not induce neuronal cell loss or degeneration in the SNpc or striatum. Additionally, there was no evidence of apoptosis, microgliosis or astrogliosis. In MPTP-treated mice, the number of TH+ neurons in the SNpc was significantly decreased and the number of activated microglia increased. Histopathological assessment found degenerating neurons/terminals in the SNpc and striatum but no evidence of apoptotic cell death. MPTP activated microglia in the SNpc and increased

  1. Abnormal Chloride Homeostasis in the Substancia Nigra Pars Reticulata Contributes to Locomotor Deficiency in a Model of Acute Liver Injury

    PubMed Central

    Wei, Yan-Yan; Chen, Jing; Dou, Ke-Feng; Wang, Ya-Yun

    2013-01-01

    Background Altered chloride homeostasis has been thought to be a risk factor for several brain disorders, while less attention has been paid to its role in liver disease. We aimed to analyze the involvement and possible mechanisms of altered chloride homeostasis of GABAergic neurons within the substantia nigra pars reticulata (SNr) in the motor deficit observed in a model of encephalopathy caused by acute liver failure, by using glutamic acid decarboxylase 67 - green fluorescent protein knock-in transgenic mice. Methods Alterations in intracellular chloride concentration in GABAergic neurons within the SNr and changes in the expression of two dominant chloride homeostasis-regulating genes, KCC2 and NKCC1, were evaluated in mice with hypolocomotion due to hepatic encephalopathy (HE). The effects of pharmacological blockade and/or activation of KCC2 and NKCC1 functions with their specific inhibitors and/or activators on the motor activity were assessed. Results In our mouse model of acute liver injury, chloride imaging indicated an increase in local intracellular chloride concentration in SNr GABAergic neurons. In addition, the mRNA and protein levels of KCC2 were reduced, particularly on neuronal cell membranes; in contrast, NKCC1 expression remained unaffected. Furthermore, blockage of KCC2 reduced motor activity in the normal mice and led to a further deteriorated hypolocomotion in HE mice. Blockade of NKCC1 was not able to normalize motor activity in mice with liver failure. Conclusion Our data suggest that altered chloride homeostasis is likely involved in the pathophysiology of hypolocomotion following HE. Drugs aimed at restoring normal chloride homeostasis would be a potential treatment for hepatic failure. PMID:23741482

  2. Ventral tegmental area/substantia nigra and prefrontal cortex rodent organotypic brain slices as an integrated model to study the cellular changes induced by oxygen/glucose deprivation and reperfusion: effect of neuroprotective agents.

    PubMed

    Colombo, Laura; Parravicini, Chiara; Lecca, Davide; Dossi, Elena; Heine, Claudia; Cimino, Mauro; Wanke, Enzo; Illes, Peter; Franke, Heike; Abbracchio, Maria P

    2014-01-01

    Unveiling the roles of distinct cell types in brain response to insults is a partially unsolved challenge and a key issue for new neuroreparative approaches. In vivo models are not able to dissect the contribution of residential microglia and infiltrating blood-borne monocytes/macrophages, which are fundamentally undistinguishable; conversely, cultured cells lack original tissue anatomical and functional complexity, which profoundly alters reactivity. Here, we tested whether rodent organotypic co-cultures from mesencephalic ventral tegmental area/substantia nigra and prefrontal cortex (VTA/SN-PFC) represent a suitable model to study changes induced by oxygen/glucose deprivation and reperfusion (OGD/R). OGD/R induced cytotoxicity to both VTA/SN and PFC slices, with higher VTA/SN susceptibility. Neurons were highly affected, with astrocytes and oligodendrocytes undergoing very mild damage. Marked reactive astrogliosis was also evident. Notably, OGD/R triggered the activation of CD68-expressing microglia and increased expression of Ym1 and Arg1, two markers of "alternatively" activated beneficial microglia. Treatment with two well-known neuroprotective drugs, the anticonvulsant agent valproic acid and the purinergic P2-antagonist PPADS, prevented neuronal damage. Thus, VTA/SN-PFC cultures are an integrated model to investigate OGD/R-induced effects on distinct cells and easily screen neuroprotective agents. The model is particularly adequate to dissect the microglia phenotypic shift in the lack of a functional vascular compartment. Copyright © 2014 Elsevier Ltd. All rights reserved.

  3. Evaluation of Parkinson disease and Alzheimer disease with the use of neuromelanin MR imaging and (123)I-metaiodobenzylguanidine scintigraphy.

    PubMed

    Miyoshi, F; Ogawa, T; Kitao, S-i; Kitayama, M; Shinohara, Y; Takasugi, M; Fujii, S; Kaminou, T

    2013-01-01

    Progressive changes in the substantia nigra pars compacta and locus ceruleus of patients with Parkinson disease and Alzheimer disease visualized by neuromelanin MRI and cardiac postganglionic sympathetic nerve function on (123)I-metaiodobenzylguanidine scintigraphy have not been fully evaluated. We compared the diagnostic value of these modalities among patients with early Parkinson disease, late Parkinson disease, and Alzheimer disease. We compared contrast ratios of signal intensity in medial and lateral regions of the substantia nigra pars compacta and locus ceruleus with those of the tegmentum of the midbrain and the pons, respectively, by use of neuromelanin MRI in patients with early Parkinson disease (n = 13), late Parkinson disease (n = 31), Alzheimer disease (n = 6), and age-matched healthy control subjects (n = 20). We calculated heart-to-mediastinum ratios on (123)I-metaiodobenzylguanidine scintigrams after setting regions of interest on the left cardiac ventricle and upper mediastinum. The signal intensity of the lateral substantia nigra pars compacta on neuromelanin MRI was significantly reduced in early and late Parkinson disease, and that of the medial substantia nigra pars compacta was gradually and stage-dependently reduced in Parkinson disease. The signal intensity of the locus ceruleus was obviously reduced in late Parkinson disease. Signal reduction was not significant in the substantia nigra pars compacta and locus ceruleus of patients with Alzheimer disease. The heart-to-mediastinum ratio on (123)I-metaiodobenzylguanidine scintigrams was stage-dependently reduced in Parkinson disease and normal in Alzheimer disease. The signal intensity ratios in substantia nigra pars compacta and locus ceruleus on neuromelanin MRI positively correlated with the heart-to-mediastinum ratio on (123)I-metaiodobenzylguanidine scintigrams. Both neuromelanin MRI and (123)I-metaiodobenzylguanidine scintigraphy can help to evaluate disease progression in Parkinson

  4. Age related rise in lactate and its correlation with lactate dehydrogenase (LDH) status in post-mitochondrial fractions isolated from different regions of brain in mice.

    PubMed

    Datta, Siddhartha; Chakrabarti, Nilkanta

    2018-04-18

    Rise in brain lactate is the hallmark of ageing. Separate studies report that ageing is associated with elevation of lactate level and alterations of lactate dehydrogenase (LDH)-A/B mRNA-expression-ratio in cerebral cortex and hippocampus. However, age related lactate rise in brain and its association with LDH status and their brain regional variations are still elusive. In the present study, level of lactate, LDH (A and B) activity and LDH-A expression were evaluated in post-mitochondrial fraction of tissues isolated from four different brain regions (cerebral cortex, hippocampus, substantia nigra and cerebellum) of young and aged mice. Lactate levels elevated in four brain regions with maximum rise in substantia nigra of aged mice. LDH-A protein expression and its activity decreased in cerebral cortex, hippocampus and substantia nigra without any changes of these parameters in cerebellum of aged mice. LDH-B activity decreased in hippocampus, substantia nigra and cerebellum whereas its activity remains unaltered in cerebral cortex of aged mice. Accordingly, the ratio of LDH-A/LDH-B-activity remains unaltered in hippocampus and substantia nigra, decreased in cerebral cortex and increased in cerebellum. Therefore, rise of lactate in three brain regions (cerebral cortex, hippocampus, substantia nigra) appeared to be not correlated with the alterations of its regulatory enzymes activities in these three brain regions, rather it supports the fact of involvement of other mechanisms, like lactate transport and/or aerobic/anaerobic metabolism as the possible cause(s) of lactate rise in these three brain regions. The increase in LDH-A/LDH-B-activity-ratio appeared to be positively correlated with elevated lactate level in cerebellum of aged mice. Overall, the present study indicates that the mechanism of rise in lactate in brain varies with brain regions where LDH status plays an important role during ageing. Copyright © 2018 Elsevier Ltd. All rights reserved.

  5. Dopamine D2 receptor-mediated G-protein activation in rat striatum: functional autoradiography and influence of unilateral 6-hydroxydopamine lesions of the substantia nigra.

    PubMed

    Newman-Tancredi, A; Cussac, D; Brocco, M; Rivet, J M; Chaput, C; Touzard, M; Pasteau, V; Millan, M J

    2001-11-30

    Unilateral 6-hydroxydopamine (6-OHDA) lesions of substantia nigra pars compacta (SNPC) neurons in rats induce behavioural hypersensitivity to dopaminergic agonists. However, the role of specific dopamine receptors is unclear, and potential alterations in their transduction mechanisms remain to be evaluated. The present study addressed these issues employing the dopaminergic agonist, quinelorane, which efficaciously stimulated G-protein activation (as assessed by [35S]GTPgammaS binding) at cloned hD2 (and hD3) receptors. At rat striatal membranes, dopamine stimulated [35S]GTPgammaS binding by 1.9-fold over basal, but its actions were only partially reversed by the selective D2/D3 receptor antagonist, raclopride, indicating the involvement of other receptor subtypes. In contrast, quinelorane-induced stimulation (48% of the effect of dopamine) was abolished by raclopride, and by the D2 receptor antagonist, L741,626. Further, novel antagonists selective for D3 and D4 receptors, S33084 and S18126, respectively, blocked the actions of quinelorane at concentrations corresponding to their affinities for D2 receptors. Quinelorane potently induced contralateral rotation in unilaterally 6-OHDA-lesioned rats, an effect abolished by raclopride and L741,626, but not by D3 and D4 receptor-selective doses of S33084 and S18126, respectively. In functional ([35S]GTPgammaS) autoradiography experiments, quinelorane stimulated G-protein activation in caudate putamen and, to a lesser extent, in nucleus accumbens and cingulate cortex of naive rats. In unilaterally SNPC-lesioned rats, quinelorane-induced G-protein activation in the caudate putamen on the non-lesioned side was similar to that seen in naive animals (approximately 50% stimulation), but significantly greater on the lesioned side (approximately 80%). This increase was both pharmacologically and regionally specific since it was reversed by raclopride, and was not observed in nucleus accumbens or cingulate cortex. In conclusion

  6. Pleiotrophin over-expression provides trophic support to dopaminergic neurons in parkinsonian rats

    PubMed Central

    2011-01-01

    Background Pleiotrophin is known to promote the survival and differentiation of dopaminergic neurons in vitro and is up-regulated in the substantia nigra of Parkinson's disease patients. To establish whether pleiotrophin has a trophic effect on nigrostriatal dopaminergic neurons in vivo, we injected a recombinant adenovirus expressing pleiotrophin in the substantia nigra of 6-hydroxydopamine lesioned rats. Results The viral vector induced pleiotrophin over-expression by astrocytes in the substantia nigra pars compacta, without modifying endogenous neuronal expression. The percentage of tyrosine hydroxylase-immunoreactive cells as well as the area of their projections in the lesioned striatum was higher in pleiotrophin-treated animals than in controls. Conclusions These results indicate that pleiotrophin over-expression partially rescues tyrosine hydroxylase-immunoreactive cell bodies and terminals of dopaminergic neurons undergoing 6-hydroxydopamine-induced degeneration. PMID:21649894

  7. Pleiotrophin over-expression provides trophic support to dopaminergic neurons in parkinsonian rats.

    PubMed

    Taravini, Irene Re; Chertoff, Mariela; Cafferata, Eduardo G; Courty, José; Murer, Mario G; Pitossi, Fernando J; Gershanik, Oscar S

    2011-06-07

    Pleiotrophin is known to promote the survival and differentiation of dopaminergic neurons in vitro and is up-regulated in the substantia nigra of Parkinson's disease patients. To establish whether pleiotrophin has a trophic effect on nigrostriatal dopaminergic neurons in vivo, we injected a recombinant adenovirus expressing pleiotrophin in the substantia nigra of 6-hydroxydopamine lesioned rats. The viral vector induced pleiotrophin over-expression by astrocytes in the substantia nigra pars compacta, without modifying endogenous neuronal expression. The percentage of tyrosine hydroxylase-immunoreactive cells as well as the area of their projections in the lesioned striatum was higher in pleiotrophin-treated animals than in controls. These results indicate that pleiotrophin over-expression partially rescues tyrosine hydroxylase-immunoreactive cell bodies and terminals of dopaminergic neurons undergoing 6-hydroxydopamine-induced degeneration.

  8. Assessment of the Effects of MPTP and Paraquat on Dopaminergic Neurons and Microglia in the Substantia Nigra Pars Compacta of C57BL/6 Mice

    PubMed Central

    Smeyne, Richard Jay; Breckenridge, Charles B.; Beck, Melissa; Jiao, Yun; Butt, Mark T.; Wolf, Jeffrey C.; Zadory, Dan; Minnema, Daniel J.; Sturgess, Nicholas C.; Travis, Kim Z.; Cook, Andrew R.; Smith, Lewis L.; Botham, Philip A.

    2016-01-01

    The neurotoxicity of paraquat dichloride (PQ) was assessed in two inbred strains of 9- or 16-week old male C57BL/6 mice housed in two different laboratories and compared to the effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). PQ was administered by intraperitoneal injections; either once (20 mg/kg) or twice (10 mg/kg) weekly for 3 weeks, while MPTP-HCl was injected 4 times on a single day (20 mg/kg/dose). Brains were collected 8, 16, 24, 48, 96 or 168 hours after the last PQ treatment, and 48 or 168 hours after MPTP treatment. Dopamine neurons in the substantia nigra pars compacta (SNpc) were identified by antibodies to tyrosine hydroxylase (TH+) and microglia were identified using Iba-1 immunoreactivity. The total number of TH+ neurons and the number of resting and activated microglia in the SNpc at 168 hours after the last dose were estimated using model- or design-based stereology, with investigators blinded to treatment. In a further analysis, a pathologist, also blinded to treatment, evaluated the SNpc and/or striatum for loss of TH+ neurons (SNpc) or terminals (striatum), cell death (as indicated by amino cupric silver uptake, TUNEL and/or caspase 3 staining) and neuroinflammation (as indicated by Iba-1 and/or GFAP staining). PQ, administered either once or twice weekly to 9- or 16-week old mice from two suppliers, had no effect on the number of TH+ neurons or microglia in the SNpc, as assessed by two groups, each blinded to treatment, using different stereological methods. PQ did not induce neuronal cell loss or degeneration in the SNpc or striatum. Additionally, there was no evidence of apoptosis, microgliosis or astrogliosis. In MPTP-treated mice, the number of TH+ neurons in the SNpc was significantly decreased and the number of activated microglia increased. Histopathological assessment found degenerating neurons/terminals in the SNpc and striatum but no evidence of apoptotic cell death. MPTP activated microglia in the SNpc and increased

  9. Trans-blood brain barrier delivery of dopamine-loaded nanoparticles reverses functional deficits in parkinsonian rats.

    PubMed

    Pahuja, Richa; Seth, Kavita; Shukla, Anshi; Shukla, Rajendra Kumar; Bhatnagar, Priyanka; Chauhan, Lalit Kumar Singh; Saxena, Prem Narain; Arun, Jharna; Chaudhari, Bhushan Pradosh; Patel, Devendra Kumar; Singh, Sheelendra Pratap; Shukla, Rakesh; Khanna, Vinay Kumar; Kumar, Pradeep; Chaturvedi, Rajnish Kumar; Gupta, Kailash Chand

    2015-05-26

    Sustained and safe delivery of dopamine across the blood brain barrier (BBB) is a major hurdle for successful therapy in Parkinson's disease (PD), a neurodegenerative disorder. Therefore, in the present study we designed neurotransmitter dopamine-loaded PLGA nanoparticles (DA NPs) to deliver dopamine to the brain. These nanoparticles slowly and constantly released dopamine, showed reduced clearance of dopamine in plasma, reduced quinone adduct formation, and decreased dopamine autoxidation. DA NPs were internalized in dopaminergic SH-SY5Y cells and dopaminergic neurons in the substantia nigra and striatum, regions affected in PD. Treatment with DA NPs did not cause reduction in cell viability and morphological deterioration in SH-SY5Y, as compared to bulk dopamine-treated cells, which showed reduced viability. Herein, we report that these NPs were able to cross the BBB and capillary endothelium in the striatum and substantia nigra in a 6-hydroxydopamine (6-OHDA)-induced rat model of PD. Systemic intravenous administration of DA NPs caused significantly increased levels of dopamine and its metabolites and reduced dopamine-D2 receptor supersensitivity in the striatum of parkinsonian rats. Further, DA NPs significantly recovered neurobehavioral abnormalities in 6-OHDA-induced parkinsonian rats. Dopamine delivered through NPs did not cause additional generation of ROS, dopaminergic neuron degeneration, and ultrastructural changes in the striatum and substantia nigra as compared to 6-OHDA-lesioned rats. Interestingly, dopamine delivery through nanoformulation neither caused alterations in the heart rate and blood pressure nor showed any abrupt pathological change in the brain and other peripheral organs. These results suggest that NPs delivered dopamine into the brain, reduced dopamine autoxidation-mediated toxicity, and ultimately reversed neurochemical and neurobehavioral deficits in parkinsonian rats.

  10. Abnormal ventral tegmental area-anterior cingulate cortex connectivity in Parkinson's disease with depression.

    PubMed

    Wei, Luqing; Hu, Xiao; Yuan, Yonggui; Liu, Weiguo; Chen, Hong

    2018-07-16

    Neuropathology suggests that Parkinson's disease (PD) with depression may involve a progressive degeneration of the nigrostriatal and mesocorticolimbic dopaminergic systems. Previous positron emission tomography (PET) and single-photon emission computed tomography (SPECT) studies have shown that dopamine changes in individual brain regions constituting the nigrostriatal and mesocorticolimbic circuits are associated with depression in PD. However, few studies have been conducted on the circuit-level alterations in this disease. The present study used resting-state fMRI and seed-based functional connectivity of putative dopaminergic midbrain regions (i.e., substantia nigra (SN) and ventral tegmental area (VTA)) to investigate the circuit-related abnormalities in PD with depression. The results showed that depressed PD (DPD) patients relative to healthy controls (HC) and non-depressed PD (NDPD) patients had increased functional connectivity between VTA and anterior cingulate cortex (ACC), demonstrating that dysfunctional mesocorticolimbic dopaminergic neurotransmission may be associated with depression in PD. Compared with HC, DPD and NDPD patients showed increased functional connectivity from SN to sensorimotor cortex, validating that alterations in the nigrostriatal circuitry could be responsible for cardinal motor features in PD. In addition, aberrant connectivity between VTA and ACC was correlated with the severity of depression in PD patients, further supporting that abnormal mesocorticolimbic system may account for depressive symptoms in PD. These results have provided potential circuit-level biomarkers of depression in PD, and suggested that resting state functional connectivity of midbrain dopaminergic nuclei may be useful for understanding the underlying pathology in PD with depression. Copyright © 2018 Elsevier B.V. All rights reserved.

  11. Changes in /sup 3/H-substance P receptor binding in the rat brain after kainic acid lesion of the corpus striatum

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Mantyh, P.W.; Hunt, S.P.

    1986-06-01

    Previous studies have indicated that the substantia nigra contains the highest concentration of substance P-like immunoreactivity (SPLI) in the brain. Paradoxically, it also appears to contain one of the lowest concentrations of substance P receptors in the brain. One possibility is that the massive amount of SPLI blocks the binding of the radioligand to the substance P receptor and/or down-regulates the number of substance P receptors present in this structure. Since greater than 95% of the SPLI within the substantia nigra originates from the corpus striatum, we have lesioned this area and measured the changes in substance P receptor concentrationmore » in the substantia nigra and other corpus striatal projection areas. A semiquantitative autoradiographic technique for measuring the binding of /sup 3/H-substance P to substance P receptors was used in conjunction with tritium-sensitive film. 3H-substance P binding was measured in both the corpus striatum and its projection areas after kainic acid lesion of the corpus striatum. At either 4 or 21 d after the lesion there was approximately a 90% loss of substance P receptors in the rostral striatum, a 74% loss in the globus pallidus, a 57% increase in receptor number in lamina I and II of the ipsilateral somatosensory cortex, and no apparent change in the number of receptors in the substantia nigra pars reticulata, superior colliculus, and central gray. These findings suggest that the low concentration of substance P receptors found within the substantia nigra is not due the massive SPLI innervation, since removal of greater than 95% of the SPLI had no measurable effect on the concentration of substance P receptors.« less

  12. Parkinson's disease: diagnostic potential of high-resolution phase difference enhanced MR imaging at 3 T.

    PubMed

    Kakeda, Shingo; Korogi, Yukunori; Yoneda, Tetsuya; Watanabe, Keita; Moriya, Junji; Murakami, Yu; Sato, Toru; Hiai, Yasuhiro; Ohnari, Norihiro; Ide, Satoru; Okada, Kazumasa; Uozumi, Takenori; Tsuji, Sadatoshi; Hirai, Toshinori; Yamashita, Yasuyuki

    2013-04-01

    To determine whether it is possible to diagnose patients with Parkinson's disease (PD) on an individual basis using magnetic resonance imaging with phase difference enhanced imaging (PADRE). PADRE delineated the crural fibres as a layer of low signal intensity and the substantia nigra as a layer of medium signal intensity in a healthy volunteer, and showed a clear boundary between the crural fibres and the substantia nigra (BCS). Twenty-four PD patients and 24 control subjects were enrolled. Contrast ratios between the substantia nigra and occipital white matter were calculated, and two radiologists independently reviewed the PADRE findings regarding BCS obscuration. Mean contrast ratio in PD patients was significantly higher than in control subjects (0.56 vs 0.39, P < 0.01). The BCS on PADRE was obscured significantly more frequently in any subgroups with PD patients compared with control subjects (P < 0.01). The observation of BCS obscuration had a sensitivity, specificity and accuracy for the diagnosis of PD of 92 %, 88 % and 90 % for radiologist 1 and 83 %, 88 % and 85 % for radiologist 2, respectively. PADRE is able to identify PD in patients as a loss of delineation between the crural fibres and the substantia nigra on an individual basis.

  13. HFE Genotype Restricts the Response to Paraquat in a Mouse Model of Neurotoxicity.

    PubMed

    Nixon, Anne M; Meadowcroft, Mark D; Neely, Elizabeth B; Snyder, Amanda M; Purnell, Carson J; Wright, Justin; Lamendella, Regina; Nandar, Wint; Huang, Xuemei; Connor, James R

    2018-05-01

    Parkinson's disease is marked clinically by motor dysfunction and pathologically by dopaminergic cell loss in the substantia nigra and iron accumulation in the substantia nigra. The driver underlying iron accumulation remains unknown and could be genetic or environmental. The HFE protein is critical for the regulation of cellular iron uptake. Mutations within this protein are associated with increased iron accumulation including in the brain. We have focused on the commonly occurring H63D variant of the HFE gene as a disease modifier in a number of neurodegenerative diseases. To investigate the role of H63D HFE genotype, we generated a mouse model in which the wild-type (WT) HFE gene is replaced by the H67D gene variant (mouse homolog of the human H63D gene variant). Using paraquat toxicity as the model for Parkinson's disease, we found that WT mice responded as expected with significantly greater motor function, loss of tyrosine hydroxylase staining and increase microglial staining in the substantia nigra, and an increase in R 2 relaxation rate within the substantia nigra of the paraquat-treated mice compared to their saline-treated counterparts. In contrast, the H67D mice showed a remarkable resistance to paraquat treatment; specifically differing from the WT mice with no changes in motor function or changes in R 2 relaxation rates following paraquat exposure. At baseline, there were differences between the H67D HFE mice and WT mice in gut microbiome profile and increased L-ferritin staining in the substantia nigra that could account for the resistance to paraquat. Of particular note, the H67D HFE mice regardless of whether or not they were treated with paraquat had significantly less tyrosine hydroxylase immunostaining than WT. Our results clearly demonstrate that the HFE genotype impacts the expression of tyrosine hydroxylase in the substantia nigra, the gut microbiome and the response to paraquat providing additional support that the HFE genotype is a disease

  14. Quantitative Susceptibility Mapping in Parkinson's Disease.

    PubMed

    Langkammer, Christian; Pirpamer, Lukas; Seiler, Stephan; Deistung, Andreas; Schweser, Ferdinand; Franthal, Sebastian; Homayoon, Nina; Katschnig-Winter, Petra; Koegl-Wallner, Mariella; Pendl, Tamara; Stoegerer, Eva Maria; Wenzel, Karoline; Fazekas, Franz; Ropele, Stefan; Reichenbach, Jürgen Rainer; Schmidt, Reinhold; Schwingenschuh, Petra

    2016-01-01

    Quantitative susceptibility mapping (QSM) and R2* relaxation rate mapping have demonstrated increased iron deposition in the substantia nigra of patients with idiopathic Parkinson's disease (PD). However, the findings in other subcortical deep gray matter nuclei are converse and the sensitivity of QSM and R2* for morphological changes and their relation to clinical measures of disease severity has so far been investigated only sparsely. The local ethics committee approved this study and all subjects gave written informed consent. 66 patients with idiopathic Parkinson's disease and 58 control subjects underwent quantitative MRI at 3T. Susceptibility and R2* maps were reconstructed from a spoiled multi-echo 3D gradient echo sequence. Mean susceptibilities and R2* rates were measured in subcortical deep gray matter nuclei and compared between patients with PD and controls as well as related to clinical variables. Compared to control subjects, patients with PD had increased R2* values in the substantia nigra. QSM also showed higher susceptibilities in patients with PD in substantia nigra, in the nucleus ruber, thalamus, and globus pallidus. Magnetic susceptibility of several of these structures was correlated with the levodopa-equivalent daily dose (LEDD) and clinical markers of motor and non-motor disease severity (total MDS-UPDRS, MDS-UPDRS-I and II). Disease severity as assessed by the Hoehn & Yahr scale was correlated with magnetic susceptibility in the substantia nigra. The established finding of higher R2* rates in the substantia nigra was extended by QSM showing superior sensitivity for PD-related tissue changes in nigrostriatal dopaminergic pathways. QSM additionally reflected the levodopa-dosage and disease severity. These results suggest a more widespread pathologic involvement and QSM as a novel means for its investigation, more sensitive than current MRI techniques.

  15. Dynamic changes of striatal and extrastriatal abnormalities in glutaric aciduria type I.

    PubMed

    Harting, Inga; Neumaier-Probst, Eva; Seitz, Angelika; Maier, Esther M; Assmann, Birgit; Baric, Ivo; Troncoso, Monica; Mühlhausen, Chris; Zschocke, Johannes; Boy, Nikolas P S; Hoffmann, Georg F; Garbade, Sven F; Kölker, Stefan

    2009-07-01

    include widening of anterior temporal and sylvian CSF spaces, pseudocysts, signal changes of substantia nigra, nucleus dentatus, thalamus, tractus tegmentalis centralis and supratentorial white matter as well as signs of delayed maturation (myelination and gyral pattern). In contrast to the striatum, extrastriatal abnormalities were variable and could regress or even normalize with time. This includes widening of sylvian fissures, delayed maturation, pallidal signal changes and pseudocysts. Based on these results, we hypothesize that neuroradiological abnormalities and neurological symptoms in glutaric aciduria type I can be explained by overlaying episodes of cerebral alterations including maturational delay of the brain in utero, acute striatal injury during a vulnerable period in infancy and chronic progressive changes that may continue lifelong. This may have widespread consequences for the pathophysiological understanding of this disease, long-term outcomes and therapeutic considerations.

  16. Direct and Retrograde Transduction of Nigral Neurons with AAV6, 8, and 9 and Intraneuronal Persistence of Viral Particles

    PubMed Central

    Aebischer, Patrick

    2013-01-01

    Abstract Recombinant adeno-associated viral (AAV) vectors of serotypes 6, 8, and 9 were characterized as tools for gene delivery to dopaminergic neurons in the substantia nigra for future gene therapeutic applications in Parkinson's disease. While vectors of all three serotypes transduced nigral dopaminergic neurons with equal efficiency when directly injected to the substantia nigra, AAV6 was clearly superior to AAV8 and AAV9 for retrograde transduction of nigral neurons after striatal delivery. For sequential transduction of nigral dopaminergic neurons, the combination of AAV9 with AAV6 proved to be more powerful than AAV8 with AAV6 or repeated AAV6 administration. Surprisingly, single-stranded viral genomes persisted in nigral dopaminergic neurons within cell bodies and axon terminals in the striatum, and intact assembled AAV capsid was enriched in nuclei of nigral neurons, 4 weeks after virus injections to the substantia nigra. 6-Hydroxydopamine (6-OHDA)–induced degeneration of dopaminergic neurons in the substantia nigra reduced the number of viral genomes in the striatum, in line with viral genome persistence in axon terminals. However, 6-OHDA–induced axonal degeneration did not induce any transsynaptic spread of AAV infection in the striatum. Therefore, the potential presence of viral particles in axons may not represent an important safety issue for AAV gene therapy applications in neurodegenerative diseases. PMID:23600720

  17. Panicolytic-like effects caused by substantia nigra pars reticulata pretreatment with low doses of endomorphin-1 and high doses of CTOP or the NOP receptors antagonist JTC-801 in male Rattus norvegicus.

    PubMed

    da Silva, Juliana Almeida; Biagioni, Audrey Franceschi; Almada, Rafael Carvalho; de Freitas, Renato Leonardo; Coimbra, Norberto Cysne

    2017-10-01

    Gamma-aminobutyric acid (GABA)ergic neurons of the substantia nigra pars reticulata (SNpr) are connected to the deep layers of the superior colliculus (dlSC). The dlSC, in turn, connect with the SNpr through opioid projections. Nociceptin/orphanin FQ peptide (N/OFQ) is a natural ligand of a Gi protein-coupled nociceptin receptor (ORL1; NOP) that is also found in the SNpr. Our hypothesis is that tectonigral opioid pathways and intranigral orphanin-mediated mechanisms modulate GABAergic nigrotectal connections. Therefore, the aim of this work was to study the role of opioid and NOP receptors in the SNpr during the modulation of defence reactions organised by the dlSC. The SNpr was pretreated with either opioid or NOP receptor agonists and antagonists, followed by dlSC treatment with bicuculline. Blockade of GABA A receptors in the dlSC elicited fear-related defensive behaviour. Pretreatment of the SNpr with naloxone benzoylhydrazone (NalBzoH), a μ-, δ-, and κ 1 -opioid receptor antagonist as well as a NOP receptor antagonist, decreased the aversive effect of bicuculline treatment on the dlSC. Either μ-opioid receptor activation or blockade by SNpr microinjection of endomorphin-1 (EM-1) and CTOP promoted pro-aversive and anti-aversive actions, respectively, that modulated the defensive responses elicited by bicuculline injection into the dlSC. Pretreatment of the SNpr with the selective NOP receptor antagonist JTC801 decreased the aversive effect of bicuculline, and microinjections of the selective NOP receptor agonist NNC 63-0532 promoted the opposite effect. These results demonstrate that opioid pathways and orphanin-mediated mechanisms have a critical role in modulating the activity of nigrotectal GABAergic pathways during the organisation of defensive behaviours.

  18. Excess amounts of 3-iodo-l-tyrosine induce Parkinson-like features in experimental approaches of Parkinsonism.

    PubMed

    Fernández-Espejo, Emilio; Bis-Humbert, Cristian

    2018-06-06

    3-iodo-l-tyrosine might play a role in Parkinson's disease since this molecule is able, at high concentration, to inhibit tyrosine-hydroxylase activity, the rate-limiting enzyme in dopamine biosynthesis. The possible Parkinson-like effects of 3-iodo-l-tyrosine were tested on three experimental approaches in mice: cultured substantia nigra neurons, the enteric nervous system of the jejunum after intra-peritoneal infusions, and the nigrostriatal system following unilateral intrabrain injections. 3-iodo-l-tyrosine, a physiological molecule, was used at concentrations higher than its serum levels in humans. Parkinson-like signs were evaluated through abnormal aggregation of α-synuclein and tyrosine-hydroxylase, loss of tyrosine-hydroxylase-expressing and striatum-projecting neurons and fibers, reduced tyrosine-hydroxylase density, and Parkinson-like motor and non-motor deficits. The retrograde tracer FluoroGold was used in the brain model. The findings revealed that excess amounts of 3-iodo-l-tyrosine induce Parkinson-like effects in the three experimental approaches. Thus, culture neurons of substantia nigra show, after 3-iodo-l-tyrosine exposure, intracytoplasmic inclusions that express α-synuclein and tyrosine-hydroxylase. Intra-peritoneal infusions of 3-iodo-l-tyrosine cause, in the long-term, α-synuclein aggregation, thicker α-synuclein-positive fibers, and loss of tyrosine-hydroxylase-positive cells and fibers in intramural plexuses and ganglia of the jejunum. Infusion of 3-iodo-l-tyrosine into the left dorsal striata of mice damages the nigrostriatal system, as revealed through lower striatal tyrosine-hydroxylase density, reduced number of tyrosine-hydroxylase-expressing and striatum-projecting neurons in the left substantia nigra, as well as the emergence of Parkinson-like behavioral deficits such as akinesia, bradykinesia, motor disbalance, and locomotion directional bias. In conclusion, excess amounts of 3-iodo-l-tyrosine induce Parkinson-like features in

  19. Substantia nigra and Parkinson disease (image)

    MedlinePlus

    ... is a slowly progressive disorder that affects movement, muscle control, and balance. Part of the disease process develops as cells are destroyed in certain parts of the brain stem, particularly the crescent-shaped cell mass known as ...

  20. The possible mechanism of Parkinson's disease progressive damage and the preventive effect of GM1 in the rat model induced by 6-hydroxydopamine.

    PubMed

    Xu, Renshi; Zhou, Yiyi; Fang, Xin; Lu, Yi; Li, Jiao; Zhang, Jie; Deng, Xia; Li, Shujuan

    2014-12-10

    The progressive pathogenesis and prevention of Parkinson's disease (PD) remains unknown at present. Therefore, the present study aimed to investigate the possible progressive pathogenesis and prevention of PD. Our study investigated the content of glutamate, mitochondria calcium, calmodulin, malonaldehyde and trace elements in striatum, cerebral cortex and hippocampus tissues; and the expression of bcl-2, bax and neuronal nitric oxide synthase (nNOS) in substantia nigra and striatum; and the change of apomorphine induced rotation behavior; and the treatmental effect of monosialotetrahexosylganglioside (GM1) intraperitoneal administration for 14 days in a PD rat model induced by 6-hydroxydopamine. The results revealed that the content of glutamate significantly decreased, and that of mitochondria calcium, calmodulin, malonaldehyde and ferrum significantly increased in striatum, cerebral cortex and hippocampus tissues; the content of magnesium significantly decreased, and that of cuprum and zinc significantly increased in cerebral cortex; the expression of bcl-2 significantly decreased, and that of bax and nNOS significantly increased in substantia nigra and striatum in PD rat. GM1 can partially improve the apomorphine induced rotation behavior and changes of glutamate, mitochondria calcium, calmodulin content in striatum of PD rat. Data suggested that dysfunction of excitatory amino acids neurotransmitter, calcium homeostasis disorder, abnormal metabolism of oxygen free radicals, abnormal trace elements distribution and/or deposition and excessive apoptosis participated in the progressive process of PD, and that GM1 could partially prevent the progressive damage. Copyright © 2014 Elsevier B.V. All rights reserved.

  1. Bright light exposure reduces TH-positive dopamine neurons: implications of light pollution in Parkinson's disease epidemiology.

    PubMed

    Romeo, Stefania; Viaggi, Cristina; Di Camillo, Daniela; Willis, Allison W; Lozzi, Luca; Rocchi, Cristina; Capannolo, Marta; Aloisi, Gabriella; Vaglini, Francesca; Maccarone, Rita; Caleo, Matteo; Missale, Cristina; Racette, Brad A; Corsini, Giovanni U; Maggio, Roberto

    2013-01-01

    This study explores the effect of continuous exposure to bright light on neuromelanin formation and dopamine neuron survival in the substantia nigra. Twenty-one days after birth, Sprague-Dawley albino rats were divided into groups and raised under different conditions of light exposure. At the end of the irradiation period, rats were sacrificed and assayed for neuromelanin formation and number of tyrosine hydroxylase (TH)-positive neurons in the substantia nigra. The rats exposed to bright light for 20 days or 90 days showed a relatively greater number of neuromelanin-positive neurons. Surprisingly, TH-positive neurons decreased progressively in the substantia nigra reaching a significant 29% reduction after 90 days of continuous bright light exposure. This decrease was paralleled by a diminution of dopamine and its metabolite in the striatum. Remarkably, in preliminary analysis that accounted for population density, the age and race adjusted Parkinson's disease prevalence significantly correlated with average satellite-observed sky light pollution.

  2. Bright light exposure reduces TH-positive dopamine neurons: implications of light pollution in Parkinson's disease epidemiology

    PubMed Central

    Romeo, Stefania; Viaggi, Cristina; Di Camillo, Daniela; Willis, Allison W.; Lozzi, Luca; Rocchi, Cristina; Capannolo, Marta; Aloisi, Gabriella; Vaglini, Francesca; Maccarone, Rita; Caleo, Matteo; Missale, Cristina; Racette, Brad A.; Corsini, Giovanni U.; Maggio, Roberto

    2013-01-01

    This study explores the effect of continuous exposure to bright light on neuromelanin formation and dopamine neuron survival in the substantia nigra. Twenty-one days after birth, Sprague–Dawley albino rats were divided into groups and raised under different conditions of light exposure. At the end of the irradiation period, rats were sacrificed and assayed for neuromelanin formation and number of tyrosine hydroxylase (TH)-positive neurons in the substantia nigra. The rats exposed to bright light for 20 days or 90 days showed a relatively greater number of neuromelanin-positive neurons. Surprisingly, TH-positive neurons decreased progressively in the substantia nigra reaching a significant 29% reduction after 90 days of continuous bright light exposure. This decrease was paralleled by a diminution of dopamine and its metabolite in the striatum. Remarkably, in preliminary analysis that accounted for population density, the age and race adjusted Parkinson's disease prevalence significantly correlated with average satellite-observed sky light pollution. PMID:23462874

  3. Neuronal inhibition and synaptic plasticity of basal ganglia neurons in Parkinson's disease

    PubMed Central

    Milosevic, Luka; Kalia, Suneil K; Hodaie, Mojgan; Lozano, Andres M; Fasano, Alfonso; Popovic, Milos R; Hutchison, William D

    2018-01-01

    Abstract Deep brain stimulation of the subthalamic nucleus is an effective treatment for Parkinson’s disease symptoms. The therapeutic benefits of deep brain stimulation are frequency-dependent, but the underlying physiological mechanisms remain unclear. To advance deep brain stimulation therapy an understanding of fundamental mechanisms is critical. The objectives of this study were to (i) compare the frequency-dependent effects on cell firing in subthalamic nucleus and substantia nigra pars reticulata; (ii) quantify frequency-dependent effects on short-term plasticity in substantia nigra pars reticulata; and (iii) investigate effects of continuous long-train high frequency stimulation (comparable to conventional deep brain stimulation) on synaptic plasticity. Two closely spaced (600 µm) microelectrodes were advanced into the subthalamic nucleus (n = 27) and substantia nigra pars reticulata (n = 14) of 22 patients undergoing deep brain stimulation surgery for Parkinson’s disease. Cell firing and evoked field potentials were recorded with one microelectrode during stimulation trains from the adjacent microelectrode across a range of frequencies (1–100 Hz, 100 µA, 0.3 ms, 50–60 pulses). Subthalamic firing attenuated with ≥20 Hz (P < 0.01) stimulation (silenced at 100 Hz), while substantia nigra pars reticulata decreased with ≥3 Hz (P < 0.05) (silenced at 50 Hz). Substantia nigra pars reticulata also exhibited a more prominent increase in transient silent period following stimulation. Patients with longer silent periods after 100 Hz stimulation in the subthalamic nucleus tended to have better clinical outcome after deep brain stimulation. At ≥30 Hz the first evoked field potential of the stimulation train in substantia nigra pars reticulata was potentiated (P < 0.05); however, the average amplitude of the subsequent potentials was rapidly attenuated (P < 0.01). This is suggestive of synaptic facilitation followed by rapid depression. Paired pulse

  4. Iron and cell death in Parkinson's disease: a nuclear microscopic study into iron-rich granules in the parkinsonian substantia nigra of primate models

    NASA Astrophysics Data System (ADS)

    Thong, P. S. P.; Watt, F.; Ponraj, D.; Leong, S. K.; He, Y.; Lee, T. K. Y.

    1999-10-01

    Parkinson's disease is a degenerative brain disease characterised by a loss of cells in the substantia nigra (SN) region of the brain and accompanying biochemical changes such as inhibition of mitochondrial function, increased iron concentrations and decreased glutathione levels in the parkinsonian SN. Though the aetiology of the disease is still unknown, the observed biochemical changes point to the involvement of oxidative stress. In particular, iron is suspected to play a role by promoting free radical production, leading to oxidative stress and cell death. The increase in iron in the parkinsonian SN has been confirmed by several research groups, both in human post-mortem brains and in brain tissue from parkinsonian animal models. However, the question remains as to whether the observed increase in iron is a cause or a consequence of the SN cell death process. Our previous study using unilaterally 1-methyl-4-phenyl-1,2,3,6-tetrahydro-pyridine (MPTP)-lesioned monkeys in a time sequence experiment has shown that the increase in bulk iron concentrations follow rather than precede dopaminergic cell death. However, changes in the localised iron concentrations, which may play a more direct role in SN cell death, may not be reflected at the bulk level. Indeed, we have observed iron-rich granules in parkinsonian SNs. From this time sequence study into the iron content of iron-rich granules in the SNs of an untreated control and unilaterally MPTP-lesioned parkinsonian models, we present the following observations: (1) Iron-rich granules are found in both control and parkinsonian SNs and are variable in size and iron content in any one model. (2) These iron-rich granules may be associated with neuromelanin granules found in the SN and are known to accumulate transition metal ions such as iron. (3) The early onset of bulk SN cell loss (35%) was accompanied by a significant elevation of iron in granules found in the MPTP-injected SN compared to the contra-lateral SN. This

  5. Stem Cell Physics. Multiple-Laser-Beam Treatment of Parkinson's Disease

    NASA Astrophysics Data System (ADS)

    Stefan, V.

    2013-03-01

    A novel method for the treatment of Parkinson's disease is proposed. Pluripotent stem cells are laser cultured, using ultrashort wavelength, (around 0.1 micron-ultraviolet radiation-with intensities of a few mW/cm2) , multiple laser beams.[2] The multiple-energy laser photons[3] interact with the neuron DNA molecules to be cloned. The laser created dopaminergic substantia nigra neurons can be, (theoretically), laser transplanted, (a higher focusing precision as compared to a syringe method), into the striatum or substantia nigra regions of the brain, or both. Supported by Nikola Tesla Labs, Stefan University.

  6. A Japanese Encephalitis Patient Presenting with Parkinsonism with Corresponding Laterality of Magnetic Resonance and Dopamine Transporter Imaging Findings.

    PubMed

    Tadokoro, Koh; Ohta, Yasuyuki; Sato, Kota; Maeki, Takahiro; Sasaki, Ryo; Takahashi, Yoshiaki; Shang, Jingwei; Takemoto, Mami; Hishikawa, Nozomi; Yamashita, Toru; Lim, Chang Kweng; Tajima, Shigeru; Abe, Koji

    2018-03-09

    Japanese encephalitis (JE) survivors often present with nigrostriatal aftereffects with parkinsonian features. A 67-year-old woman with JE showed right-dominant clinical parkinsonism and left-dominant substantia nigra lesions after magnetic resonance imaging (MRI). Dopamine transporter (DAT) imaging using 123 I-labeled 2β-carbomethoxy-3β-(4-iodophenyl)-N-(3-fluoropropyl)-nortropane ( 123 I-FP-CIT) revealed a corresponding left-dominant decrease. The present case is the first to reveal a clear match of laterality between clinical parkinsonism, MRI-based substantia nigra lesions, and impaired DAT in presynaptic dopaminergic neurons in JE.

  7. Transcranial sonography findings related to depression in parkinsonian disorders: cross-sectional study in 126 patients.

    PubMed

    Bouwmans, Angela E P; Weber, Wim E J; Leentjens, Albert F G; Mess, Werner H

    2016-01-01

    Background. Transcranial sonography (TCS) has emerged as a potential diagnostic tool for Parkinson's disease. Recent research has suggested that abnormal echogenicity of substantia nigra, raphe nuclei and third ventricle is associated with increased risk of depression among these patients. We sought to reproduce these findings in an ongoing larger study of patients with parkinsonian syndromes. Methods. A total of 126 patients with parkinsonian symptoms underwent the Hamilton Depression Scale, and TCS of the substantia nigra (SN) (n = 126), the raphe nuclei (RN) (n = 80) and the third ventricle (n = 57). We then calculated the correlation between depression and hyper-echogenic SN, hypo-echogenic RN and a wider third ventricle. Results. In patients with PD we found no significant difference of the SN between non-depressed and depressed patients (46% vs. 22%; p = 0.18). Non-depressed patients with other parkinsonisms more often had hyperechogenicity of the SN than depressed patients (51% vs. 0%; p = 0.01). We found no relation between depression and the echogenicity of the RN or the width of the third ventricle. Conclusions. In patients with parkinsonian syndromes, we found no association between depression and hyper-echogenic SN, hypo-echogenic RN or a wider third ventricle, as determined by transcranial sonography.

  8. Methamphetamine and Parkinson's Disease

    PubMed Central

    Granado, Noelia; Ares-Santos, Sara; Moratalla, Rosario

    2013-01-01

    Parkinson's disease (PD) is a neurodegenerative disorder predominantly affecting the elderly. The aetiology of the disease is not known, but age and environmental factors play an important role. Although more than a dozen gene mutations associated with familial forms of Parkinson's disease have been described, fewer than 10% of all cases can be explained by genetic abnormalities. The molecular basis of Parkinson's disease is the loss of dopamine in the basal ganglia (caudate/putamen) due to the degeneration of dopaminergic neurons in the substantia nigra, which leads to the motor impairment characteristic of the disease. Methamphetamine is the second most widely used illicit drug in the world. In rodents, methamphetamine exposure damages dopaminergic neurons in the substantia nigra, resulting in a significant loss of dopamine in the striatum. Biochemical and neuroimaging studies in human methamphetamine users have shown decreased levels of dopamine and dopamine transporter as well as prominent microglial activation in the striatum and other areas of the brain, changes similar to those observed in PD patients. Consistent with these similarities, recent epidemiological studies have shown that methamphetamine users are almost twice as likely as non-users to develop PD, despite the fact that methamphetamine abuse and PD have distinct symptomatic profiles. PMID:23476887

  9. Transcranial sonography findings related to depression in parkinsonian disorders: cross-sectional study in 126 patients

    PubMed Central

    Bouwmans, Angela E.P.; Leentjens, Albert F.G.; Mess, Werner H.

    2016-01-01

    Background. Transcranial sonography (TCS) has emerged as a potential diagnostic tool for Parkinson’s disease. Recent research has suggested that abnormal echogenicity of substantia nigra, raphe nuclei and third ventricle is associated with increased risk of depression among these patients. We sought to reproduce these findings in an ongoing larger study of patients with parkinsonian syndromes. Methods. A total of 126 patients with parkinsonian symptoms underwent the Hamilton Depression Scale, and TCS of the substantia nigra (SN) (n = 126), the raphe nuclei (RN) (n = 80) and the third ventricle (n = 57). We then calculated the correlation between depression and hyper-echogenic SN, hypo-echogenic RN and a wider third ventricle. Results. In patients with PD we found no significant difference of the SN between non-depressed and depressed patients (46% vs. 22%; p = 0.18). Non-depressed patients with other parkinsonisms more often had hyperechogenicity of the SN than depressed patients (51% vs. 0%; p = 0.01). We found no relation between depression and the echogenicity of the RN or the width of the third ventricle. Conclusions. In patients with parkinsonian syndromes, we found no association between depression and hyper-echogenic SN, hypo-echogenic RN or a wider third ventricle, as determined by transcranial sonography. PMID:27231659

  10. Scanning electron microscopy of tinea nigra.

    PubMed

    Guarenti, Isabelle Maffei; Almeida, Hiram Larangeira de; Leitão, Aline Hatzenberger; Rocha, Nara Moreira; Silva, Ricardo Marques E

    2014-01-01

    Tinea nigra is a rare superficial mycosis caused by Hortaea werneckii. This infection presents as asymptomatic brown to black maculae mostly in palmo-plantar regions. We performed scanning electron microscopy of a superficial shaving of a tinea nigra lesion. The examination of the outer surface of the sample showed the epidermis with corneocytes and hyphae and elimination of fungal filaments. The inner surface of the sample showed important aggregation of hyphae among keratinocytes, which formed small fungal colonies. The ultrastructural findings correlated with those of dermoscopic examination - the small fungal aggregations may be the dark spicules seen on dermoscopy - and also allowed to document the mode of dissemination of tinea nigra, showing how hyphae are eliminated on the surface of the lesion.

  11. Scanning electron microscopy of tinea nigra*

    PubMed Central

    Guarenti, Isabelle Maffei; de Almeida, Hiram Larangeira; Leitão, Aline Hatzenberger; Rocha, Nara Moreira; Silva, Ricardo Marques e

    2014-01-01

    Tinea nigra is a rare superficial mycosis caused by Hortaea werneckii. This infection presents as asymptomatic brown to black maculae mostly in palmo-plantar regions. We performed scanning electron microscopy of a superficial shaving of a tinea nigra lesion. The examination of the outer surface of the sample showed the epidermis with corneocytes and hyphae and elimination of fungal filaments. The inner surface of the sample showed important aggregation of hyphae among keratinocytes, which formed small fungal colonies. The ultrastructural findings correlated with those of dermoscopic examination - the small fungal aggregations may be the dark spicules seen on dermoscopy - and also allowed to document the mode of dissemination of tinea nigra, showing how hyphae are eliminated on the surface of the lesion. PMID:24770516

  12. Attenuation of microglial RANTES by NEMO-binding domain peptide inhibits the infiltration of CD8(+) T cells in the nigra of hemiparkinsonian monkey.

    PubMed

    Roy, A; Mondal, S; Kordower, J H; Pahan, K

    2015-08-27

    Parkinson's disease (PD) is a progressive neurodegenerative disease characterized by the loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc). Despite intense investigations, little is known about its pathological mediators. Here, we report the marked upregulation of RANTES (regulated on activation, normal T cell expressed and secreted) and eotaxin, chemokines that are involved in T cell trafficking, in the serum of hemiparkinsonian monkeys. Interestingly, 1-methyl-4-phenylpyridinium (MPP(+)), a Parkinsonian toxin, increased the expression of RANTES and eotaxin in mouse microglial cells. The presence of NF-κB binding sites in promoters of RANTES and eotaxin and down-regulation of these genes by NEMO-binding domain (NBD) peptide, selective inhibitor of induced NF-κB activation, in MPP(+)-stimulated microglial cells suggest that the activation of NF-κB plays an important role in the upregulation of these two chemokines. Consistently, serum enzyme-linked immuno assay (ELISA) and nigral immunohistochemistry further confirmed that these chemokines were strongly upregulated in MPTP-induced hemiparkinsonian monkeys and that treatment with NBD peptides effectively inhibited the level of these chemokines. Furthermore, the microglial upregulation of RANTES in the nigra of hemiparkinsonian monkeys could be involved in the altered adaptive immune response in the brain as we observed greater infiltration of CD8(+) T cells around the perivascular niche and deep brain parenchyma of hemiparkinsonian monkeys as compared to control. The treatment of hemiparkinsonian monkeys with NBD peptides decreased the microglial expression of RANTES and attenuated the infiltration of CD8(+) T cells in nigra. These results indicate the possible involvement of chemokine-dependent adaptive immune response in Parkinsonism. Copyright © 2015 IBRO. Published by Elsevier Ltd. All rights reserved.

  13. Identification of four areas each enriched in a unique muscarinic receptor subtype

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Hoss, W.; Ellerbrock, B.R.; Goldman, P.S.

    The affinities of muscarinic agonists and antagonists were determined by autoradiography and image analysis in selected areas of the rat brain. IC{sub 50} values and Hill coefficients for the inhibition of the binding of 0.2 nM ({sup 3}H)-QNB to dentate gyrus, superior colliculus, rhomboid thalamus and substantia nigra were measured in coronal sections. Pirenzepine displayed a high affinity for receptors in the dentate gyrus and AF-DX 116, the superior colliculus. Both pirenzepine and AF-DX 116 had high affinities for the substantia nigra and low affinities for the rhomboid thalamus. Gallamine displayed a 50-fold preference for superior colliculus over dentate gyrusmore » receptors. Amitriptyline was less selective, showing a modest preference for substantia nigra receptors and 4-DAMP was essentially nonselective. Carbachol was the most selective agonist with a 4000-fold preference for superior colliculus over dentate gyrus receptors. Other agonists except RS 86 were also selective for superior colliculus receptors in the order carbachol >> arecoline > bethanechol > McN A343 = oxotremorine = pilocarpine.« less

  14. Region specific regulation of glutamic acid decarboxylase mRNA expression by dopamine neurons in rat brain.

    PubMed

    Lindefors, N; Brene, S; Herrera-Marschitz, M; Persson, H

    1989-01-01

    In situ hybridization histochemistry and RNA blots were used to study the expression of glutamic acid decarboxylase (GAD) mRNA in rats with or without a unilateral lesion of midbrain dopamine neurons. Two populations of GAD mRNA positive neurons were found in the intact caudate-putamen, substantia nigra and fronto-parietal cortex. In caudate-putamen, only one out of ten of the GAD mRNA positive neurons expressed high levels, while in substantia nigra every second of the positive neurons expressed high levels of GAD mRNA. Relatively few, but intensively labelled neurons were found in the intact fronto-parietal cerebral cortex. In addition, one out of six of the GAD mRNA positive neurons in the fronto-parietal cortex showed a low labeling. On the ipsilateral side, the forebrain dopamine deafferentation induced an increase in the number of neurons expressing high levels of GAD mRNA in caudate-putamen, and a decrease in fronto-parietal cortex. A smaller decrease was also seen in substantia nigra. However, the total number of GAD mRNA positive neurons were not significantly changed in any of these brain regions. The changes in the levels of GAD mRNA after the dopamine lesion were confirmed by RNA blot analysis. Hence, midbrain dopamine neurons appear to control neuronal expression of GAD mRNA by a tonic down-regulation in a fraction of GAD mRNA positive neurons in caudate-putamen, and a tonic up-regulation in a fraction of GAD mRNA positive neurons in fronto-parietal cortex and substantia nigra.

  15. Separation of Dalbergia nigra from Dalbergia spruceana

    Treesearch

    Regis B. Miller; Michael C. Wiemann

    2006-01-01

    The wood anatomical characteristics of Dalbergia nigra and Dalbergia spruceana are too similar to permit reliable species separation, which is sometimes important because D. nigra is a Convention on International Trade in Endangered Species-protected species whereas D. spruceana is not. However, the density, water fluorescence, and ethanol fluorescence of heartwood...

  16. Brainstem pathology in spasmodic dysphonia

    PubMed Central

    Simonyan, Kristina; Ludlow, Christy L.; Vortmeyer, Alexander O.

    2009-01-01

    Spasmodic dysphonia (SD) is a primary focal dystonia of unknown pathophysiology, characterized by involuntary spasms in the laryngeal muscles during speech production. We examined two rare cases of postmortem brainstem tissue from SD patients compared to four controls. In SD patients, small clusters of inflammation were found in the reticular formation surrounding solitary tract, spinal trigeminal and ambigual nuclei, inferior olive and pyramids. Mild neuronal degeneration and depigmentation were observed in the substantia nigra and locus coeruleus. No abnormal protein accumulations and no demyelination or axonal degeneration were found. These neuropathological findings may provide insights into the pathophysiology of SD. PMID:19795469

  17. A neurocomputational account of reward and novelty processing and effects of psychostimulants in attention deficit hyperactivity disorder.

    PubMed

    Sethi, Arjun; Voon, Valerie; Critchley, Hugo D; Cercignani, Mara; Harrison, Neil A

    2018-05-01

    aberrant substantia nigra/ventral tegmental area novelty processing plays an important role in the suboptimal reward-related decision-making characteristic of attention deficit hyperactivity disorder. Compared to effects in controls, abnormalities in novelty processing and reward-related learning were improved by stimulant medication, suggesting that they may be disorder-specific targets for the pharmacological management of attention deficit hyperactivity disorder symptoms.

  18. Widespread abnormality of the γ-aminobutyric acid-ergic system in Tourette syndrome

    PubMed Central

    Bagic, Anto; Simmons, Janine M.; Mari, Zoltan; Bonne, Omer; Xu, Ben; Kazuba, Diane; Herscovitch, Peter; Carson, Richard E.; Murphy, Dennis L.; Drevets, Wayne C.; Hallett, Mark

    2012-01-01

    Dysfunction of the γ-aminobutyric acid-ergic system in Tourette syndrome may conceivably underlie the symptoms of motor disinhibition presenting as tics and psychiatric manifestations, such as attention deficit hyperactivity disorder and obsessive–compulsive disorder. The purpose of this study was to identify a possible dysfunction of the γ-aminobutyric acid-ergic system in Tourette patients, especially involving the basal ganglia-thalamo-cortical circuits and the cerebellum. We studied 11 patients with Tourette syndrome and 11 healthy controls. Positron emission tomography procedure: after injection of 20 mCi of [11C]flumazenil, dynamic emission images of the brain were acquired. Structural magnetic resonance imaging scans were obtained to provide an anatomical framework for the positron emission tomography data analysis. Images of binding potential were created using the two-step version of the simplified reference tissue model. The binding potential images then were spatially normalized, smoothed and compared between groups using statistical parametric mapping. We found decreased binding of GABAA receptors in Tourette patients bilaterally in the ventral striatum, globus pallidus, thalamus, amygdala and right insula. In addition, the GABAA receptor binding was increased in the bilateral substantia nigra, left periaqueductal grey, right posterior cingulate cortex and bilateral cerebellum. These results are consistent with the longstanding hypothesis that circuits involving the basal ganglia and thalamus are disinhibited in Tourette syndrome patients. In addition, the abnormalities in GABAA receptor binding in the insula and cerebellum appear particularly noteworthy based upon recent evidence implicating these structures in the generation of tics. PMID:22577221

  19. Sambucus nigra linn., a new record from valley of flowers.

    PubMed

    Vikramaditya; Sharma, K N

    1999-01-01

    Under the present paper, authors have reposted finding of Sambucus nigra L. as new introduction in medicinal plans in the flora of "Valley of flowers'. Sambucus nigra L. Originally is an European plant and is very important for its medicinal potential, being used in various systems of medicine to cure number of ailments. In natural order Sambucus nigra L. belongs to family caprifoliaceae.

  20. Late-onset Parkinsonism in NFκB/c-Rel-deficient mice

    PubMed Central

    Baiguera, Cristina; Alghisi, Manuela; Pinna, Annalisa; Bellucci, Arianna; De Luca, Maria Antonietta; Frau, Lucia; Morelli, Micaela; Ingrassia, Rosaria; Benarese, Marina; Porrini, Vanessa; Pellitteri, Michele; Bertini, Giuseppe; Fabene, Paolo Francesco; Sigala, Sandra; Spillantini, Maria Grazia; Liou, Hsiou-Chi; Spano, Pier Franco

    2012-01-01

    Activation of the nuclear factor κB/c-Rel can increase neuronal resilience to pathological noxae by regulating the expression of pro-survival manganese superoxide dismutase (MnSOD, now known as SOD2) and Bcl-xL genes. We show here that c-Rel-deficient (c-rel−/−) mice developed a Parkinson’s disease-like neuropathology with ageing. At 18 months of age, c-rel−/− mice exhibited a significant loss of dopaminergic neurons in the substantia nigra pars compacta, as assessed by tyrosine hydroxylase-immunoreactivity and Nissl staining. Nigral degeneration was accompanied by a significant loss of dopaminergic terminals and a significant reduction of dopamine and homovanillic acid levels in the striatum. Mice deficient of the c-Rel factor exhibited a marked immunoreactivity for fibrillary α-synuclein in the substantia nigra pars compacta as well as increased expression of divalent metal transporter 1 (DMT1) and iron staining in both the substantia nigra pars compacta and striatum. Aged c-rel−/− mouse brain were characterized by increased microglial reactivity in the basal ganglia, but no astrocytic reaction. In addition, c-rel−/− mice showed age-dependent deficits in locomotor and total activity and various gait-related deficits during a catwalk analysis that were reminiscent of bradykinesia and muscle rigidity. Both locomotor and gait-related deficits recovered in c-rel−/− mice treated with l-3,4-dihydroxyphenylalanine. These data suggest that c-Rel may act as a regulator of the substantia nigra pars compacta resilience to ageing and that aged c-rel−/− mice may be a suitable model of Parkinson’s disease. PMID:22915735

  1. The Significance of Brain Transcranial Sonography in Burning Mouth Syndrome: a Pilot Study.

    PubMed

    Zavoreo, Iris; Vučićević, Vanja; Boras; Zadravec, Dijana; Bašić, Vanja; Kes; Ciliga, Dubravka; Gabrić, Dragana

    2017-03-01

    Burning mouth syndrome (BMS) is a chronic disorder which is affecting mostly postmenopausal women and is characterized by burning symptoms in the oral cavity on the clinically healthy oral mucosa. Also, the results of previous studies suggested a possible role of peripheral and/or central neurological disturbances in these patients. The aim of this study was to analyze patients with burning mouth syndrome using transcranial sonography. By use of transcranial sonography of the brain parenchyma, substantia nigra , midbrain raphe and brain nucleus were evaluated in 20 patients with BMS (64.7±12.3 years) and 20 controls with chronic pain in the lumbosacral region (61.5±15). Statistical analysis was performed by use of Student t test with significance set at p<0.05. The results of this study have shown hypoechogenicity of the substantia nigra and midbrain raphe as well as hyperechogenicity of the brain nucleus in BMS patients (p<0,05) as compared to controls. Altered transcranial sonography findings of the brain parenchyma , midbrain raphe and brain nucl eus in patients with burning mouth syndrome might reflect central disturbances within this syndrome. Burning Mouth Syndrome; Transcranial Sonography; substantia nigra; Midbrain Raphe Nuclei; Red Nucleus.

  2. Decreased expression of serum- and glucocorticoid-inducible kinase 1 (SGK1) promotes alpha-synuclein increase related with down-regulation of dopaminergic cell in the Substantia Nigra of chronic MPTP-induced Parkinsonism mice and in SH-SY5Y cells.

    PubMed

    Yeo, Sujung; Sung, Backil; Hong, Yeon-Mi; van den Noort, Maurits; Bosch, Peggy; Lee, Sook-Hyun; Song, Jongbeom; Park, Sang-Kyun; Lim, Sabina

    2018-06-30

    Parkinson's disease (PD) is a chronically progressive neurodegenerative disease, with its main pathological hallmarks being a dramatic loss of dopaminergic neurons predominantly in the Substantia Nigra (SN), and the formations of intracytoplasmic Lewy bodies and dystrophic neurites. Alpha-synuclein (α-syn), widely recognized as the most prominent element of the Lewy body, is one of the representative hallmarks in PD. However, the mechanisms behind the increased α-syn expression and aggregation have not yet been clarified. To examine what causes α-syn expression to increase, we analyzed the pattern of gene expression in the SN of mice intoxicated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), where down-regulation of dopaminergic cells occurred. We identified serum- and glucocorticoid-dependent kinase 1 (SGK1) as one of the genes that is evidently downregulated in chronic MPTP-intoxication. The results of Western blot analyses showed that, together with the down-regulation of dopaminergic cells, the decrease in SGK1 expression increased α-syn expression in the SN in a chronic MPTP-induced Parkinsonism mouse. For an examination of the expression correlation between SGK1 and α-syn, SH-5YSY cells were knocked down with SGK1 siRNA then, the downregulation of dopaminergic cells and the increase in the expression of α-syn were observed. These results suggest that decreased expression of SGK1 may play a critical role in increasing the expression of α-syn, which is related with dopaminergic cell death in the SN of chronic MPTP-induced Parkinsonism mice and in SH-SY5Y cells. Copyright © 2018. Published by Elsevier B.V.

  3. Exposure to the cytokine EGF leads to abnormal hyperactivity of pallidal GABA neurons: implications for schizophrenia and its modeling.

    PubMed

    Sotoyama, Hidekazu; Namba, Hisaaki; Chiken, Satomi; Nambu, Atsushi; Nawa, Hiroyuki

    2013-08-01

    Previous studies on a cytokine model for schizophrenia reveal that the hyperdopaminergic innervation and neurotransmission in the globus pallidus (GP) is involved in its behavioral impairments. Here, we further explored the physiological consequences of the GP abnormality in the indirect pathway, using the same schizophrenia model established by perinatal exposure to epidermal growth factor (EGF). Single-unit recordings revealed that the neural activity from the lateral GP was elevated in EGF-treated rats in vivo and in vitro (i.e., slice preparations), whereas the central area of the GP exhibited no significant differences. The increase in the pallidal activity was normalized by subchronic treatment with risperidone, which is known to ameliorate their behavioral deficits. We also monitored extracellular GABA concentrations in the substantia nigra, one of the targets of pallidal efferents. There was a significant increase in basal GABA levels in EGF-treated rats, whereas high potassium-evoked GABA effluxes and glutamate levels were not affected. A neurotoxic lesion in the GP of EGF-treated rats normalized GABA concentrations to control levels. Corroborating our in vivo results, GABA release from GP slices was elevated in EGF-treated animals. These findings suggest that the hyperactivity and enhanced GABA release of GP neurons represent the key pathophysiological features of this cytokine-exposure model for schizophrenia. © 2013 International Society for Neurochemistry.

  4. SAMBUCUS NIGRA LINN., A NEW RECORD FROM VALLEY OF FLOWERS

    PubMed Central

    Vikramaditya; Sharma, Kedar Nath

    1999-01-01

    Under the present paper, authors have reposted finding of Sambucus nigra L. as new introduction in medicinal plans in the flora of “Valley of flowers’. Sambucus nigra L. Originally is an European plant and is very important for its medicinal potential, being used in various systems of medicine to cure number of ailments. In natural order Sambucus nigra L. belongs to family caprifoliaceae. PMID:22556907

  5. Cloning of the cocaine-sensitive bovine dopamine transporter

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Usdin, T.B.; Chen, C.; Brownstein, M.J.

    1991-12-15

    A cDNA encoding the dopamine transporter from bovine brain substantia nigra was identified on the basis of its structural homology to other, recently cloned, neurotransmitter transporters. The sequence of the 693-amino acid protein is quite similar to those of the rat {gamma}-aminobutyric acid, human norepinephrine, and rat serotonin transporters. Dopamine transporter mRNA was detected by in situ hybridization in the substantia nigra but not in the locus coeruleus, raphe, caudate, or other brain areas. ({sup 3}H)Dopamine accumulation in tissue culture cells transfected with the cDNA was inhibited by amphetamine, cocaine, and specific inhibitors of dopamine transports, including GBR12909.

  6. Encephalopathy and Neuropathy due to Glue, Paint Thinner, and Gasoline Sniffing in Trinidad and Tobago-MRI Findings

    PubMed Central

    Ramcharan, Kanterpersad; Ramesar, Amrit; Ramdath, Moshanti; Teelucksingh, Joel; Gosein, Maria

    2014-01-01

    A 29-year-old male petrol station pump attendant was admitted with ataxia and clinical evidence of a sensorimotor polyneuropathy which developed over the preceding 3 months. He had cognitive dysfunction, hearing loss, and cerebellar clinical abnormalities that came on slowly over the three years. He had a fifteen-year history of sniffing mostly glue, occasionally paint thinners, and, in the recent two years, gasoline. Magnetic resonance brain imaging showed abnormalities of the cerebral cortex, cerebral white matter, corpus callosum, hippocampus, brainstem and cerebellar atrophy, hypointensities of basal ganglia, red nuclei, and substantia nigra as previously described in toluene sniffing. Abstinence for six months led to partial clinical improvement. Clinicians need to be aware of this preventable entity which has peculiar radiological findings which are being increasingly accepted as typical. PMID:25045557

  7. Encephalopathy and Neuropathy due to Glue, Paint Thinner, and Gasoline Sniffing in Trinidad and Tobago-MRI Findings.

    PubMed

    Ramcharan, Kanterpersad; Ramesar, Amrit; Ramdath, Moshanti; Teelucksingh, Joel; Gosein, Maria

    2014-01-01

    A 29-year-old male petrol station pump attendant was admitted with ataxia and clinical evidence of a sensorimotor polyneuropathy which developed over the preceding 3 months. He had cognitive dysfunction, hearing loss, and cerebellar clinical abnormalities that came on slowly over the three years. He had a fifteen-year history of sniffing mostly glue, occasionally paint thinners, and, in the recent two years, gasoline. Magnetic resonance brain imaging showed abnormalities of the cerebral cortex, cerebral white matter, corpus callosum, hippocampus, brainstem and cerebellar atrophy, hypointensities of basal ganglia, red nuclei, and substantia nigra as previously described in toluene sniffing. Abstinence for six months led to partial clinical improvement. Clinicians need to be aware of this preventable entity which has peculiar radiological findings which are being increasingly accepted as typical.

  8. Occupancy of striatal and extrastriatal dopamine D2/D3 receptors by olanzapine and haloperidol.

    PubMed

    Kessler, Robert M; Ansari, Mohammad Sib; Riccardi, Patrizia; Li, Rui; Jayathilake, Karuna; Dawant, Benoit; Meltzer, Herbert Y

    2005-12-01

    There have been conflicting reports as to whether olanzapine produces lower occupancy of striatal dopamine D(2)/D(3) receptor than typical antipsychotic drugs and preferential occupancy of extrastriatal dopamine D(2)/D(3) receptors. We performed [(18)F] fallypride PET studies in six schizophrenic subjects treated with olanzapine and six schizophrenic subjects treated with haloperidol to examine the occupancy of striatal and extrastriatal dopamine receptors by these antipsychotic drugs. [(18)F] setoperone PET studies were performed in seven olanzapine-treated subjects to determine 5-HT(2A) receptor occupancy. Occupancy of dopamine D(2)/D(3) receptors by olanzapine was not significantly different from that seen with haloperidol in the putamen, ventral striatum, medial thalamus, amygdala, or temporal cortex, that is, 67.5-78.2% occupancy; olanzapine produced no preferential occupancy of dopamine D(2)/D(3) receptors in the ventral striatum, medial thalamus, amygdala, or temporal cortex. There was, however, significantly lower occupancy of substantia nigra/VTA dopamine D(2)/D(3) receptors in olanzapine-treated compared to haloperidol-treated subjects, that is, 40.2 vs 59.3% (p=0.0014, corrected for multiple comparisons); in olanzapine-treated subjects, the substantia nigra/VTA was the only region with significantly lower dopamine D(2)/D(3) receptor occupancy than the putamen, that is, 40.2 vs 69.2% (p<0.001, corrected for multiple comparison). Occupancy of 5-HT(2A) receptors was 85-93% in the olanzapine- treated subjects. The results of this study demonstrated that olanzapine does not produce preferential occupancy of extrastriatal dopamine D(2)/D(3) receptors but does spare substantia nigra/VTA receptors. Sparing of substantia nigra/VTA dopamine D(2)/D(3) receptor occupancy may contribute to the low incidence of extrapyramidal side effects in olanzapine-treated patients.

  9. DOE Office of Scientific and Technical Information (OSTI.GOV)

    Strittmatter, S.M.; Lo, M.M.S.; Javitch, J.A.

    The authors have visualized angiotensin-converting enzyme (ACE; dipeptidyl carboxypeptidase, peptidylpeptide hydrolase, EC 3.4.15.1) in rat brain by in vitro (/sup 3/H)captopril autoradiography. (/sup 3/H)Captopril binding to brain slices displays a high affinity (K/sub d/ = 1.8 x 10/sup -9/ M) and a pharmacological profile similar to that of ACE activity. Very high densities of (/sup 3/H)captopril binding were found in the choroid plexus and the subfornical organ. High densities were present in the caudate putamen and substantia nigra, zona reticulata. Moderate levels were found in the entopeduncular nucleus, globus pallidus, and median eminence of the hypothalamus. Lower levels were detectablemore » in the supraoptic and paraventricular nuclei of the hypothalamus, the media habenula, the median preoptic area, and the locus coeruleus. Injection of ibotenic acid or colchicine into the caudate putamen decreased (/sup 3/H)captopril-associated autoradiographic grains by 85% in the ipsilateral caudate putamen and by > 50% in the ipsilateral substantia nigra. Thus, ACE in the substantia nigra is located on presynaptic terminals of axons originating from the caudate putamen, and ACE in the caudate putamen is situated in neuronal perikarya or at the terminals of striatal interneurons. The lack of effect of similar injections into the substantia nigra confirmed that the caudate putamen injections did not cause trans-synaptic changes. The presence of (/sup 3/H)captopril binding is consistent with an ACE-mediated production of angiotensin II in some brain regions. Although (/sup 3/H)captopril autoradiography reveals ACE in a striatonigral pathway, there is no evidence for angiotensin II involvement in such a neuronal pathway. 26 references, 4 figures, 2 tables.« less

  10. [Effects of simultaneous transplant of foetal mesencephalic cells in the striatum and the subthalamic nucleus of hemiparkinsonian rats].

    PubMed

    Pavón-Fuentes, N; Macías-González, R; Blanco-Lezcano, L; Alvarez-González, L; Martínez-Martí, L; Castillo-Díaz, L; De La Cuétara Bernal, K; Díaz, C; Lorigados-Pedre, L; Coro, Y; García-Varona, A Y; Rosillo, J C; Díaz, E

    The main strategy followed in neural transplants as a method of treatment for Parkinson s disease, both experimental and clinical, has been to introduce foetal mesencephalic cells into the target area: the striatum. However, when the dopaminergic cells in the substantia nigra degenerate, not only is the dopaminergic innervation of the striatum affected but also other nuclei: globus pallidus, substantia nigra, substantia nigra pars reticulata and subthalamic nucleus. A series of data from pharmacological and physiological studies offer strong evidence that the dopamine released in these nuclei may play an important role in regulating the output nuclei of the basal ganglia. To evaluate the effect of transplanting foetal mesencephalic cells on the behaviour of 6 OH DA rats when introduced into the striatum and the subthalamic nucleus. 6 OH DA was used to induce lesions in the substantia nigra of rats, which were divided into several experimental groups. The rotating activity induced by D amphetamine (5 mg/kg, intraperitoneally) and apomorphine (0.05 mg/kg, subcutaneously) was evaluated before and three months after the transplant in all the experimental groups, except in the control group of healthy rats. The hemiparkinsonian rats received a total of 350,000 foetal ventral mesencephalic cells, which were implanted within small deposits in the striatum (8) and in the subthalamic nucleus (4). Rotation induced by both drugs was significantly lower (p= 0.05) in animals that had had dopaminergic cells transplanted into the striatum body. No significant improvement in this behaviour was to be found when transplants were limited to just the subthalamus or, simultaneously, also to the striatum. A significant increase in rotating behaviour induced by apomorphine was observed in the group which received a transplant in just the subthalamus.

  11. Nicotinamide prevents the long-term effects of perinatal asphyxia on basal ganglia monoamine systems in the rat.

    PubMed

    Bustamante, D; Goiny, M; Aström, G; Gross, J; Andersson, K; Herrera-Marschitz, M

    2003-01-01

    Asphyxia during birth can cause gross brain damage, but also subtle perturbations expressed as biochemical or motor deficits with late onset in life. Thus, it has been shown that brain dopamine levels can be increased or decreased depending upon the severity of the insult, and the region where the levels are determined. In this study, perinatal asphyxia was evoked by immersing pup-containing uterus horns removed by hysterectomy in a water bath at 37 degrees C for various periods of time from 0 to 20 min. After the insult, the pups were delivered, given to surrogate mothers, treated with nicotinamide, further observed and finally, 4 weeks later, killed for monoamine biochemistry of tissue samples taken from substantia nigra, neostriatum and nucleus accumbens. The main effect of perinatal asphyxia was a decrease in dopamine and metabolite levels in nucleus accumbens, and a paradoxical increase in the substantia nigra. Nicotinamide (100 mg/kg i.p., once a day for 3 days, beginning 24 h after the perinatal asphyctic insult) prevented the effect of asphyxia in nucleus accumbens. Furthermore, striatal dopamine levels were increased by nicotinamide in asphyctic animals. No apparent changes were observed in substantia nigra. A prominent unexpected effect of perinatal asphyxia alone was on the levels of the metabolite of 5-hydroxytryptamine, 5-hydroxyindoleacetic acid (5-HIAA), which were increased in substantia nigra and decreased in both neostriatum and accumbens. However, nicotinamide increased 5-HIAA levels in all regions, which appeared to be related to the extent of the asphyctic insult. These results suggest that nicotinamide is a useful treatment against the long-term consequences produced by perinatal asphyxia on brain monoamine systems, and that there is a therapeutic window following the insult, providing a therapeutic opportunity to protect the brain.

  12. Susceptibility of ascending dopamine projections to 6-hydroxydopamine in rats: effect of hypothermia.

    PubMed

    Grant, R J; Clarke, P B S

    2002-01-01

    The aims of this study were to determine (1) whether mesolimbic and nigrostriatal DA cell bodies degenerate to different extents after 6-hydroxydopamine (6-OHDA) is administered into their respective terminal fields and (2) whether hypothermia, associated with sodium pentobarbital anesthesia, protects DA neurons from the toxic effects of 6-OHDA. To address these questions, 6-OHDA or vehicle was infused into either the ventral or dorsal striatum or into the medial forebrain bundle, under conditions of brain normothermia or hypothermia. Two weeks post-surgery, tyrosine hydroxylase-positive cell bodies were counted in the ventral tegmental area (VTA) and substantia nigra. In addition, autoradiographic labeling of tyrosine hydroxylase protein and dopamine transporter was quantified in dopamine terminal fields and cell body areas. Overall, DA cell bodies in the VTA were substantially less susceptible than those in the substantia nigra to depletion of dopaminergic markers. Hypothermia provided two types of neuroprotection. The first occurred when 6-OHDA was administered into the dorsal striatum, and was associated with a 30-50% increase in residual dopaminergic markers in the lateral portion of the VTA. The second neuroprotective effect of hypothermia occurred when 6-OHDA was given into the medial forebrain bundle. This was associated with a 200-300% increase in residual dopaminergic markers in the mesolimbic and nigrostriatal terminal fields; no significant protection occurred in the cell body regions.Collectively, these findings show that (1) the dopaminergic somata in the substantia nigra are more susceptible than those in the VTA to 6-OHDA-induced denervation, and (2) hypothermia can provide anatomically selective neuroprotection within the substantia nigra-VTA cell population. The continued survival of mesolimbic dopamine cell bodies after a 6-OHDA lesion may have functional implications relating to drugs of abuse, as somatodendritic release of dopamine in the VTA

  13. Hemisphere, gender and age-related effects on iron deposition in deep gray matter revealed by quantitative susceptibility mapping.

    PubMed

    Gong, Nan-Jie; Wong, Chun-Sing; Hui, Edward S; Chan, Chun-Chung; Leung, Lam-Ming

    2015-10-01

    The purpose of this work was to investigate the effects of hemispheric location, gender and age on susceptibility value, as well as the association between susceptibility value and diffusional metrics, in deep gray matter. Iron content was estimated in vivo using quantitative susceptibility mapping. Microstructure was probed using diffusional kurtosis imaging. Regional susceptibility and diffusional metrics were measured for the putamen, caudate nucleus, globus pallidus, thalamus, substantia nigra and red nucleus in 42 healthy adults (age range 25-78 years). Susceptibility value was significantly higher in the left than the right side of the caudate nucleus (P = 0.043) and substantia nigra (P < 0.001). Women exhibited lower susceptibility values than men in the thalamus (P < 0.001) and red nucleus (P = 0.032). Significant age-related increases of susceptibility were observed in the putamen (P < 0.001), red nucleus (P < 0.001), substantia nigra (P = 0.004), caudate nucleus (P < 0.001) and globus pallidus (P = 0.017). The putamen exhibited the highest rate of iron accumulation with aging (slope of linear regression = 0.73 × 10(-3) ppm/year), which was nearly twice those in substantia nigra (slope = 0.40 × 10(-3) ppm/year) and caudate nucleus (slope = 0.39 × 10(-3) ppm/year). Significant positive correlations between the susceptibility value and diffusion measurements were observed for fractional anisotropy (P = 0.045) and mean kurtosis (P = 0.048) in the putamen without controlling for age. Neither correlation was significant after controlling for age. Hemisphere, gender and age-related differences in iron measurements were observed in deep gray matter. Notably, the putamen exhibited the highest rate of increase in susceptibility with aging. Correlations between susceptibility value and microstructural measurements were inconclusive. These findings could provide new clues for unveiling mechanisms underlying iron-related neurodegenerative diseases. Copyright

  14. Nigral dopamine type-1 receptors are reduced in Huntington's disease: A postmortem autoradiographic study using ( sup 3 H)SCH 23390 and correlation with ( sup 3 H)forskolin binding

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Filloux, F.; Wagster, M.V.; Folstein, S.

    1990-11-01

    Intrastriatal injection of excitatory amino acids, particularly quinolinic acid, has been proposed as an animal model of Huntington's disease. Such neurotoxic lesions of caudate-putamen result in marked dopamine type-1 (D1) receptor losses in the injected nuclei as well as in the ipsilateral substantia nigra pars reticulata. Postmortem human substantia nigra from Huntington's disease brains and from control brains were examined using in vitro autoradiography. A marked reduction in ({sup 3}H)SCH 23390 binding (labeling D1 receptors) in the substantia nigra of postmortem brains of Huntington's patients was identified, thus paralleling the alterations seen in the animal models. A positive, statistically significantmore » correlation was also encountered between D1 receptor binding (labeled by ({sup 3}H)SCH 23390) and ({sup 3}H)forskolin binding (which identifies adenylate cyclase, a second messenger system linked to D1 receptor activation). The results suggest that in the human--as in lower vertebrates--D1 receptors are located on striatonigral terminals and that D1 receptor loss tends to be paralleled by a reduction in adenylate cyclase. Radioactive agents selective for the D1 receptor may prove useful in future studies of Huntington's disease using positron emission tomography scanning.« less

  15. The Significance of Brain Transcranial Sonography in Burning Mouth Syndrome: a Pilot Study

    PubMed Central

    Zavoreo, Iris; Vučićević, Vanja; Zadravec, Dijana; Bašić, Vanja; Kes; Ciliga, Dubravka; Gabrić, Dragana

    2017-01-01

    Objective Burning mouth syndrome (BMS) is a chronic disorder which is affecting mostly postmenopausal women and is characterized by burning symptoms in the oral cavity on the clinically healthy oral mucosa. Also, the results of previous studies suggested a possible role of peripheral and/or central neurological disturbances in these patients. The aim of this study was to analyze patients with burning mouth syndrome using transcranial sonography. Methods By use of transcranial sonography of the brain parenchyma, substantia nigra, midbrain raphe and brain nucleus were evaluated in 20 patients with BMS (64.7±12.3 years) and 20 controls with chronic pain in the lumbosacral region (61.5±15). Statistical analysis was performed by use of Student t test with significance set at p<0.05. Results The results of this study have shown hypoechogenicity of the substantia nigra and midbrain raphe as well as hyperechogenicity of the brain nucleus in BMS patients (p<0,05) as compared to controls. Conclusions Altered transcranial sonography findings of the brain parenchyma, midbrain raphe and brain nucleus in patients with burning mouth syndrome might reflect central disturbances within this syndrome. Key words Burning Mouth Syndrome; Transcranial Sonography; substantia nigra; Midbrain Raphe Nuclei; Red Nucleus PMID:28740270

  16. Differential loss of striatal projection neurons in Huntington disease

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Reiner, A.; Albin, R.L.; Anderson, K.D.

    1988-08-01

    Huntington disease (HD) is characterized by the loss of striatal projection neurons, which constitute the vast majority of striatal neurons. To determine whether there is differential loss among different populations of striatal projection neurons, the integrity of the axon terminal plexuses arising from the different populations of substance P-containing and enkephalin-containing striatal projection neurons was studied in striatal target areas by immunohistochemistry. Analysis of 17 HD specimens indicated that in early and middle stages of HD, enkephalin-containing neurons projecting to the external segment of the globus pallidus were much more affected than substance P-containing neurons projecting to the internal pallidalmore » segment. Furthermore, substance P-containing neurons projecting to the substantia nigra pars reticulata were more affected than those projecting to the substantia nigra pars compacta. At the most advanced stages of the disease, projections to all striatal target areas were depleted, with the exception of some apparent sparing of the striatal projection to the substantia nigra pars compacta. These finding may explain some of the clinical manifestations and pharmacology of HD. They also may aid in identifying the neural defect underlying HD and provide additional data with which to evaluate current models of HD pathogenesis.« less

  17. Dermoscopy revealing a case of Tinea Nigra*

    PubMed Central

    Criado, Paulo Ricardo; Delgado, Lívia; Pereira, Gustavo Alonso

    2013-01-01

    Dermoscopy has being used over the past twenty years as a noninvasive aid in the diagnosis of innumerable skin conditions, including infectious diseases and infestations (Entodermoscopy).Tinea nigra is a superficial phaeohyfomycosis that affects mainly the glabrous skin of palms and soles. We describe a 14 year-old girl with a three-month history of an enlarging brown patch of her hand diagnosed as Tinea Nigra following clinical and dermoscopy examination.These images emphasize the importance of dermoscopy as a diagnostic tool in the daily routine of dermatologists. PMID:23539019

  18. Progression marker of Parkinson's disease: a 4-year multi-site imaging study.

    PubMed

    Burciu, Roxana G; Ofori, Edward; Archer, Derek B; Wu, Samuel S; Pasternak, Ofer; McFarland, Nikolaus R; Okun, Michael S; Vaillancourt, David E

    2017-08-01

    Progression markers of Parkinson's disease are crucial for successful therapeutic development. Recently, a diffusion magnetic resonance imaging analysis technique using a bitensor model was introduced allowing the estimation of the fractional volume of free water within a voxel, which is expected to increase in neurodegenerative disorders such as Parkinson's disease. Prior work demonstrated that free water in the posterior substantia nigra was elevated in Parkinson's disease compared to controls across single- and multi-site cohorts, and increased over 1 year in Parkinson's disease but not in controls at a single site. Here, the goal was to validate free water in the posterior substantia nigra as a progression marker in Parkinson's disease, and describe the pattern of progression of free water in patients with a 4-year follow-up tested in a multicentre international longitudinal study of de novo Parkinson's disease (http://www.ppmi-info.org/). The analyses examined: (i) 1-year changes in free water in 103 de novo patients with Parkinson's disease and 49 controls; (ii) 2- and 4-year changes in free water in a subset of 46 patients with Parkinson's disease imaged at baseline, 12, 24, and 48 months; (iii) whether 1- and 2-year changes in free water predict 4-year changes in the Hoehn and Yahr scale; and (iv) the relationship between 4-year changes in free water and striatal binding ratio in a subgroup of Parkinson's disease who had undergone both diffusion and dopamine transporter imaging. Results demonstrated that: (i) free water level in the posterior substantia nigra increased over 1 year in de novo Parkinson's disease but not in controls; (ii) free water kept increasing over 4 years in Parkinson's disease; (iii) sex and baseline free water predicted 4-year changes in free water; (iv) free water increases over 1 and 2 years were related to worsening on the Hoehn and Yahr scale over 4 years; and (v) the 4-year increase in free water was associated with the 4-year

  19. Dermoscopy improves diagnosis of tinea nigra: a study of 50 cases.

    PubMed

    Piliouras, Peter; Allison, Scott; Rosendahl, Cliff; Buettner, Petra G; Weedon, David

    2011-08-01

    Tinea nigra is a relatively uncommon dematiaceous fungal infection of the palms and soles, which clinically may mimic a melanocytic lesion. We sought to ascertain how frequently misdiagnosis of this infection occurred and whether the use of dermoscopy helped in its diagnosis. Fifty consecutive cases of tinea nigra diagnosed at a dermatopathology laboratory were examined with regard to the clinical diagnosis, use of dermoscopy and the mode of management. Of the 50 cases, 21 (42.0%) were treated by shave or surgical excision. The clinical diagnosis of tinea nigra was made in five cases (10.0%) and suggested along with other diagnoses in a further two cases (4.0%). The dermatologists (n = 9) gave the correct diagnosis in four patients (44.4%), the general practitioners (n = 38) gave the correct diagnosis in one patient (2.6%) and the three surgeons involved did not give the correct diagnosis. When dermoscopy was used, in seven of 13 (53.8%) cases tinea nigra was suggested as a probable diagnosis but when dermoscopy was not used (n = 37) tinea nigra was not clinically diagnosed (P < 0.001). The diagnosis of tinea nigra is significantly improved by dermoscopy, the disease should be considered as a cause of palmar or plantar pigmentation. © 2011 The Authors; Australasian Journal of Dermatology © 2011 The Australasian College of Dermatologists.

  20. Monoamine neurons in the human brain stem: anatomy, magnetic resonance imaging findings, and clinical implications.

    PubMed

    Sasaki, Makoto; Shibata, Eri; Tohyama, Koujiro; Kudo, Kohsuke; Endoh, Jin; Otsuka, Kotaro; Sakai, Akio

    2008-11-19

    By using high-resolution, conventional, and neuromelanin-sensitive magnetic resonance imaging techniques, we reviewed the normal anatomy of the nuclei consisting of monoamine neurons such as dopaminergic, noradrenergic, and serotoninergic neurons and noted the changes in these nuclei that occur in some degenerative and psychiatric disorders. Multimodal MR images can directly or indirectly help in identifying the substantia nigra, locus ceruleus, and raphe nuclei that contain monoamine neurons. Neuromelanin-sensitive magnetic resonance imaging can detect signal alterations in the substantia nigra pars compacta and/or locus ceruleus that occur in Parkinson's disease and psychiatric disorders such as depression and schizophrenia. This technique seems to be promising for the noninvasive evaluation of the pathological or functional changes in the monoamine system that occur in degenerative and psychiatric disorders.

  1. Control of the subthalamic innervation of substantia nigra pars reticulata by D1 and D2 dopamine receptors.

    PubMed

    Ibañez-Sandoval, Osvaldo; Hernández, Adán; Florán, Benjamin; Galarraga, Elvira; Tapia, Dagoberto; Valdiosera, Rene; Erlij, David; Aceves, Jorge; Bargas, José

    2006-03-01

    The effects of activating dopaminergic D1 and D2 class receptors of the subthalamic projections that innervate the pars reticulata of the subtantia nigra (SNr) were explored in slices of the rat brain using the whole cell patch-clamp technique. Excitatory postsynaptic currents (EPSCs) that could be blocked by 6-cyano-7-nitroquinoxalene-2,3-dione and D-(-)-2-amino-5-phosphonopentanoic acid were evoked onto reticulata GABAergic projection neurons by local field stimulation inside the subthalamic nucleus in the presence of bicuculline. Bath application of (RS)-2,3,4,5-tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine hydrochloride (SKF-38393), a dopaminergic D1-class receptor agonist, increased evoked EPSCs by approximately 30% whereas the D2-class receptor agonist, trans-(-)-4aR-4,4a,5,6,7,8,8a,9-octahydro-5-propyl-1H-pyrazolo(3,4-g)quinoline (quinpirole), reduced EPSCs by approximately 25%. These apparently opposing actions were blocked by the specific D1- and D2-class receptor antagonists: R-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetra-hydro-1H-3-benzazepinehydrochloride (SCH 23390) and S-(-)-5-amino-sulfonyl-N-[(1-ethyl-2-pyrrolidinyl)-methyl]-2-methoxybenzamide (sulpiride), respectively. Both effects were accompanied by changes in the paired-pulse ratio, indicative of a presynaptic site of action. The presynaptic location of dopamine receptors at the subthalamonigral projections was confirmed by mean-variance analysis. The effects of both SKF-38393 and quinpirole could be observed on terminals contacting the same postsynaptic neuron. Sulpiride and SCH 23390 enhanced and reduced the evoked EPSC, respectively, suggesting a constitutive receptor activation probably arising from endogenous dopamine. These data suggest that dopamine presynaptically modulates the subthalamic projection that targets GABAergic neurons of the SNr. Implications of this modulation for basal ganglia function are discussed.

  2. Programming of Dopaminergic Neurons by Neonatal Sex Hormone Exposure: Effects on Dopamine Content and Tyrosine Hydroxylase Expression in Adult Male Rats

    PubMed Central

    Espinosa, Pedro; Silva, Roxana A.; Sanguinetti, Nicole K.; Venegas, Francisca C.; Riquelme, Raul; González, Luis F.; Cruz, Gonzalo; Renard, Georgina M.; Moya, Pablo R.; Sotomayor-Zárate, Ramón

    2016-01-01

    We sought to determine the long-term changes produced by neonatal sex hormone administration on the functioning of midbrain dopaminergic neurons in adult male rats. Sprague-Dawley rats were injected subcutaneously at postnatal day 1 and were assigned to the following experimental groups: TP (testosterone propionate of 1.0 mg/50 μL); DHT (dihydrotestosterone of 1.0 mg/50 μL); EV (estradiol valerate of 0.1 mg/50 μL); and control (sesame oil of 50 μL). At postnatal day 60, neurochemical studies were performed to determine dopamine content in substantia nigra-ventral tegmental area and dopamine release in nucleus accumbens. Molecular (mRNA expression of tyrosine hydroxylase) and cellular (tyrosine hydroxylase immunoreactivity) studies were also performed. We found increased dopamine content in substantia nigra-ventral tegmental area of TP and EV rats, in addition to increased dopamine release in nucleus accumbens. However, neonatal exposure to DHT, a nonaromatizable androgen, did not affect midbrain dopaminergic neurons. Correspondingly, compared to control rats, levels of tyrosine hydroxylase mRNA and protein were significantly increased in TP and EV rats but not in DHT rats, as determined by qPCR and immunohistochemistry, respectively. Our results suggest an estrogenic mechanism involving increased tyrosine hydroxylase expression, either by direct estrogenic action or by aromatization of testosterone to estradiol in substantia nigra-ventral tegmental area. PMID:26904299

  3. Programming of Dopaminergic Neurons by Neonatal Sex Hormone Exposure: Effects on Dopamine Content and Tyrosine Hydroxylase Expression in Adult Male Rats.

    PubMed

    Espinosa, Pedro; Silva, Roxana A; Sanguinetti, Nicole K; Venegas, Francisca C; Riquelme, Raul; González, Luis F; Cruz, Gonzalo; Renard, Georgina M; Moya, Pablo R; Sotomayor-Zárate, Ramón

    2016-01-01

    We sought to determine the long-term changes produced by neonatal sex hormone administration on the functioning of midbrain dopaminergic neurons in adult male rats. Sprague-Dawley rats were injected subcutaneously at postnatal day 1 and were assigned to the following experimental groups: TP (testosterone propionate of 1.0 mg/50 μL); DHT (dihydrotestosterone of 1.0 mg/50 μL); EV (estradiol valerate of 0.1 mg/50 μL); and control (sesame oil of 50 μL). At postnatal day 60, neurochemical studies were performed to determine dopamine content in substantia nigra-ventral tegmental area and dopamine release in nucleus accumbens. Molecular (mRNA expression of tyrosine hydroxylase) and cellular (tyrosine hydroxylase immunoreactivity) studies were also performed. We found increased dopamine content in substantia nigra-ventral tegmental area of TP and EV rats, in addition to increased dopamine release in nucleus accumbens. However, neonatal exposure to DHT, a nonaromatizable androgen, did not affect midbrain dopaminergic neurons. Correspondingly, compared to control rats, levels of tyrosine hydroxylase mRNA and protein were significantly increased in TP and EV rats but not in DHT rats, as determined by qPCR and immunohistochemistry, respectively. Our results suggest an estrogenic mechanism involving increased tyrosine hydroxylase expression, either by direct estrogenic action or by aromatization of testosterone to estradiol in substantia nigra-ventral tegmental area.

  4. Diversity in tree species in southeastern Ohio Betula nigra L. communities

    Treesearch

    Larry D. Cribben; Dina D. Scacchetti

    1976-01-01

    Quantitative data were obtained for arboreal species within 50 lowland forests in southeastern Ohio. Thirty-seven communities were dominated by Betula nigra L. and 13 were dominated by Acer saccharinum L. The acidic soils collected from B. nigra communities contained toxic concentrations of exchangeable aluminum...

  5. Iron as a risk factor in neurological diseases

    NASA Astrophysics Data System (ADS)

    Galazka-Friedman, Jolanta

    2008-02-01

    In this review the properties of iron in various human brain structures (e.g. Substantia nigra, globus pallidus, hippocampus) were analyzed to assess the possibility of initiation of oxidative stress leading to such diseases as Parkinson’s and Alzheimer’s disease, and progressive supranuclear palsy. Our own studies with the use of Mössbauer spectroscopy, electron microscopy and enzyme-linked immuno-absorbent assay (ELISA) were confronted with other methods used in other laboratories. Our results suggest that hippocampus is the most fragile for oxidative stress structure in human brain (the death of nervous cells in hippocampus leads to Alzheimer’s disease). Changes in iron metabolism were also found in substantia nigra (the death of nervous cells of this structure produces Parkinson’s disease) and in globus pallidus (neurodegeneration of this structure causes progressive supranuclear palsy).

  6. Nrxn3 upregulation in the globus pallidus of mice developing cocaine addiction

    PubMed Central

    Kelai, Sabah; Maussion, Gilles; Noble, Florence; Boni, Claudette; Ramoz, Nicolas; Moalic, Jean-Marie; Peuchmaur, Michel; Gorwood, Philip; Simonneau, Michel

    2008-01-01

    Dysfunctions affecting the connections of basal ganglia lead to major neurological and psychiatric disorders. We investigated levels of mRNA for three neurexins (Nrxn) and three neuroligins (Nlgn) in the globus pallidus, subthalamic nucleus, and substantia nigra, in control conditions and after short-term exposure to cocaine. The expression of Nrxn2β and Nlgn3 in the substantia nigra and Nlgn1in the subthalamic nucleus depended on genetic background. The development of short-term cocaine appetence induced an increase in Nrxn3β expression in the globus pallidus. Human NRXN3 has recently been linked to several addictions. Thus, NRXN3 adhesion molecules may play an important role in the synaptic plasticity of neurons involved in the indirect pathways of basal ganglia, in which they regulate reward-related learning. PMID:18418251

  7. Nrxn3 upregulation in the globus pallidus of mice developing cocaine addiction.

    PubMed

    Kelai, Sabah; Maussion, Gilles; Noble, Florence; Boni, Claudette; Ramoz, Nicolas; Moalic, Jean-Marie; Peuchmaur, Michel; Gorwood, Philip; Simonneau, Michel

    2008-05-07

    Dysfunctions affecting the connections of basal ganglia lead to major neurological and psychiatric disorders. We investigated levels of mRNA for three neurexins (Nrxn) and three neuroligins (Nlgn) in the globus pallidus, subthalamic nucleus, and substantia nigra, in control conditions and after short-term exposure to cocaine. The expression of Nrxn2beta and Nlgn3 in the substantia nigra and Nlgn1 in the subthalamic nucleus depended on genetic background. The development of short-term cocaine appetence induced an increase in Nrxn3beta expression in the globus pallidus. Human NRXN3 has recently been linked to several addictions. Thus, NRXN3 adhesion molecules may play an important role in the synaptic plasticity of neurons involved in the indirect pathways of basal ganglia, in which they regulate reward-related learning.

  8. Adventitious shoot regeneration from in vitro leaf explants of Fraxinus nigra

    Treesearch

    Jun Hyung Lee; Paula M. Pijut

    2017-01-01

    Black ash (Fraxinus nigra) is an endangered hardwood tree species under threat of extirpation by the emerald ash borer (EAB), an aggressive exotic phloemfeeding beetle. We have developed an efficient regeneration system through adventitious shoot organogenesis in F. nigra using in vitro-derived leaf explants. Two types of leaf...

  9. Evaluation of phenolic compounds and lipid-lowering effect of Morus nigra leaves extract.

    PubMed

    Zeni, Ana Lúcia B; Moreira, Tatianne D; Dalmagro, Ana Paula; Camargo, Anderson; Bini, Larissa A; Simionatto, Edésio L; Scharf, Dilamara R

    2017-01-01

    Morus nigra L. (Moraceae) is a tree known as black mulberry and the leaves are used in folk medicine in the treatment of diabetes, high cholesterol and menopause symptoms. The aim of this study was to evaluate the M. nigra leaves phytochemical profile in different extractions and the hypolipidemic effect of the infusion comparing to the fenofibrate. Morus nigra infusion (MN) showed higher amounts of phenolics and flavonoids (83.85 mg/g and 79.96 µg/g, respectively), as well as antioxidant activity (83.85%) than decoction or hydromethanolic extracts. Although, decoction showed the best result for ascorbic acid (4.35 mg/100 g) than hydromethanolic or infusion (2.51 or 2.13 mg/100 g, respectively). The phenolic acids gallic, chlorogenic and caffeic and the flavonoids quercetin, rutin and catechin were found in the M. nigra extracts. Hyperlipidemic rats treated with 100, 200 or 400 mg/kg of MN decreased serum cholesterol, triglycerides and normalized lipoproteins. Furthermore, MN inhibited lipid peroxidation in liver, kidney and brain of hyperlipidemic rats. This study provides evidence that M. nigra leaves extracts are rich in polyphenols, mainly chlorogenic acid, which normalized hyperlipidemic disturbance. The results suggest a potential therapeutic effect of the M. nigra leaves infusion on dislipidemic condition and related oxidative stress.

  10. Early diagnosis of Parkinson's disease.

    PubMed

    Becker, Georg; Müller, Antje; Braune, Stefan; Büttner, Thomas; Benecke, Reiner; Greulich, Wolfgang; Klein, Wolfgang; Mark, Günter; Rieke, Jürgen; Thümler, Reiner

    2002-10-01

    In idiopathic Parkinson's disease (IPD) approximately 60 % of the nigrostriatal neurons of the substantia nigra (SN) are degenerated before neurologists can establish the diagnosis according to the widely accepted clinical diagnostic criteria. It is conceivable that neuroprotective therapy starting at such an 'advanced stage' of the disease will fail to stop the degenerative process. Therefore, the identification of patients at risk and at earlier stages of the disease appears to be essential for any successful neuroprotection. The discovery of several genetic mutations associated with IPD raises the possibility that these, or other biomarkers, of the disease may help to identify persons at risk of IPD. Transcranial ultrasound have shown susceptibility factors for IPD related to an increased iron load of the substantia nigra. In the early clinical phase, a number of motor and particularly non-motor signs emerge, which can be identified by the patients and physicians years before the diagnosis is made, notably olfactory dysfunction, depression, or 'soft' motor signs such as changes in handwriting, speech or reduced ambulatory arm motion. These signs of the early, prediagnostic phase of IPD can be detected by inexpensive and easy-to-administer tests. As one single instrument will not be sensitive enough, a battery of tests has to be composed measuring independent parameters of the incipient disease. Subjects with abnormal findings in this test battery should than be submitted to nuclear medicine examinations to quantify the extent of dopaminergic injury and to reach the goal of a reliable, early diagnosis.

  11. Brain region-dependent differential expression of alpha-synuclein.

    PubMed

    Taguchi, Katsutoshi; Watanabe, Yoshihisa; Tsujimura, Atsushi; Tanaka, Masaki

    2016-04-15

    α-Synuclein, the major constituent of Lewy bodies (LBs), is normally expressed in presynapses and is involved in synaptic function. Abnormal intracellular aggregation of α-synuclein is observed as LBs and Lewy neurites in neurodegenerative disorders, such as Parkinson's disease (PD) or dementia with Lewy bodies. Accumulated evidence suggests that abundant intracellular expression of α-synuclein is one of the risk factors for pathological aggregation. Recently, we reported differential expression patterns of α-synuclein between excitatory and inhibitory hippocampal neurons. Here we further investigated the precise expression profile in the adult mouse brain with special reference to vulnerable regions along the progression of idiopathic PD. The results show that α-synuclein was highly expressed in the neuronal cell bodies of some early PD-affected brain regions, such as the olfactory bulb, dorsal motor nucleus of the vagus, and substantia nigra pars compacta. Synaptic expression of α-synuclein was mostly accompanied by expression of vesicular glutamate transporter-1, an excitatory presynaptic marker. In contrast, expression of α-synuclein in the GABAergic inhibitory synapses was different among brain regions. α-Synuclein was clearly expressed in inhibitory synapses in the external plexiform layer of the olfactory bulb, globus pallidus, and substantia nigra pars reticulata, but not in the cerebral cortex, subthalamic nucleus, or thalamus. These results suggest that some neurons in early PD-affected human brain regions express high levels of perikaryal α-synuclein, as happens in the mouse brain. Additionally, synaptic profiles expressing α-synuclein are different in various brain regions. © 2015 Wiley Periodicals, Inc.

  12. Vulnerable Parkin Loss-of-Function Drosophila Dopaminergic Neurons Have Advanced Mitochondrial Aging, Mitochondrial Network Loss and Transiently Reduced Autophagosome Recruitment.

    PubMed

    Cackovic, Juliana; Gutierrez-Luke, Susana; Call, Gerald B; Juba, Amber; O'Brien, Stephanie; Jun, Charles H; Buhlman, Lori M

    2018-01-01

    Selective degeneration of substantia nigra dopaminergic (DA) neurons is a hallmark pathology of familial Parkinson's disease (PD). While the mechanism of degeneration is elusive, abnormalities in mitochondrial function and turnover are strongly implicated. An Autosomal Recessive-Juvenile Parkinsonism (AR-JP) Drosophila melanogaster model exhibits DA neurodegeneration as well as aberrant mitochondrial dynamics and function. Disruptions in mitophagy have been observed in parkin loss-of-function models, and changes in mitochondrial respiration have been reported in patient fibroblasts. Whether loss of parkin causes selective DA neurodegeneration in vivo as a result of lost or decreased mitophagy is unknown. This study employs the use of fluorescent constructs expressed in Drosophila DA neurons that are functionally homologous to those of the mammalian substantia nigra. We provide evidence that degenerating DA neurons in parkin loss-of-function mutant flies have advanced mitochondrial aging, and that mitochondrial networks are fragmented and contain swollen organelles. We also found that mitophagy initiation is decreased in park ( Drosophila parkin/PARK2 ortholog) homozygous mutants, but autophagosome formation is unaffected, and mitochondrial network volumes are decreased. As the fly ages, autophagosome recruitment becomes similar to control, while mitochondria continue to show signs of damage, and climbing deficits persist. Interestingly, aberrant mitochondrial morphology, aging and mitophagy initiation were not observed in DA neurons that do not degenerate. Our results suggest that parkin is important for mitochondrial homeostasis in vulnerable Drosophila DA neurons, and that loss of parkin-mediated mitophagy may play a role in degeneration of relevant DA neurons or motor deficits in this model.

  13. Geochemical peculiarities of black poplar leaves (Populus nigra L.) in the sites with heavy metals intensive fallouts

    NASA Astrophysics Data System (ADS)

    Yalaltdinova, Albina; Baranovskaya, Natalya; Rikhvanov, Leonid; Matveenko, Irina

    2013-04-01

    The article deals with the content of 28 chemical elements in the leaves ash of black poplar (Populus nigra L.) growing in Ust-Kamenogorsk city area. It is the major industrial center of Kazakhstan Republic on the territory where the industrial giants of non-ferrous metallurgy and nuclear energy are situated. Comparative analysis with the similar data obtained from leaves ash of Populus nigra L. in Tomsk, Ekibastuz, and Pavlodar cities has revealed that in comparison with other urban areas, leaves ash of black poplar (Populus nigra L.) from Ust-Kamenogorsk city is characterized by elevated concentration rates of Ta, U, Zn, Ag, As, Sb, Br, Sr and Na. Within the city, the sites and areas with abnormal contents of typomorphic pollutants have been revealed. In the central part of the city, in the vicinity of lead-zinc plant and Ulba metallurgical plant, the highest concentrations of Ta, U, Zn, Ag, Au, As, Sb, Cr and Fe were marked. In the northeast, where the titanium-magnesium plant is located, elevated concentrations of Br and Sr were stated. Thus, the impact of major city enterprises which are the main sources of heavy metals is reflected in the element composition. Zn, As, Sb, Ag and Au comes from lead-zinc plant and its refinery plants, while Ulba metallurgical plant can be considered source of Ta and U in the environment, producing tantalum and fuel pellets for nuclear power plants. These companies, due to the current objective circumstances, are located in the central part of the city, have a significant negative effect on the environment and form the risk factors for human health.

  14. Expression of lactoferrin receptors is increased in the mesencephalon of patients with Parkinson disease.

    PubMed Central

    Faucheux, B A; Nillesse, N; Damier, P; Spik, G; Mouatt-Prigent, A; Pierce, A; Leveugle, B; Kubis, N; Hauw, J J; Agid, Y

    1995-01-01

    The degeneration of nigral dopaminergic neurons in Parkinson disease is believed to be associated with oxidative stress. Since iron levels are increased in the substantia nigra of parkinsonian patients and this metal catalyzes the formation of free radicals, it may be involved in the mechanisms of nerve cell death. The cause of nigral iron increase is not understood. Iron acquisition by neurons may occur from iron-transferrin complexes with a direct interaction with specific membrane receptors, but recent results have shown a low density of transferrin receptors in the substantia nigra. To investigate whether neuronal death in Parkinson disease may be associated with changes in a pathway supplementary to that of transferrin, lactoferrin (lactotransferrin) receptor expression was studied in the mesencephalon. In this report we present evidence from immunohistochemical staining of postmortem human brain tissue that lactoferrin receptors are localized on neurons (perikarya, dendrites, axons), cerebral microvasculature, and, in some cases, glial cells. In parkinsonian patients, lactoferrin receptor immunoreactivity on neurons and microvessels was increased and more pronounced in those regions of the mesencephalon where the loss of dopaminergic neurons is severe. Moreover, in the substantia nigra, the intensity of immunoreactivity on neurons and microvessels was higher for patients with higher nigral dopaminergic loss. These data suggest that lactoferrin receptors on vulnerable neurons may increase intraneuronal iron levels and contribute to the degeneration of nigral dopaminergic neurons in Parkinson disease. Images Fig. 1 Fig. 2 PMID:7568181

  15. Tamoxifen protects male mice nigrostriatal dopamine against methamphetamine-induced toxicity.

    PubMed

    Bourque, Mélanie; Liu, Bin; Dluzen, Dean E; Di Paolo, Thérèse

    2007-11-01

    The selective estrogen receptor modulator tamoxifen and estradiol were shown to protect nigrostriatal dopamine concentration loss by methamphetamine in female mice whereas male mice were protected only by tamoxifen. The present study examined the protective properties of tamoxifen in male mice on several nigrostriatal dopaminergic markers and body temperature. Intact male mice were administered 12.5 or 50 microg tamoxifen 24 h before methamphetamine treatment. Basal body temperatures of male mice remained unchanged by the tamoxifen treatment. Methamphetamine reduced striatal dopamine and its metabolites 3,4-dihydroxyphenylacetic acid and homovanillic acid concentrations, striatal and substantia nigra dopamine and vesicular monoamine transporter specific binding as well substantia nigra dopamine and vesicular monoamine transporter mRNA levels and increased striatal preproenkephalin mRNA levels. These methamphetamine effects were not altered by 12.5 microg tamoxifen except for increased striatal dopamine metabolites and turnover. Tamoxifen at 50 microg reduced the methamphetamine effect on striatal dopamine concentration, dopamine transporter specific binding and prevented the increase in preproenkephalin mRNA levels; in the substantia nigra tamoxifen prevented the decrease of dopamine transporter mRNA levels. The present results show a tamoxifen dose-dependent prevention of loss of various dopaminergic markers against methamphetamine-induced toxicity in male mice. Since this is the only known hormonal protection of male mice against methamphetamine toxicity, these findings provide important new information on specific parameters of nigrostriatal dopaminergic function preserved by tamoxifen.

  16. Production and characterization of interspecific somatic hybrids between Brassica oleracea var. botrytis and B. nigra and their progenies for the selection of advanced pre-breeding materials.

    PubMed

    Wang, Gui-xiang; Tang, Yu; Yan, Hong; Sheng, Xiao-guang; Hao, Wei-Wei; Zhang, Li; Lu, Kun; Liu, Fan

    2011-10-01

    Somatic hybridization is a potential method for gene transfer from wild relatives to cultivated crops that can overcome sexual incompatibilities of two distantly related species. In this study, interspecific asymmetric somatic hybrids of Brassica oleracea var. botrytis (cauliflower) and Brassica nigra (black mustard) were obtained by protoplast fusion and their backcrossed (BC(3)) and selfed (S(3)) offspring were analyzed. Cytological analysis showed that the B. nigra chromosomes were successively eliminated in the backcrosses with cauliflower. The fertility of the hybrid progenies was quite different due to the asynchronous and abnormal chromosome behavior of pollen mother cells (PMC) during meiosis. Analysis of sequence-related amplified polymorphism (SRAP) showed that all of these hybrids mainly had the DNA banding pattern from the two parents with some alterations. Genetically, the selfed generations were closer to B. nigra, while the backcrossed generations were closer to the cauliflower parent. Analysis of cleaved amplified polymorphic sequences (CAPS) and restriction fragment length polymorphisms (RFLP) showed that all somatic hybrids in this study contained chloroplast (cp) DNA of the donor parent black mustard, while mitochondrial (mt) DNA showed evidence of recombination and variations in the regions analyzed. Furthermore, three BC(3) plants (originated from somatic hybrids 3, 4, 10) with 2-8 B. nigra-derived chromosomes shown by genomic in situ hybridization (GISH) displayed a more cauliflower-like morphology and high resistance to black-rot. These plants were obtained as bridge materials for further analysis and breeding.

  17. AC-186, a Selective Nonsteroidal Estrogen Receptor β Agonist, Shows Gender Specific Neuroprotection in a Parkinson’s Disease Rat Model

    PubMed Central

    2013-01-01

    Drugs that selectively activate estrogen receptor β (ERβ) are potentially safer than the nonselective estrogens currently used in hormonal replacement treatments that activate both ERβ and ERα. The selective ERβ agonist AC-186 was evaluated in a rat model of Parkinson’s disease induced through bilateral 6-hydroxydopamine lesions of the substantia nigra. In this model, AC-186 prevented motor, cognitive, and sensorimotor gating deficits and mitigated the loss of dopamine neurons in the substantia nigra, in males, but not in females. Furthermore, in male rats, 17β-estradiol, which activates ERβ and ERα with equal potency, did not show the same neuroprotective benefits as AC-186. Hence, in addition to a beneficial safety profile for use in both males and females, a selective ERβ agonist has a differentiated pharmacological profile compared to 17β-estradiol in males. PMID:23898966

  18. Dalnigrin, a neoflavonoid marker for the identification of Brazilian rosewood (Dalbergia nigra) in CITES enforcement.

    PubMed

    Kite, Geoffrey C; Green, Paul W C; Veitch, Nigel C; Groves, Madeleine C; Gasson, Peter E; Simmonds, Monique S J

    2010-07-01

    International trade in Brazilian rosewood, Dalbergia nigra (Vell.) Allemão ex Benth., is regulated by the Convention on International Trade in Endangered Species of Wild Fauna and Flora (CITES). One problem in enforcing these regulations is the difficulty in distinguishing the wood of D. nigra from that of a closely-related but unregulated species, Dalbergia spruceana Benth. Using LC-MS to analyse methanol extracts of xylaria specimens, we identified a chemical marker for D. nigra heartwood, and determined its structure as the neoflavonoid 6-hydroxy-7-methoxy-4-(4-methoxyphenyl)-2H-1-benzopyran-2-one (4'-O-methylmelanettin; dalnigrin), using spectroscopic techniques. Dalnigrin was present in all nine available heartwood specimens of D. nigra, but it was not detected in extracts of 59 other heartwood samples representing 15 species of Dalbergia, including D. spruceana. Five other phenolic compounds were also isolated from D. nigra heartwood and similarly identified as the neoflavonoids 3'-hydroxymelanettin, melanettin, melannein and dalbergin, and the isoflavone caviunin. In extracts of D. spruceana heartwood, pseudobaptigenin was identified by LC-MS to be a major phenolic component that was not detected in wood extracts of D. nigra. We conclude that chemical analysis, in combination with anatomical investigation, can provide persuasive evidence to support the positive identification of untreated heartwood of D. nigra. 2010 Elsevier Ltd. All rights reserved.

  19. Genetic transformation of black walnut (Juglans nigra)

    Treesearch

    Michael J. Bosela; Gurpreet S. Smagh; Charles H. Michler

    2004-01-01

    Disarmed Agrobacterium tumefaciens strains with binary vectors carrying transgenes for kanamycin resistance (npt II) and β-glucuronidase (GUS, uidA) were used for the genetic transformation of Eastern black walnut (Juglans nigra) somatic embryos. In total, explants from 16 embryo lines...

  20. Antioxidant and anxiolytic activities of Crataegus nigra Wald. et Kit. berries.

    PubMed

    Popovic-Milenkovic, Marija T; Tomovic, Marina T; Brankovic, Snezana R; Ljujic, Biljana T; Jankovic, Slobodan M

    2014-01-01

    Hawthorn has been present for a long time in traditional medicine as antihypertensive, hypolipidemic, anti-inflammatory, gastroprotective, antimicrobial agent. Hawthorn can be used for the cure of stress, nervousness but there is no published paper about actions of Crataegus nigra Wald. et Kit. fruits. The present study was carried out to test free-radical-scavenging and anxiolytic activity of C. nigra fruits. DPPH (alpha,alpha-diphenyl-beta-picrylhydrazyl) assay was used to measure antioxidant activity. BHT, BHA, PG, quercetin and rutin were used as standards. The total amount of phenolic compounds, procyanidins, and flavonoids in the extracts, was determined spectrophotometrically. Results were expressed as equivalents of gallic acid, cyanidin chloride and quercetin equivalents, respectively. LC-MS/MS was used for identification and quantification of phenolic composition. The anxiety effect, expressed as the difference in time spent in the open and closed arms, was measured and compared between groups. Phenolic compound content of Crataegus nigra fruits was 72.7 mg/g. Yield of total flavonoid aglycones was 0.115 mg/g. Procyanidins were 5.6 mg/g. DPPH radical-scavenging capacity of the extracts showed linear concentration dependency, IC50 value were 27.33 microg/mL. Anxiolytic effect was observed. Species Crataegus nigra fruits hydroalcoholic extract showed antioxidant and anxiolytic activity.

  1. Structural and functional abnormalities of the motor system in developmental stuttering

    PubMed Central

    Watkins, Kate E.; Smith, Stephen M.; Davis, Steve; Howell, Peter

    2007-01-01

    Summary Though stuttering is manifest in its motor characteristics, the cause of stuttering may not relate purely to impairments in the motor system as stuttering frequency is increased by linguistic factors, such as syntactic complexity and length of utterance, and decreased by changes in perception, such as masking or altering auditory feedback. Using functional and diffusion imaging, we examined brain structure and function in the motor and language areas in a group of young people who stutter. During speech production, irrespective of fluency or auditory feedback, the people who stuttered showed overactivity relative to controls in the anterior insula, cerebellum and midbrain bilaterally and underactivity in the ventral premotor, Rolandic opercular and sensorimotor cortex bilaterally and Heschl’s gyrus on the left. These results are consistent with a recent meta-analysis of functional imaging studies in developmental stuttering. Two additional findings emerged from our study. First, we found overactivity in the midbrain, which was at the level of the substantia nigra and extended to the pedunculopontine nucleus, red nucleus and subthalamic nucleus. This overactivity is consistent with suggestions in previous studies of abnormal function of the basal ganglia or excessive dopamine in people who stutter. Second, we found underactivity of the cortical motor and premotor areas associated with articulation and speech production. Analysis of the diffusion data revealed that the integrity of the white matter underlying the underactive areas in ventral premotor cortex was reduced in people who stutter. The white matter tracts in this area via connections with posterior superior temporal and inferior parietal cortex provide a substrate for the integration of articulatory planning and sensory feedback, and via connections with primary motor cortex, a substrate for execution of articulatory movements. Our data support the conclusion that stuttering is a disorder related

  2. Structural and functional abnormalities of the motor system in developmental stuttering.

    PubMed

    Watkins, Kate E; Smith, Stephen M; Davis, Steve; Howell, Peter

    2008-01-01

    Though stuttering is manifest in its motor characteristics, the cause of stuttering may not relate purely to impairments in the motor system as stuttering frequency is increased by linguistic factors, such as syntactic complexity and length of utterance, and decreased by changes in perception, such as masking or altering auditory feedback. Using functional and diffusion imaging, we examined brain structure and function in the motor and language areas in a group of young people who stutter. During speech production, irrespective of fluency or auditory feedback, the people who stuttered showed overactivity relative to controls in the anterior insula, cerebellum and midbrain bilaterally and underactivity in the ventral premotor, Rolandic opercular and sensorimotor cortex bilaterally and Heschl's gyrus on the left. These results are consistent with a recent meta-analysis of functional imaging studies in developmental stuttering. Two additional findings emerged from our study. First, we found overactivity in the midbrain, which was at the level of the substantia nigra and extended to the pedunculopontine nucleus, red nucleus and subthalamic nucleus. This overactivity is consistent with suggestions in previous studies of abnormal function of the basal ganglia or excessive dopamine in people who stutter. Second, we found underactivity of the cortical motor and premotor areas associated with articulation and speech production. Analysis of the diffusion data revealed that the integrity of the white matter underlying the underactive areas in ventral premotor cortex was reduced in people who stutter. The white matter tracts in this area via connections with posterior superior temporal and inferior parietal cortex provide a substrate for the integration of articulatory planning and sensory feedback, and via connections with primary motor cortex, a substrate for execution of articulatory movements. Our data support the conclusion that stuttering is a disorder related primarily

  3. Sambucus nigra extracts inhibit infectious bronchitis virus at an early point during replication

    PubMed Central

    2014-01-01

    Background Infectious bronchitis virus (IBV) is a pathogenic chicken coronavirus. Currently, vaccination against IBV is only partially protective; therefore, better preventions and treatments are needed. Plants produce antimicrobial secondary compounds, which may be a source for novel anti-viral drugs. Non-cytotoxic, crude ethanol extracts of Rhodiola rosea roots, Nigella sativa seeds, and Sambucus nigra fruit were tested for anti-IBV activity, since these safe, widely used plant tissues contain polyphenol derivatives that inhibit other viruses. Results Dose–response cytotoxicity curves on Vero cells using trypan blue staining determined the highest non-cytotoxic concentrations of each plant extract. To screen for IBV inhibition, cells and virus were pretreated with extracts, followed by infection in the presence of extract. Viral cytopathic effect was assessed visually following an additional 24 h incubation with extract. Cells and supernatants were harvested separately and virus titers were quantified by plaque assay. Variations of this screening protocol determined the effects of a number of shortened S. nigra extract treatments. Finally, S. nigra extract-treated virions were visualized by transmission electron microscopy with negative staining. Virus titers from infected cells treated with R. rosea and N. sativa extracts were not substantially different from infected cells treated with solvent alone. However, treatment with S. nigra extracts reduced virus titers by four orders of magnitude at a multiplicity of infection (MOI) of 1 in a dose-responsive manner. Infection at a low MOI reduced viral titers by six orders of magnitude and pretreatment of virus was necessary, but not sufficient, for full virus inhibition. Electron microscopy of virions treated with S. nigra extract showed compromised envelopes and the presence of membrane vesicles, which suggested a mechanism of action. Conclusions These results demonstrate that S. nigra extract can inhibit IBV at

  4. The complete chloroplast genome of two Brassica species, Brassica nigra and B. Oleracea.

    PubMed

    Seol, Young-Joo; Kim, Kyunghee; Kang, Sang-Ho; Perumal, Sampath; Lee, Jonghoon; Kim, Chang-Kug

    2017-03-01

    The two Brassica species, Brassica nigra and Brassica oleracea, are important agronomic crops. The chloroplast genome sequences were generated by de novo assembly using whole genome next-generation sequences. The chloroplast genomes of B. nigra and B. oleracea were 153 633 bp and 153 366 bp in size, respectively, and showed conserved typical chloroplast structure. The both chloroplast genomes contained a total of 114 genes including 80 protein-coding genes, 30 tRNA genes, and 4 rRNA genes. Phylogenetic analysis revealed that B. oleracea is closely related to B. rapa and B. napus but B. nigra is more diverse than the neighbor species Raphanus sativus.

  5. AAV1/2-induced overexpression of A53T-α-synuclein in the substantia nigra results in degeneration of the nigrostriatal system with Lewy-like pathology and motor impairment: a new mouse model for Parkinson's disease.

    PubMed

    Ip, Chi Wang; Klaus, Laura-Christin; Karikari, Akua A; Visanji, Naomi P; Brotchie, Jonathan M; Lang, Anthony E; Volkmann, Jens; Koprich, James B

    2017-02-01

    α-Synuclein is a protein implicated in the etiopathogenesis of Parkinson's disease (PD). AAV1/2-driven overexpression of human mutated A53T-α-synuclein in rat and monkey substantia nigra (SN) induces degeneration of nigral dopaminergic neurons and decreases striatal dopamine and tyrosine hydroxylase (TH). Given certain advantages of the mouse, especially it being amendable to genetic manipulation, translating the AAV1/2-A53T α-synuclein model to mice would be of significant value. AAV1/2-A53T α-synuclein or AAV1/2 empty vector (EV) at a concentration of 5.16 x 10 12 gp/ml were unilaterally injected into the right SN of male adult C57BL/6 mice. Post-mortem examinations included immunohistochemistry to analyze nigral α-synuclein, Ser129 phosphorylated α-synuclein and TH expression, striatal dopamine transporter (DAT) levels by autoradiography and dopamine levels by high performance liquid chromatography. At 10 weeks, in AAV1/2-A53T α-synuclein mice there was a 33% reduction in TH+ dopaminergic nigral neurons (P < 0.001), 29% deficit in striatal DAT binding (P < 0.05), 38% and 33% reductions in dopamine (P < 0.001) and DOPAC (P < 0.01) levels and a 60% increase in dopamine turnover (homovanilic acid/dopamine ratio; P < 0.001). Immunofluorescence showed that the AAV1/2-A53T α-synuclein injected mice had widespread nigral and striatal expression of vector-delivered A53T-α-synuclein. Concurrent staining with human PD SN samples using gold standard histological methodology for Lewy pathology detection by proteinase K digestion and application of specific antibody raised against human Lewy body α-synuclein (LB509) and Ser129 phosphorylated α-synuclein (81A) revealed insoluble α-synuclein aggregates in AAV1/2-A53T α-synuclein mice resembling Lewy-like neurites and bodies. In the cylinder test, we observed significant paw use asymmetry in the AAV1/2-A53T α-synuclein group when compared to EV controls at 5 and 9 weeks post injection (P

  6. A new family of dispersed repeats from Brassica nigra: characterization and localization.

    PubMed

    Kapila, R; Negi, M S; This, P; Delseny, M; Srivastava, P S; Lakshmikumaran, M

    1996-11-01

    The 459-bp HindIII (pBN-4) and the 1732-bp Eco RI (pBNE8) fragments from the Brassica nigra genome were cloned and shown to be members of a dispersed repeat family. Of the three major diploid Brassica species, the repeat pBN-4 was found to be highly specific for the B. nigra genome. The family also hybridized to Sinapis arvensis showing that B. nigra had a closer relationship with the S. arvensis genome than with B. oleracea or B. campestris. The clone pBNE8 showed homology to a number of tRNA species indicating that this family of repeats may have originated from a tRNA sequence. The species-specific 459-bp repeat pBN-4 was localized on the B. nigra chromosomes using monosomic addition lines. In addition to the localization of pBN-4, the chromosomal distribution of two other species-specific repeats, pBN34 and pBNBH35 (reported earlier), was studied. The dispersed repeats pBN-4 and pBNBH35 were found to be present on all of the chromosomes, whereas the tandem repeat pBN34 was localized on two chromosomes.

  7. Parkin disease: a clinicopathologic entity?

    PubMed

    Doherty, Karen M; Silveira-Moriyama, Laura; Parkkinen, Laura; Healy, Daniel G; Farrell, Michael; Mencacci, Niccolo E; Ahmed, Zeshan; Brett, Francesca M; Hardy, John; Quinn, Niall; Counihan, Timothy J; Lynch, Timothy; Fox, Zoe V; Revesz, Tamas; Lees, Andrew J; Holton, Janice L

    2013-05-01

    Mutations in the gene encoding parkin (PARK2) are the most common cause of autosomal recessive juvenile-onset and young-onset parkinsonism. The few available detailed neuropathologic reports suggest that homozygous and compound heterozygous parkin mutations are characterized by severe substantia nigra pars compacta neuronal loss. To investigate whether parkin-linked parkinsonism is a different clinicopathologic entity to Parkinson disease (PD). We describe the clinical, genetic, and neuropathologic findings of 5 unrelated cases of parkin disease and compare them with 5 pathologically confirmed PD cases and 4 control subjects. The PD control cases and normal control subjects were matched first for age at death then disease duration (PD only) for comparison. Presenting signs in the parkin disease cases were hand or leg tremor often combined with dystonia. Mean age at onset was 34 years; all cases were compound heterozygous for mutations of parkin. Freezing of gait, postural deformity, and motor fluctuations were common late features. No patients had any evidence of cognitive impairment or dementia. Neuronal counts in the substantia nigra pars compacta revealed that neuronal loss in the parkin cases was as severe as that seen in PD, but relative preservation of the dorsal tier was seen in comparison with PD (P = .04). Mild neuronal loss was identified in the locus coeruleus and dorsal motor nucleus of the vagus, but not in the nucleus basalis of Meynert, raphe nucleus, or other brain regions. Sparse Lewy bodies were identified in 2 cases (brainstem and cortex). These findings support the notion that parkin disease is characterized by a more restricted morphologic abnormality than is found in PD, with predominantly ventral nigral degeneration and absent or rare Lewy bodies.

  8. Fraxinus nigra (black ash) dieback in Minnesota: Regional variation and potential contributing factors

    Treesearch

    Brian J. Palik; Michael E. Ostry; Robert C. Venette; Ebrahim Abdela

    2011-01-01

    Extensive tree dieback is a recurrent issue in many regions. Crown dieback of Fraxinus nigra Marsh. (black ash; brown ash) in the northeastern and north central United States is an example. F. nigra is a widely distributed hardwood that is often the dominant species in wetland forests from Manitoba to Newfoundland and West...

  9. Adventitious shoot regeneration of Fraxinus nigra Marsh

    Treesearch

    Rochelle R. Beasley; Paula M. Pijut

    2010-01-01

    Fraxinus nigra Marsh. (black ash) is a native ash species occurring in Newfoundland west to Manitoba and south to Iowa, Illinois, West Virginia, and Virginia. Although it is not a commercially important species, it has significant ethnobotanical importance to Native American tribes of the eastern United States.

  10. Dermatosis papulosa nigra in a young child.

    PubMed

    Babapour, R; Leach, J; Levy, H

    1993-12-01

    Dermatosis papulosa nigra was diagnosed in a 3-year-old black boy. This follicular nevoid condition, which is common in adult blacks, is seldom diagnosed in prepubescent children. The diagnosis was confirmed by the biopsy specimen that showed features of epidermal acanthosis and papillomatosis, similar to seborrheic keratosis.

  11. Brain monoamine oxidase B and A in human parkinsonian dopamine deficiency disorders.

    PubMed

    Tong, Junchao; Rathitharan, Gausiha; Meyer, Jeffrey H; Furukawa, Yoshiaki; Ang, Lee-Cyn; Boileau, Isabelle; Guttman, Mark; Hornykiewicz, Oleh; Kish, Stephen J

    2017-09-01

    See Jellinger (doi:10.1093/awx190) for a scientific commentary on this article. The enzyme monoamine oxidases (B and A subtypes, encoded by MAOB and MAOA, respectively) are drug targets in the treatment of Parkinson's disease. Inhibitors of MAOB are used clinically in Parkinson's disease for symptomatic purposes whereas the potential disease-modifying effect of monoamine oxidase inhibitors is debated. As astroglial cells express high levels of MAOB, the enzyme has been proposed as a brain imaging marker of astrogliosis, a cellular process possibly involved in Parkinson's disease pathogenesis as elevation of MAOB in astrocytes might be harmful. Since brain monoamine oxidase status in Parkinson's disease is uncertain, our objective was to measure, by quantitative immunoblotting in autopsied brain homogenates, protein levels of both monoamine oxidases in three different degenerative parkinsonian disorders: Parkinson's disease (n = 11), multiple system atrophy (n = 11), and progressive supranuclear palsy (n = 16) and in matched controls (n = 16). We hypothesized that if MAOB is 'substantially' localized to astroglial cells, MAOB levels should be generally associated with standard astroglial protein measures (e.g. glial fibrillary acidic protein). MAOB levels were increased in degenerating putamen (+83%) and substantia nigra (+10%, non-significant) in multiple system atrophy; in caudate (+26%), putamen (+27%), frontal cortex (+31%) and substantia nigra (+23%) of progressive supranuclear palsy; and in frontal cortex (+33%), but not in substantia nigra of Parkinson's disease, a region we previously reported no increase in astrocyte protein markers. Although the magnitude of MAOB increase was less than those of standard astrocytic markers, significant positive correlations were observed amongst the astrocyte proteins and MAOB. Despite suggestions that MAOA (versus MAOB) is primarily responsible for metabolism of dopamine in dopamine neurons, there was no loss of the

  12. Sydenham chorea: clinical, EEG, MRI and SPECT findings in the early stage of the disease.

    PubMed

    Heye, N; Jergas, M; Hötzinger, H; Farahati, J; Pöhlau, D; Przuntek, H

    1993-02-01

    An 18-year-old man suffered from acute Sydenham chorea appearing coincidently with beta-haemolytic streptococcal throat infection. Imaging techniques documented lesions of basal ganglia and substantia nigra. In the early course of the disease vascular lesions may be important pathogenetic mechanisms of this acquired movement disorder.

  13. The Interaction between Root Herbivory and Competitive Ability of Native and Invasive-Range Populations of Brassica nigra

    PubMed Central

    Oduor, Ayub M. O.; Stift, Marc; van Kleunen, Mark

    2015-01-01

    The evolution of increased competitive ability (EICA) hypothesis predicts that escape from intense herbivore damage may enable invasive plants to evolve higher competitive ability in the invasive range. Below-ground root herbivory can have a strong impact on plant performance, and invasive plants often compete with multiple species simultaneously, but experimental approaches in which EICA predictions are tested with root herbivores and in a community setting are rare. Here, we used Brassica nigra plants from eight invasive- and seven native-range populations to test whether the invasive-range plants have evolved increased competitive ability when competing with Achillea millefolium and with a community (both with and without A. millefolium). Further, we tested whether competitive interactions depend on root herbivory on B. nigra by the specialist Delia radicum. Without the community, competition with A. millefolium reduced biomass of invasive- but not of native-range B. nigra. With the community, invasive-range B. nigra suffered less than native-range B. nigra. Although the overall effect of root herbivory was not significant, it reduced the negative effect of the presence of the community. The community produced significantly less biomass when competing with B. nigra, irrespective of the range of origin, and independent of the presence of A. millefolium. Taken together, these results offer no clear support for the EICA hypothesis. While native-range B. nigra plants appear to be better in dealing with a single competitor, the invasive-range plants appear to be better in dealing with a more realistic multi-species community. Possibly, this ability of tolerating multiple competitors simultaneously has contributed to the invasion success of B. nigra in North America. PMID:26517125

  14. Elevation of neuropeptide Y (NPY) in substantia innominata in Alzheimer's type dementia.

    PubMed

    Allen, J M; Ferrier, I N; Roberts, G W; Cross, A J; Adrian, T E; Crow, T J; Bloom, S R

    1984-06-01

    Concentrations of neuropeptide Y (NPY) have been determined in 12 areas of control brains and compared to those found in brains from patients with Alzheimer's type dementia (ATD). The distribution of NPY in the control brains was compared with those reported previously. Highest concentrations were identified in the subcortical structures, in particular, nucleus accumbens (203 +/- 21.7 pmol/g), amygdala (136.7 +/- 15.8 pmol/g), and substantia innominata (109.0 +/- 12.6 pmol/g). A significant elevation in NPY concentrations was identified in the region of the substantia innominata of Alzheimer brains (controls: 109.0 +/- 12.6 pmol/g, ATD: 206 +/- 28.2 pmol/g, P less than 0.001). This change in NPY concentration was similar to the increase in somatostatin concentration in this region of ATD brain. In contrast, although cortical concentrations of somatostatin were reduced in ATD, no change was found in the concentrations of NPY in the 4 regions of cerebral cortex and the remaining subcortical areas examined.

  15. Regional distribution of neuropeptide Y mRNA in postmortem human brain.

    PubMed

    Brené, S; Lindefors, N; Kopp, J; Sedvall, G; Persson, H

    1989-12-01

    The distribution of messenger RNA encoding neuropeptide Y (NPY) was studied in 11 different postmortem human brain regions using in situ hybridization histochemistry, and RNA blot analysis. In situ hybridization data revealed that the highest numerical density of labeled cells corresponded to neurons in accumbens area, caudate nucleus, putamen, and substantia innominata. Significantly fewer NPY mRNA-containing neurons were found in frontal and parietal cortex, amygdaloid body and dentate gyrus. No NPY mRNA-containing cells were found in substantia nigra. NPY mRNA-positive neurons from all regions studied showed relatively similar labeling, as revealed by computerized image analysis. Blot analysis showed an approximately 0.8 kb NPY mRNA in all brain regions studied, except in substantia nigra and cerebellum. Densitometric scanning of the autoradiograms revealed levels of NPY mRNA in the following order: putamen greater than caudate nucleus greater than frontal cortex (Brodmann areas 4 and 6) greater than temporal cortex (Brodmann area 38) greater than parietal cortex (Brodmann areas 5 and 7) greater than frontal cortex (Brodmann area 11). Hence, although NPY mRNA is widely distributed in neurons of the human brain large regional variation exists, with the highest expression in accumbens area and parts of the basal ganglia.

  16. Tinea nigra presenting speckled or "salt and pepper" pattern.

    PubMed

    Rossetto, André Luiz; Cruz, Rosana Cé Bella; Haddad, Vidal Junior

    2014-06-01

    A 7-year-old Caucasian female resident of the southern coast of Brazil presented dark spots on the left palm that converged to a unique macule with speckled pattern at about 1 month. The mycological exam and the fungi culture were typical of Hortaea werneckii, the agent of the superficial mycosis Tinea nigra. The patient received butenafine hydrochloride 1% for 30 days, resulting in a complete remission of the lesion. At a follow-up visit 12 months after treatment, there was no lesion recurrence. We describe a form of rare geographical Tinea nigra with a speckled pattern. The "salt and pepper" aspect should be taken into consideration when the mycosis was suspected. © The American Society of Tropical Medicine and Hygiene.

  17. Phosphodiesterase-10A Inverse Changes in Striatopallidal and Striatoentopeduncular Pathways of a Transgenic Mouse Model of DYT1 Dystonia.

    PubMed

    D'Angelo, Vincenza; Castelli, Valentina; Giorgi, Mauro; Cardarelli, Silvia; Saverioni, Ilaria; Palumbo, Francesca; Bonsi, Paola; Pisani, Antonio; Giampà, Carmela; Sorge, Roberto; Biagioni, Stefano; Fusco, Francesca R; Sancesario, Giuseppe

    2017-02-22

    We report that changes of phosphodiesterase-10A (PDE10A) can map widespread functional imbalance of basal ganglia circuits in a mouse model of DYT1 dystonia overexpressing mutant torsinA. PDE10A is a key enzyme in the catabolism of second messenger cAMP and cGMP, whose synthesis is stimulated by D1 receptors and inhibited by D2 receptors preferentially expressed in striatoentopeducuncular/substantia nigra or striatopallidal pathways, respectively. PDE10A was studied in control mice (NT) and in mice carrying human wild-type torsinA (hWT) or mutant torsinA (hMT). Quantitative analysis of PDE10A expression was assessed in different brain areas by rabbit anti-PDE10A antibody immunohistochemistry and Western blotting. PDE10A-dependent cAMP hydrolyzing activity and PDE10A mRNA were also assessed. Striatopallidal neurons were identified by rabbit anti-enkephalin antibody.In NT mice, PDE10A is equally expressed in medium spiny striatal neurons and in their projections to entopeduncular nucleus/substantia nigra and to external globus pallidus. In hMT mice, PDE10A content selectively increases in enkephalin-positive striatal neuronal bodies; moreover, PDE10A expression and activity in hMT mice, compared with NT mice, significantly increase in globus pallidus but decrease in entopeduncular nucleus/substantia nigra. Similar changes of PDE10A occur in hWT mice, but such changes are not always significant. However, PDE10A mRNA expression appears comparable among NT, hWT, and hMT mice.In DYT1 transgenic mice, the inverse changes of PDE10A in striatoentopeduncular and striatopallidal projections might result over time in an imbalance between direct and indirect pathways for properly focusing movement. The decrease of PDE10A in the striatoentopeduncular/nigral projections might lead to increased intensity and duration of D1-stimulated cAMP/cGMP signaling; conversely, the increase of PDE10A in the striatopallidal projections might lead to increased intensity and duration of D2

  18. Neutralization of RANTES and Eotaxin Prevents the Loss of Dopaminergic Neurons in a Mouse Model of Parkinson Disease*

    PubMed Central

    Chandra, Goutam; Rangasamy, Suresh B.; Roy, Avik; Kordower, Jeffrey H.; Pahan, Kalipada

    2016-01-01

    Parkinson disease (PD) is second only to Alzheimer disease as the most common human neurodegenerative disorder. Despite intense investigation, no interdictive therapy is available for PD. Recent studies indicate that both innate and adaptive immune processes are active in PD. Accordingly, we found a rapid increase in RANTES (regulated on activation normal T cell expressed and secreted) and eotaxin, chemokines that are involved in T cell trafficking, in vivo in the substantia nigra pars compacta and the serum of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-intoxicated mice. RANTES and eotaxin were also up-regulated in the substantia nigra pars compacta of post-mortem PD brains as compared with age-matched controls. Therefore, we investigated whether neutralization of RANTES and eotaxin could protect against nigrostriatal degeneration in MPTP-intoxicated mice. Interestingly, after peripheral administration, functional blocking antibodies against RANTES and eotaxin reduced the infiltration of CD4+ and CD8+ T cells into the nigra, attenuated nigral expression of proinflammatory molecules, and suppressed nigral activation of glial cells. These findings paralleled dopaminergic neuronal protection, normalized striatal neurotransmitters, and improved motor functions in MPTP-intoxicated mice. Therefore, we conclude that attenuation of the chemokine-dependent adaptive immune response may be of therapeutic benefit for PD patients. PMID:27226559

  19. The Transcription Factor Orthodenticle Homeobox 2 Influences Axonal Projections and Vulnerability of Midbrain Dopaminergic Neurons

    ERIC Educational Resources Information Center

    Chung, Chee Yeun; Licznerski, Pawel; Alavian, Kambiz N.; Simeone, Antonio; Lin, Zhicheng; Martin, Eden; Vance, Jeffery; Isacson, Ole

    2010-01-01

    Two adjacent groups of midbrain dopaminergic neurons, A9 (substantia nigra pars compacta) and A10 (ventral tegmental area), have distinct projections and exhibit differential vulnerability in Parkinson's disease. Little is known about transcription factors that influence midbrain dopaminergic subgroup phenotypes or their potential role in disease.…

  20. Development of Brassica oleracea-nigra monosomic alien addition lines: genotypic, cytological and morphological analyses.

    PubMed

    Tan, Chen; Cui, Cheng; Xiang, Yi; Ge, Xianhong; Li, Zaiyun

    2017-12-01

    We report the development and characterization of Brassica oleracea - nigra monosomic alien addition lines (MAALs) to dissect the Brassica B genome. Brassica nigra (2n = 16, BB) represents the diploid Brassica B genome which carries many useful genes and traits for breeding but received limited studies. To dissect the B genome from B. nigra, the triploid F 1 hybrid (2n = 26, CCB) obtained previously from the cross B. oleracea var. alboglabra (2n = 18, CC) × B. nigra was used as the maternal parent and backcrossed successively to parental B. oleracea. The progenies in BC 1 to BC 3 generations were analyzed by the methods of FISH and SSR markers to screen the monosomic alien addition lines (MAALs) with each of eight different B-genome chromosomes added to C genome (2n = 19, CC + 1B 1-8 ), and seven different MAALs were established, except for the one with chromosome B2 which existed in one triple addition. Most of these MAALs were distinguishable morphologically from each other, as they expressed the characters from B. nigra differently and at variable extents. The alien chromosome remained unpaired as a univalent in 86.24% pollen mother cells at diakinesis or metaphase I, and formed a trivalent with two C-genome chromosomes in 13.76% cells. Transmission frequency of all the added chromosomes was far higher through the ovules (averagely 14.40%) than the pollen (2.64%). The B1, B4 and B5 chromosomes were transmitted by female at much higher rates (22.38-30.00%) than the other four (B3, B6, B7, B8) (5.04-8.42%). The MAALs should be valuable for exploiting the genome structure and evolution of B. nigra.

  1. Quantitative Susceptibility Mapping of the Midbrain in Parkinson’s Disease

    PubMed Central

    Du, Guangwei; Liu, Tian; Lewis, Mechelle M.; Kong, Lan; Wang, Yi; Connor, James; Mailman, Richard B.; Huang, Xuemei

    2017-01-01

    Background Parkinson’s disease (PD) is marked pathologically by dopamine neuron loss and iron overload in the substantia nigra pars compacta. Midbrain iron content is reported to be increased in PD based on magnetic resonance imaging (MRI) R2* changes. Because quantitative susceptibility mapping is a novel MRI approach to measure iron content, we compared it with R2* for assessing midbrain changes in PD. Methods Quantitative susceptibility mapping and R2* maps were obtained from 47 PD patients and 47 healthy controls. Midbrain susceptibility and R2* values were analyzed by using both voxel-based and region-of-interest approaches in normalized space, and analyzed along with clinical data, including disease duration, Unified Parkinson’s Disease Rating Scale (UPDRS) I, II, and III sub-scores, and levodopa-equivalent daily dosage. All studies were done while PD patients were “on drug.” Results Compared with controls, PD patients showed significantly increased susceptibility values in both right (cluster size = 106 mm3) and left (164 mm3) midbrain, located ventrolateral to the red nucleus that corresponded to the substantia nigra pars compacta. Susceptibility values in this region were correlated significantly with disease duration, UPDRS II, and levodopa-equivalent daily dosage. Conversely, R2* was increased significantly only in a much smaller region (62 mm3) of the left lateral substantia nigra pars compacta and was not significantly correlated with clinical parameters. Conclusion The use of quantitative susceptibility mapping demonstrated marked nigral changes that correlated with clinical PD status more sensitively than R2*. These data suggest that quantitative susceptibility mapping may be a superior imaging biomarker to R2* for estimating brain iron levels in PD. PMID:26362242

  2. Interplay between aggression, brain monoamines and fur color mutation in the American mink.

    PubMed

    Kulikov, A V; Bazhenova, E Y; Kulikova, E A; Fursenko, D V; Trapezova, L I; Terenina, E E; Mormede, P; Popova, N K; Trapezov, O V

    2016-11-01

    Domestication of wild animals alters the aggression towards humans, brain monoamines and coat pigmentation. Our aim is the interplay between aggression, brain monoamines and depigmentation. The Hedlund white mutation in the American mink is an extreme case of depigmentation observed in domesticated animals. The aggressive (-2.06 ± 0.03) and tame (+3.5 ± 0.1) populations of wild-type dark brown color (standard) minks were bred during 17 successive generations for aggressive or tame reaction towards humans, respectively. The Hedlund mutation was transferred to the aggressive and tame backgrounds to generate aggressive (-1.2 ± 0.1) and tame (+3.0 ± 0.2) Hedlund minks. Four groups of 10 males with equal expression of aggressive (-2) or tame (+5) behavior, standard or with the Hedlund mutation, were selected to study biogenic amines in the brain. Decreased levels of noradrenaline in the hypothalamus, but increased concentrations of the serotonin metabolite, 5-hydroxyindoleacetic acid and dopamine metabolite, homovanillic acid, in the striatum were measured in the tame compared with the aggressive standard minks. The Hedlund mutation increased noradrenaline level in the hypothalamus and substantia nigra, serotonin level in the substantia nigra and striatum and decreased dopamine concentration in the hypothalamus and striatum. Significant interaction effects were found between the Hedlund mutation and aggressive behavior on serotonin metabolism in the substantia nigra (P < 0.001), dopamine level in the midbrain (P < 0.01) and its metabolism in the striatum (P < 0.05). These results provide the first experimental evidence of the interplay between aggression, brain monoamines and the Hedlund mutation in the American minks. © 2016 John Wiley & Sons Ltd and International Behavioural and Neural Genetics Society.

  3. Neurturin overexpression in dopaminergic neurons induces presynaptic and postsynaptic structural changes in rats with chronic 6-hydroxydopamine lesion

    PubMed Central

    Reyes-Corona, David; Vázquez-Hernández, Nallely; Escobedo, Lourdes; Orozco-Barrios, Carlos E.; Ayala-Davila, Jose; Moreno, Mario Gil; Amaro-Lara, Miriam E.; Flores-Martinez, Yazmin M.; Espadas-Alvarez, Armando J.; Fernandez-Parrilla, Manuel A.; Gonzalez-Barrios, Juan A.; Gutierrez-Castillo, ME; González-Burgos, Ignacio

    2017-01-01

    The structural effect of neurturin (NRTN) on the nigrostriatal dopaminergic system in animals remains unknown, although NRTN has been shown to be effective in Parkinson’s disease animal models. Herein, we aimed to demonstrate that NRTN overexpression in dopaminergic neurons stimulates both neurite outgrowths in the nigrostriatal pathway and striatal dendritic spines in aging rats with chronic 6-hydroxydopamine (6-OHDA) lesion. At week 12 after lesion, pTracer-mNRTN-His or pGreenLantern-1 plasmids were intranigrally transfected using the NTS-polyplex nanoparticles system. We showed that the transgenic expression in dopaminergic neurons remained until the end of the study (12 weeks). Only animals expressing NRTN-His showed recovery of tyrosine hydroxylase (TH)+ cells (28 ± 2%), their neurites (32 ± 2%) and the neuron-specific cytoskeletal marker β-III-tubulin in the substantia nigra; striatal TH(+) fibers were also recovered (52 ± 3%), when compared to the healthy condition. Neurotensin receptor type 1 levels were also significantly recovered in the substantia nigra and striatum. Dopamine recovery was 70 ± 4% in the striatum and complete in the substantia nigra. The number of dendritic spines of striatal medium spiny neurons was also significantly increased, but the recovery was not complete. Drug-activated circling behavior decreased by 73 ± 2% (methamphetamine) and 89 ± 1% (apomorphine). Similar decrease was observed in the spontaneous motor behavior. Our results demonstrate that NRTN causes presynaptic and postsynaptic restoration of the nigrostriatal dopaminergic system after a 6-OHDA-induced chronic lesion. However, those improvements did not reach the healthy condition, suggesting that NRTN exerts lesser neurotrophic effects than other neurotrophic approaches. PMID:29176874

  4. Neurturin overexpression in dopaminergic neurons induces presynaptic and postsynaptic structural changes in rats with chronic 6-hydroxydopamine lesion.

    PubMed

    Reyes-Corona, David; Vázquez-Hernández, Nallely; Escobedo, Lourdes; Orozco-Barrios, Carlos E; Ayala-Davila, Jose; Moreno, Mario Gil; Amaro-Lara, Miriam E; Flores-Martinez, Yazmin M; Espadas-Alvarez, Armando J; Fernandez-Parrilla, Manuel A; Gonzalez-Barrios, Juan A; Gutierrez-Castillo, M E; González-Burgos, Ignacio; Martinez-Fong, Daniel

    2017-01-01

    The structural effect of neurturin (NRTN) on the nigrostriatal dopaminergic system in animals remains unknown, although NRTN has been shown to be effective in Parkinson's disease animal models. Herein, we aimed to demonstrate that NRTN overexpression in dopaminergic neurons stimulates both neurite outgrowths in the nigrostriatal pathway and striatal dendritic spines in aging rats with chronic 6-hydroxydopamine (6-OHDA) lesion. At week 12 after lesion, pTracer-mNRTN-His or pGreenLantern-1 plasmids were intranigrally transfected using the NTS-polyplex nanoparticles system. We showed that the transgenic expression in dopaminergic neurons remained until the end of the study (12 weeks). Only animals expressing NRTN-His showed recovery of tyrosine hydroxylase (TH)+ cells (28 ± 2%), their neurites (32 ± 2%) and the neuron-specific cytoskeletal marker β-III-tubulin in the substantia nigra; striatal TH(+) fibers were also recovered (52 ± 3%), when compared to the healthy condition. Neurotensin receptor type 1 levels were also significantly recovered in the substantia nigra and striatum. Dopamine recovery was 70 ± 4% in the striatum and complete in the substantia nigra. The number of dendritic spines of striatal medium spiny neurons was also significantly increased, but the recovery was not complete. Drug-activated circling behavior decreased by 73 ± 2% (methamphetamine) and 89 ± 1% (apomorphine). Similar decrease was observed in the spontaneous motor behavior. Our results demonstrate that NRTN causes presynaptic and postsynaptic restoration of the nigrostriatal dopaminergic system after a 6-OHDA-induced chronic lesion. However, those improvements did not reach the healthy condition, suggesting that NRTN exerts lesser neurotrophic effects than other neurotrophic approaches.

  5. Usefulness of quantitative susceptibility mapping for the diagnosis of Parkinson disease.

    PubMed

    Murakami, Y; Kakeda, S; Watanabe, K; Ueda, I; Ogasawara, A; Moriya, J; Ide, S; Futatsuya, K; Sato, T; Okada, K; Uozumi, T; Tsuji, S; Liu, T; Wang, Y; Korogi, Y

    2015-06-01

    Quantitative susceptibility mapping allows overcoming several nonlocal restrictions of susceptibility-weighted and phase imaging and enables quantification of magnetic susceptibility. We compared the diagnostic accuracy of quantitative susceptibility mapping and R2* (1/T2*) mapping to discriminate between patients with Parkinson disease and controls. For 21 patients with Parkinson disease and 21 age- and sex-matched controls, 2 radiologists measured the quantitative susceptibility mapping values and R2* values in 6 brain structures (the thalamus, putamen, caudate nucleus, pallidum, substantia nigra, and red nucleus). The quantitative susceptibility mapping values and R2* values of the substantia nigra were significantly higher in patients with Parkinson disease (P < .01); measurements in other brain regions did not differ significantly between patients and controls. For the discrimination of patients with Parkinson disease from controls, receiver operating characteristic analysis suggested that the optimal cutoff values for the substantia nigra, based on the Youden Index, were >0.210 for quantitative susceptibility mapping and >28.8 for R2*. The sensitivity, specificity, and accuracy of quantitative susceptibility mapping were 90% (19 of 21), 86% (18 of 21), and 88% (37 of 42), respectively; for R2* mapping, they were 81% (17 of 21), 52% (11 of 21), and 67% (28 of 42). Pair-wise comparisons showed that the areas under the receiver operating characteristic curves were significantly larger for quantitative susceptibility mapping than for R2* mapping (0.91 versus 0.69, P < .05). Quantitative susceptibility mapping showed higher diagnostic performance than R2* mapping for the discrimination between patients with Parkinson disease and controls. © 2015 by American Journal of Neuroradiology.

  6. Stop! border ahead: Automatic detection of subthalamic exit during deep brain stimulation surgery.

    PubMed

    Valsky, Dan; Marmor-Levin, Odeya; Deffains, Marc; Eitan, Renana; Blackwell, Kim T; Bergman, Hagai; Israel, Zvi

    2017-01-01

    Microelectrode recordings along preplanned trajectories are often used for accurate definition of the subthalamic nucleus (STN) borders during deep brain stimulation (DBS) surgery for Parkinson's disease. Usually, the demarcation of the STN borders is performed manually by a neurophysiologist. The exact detection of the borders is difficult, especially detecting the transition between the STN and the substantia nigra pars reticulata. Consequently, demarcation may be inaccurate, leading to suboptimal location of the DBS lead and inadequate clinical outcomes. We present machine-learning classification procedures that use microelectrode recording power spectra and allow for real-time, high-accuracy discrimination between the STN and substantia nigra pars reticulata. A support vector machine procedure was tested on microelectrode recordings from 58 trajectories that included both STN and substantia nigra pars reticulata that achieved a 97.6% consistency with human expert classification (evaluated by 10-fold cross-validation). We used the same data set as a training set to find the optimal parameters for a hidden Markov model using both microelectrode recording features and trajectory history to enable real-time classification of the ventral STN border (STN exit). Seventy-three additional trajectories were used to test the reliability of the learned statistical model in identifying the exit from the STN. The hidden Markov model procedure identified the STN exit with an error of 0.04 ± 0.18 mm and detection reliability (error < 1 mm) of 94%. The results indicate that robust, accurate, and automatic real-time electrophysiological detection of the ventral STN border is feasible. © 2016 International Parkinson and Movement Disorder Society. © 2016 International Parkinson and Movement Disorder Society.

  7. Atorvastatin protects GABAergic and dopaminergic neurons in the nigrostriatal system in an experimental rat model of transient focal cerebral ischemia.

    PubMed

    Sabogal, Angélica María; Arango, César Augusto; Cardona, Gloria Patricia; Céspedes, Ángel Enrique

    2014-01-01

    Cerebral ischemia is the third leading cause of death and the primary cause of permanent disability worldwide. Atorvastatin is a promising drug with neuroprotective effects that may be useful for the treatment of stroke. However, the effects of atorvastatin on specific neuronal populations within the nigrostriatal system following cerebral ischemia are unknown. To evaluate the effects of atorvastatin on dopaminergic and GABAergic neuronal populations in exofocal brain regions in a model of transient occlusion of the middle cerebral artery. Twenty-eight male eight-week-old Wistar rats were used in this study. Both sham and ischemic rats were treated with atorvastatin (10 mg/kg) or carboxymethylcellulose (placebo) by gavage at 6, 24, 48 and 72 hours post-reperfusion. We analyzed the immunoreactivity of glutamic acid decarboxylase and tyrosine hydroxylase in the globus pallidus, caudate putamen and substantia nigra. We observed neurological damage and cell loss in the caudate putamen following ischemia. We also found an increase in tyrosine hydroxylase immunoreactivity in the medial globus pallidus and substantia nigra reticulata, as well as a decrease in glutamic acid decarboxylase immunoreactivity in the lateral globus pallidus in ischemic animals treated with a placebo. However, atorvastatin treatment was able to reverse these effects, significantly decreasing tyrosine hydroxylase levels in the medial globus pallidus and substantia nigra reticulata and significantly increasing glutamic acid decarboxylase levels in the lateral globus pallidus. Our data suggest that post-ischemia treatment with atorvastatin can have neuro-protective effects in exofocal regions far from the ischemic core by modulating the GABAergic and dopaminergic neuronal populations in the nigrostriatal system, which could be useful for preventing neurological disorders.

  8. Protection of dopaminergic neurons by 5-lipoxygenase inhibitor.

    PubMed

    Kang, Kai-Hsiang; Liou, Horng-Hui; Hour, Mann-Jen; Liou, Houng-Chi; Fu, Wen-Mei

    2013-10-01

    Neuroinflammation and oxidative stress are important factors that induce neurodegeneration in age-related neurological disorders. 5-Lipoxygenase (5-LOX) is the enzyme responsible for catalysing the synthesis of leukotriene or 5-HETE from arachidonic acid. 5-LOX is expressed in the central nervous system and may cause neurodegenerative disease. In this study, we investigated the effect of the pharmacological inhibition of 5-lipoxygenase on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)/MPP(+)-induced dopaminergic neuronal death in midbrain neuron-glia co-cultures and in mice. It was found that 5-LOX was over-expressed in astrocytes after the injection of MPTP into C57BL6 mice. MK-886, a specific inhibitor of 5-LOX activating protein (FLAP), significantly increased [(3)H]-dopamine uptake, a functional indicator of the integrity of dopaminergic neurons, in midbrain cultures or the SH-SY5Y human dopaminergic cell line following MPP(+) treatment. In addition, LTB₄, one of 5-LOX's downstream products, was increased in the striatum and substantia nigra following MPTP injection in mice. LTB₄ but not LTD₄ and 5-HETE enhanced MPP(+)-induced neurotoxicity in primary midbrain cultures. MK-886 administration increased the number of tyrosine hydroxylase-positive neurons in the substantia nigra and the dopamine content in the striatum in MPTP-induced parkinsonian mice. Furthermore, the MPTP-induced upregulation of LTB₄ in the striatum and substantia nigra was antagonised by MK-886. These results suggest that 5-LOX inhibitors may be developed as novel neuroprotective agents and LTB₄ may play an important pathological role in Parkinson's disease. Copyright © 2013 Elsevier Ltd. All rights reserved.

  9. Magnetic Resonance Imaging Features of the Nigrostriatal System: Biomarkers of Parkinson’s Disease Stages?

    PubMed Central

    Hopes, Lucie; Grolez, Guillaume; Moreau, Caroline; Lopes, Renaud; Ryckewaert, Gilles; Carrière, Nicolas; Auger, Florent; Laloux, Charlotte; Petrault, Maud; Devedjian, Jean-Christophe; Bordet, Regis; Defebvre, Luc; Jissendi, Patrice; Delmaire, Christine; Devos, David

    2016-01-01

    Introduction Magnetic resonance imaging (MRI) can be used to identify biomarkers in Parkinson’s disease (PD); R2* values reflect iron content related to high levels of oxidative stress, whereas volume and/or shape changes reflect neuronal death. We sought to assess iron overload in the nigrostriatal system and characterize its relationship with focal and overall atrophy of the striatum in the pivotal stages of PD. Methods Twenty controls and 70 PD patients at different disease stages (untreated de novo patients, treated early-stage patients and advanced-stage patients with L-dopa-related motor complications) were included in the study. We determined the R2* values in the substantia nigra, putamen and caudate nucleus, together with striatal volume and shape analysis. We also measured R2* in an acute MPTP mouse model and in a longitudinal follow-up two years later in the early-stage PD patients. Results The R2* values in the substantia nigra, putamen and caudate nucleus were significantly higher in de novo PD patients than in controls. Early-stage patients displayed significantly higher R2* values in the substantia nigra (with changes in striatal shape), relative to de novo patients. Measurements after a two-year follow-up in early-stage patients and characterization of the acute MPTP mouse model confirmed that R2* changed rapidly with disease progression. Advanced-stage patients displayed significant atrophy of striatum, relative to earlier disease stages. Conclusion Each pivotal stage in PD appears to be characterized by putative nigrostriatal MRI biomarkers: iron overload at the de novo stage, striatal shape changes at early-stage disease and generalized striatal atrophy at advanced disease. PMID:27035571

  10. Tinea nigra: successful treatment with topical butenafine*

    PubMed Central

    Rossetto, André Luiz; Cruz, Rosana Cé Bella

    2012-01-01

    The authors report a case of Tinea nigra in an 8-year-old child, male, from Itajaí, SC, Brazil, with lesions of the macular hyperchromic type, unique, asymptomatic, localized in the right palmar area. The lesion was treated with the topical antifungal butenafine, with remission of symptoms and without recurrence at follow-up for two years. PMID:23197223

  11. Mitochondrial control of cell bioenergetics in Parkinson’s disease

    PubMed Central

    Requejo-Aguilar, Raquel; Bolaños, Juan P.

    2016-01-01

    Parkinson disease (PD) is a neurodegenerative disorder characterized by a selective loss of dopaminergic neurons in the substantia nigra. The earliest biochemical signs of the disease involve failure in mitochondrial-endoplasmic reticulum cross talk and lysosomal function, mitochondrial electron chain impairment, mitochondrial dynamics alterations, and calcium and iron homeostasis abnormalities. These changes are associated with increased mitochondrial reactive oxygen species (mROS) and energy deficiency. Recently, it has been reported that, as an attempt to compensate for the mitochondrial dysfunction, neurons invoke glycolysis as a low-efficient mode of energy production in models of PD. Here, we review how mitochondria orchestrate the maintenance of cellular energetic status in PD, with special focus on the switch from oxidative phosphorylation to glycolysis, as well as the implication of endoplasmic reticulum and lysosomes in the control of bioenergetics. PMID:27091692

  12. Tinea nigra Presenting Speckled or “Salt and Pepper” Pattern

    PubMed Central

    Rossetto, André Luiz; Cruz, Rosana Cé Bella; Junior, Vidal Haddad

    2014-01-01

    A 7-year-old Caucasian female resident of the southern coast of Brazil presented dark spots on the left palm that converged to a unique macule with speckled pattern at about 1 month. The mycological exam and the fungi culture were typical of Hortaea werneckii, the agent of the superficial mycosis Tinea nigra. The patient received butenafine hydrochloride 1% for 30 days, resulting in a complete remission of the lesion. At a follow-up visit 12 months after treatment, there was no lesion recurrence. We describe a form of rare geographical Tinea nigra with a speckled pattern. The “salt and pepper” aspect should be taken into consideration when the mycosis was suspected. PMID:24898980

  13. Horizontal and Vertical Attentional Orienting in Parkinson's Disease

    ERIC Educational Resources Information Center

    Nys, Gudrun M. S.; Santens, Patrick; Vingerhoets, Guy

    2010-01-01

    Patients with Parkinson's disease (PD) typically suffer from an asymmetric degeneration of dopaminergic cells in the substantia nigra, resulting in right-sided (RPD) or left-sided (LPD) predominance of motor symptomatology. As the dopaminergic system is also involved in attention, we examined horizontal and vertical orienting of attention in LPD…

  14. Demyelination of subcortical nuclei in multiple sclerosis

    NASA Astrophysics Data System (ADS)

    Krutenkova, E.; Aitmagambetova, G.; Khodanovich, M.; Bowen, J.; Gangadharan, B.; Henson, L.; Mayadev, A.; Repovic, P.; Qian, P.; Yarnykh, V.

    2016-02-01

    Myelin containing in basal ganglia in multiple sclerosis patients was evaluated using new noninvasive quantitative MRI method fast whole brain macromolecular proton fraction mapping. Myelin level in globus pallidus and putamen significantly decreased in multiple sclerosis patients as compared with healthy control subjects but not in substantia nigra and caudate nucleus.

  15. Activation of Midbrain Structures by Associative Novelty and the Formation of Explicit Memory in Humans

    ERIC Educational Resources Information Center

    Schott, Bjorn H.; Sellner, Daniela B.; Lauer, Corinna-J.; Habib, Reza; Frey, Julietta U.; Guderian, Sebastian; Heinze, Hans-Jochen; Duzel, Emrah

    2004-01-01

    Recent evidence suggests a close functional relationship between memory formation in the hippocampus and dopaminergic neuromodulation originating in the ventral tegmental area and medial substantia nigra of the midbrain. Here we report midbrain activation in two functional MRI studies of visual memory in healthy young adults. In the first study,…

  16. Behavioral Specifications of Reward-Associated Long-Term Memory Enhancement in Humans

    ERIC Educational Resources Information Center

    Wittmann, Bianca C.; Dolan, Raymond J.; Duzel, Emrah

    2011-01-01

    Recent functional imaging studies link reward-related activation of the midbrain substantia nigra-ventral tegmental area (SN/VTA), the site of origin of ascending dopaminergic projections, with improved long-term episodic memory. Here, we investigated in two behavioral experiments how (1) the contingency between item properties and reward, (2) the…

  17. Bidirectional Plasticity in Striatonigral Synapses: A Switch to Balance Direct and Indirect Basal Ganglia Pathways

    ERIC Educational Resources Information Center

    Aceves, Jose J.; Rueda-Orozco, Pavel E.; Hernandez-Martinez, Ricardo; Galarraga, Elvira; Bargas, Jose

    2011-01-01

    There is no hypothesis to explain how direct and indirect basal ganglia (BG) pathways interact to reach a balance during the learning of motor procedures. Both pathways converge in the substantia nigra pars reticulata (SNr) carrying the result of striatal processing. Unfortunately, the mechanisms that regulate synaptic plasticity in striatonigral…

  18. Regeneration of plants from Fraxinus nigra Marsh. hypocotyls

    Treesearch

    Rochelle R. Beasley; Paula M. Pijut

    2013-01-01

    Fraxinus nigra Marsh. (black ash) is a native North American hardwood tree species that is ecologically important and has ethnobotanical significance to American Indian communities of the eastern United States. Black ash has immature embryos at seed set, combined with complex stratification requirements, making natural regeneration difficult. This,...

  19. Antioxidant effect of Morus nigra on Chagas disease progression.

    PubMed

    Montenote, Michelly Cristina; Wajsman, Vithor Zuccaro; Konno, Yoichi Takaki; Ferreira, Paulo César; Silva, Regildo Márcio Gonçalves; Therezo, Altino Luiz Silva; Silva, Luciana Pereira; Martins, Luciamáre Perinetti Alves

    2017-11-06

    Considering the widespread popular use of Morus nigra and the amount of scientific information on its antioxidant and anti-inflammatory activity, the effectiveness of this phytotherapeutic compound in the parasitemia progression during the acute phase of Chagas disease and its role in the development of the inflammatory process as well as its effects on the oxidative damage in the chronic phase of infection were evaluated. Thus, 96 male Swiss mice were randomly divided into eight groups, four groups were uninfected controls, and four groups were intraperitoneally infected with 5.0 x 104 blood trypomastigotes forms of T. cruzi QM2 strain. Four batches composed of one uninfected and one infected group were respectively treated with 70% alcohol solution and 25 μL, 50 μL and 75 μL of the phytotherapeutic compound. Levels of antioxidant elements (TBARS, FRAP, GSH and Sulfhydryl groups) were measured in plasma samples. The phytotherapeutic compound's antioxidant activity was measured by polyphenol and total flavonoid quantification, DPPH, NO, and FRAP method. Our results showed that the vehicle influenced some of the results that may have physiological relevance in Chagas disease. However, an important action of M. nigra tincture was observed in the progression of Chagas disease, since our results demonstrated a reduction in parasitemia of treated groups when compared to controls, especially in the group receiving 25 µL. However, in the chronic phase, the 50-µL dosage presented a better activity on some antioxidant defenses and minimized the tissue inflammatory process. Results indicated an important action of M. nigra tincture on the Chagas disease progression.

  20. Exposure to cannabinoid agonist WIN 55,212-2 during early adolescence increases alcohol preference and anxiety in CD1 mice.

    PubMed

    Frontera, Jimena Laura; Gonzalez Pini, Victoria María; Messore, Fernando Luis; Brusco, Alicia

    2018-05-16

    The endocannabinoid (eCB) system is involved in the modulation of the reward system and participates in the reinforcing effects of different drugs of abuse, including alcohol. The most abundant receptor of the eCB system in the central nervous system is the CB1 receptor (CB1R), which is predominantly expressed in areas involved in drug addiction, such as the nucleus accumbens, the ventral tegmental area, the substantia nigra and the raphe nucleus. CB1R is expressed in early stages during development, and reaches maximum levels during early adolescence. In addition, cannabinoid receptor 2 has been found expressed also in the central nervous system at postsynaptic level. In order to analyze the participation of the eCB system on ethanol (EtOH) preference, mice were exposed to cannabinoid agonist WIN 55,212-2 (WIN) for 5 consecutive days during early adolescence. Anxiety tests were performed the day after WIN treatment withdrawal, and EtOH preference was measured throughout adolescence. Mice exposed to WIN during early adolescence exhibited a significant increase in EtOH intake and preference after treatment. Moreover, WIN exposure during early adolescence induced an anxiogenic effect. Morphometric analysis revealed higher dendritic ramifications and fewer dendritic spines in neurons of the substantia nigra pars compacta in WIN-treated mice. On the other hand, immunohistochemical analysis revealed an increase in the number of tryptophan hydroxylase-expressing neurons in the dorsal raphe nucleus but no differences were found in the ventral tegmental area or substantia nigra pars compacta for tyrosine hydroxylase-expressing neurons. These results demonstrate that exposure to WIN in early adolescence can affect neural development and induce alcohol preference and anxiety-like behavior during late adolescence. Copyright © 2018 Elsevier Ltd. All rights reserved.

  1. Protective role of apigenin on rotenone induced rat model of Parkinson's disease: Suppression of neuroinflammation and oxidative stress mediated apoptosis.

    PubMed

    Anusha, Chandran; Sumathi, Thangarajan; Joseph, Leena Dennis

    2017-05-01

    Parkinson's disease (PD) is a neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra which is associated with oxidative stress, neuroinflammation and apoptosis. Apigenin (AGN), a non-mutagenic flavone found in fruits and vegetables, exhibits a variety of biological effects including anti-apoptotic, anti-inflammatory, and free radical scavenging activities. The current study was aimed to investigate the neuroprotective effects and molecular mechanisms of AGN in a rat model of PD induced by rotenone (ROT). Unilateral stereotaxic intranigral infusion of ROT caused the loss of tyrosine hydroxylase (TH) immunoreactivity in striatum and substantia nigra. AGN treatment (10 and 20 mg/kg, i.p.) showed a significant improvement in behavioral, biochemical and mitochondrial enzyme activities as compared to ROT exposed rats. The mRNA expression of inflammatory markers and neurotrophic factors was quantified by reverse transcriptase polymerase chain reaction (RT-PCR). Administration of AGN significantly attenuated the upregulation of NF-κB gene expression in ROT induced group and prevented the neuroinflammation in substantia nigra pars compacta (SNpc). Further, AGN inhibited the release of pro-inflammatory cytokines TNF- α, IL-6 and pro-inflammatory enzyme iNOS-1 induced by ROT. Additionally, AGN prevents the reduction of neurotrophic factors BDNF and GDNF mRNA expression in ROT lesioned rats. Immunoblot results illustrated that AGN treatment downregulated α-synuclein aggregation and upregulated the TH protein expression as well as dopamine D2 receptor (D2R) expression in ROT lesioned rats. Thus, the present findings collectively suggest that AGN exerts its neuroprotection in ROT model of PD and may act as an effective agent for treatment of PD. Copyright © 2017 Elsevier B.V. All rights reserved.

  2. Ghrelin-AMPK Signaling Mediates the Neuroprotective Effects of Calorie Restriction in Parkinson's Disease

    PubMed Central

    Bayliss, Jacqueline A.; Lemus, Moyra B.; Stark, Romana; Santos, Vanessa V.; Thompson, Aiysha; Rees, Daniel J.; Galic, Sandra; Elsworth, John D.; Kemp, Bruce E.; Davies, Jeffrey S.

    2016-01-01

    Calorie restriction (CR) is neuroprotective in Parkinson's disease (PD) although the mechanisms are unknown. In this study we hypothesized that elevated ghrelin, a gut hormone with neuroprotective properties, during CR prevents neurodegeneration in an 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of PD. CR attenuated the MPTP-induced loss of substantia nigra (SN) dopamine neurons and striatal dopamine turnover in ghrelin WT but not KO mice, demonstrating that ghrelin mediates CR's neuroprotective effect. CR elevated phosphorylated AMPK and ACC levels in the striatum of WT but not KO mice suggesting that AMPK is a target for ghrelin-induced neuroprotection. Indeed, exogenous ghrelin significantly increased pAMPK in the SN. Genetic deletion of AMPKβ1 and 2 subunits only in dopamine neurons prevented ghrelin-induced AMPK phosphorylation and neuroprotection. Hence, ghrelin signaling through AMPK in SN dopamine neurons mediates CR's neuroprotective effects. We consider targeting AMPK in dopamine neurons may recapitulate neuroprotective effects of CR without requiring dietary intervention. SIGNIFICANCE STATEMENT The neuroprotective mechanisms of calorie restriction (CR) in Parkinson's disease are unknown. Indeed, the difficulty to adhere to CR necessitates an alternative method to recapitulate the neuroprotective benefits of CR while bypassing dietary constraints. Here we show that CR increases plasma ghrelin, which targets substantia nigra dopamine to maintain neuronal survival. Selective deletion on AMPK beta1 and beta2 subunits only in DAT cre-expressing neurons shows that the ghrelin-induced neuroprotection requires activation of AMPK in substantia nigra dopamine neurons. We have discovered ghrelin as a key metabolic signal, and AMPK in dopamine neurons as its target, which links calorie restriction with neuroprotection in Parkinson's disease. Thus, targeting AMPK in dopamine neurons may provide novel neuroprotective benefits in Parkinson's disease. PMID

  3. Parkinson's disease: in vivo metabolic changes in the frontal and parietal cortices in 6-OHDA treated rats during different periods.

    PubMed

    Hou, Zhongyu; Zhang, Zhonghe; Meng, Haiwei; Lin, Xiangtao; Sun, Bo; Lei, Hao; Fang, Ke; Fang, Fang; Liu, Maili; Liu, Shuwei

    2014-02-01

    This study aims to investigate metabolic changes in frontal and parietal cortices in the 6-OHDA induced Parkinson's rats. Ratios of N-acetyl-aspartic acid/creatine (NAA/Cr), choline/creatine (Cho/Cr), and glumatic acid and glutamine glutaminic acid/creatine (Glx/Cr) of regions of interests (ROIs) in the frontal and parietal cortices, and the substantia nigra were analyzed. NAA/Cr, Cho/Cr and Glx/Cr in the frontal and parietal cortices in the lesion side did not show any significant differences two weeks after operation compared with the contralateral side (p > 0.05). NAA/Cr in the frontal cortex in the lesion side was significantly lower in the five weeks after operation; Cho/Cr remained normal; Glx/Cr increased (p < 0.05), and all ratios of parietal cortex were normal. In the eight weeks after operation, NAA/Cr in the frontal cortex in the lesion side was lower than that of the five weeks (p < 0.01), Cho/Cr still remained normal while Glx/Cr was higher than before (p < 0.01). Regarding the parietal cortex, NAA/Cr increased significantly, while Cho/Cr and Glx/Cr remained normal. In the 12 weeks after operation, NAA/Cr, Cho/Cr and Glx/Cr in frontal cortex were consistent with that of the eight weeks, while they remained at the normal level in parietal cortex. The NAA/Cr in the substantia nigra decreased and Cho/Cr increased significantly during 2-8 weeks, and remained at the same level during 8-12 weeks. There are metabolic disturbances in PD rats. The transient hyperfunction in the parietal cortex can be considered as a compensation for the dysfunction of the frontal cortex and substantia nigra.

  4. Allosteric modulation of the group III mGlu4 receptor provides functional neuroprotection in the 6-hydroxydopamine rat model of Parkinson's disease

    PubMed Central

    Betts, Matthew J; O'Neill, Michael J; Duty, Susan

    2012-01-01

    BACKGROUND AND PURPOSE We recently reported that broad spectrum agonist-induced activation of presynaptic group III metabotropic glutamate (mGlu) receptors within the substantia nigra pars compacta using L-2-amino-4-phosphonobutyrate provided functional neuroprotection in the 6-hydroxydopamine lesion rat model of Parkinson's disease. The aim of this study was to establish whether selective activation of the mGlu4 receptor alone could afford similar functional neuroprotection. EXPERIMENTAL APPROACH The neuroprotective effects of 8 days of supranigral treatment with a positive allosteric modulator of mGlu4 receptors, (+/−)-cis-2-(3,5-dichlorphenylcarbamoyl)cyclohexanecarboxylic acid (VU0155041), were investigated in rats with unilateral 6-hydroxydopamine lesions. The effects of VU0155041 treatment on motor function were assessed using both habitual (cylinder test) and forced (adjusted stepping, amphetamine-induced rotations) behavioural tests. Nigrostriatal tract integrity was examined by analysis of tyrosine hydroxylase, dopa decarboxylase or dopamine levels in the striatum and tyrosine hydroxylase-positive cell counts in the substantia nigra pars compacta. KEY RESULTS VU0155041 provided around 40% histological protection against a unilateral 6-hydroxydopamine lesion as well as significant preservation of motor function. These effects were inhibited by pre-treatment with (RS)-α-cyclopropyl-4-phosphonophenylglycine, confirming a receptor-mediated response. Reduced levels of inflammatory markers were also evident in the brains of VU0155041-treated animals. CONCLUSIONS AND IMPLICATIONS Allosteric potentiation of mGlu4 receptors in the substantia nigra pars compacta provided neuroprotective effects in the 6-hydroxydopamine rat model A reduced inflammatory response may contribute, in part, to this action. In addition to the reported symptomatic effects, activation of mGlu4 receptors may also offer a novel approach for slowing the progressive degeneration observed in

  5. X-Ray Fluorescence Imaging: A New Tool for Studying Manganese Neurotoxicity

    PubMed Central

    Robison, Gregory; Zakharova, Taisiya; Fu, Sherleen; Jiang, Wendy; Fulper, Rachael; Barrea, Raul; Marcus, Matthew A.; Zheng, Wei; Pushkar, Yulia

    2012-01-01

    The neurotoxic effect of manganese (Mn) establishes itself in a condition known as manganism or Mn induced parkinsonism. While this condition was first diagnosed about 170 years ago, the mechanism of the neurotoxic action of Mn remains unknown. Moreover, the possibility that Mn exposure combined with other genetic and environmental factors can contribute to the development of Parkinson's disease has been discussed in the literature and several epidemiological studies have demonstrated a correlation between Mn exposure and an elevated risk of Parkinson's disease. Here, we introduce X-ray fluorescence imaging as a new quantitative tool for analysis of the Mn distribution in the brain with high spatial resolution. The animal model employed mimics deficits observed in affected human subjects. The obtained maps of Mn distribution in the brain demonstrate the highest Mn content in the globus pallidus, the thalamus, and the substantia nigra pars compacta. To test the hypothesis that Mn transport into/distribution within brain cells mimics that of other biologically relevant metal ions, such as iron, copper, or zinc, their distributions were compared. It was demonstrated that the Mn distribution does not follow the distributions of any of these metals in the brain. The majority of Mn in the brain was shown to occur in the mobile state, confirming the relevance of the chelation therapy currently used to treat Mn intoxication. In cells with accumulated Mn, it can cause neurotoxic action by affecting the mitochondrial respiratory chain. This can result in increased susceptibility of the neurons of the globus pallidus, thalamus, and substantia nigra pars compacta to various environmental or genetic insults. The obtained data is the first demonstration of Mn accumulation in the substantia nigra pars compacta, and thus, can represent a link between Mn exposure and its potential effects for development of Parkinson's disease. PMID:23185282

  6. Complete mitochondrial genome sequence of black mustard (Brassica nigra; BB) and comparison with Brassica oleracea (CC) and Brassica carinata (BBCC).

    PubMed

    Yamagishi, Hiroshi; Tanaka, Yoshiyuki; Terachi, Toru

    2014-11-01

    Crop species of Brassica (Brassicaceae) consist of three monogenomic species and three amphidiploid species resulting from interspecific hybridizations among them. Until now, mitochondrial genome sequences were available for only five of these species. We sequenced the mitochondrial genome of the sixth species, Brassica nigra (nuclear genome constitution BB), and compared it with those of Brassica oleracea (CC) and Brassica carinata (BBCC). The genome was assembled into a 232 145 bp circular sequence that is slightly larger than that of B. oleracea (219 952 bp). The genome of B. nigra contained 33 protein-coding genes, 3 rRNA genes, and 17 tRNA genes. The cox2-2 gene present in B. oleracea was absent in B. nigra. Although the nucleotide sequences of 52 genes were identical between B. nigra and B. carinata, the second exon of rps3 showed differences including an insertion/deletion (indel) and nucleotide substitutions. A PCR test to detect the indel revealed intraspecific variation in rps3, and in one line of B. nigra it amplified a DNA fragment of the size expected for B. carinata. In addition, the B. carinata lines tested here produced DNA fragments of the size expected for B. nigra. The results indicate that at least two mitotypes of B. nigra were present in the maternal parents of B. carinata.

  7. Alpha-synuclein: relating metals to structure, function and inhibition.

    PubMed

    McDowall, J S; Brown, D R

    2016-04-01

    Alpha-synuclein has long been studied due to its involvement in the progression of Parkinson's disease (PD), a common neurodegenerative disorder, although a consensus on the exact function of this protein is elusive. This protein shows remarkable structural plasticity and this property is important for both correct cellular function and pathological progression of PD. Formation of intracellular oligomeric species within the substantia nigra correlates with disease progression and it has been proposed that formation of a partially folded intermediate is key to the initiation of the fibrillisation process. Many factors can influence changes in the structure of alpha-synuclein such as disease mutations and interaction with metals and neurotransmitters. High concentrations of both dopamine and metals are present in the substantia nigra making this an ideal location for both the structural alteration of alpha-synuclein and the production of toxic oxygen species. The recent proposal that alpha-synuclein is a ferrireductase is important as it can possibly catalyse the formation of such reactive species and as a result exacerbate neurodegeneration.

  8. Brainstem Alzheimer’s-Like Pathology in the Triple Transgenic Mouse Model of Alzheimer’s Disease

    PubMed Central

    Overk, Cassia R.; Kelley, Christy M.; Mufson, Elliott J.

    2011-01-01

    The triple transgenic mouse (3xTgAD), harboring human APPSwe, PS1M146V and TauP301L genes, develops age-dependent forebrain intraneuronal Aβ and tau and extraneuronal plaques. We evaluated brainstem AD-like pathology using 6E10, AT8, and Alz50 antibodies and unbiased stereology in young and old 3xTgAD mice. Intraneuronal Aβ occurred in the tectum, periaqueductal gray, substantia nigra, red nucleus, tegmentum and mesencephalic V nucleus at all ages. Aβ-positive neuron numbers significantly decreased in the superior colliculus and substantia nigra while AT8-positive superior colliculus, red nucleus, principal sensory V, vestibular nuclei, and tegmental neurons significantly increased between 2 and 12 months. Alz50-positive neuron numbers increased only in the inferior colliculus between these ages. Dual labeling revealed a few Aβ- and tau- positive neurons. Plaques occurred only in the pons of female 3xTgAD mice starting at 9 months. 3xTgAD mice provide a platform to define in vivo mechanisms of Aβ and tau brainstem pathology. PMID:19524671

  9. Lentivirus-mediated delivery of sonic hedgehog into the striatum stimulates neuroregeneration in a rat model of Parkinson disease.

    PubMed

    Zhang, Yi; Dong, Weiren; Guo, Suiqun; Zhao, Shu; He, Suifen; Zhang, Lihua; Tang, Yinjuan; Wang, Haihong

    2014-12-01

    Parkinson disease (PD) is a progressive neurodegenerative disorder in which the nigrostriatal pathway, consisting of dopaminergic neuronal projections from the substantia nigra to the striatum, degenerates. Viral transduction is currently the most promising in vivo strategy for delivery of therapeutic proteins into the brain for treatment of PD. Sonic hedgehog (Shh) is necessary for cell proliferation, differentiation and neuroprotection in the central nervous system. In this study, we investigated the effects of overexpressed N-terminal product of SHH (SHH-N) in a PD model rat. A lentiviral vector containing SHH-N was stereotactically injected into the striatum 24 h after a striatal 6-OHDA lesion. We found that overexpressed SHH-N attenuated behavioral deficits and reduced the loss of dopamine neurons in the substantia nigra and the loss of dopamine fibers in the striatum. In addition, fluoro-ruby-labeled nigrostriatal projections were also repaired. Together, our results demonstrate the feasibility and efficacy of using the strategy of lentivirus-mediated Shh-N delivery to delay nigrostriatal pathway degeneration. This strategy holds the potential for therapeutic application in the treatment of PD.

  10. Neuroprotective effects of the antiparkinson drug Mucuna pruriens.

    PubMed

    Manyam, Bala V; Dhanasekaran, Muralikrishnan; Hare, Theodore A

    2004-09-01

    Mucuna pruriens possesses significantly higher antiparkinson activity compared with levodopa in the 6-hydroxydopamine (6-OHDA) lesioned rat model of Parkinson's disease. The present study evaluated the neurorestorative effect of Mucuna pruriens cotyledon powder on the nigrostriatal tract of 6-OHDA lesioned rats. Mucuna pruriens cotyledon powder significantly increased the brain mitochondrial complex-I activity but did not affect the total monoamine oxidase activity (in vitro). Unlike synthetic levodopa treatment, Mucuna pruriens cotyledon powder treatment significantly restored the endogenous levodopa, dopamine, norepinephrine and serotonin content in the substantia nigra. Nicotine adenine dinucleotide (NADH) and coenzyme Q-10, that are shown to have a therapeutic benefit in Parkinson's disease, were present in the Mucuna pruriens cotyledon powder. Earlier studies showed that Mucuna pruriens treatment controls the symptoms of Parkinson's disease. This additional finding of a neurorestorative benefit by Mucuna pruriens cotyledon powder on the degenerating dopaminergic neurons in the substantia nigra may be due to increased complex-I activity and the presence of NADH and coenzyme Q-10. Copyright (c) 2004 John Wiley & Sons, Ltd.

  11. Effects of perinatal asphyxia on cell survival, neuronal phenotype and neurite growth evaluated with organotypic triple cultures.

    PubMed

    Klawitter, V; Morales, P; Johansson, S; Bustamante, D; Goiny, M; Gross, J; Luthman, J; Herrera-Marschitz, M

    2005-03-01

    The effect of perinatal asphyxia on brain development was studied with organotypic cultures from substantia nigra, neostriatum and neocortex. Asphyxia was induced by immersing foetuses-containing uterine horns removed from ready-to-deliver rats into a water bath for 20 min. Following asphyxia, the pups were nursed by a surrogate dam and sacrificed after three days for preparing organotypic cultures. Non-asphyxiated caesarean-delivered pups were used as controls. Morphological features and cell viability were recorded during in vitro development. At day in vitro (DIV) 24, the cultures were treated for immunocytochemistry using antibodies against the N-methyl-D-aspartate receptor subunit 1 (NR1) and tyrosine hydroxylase (TH). While in vitro survival was similar in cultures from both asphyxiated and control animals, differences were observed when the neuronal phenotype was assessed. Compared to controls, the total number of NR1-positive neurons in substantia nigra, as well as the number of secondary to higher level branching of TH-positive neurites from asphyxiated pups were decreased, illustrating the vulnerability of the dopaminergic systems to perinatal asphyxia.

  12. Enriched environment protects the nigrostriatal dopaminergic system and induces astroglial reaction in the 6-OHDA rat model of Parkinson's disease.

    PubMed

    Anastasía, Agustín; Torre, Luciana; de Erausquin, Gabriel A; Mascó, Daniel H

    2009-05-01

    Enriched environment (EE) is neuroprotective in several animal models of neurodegeneration. It stimulates the expression of trophic factors and modifies the astrocyte cell population which has been said to exert neuroprotective effects. We have investigated the effects of EE on 6-hydroxydopamine (6-OHDA)-induced neuronal death after unilateral administration to the medial forebrain bundle, which reaches 85-95% of dopaminergic neurons in the substantia nigra after 3 weeks. Continuous exposure to EE 3 weeks before and after 6-OHDA injection prevents neuronal death (assessed by tyrosine hydroxylase staining), protects the nigrostriatal pathway (assessed by Fluorogold retrograde labeling) and reduces motor impairment. Four days after 6-OHDA injection, EE was associated with a marked increase in glial fibrillary acidic protein staining and prevented neuronal death (assessed by Fluoro Jade-B) but not partial loss of tyrosine hydroxylase staining in the anterior substantia nigra. These results robustly demonstrate that EE preserves the entire nigrostriatal system against 6-OHDA-induced toxicity, and suggests that an early post-lesion astrocytic reaction may participate in the neuroprotective mechanism.

  13. HIV-1 gp120 neurotoxicity proximally and at a distance from the point of exposure: protection by rSV40 delivery of antioxidant enzymes.

    PubMed

    Louboutin, Jean-Pierre; Agrawal, Lokesh; Reyes, Beverly A S; Van Bockstaele, Elisabeth J; Strayer, David S

    2009-06-01

    Toxicity of HIV-1 envelope glycoprotein (gp120) for substantia nigra (SN) neurons may contribute to the Parkinsonian manifestations often seen in HIV-1-associated dementia (HAD). We studied the neurotoxicity of gp120 for dopaminergic neurons and potential neuroprotection by antioxidant gene delivery. Rats were injected stereotaxically into their caudate-putamen (CP); CP and (substantia nigra) SN neuron loss was quantified. The area of neuron loss extended several millimeters from the injection site, approximately 35% of the CP area. SN neurons, outside of this area of direct neurotoxicity, were also severely affected. Dopaminergic SN neurons (expressing tyrosine hydroxylase, TH, in the SN and dopamine transporter, DAT, in the CP) were mostly affected: intra-CP gp120 caused approximately 50% DAT+ SN neuron loss. Prior intra-CP gene delivery of Cu/Zn superoxide dismutase (SOD1) or glutathione peroxidase (GPx1) protected SN neurons from intra-CP gp120. Thus, SN dopaminergic neurons are highly sensitive to HIV-1 gp120-induced neurotoxicity, and antioxidant gene delivery, even at a distance, is protective.

  14. Selective updating of working memory content modulates meso-cortico-striatal activity.

    PubMed

    Murty, Vishnu P; Sambataro, Fabio; Radulescu, Eugenia; Altamura, Mario; Iudicello, Jennifer; Zoltick, Bradley; Weinberger, Daniel R; Goldberg, Terry E; Mattay, Venkata S

    2011-08-01

    Accumulating evidence from non-human primates and computational modeling suggests that dopaminergic signals arising from the midbrain (substantia nigra/ventral tegmental area) mediate striatal gating of the prefrontal cortex during the selective updating of working memory. Using event-related functional magnetic resonance imaging, we explored the neural mechanisms underlying the selective updating of information stored in working memory. Participants were scanned during a novel working memory task that parses the neurophysiology underlying working memory maintenance, overwriting, and selective updating. Analyses revealed a functionally coupled network consisting of a midbrain region encompassing the substantia nigra/ventral tegmental area, caudate, and dorsolateral prefrontal cortex that was selectively engaged during working memory updating compared to the overwriting and maintenance of working memory content. Further analysis revealed differential midbrain-dorsolateral prefrontal interactions during selective updating between low-performing and high-performing individuals. These findings highlight the role of this meso-cortico-striatal circuitry during the selective updating of working memory in humans, which complements previous research in behavioral neuroscience and computational modeling. Published by Elsevier Inc.

  15. Neutralization of RANTES and Eotaxin Prevents the Loss of Dopaminergic Neurons in a Mouse Model of Parkinson Disease.

    PubMed

    Chandra, Goutam; Rangasamy, Suresh B; Roy, Avik; Kordower, Jeffrey H; Pahan, Kalipada

    2016-07-15

    Parkinson disease (PD) is second only to Alzheimer disease as the most common human neurodegenerative disorder. Despite intense investigation, no interdictive therapy is available for PD. Recent studies indicate that both innate and adaptive immune processes are active in PD. Accordingly, we found a rapid increase in RANTES (regulated on activation normal T cell expressed and secreted) and eotaxin, chemokines that are involved in T cell trafficking, in vivo in the substantia nigra pars compacta and the serum of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-intoxicated mice. RANTES and eotaxin were also up-regulated in the substantia nigra pars compacta of post-mortem PD brains as compared with age-matched controls. Therefore, we investigated whether neutralization of RANTES and eotaxin could protect against nigrostriatal degeneration in MPTP-intoxicated mice. Interestingly, after peripheral administration, functional blocking antibodies against RANTES and eotaxin reduced the infiltration of CD4(+) and CD8(+) T cells into the nigra, attenuated nigral expression of proinflammatory molecules, and suppressed nigral activation of glial cells. These findings paralleled dopaminergic neuronal protection, normalized striatal neurotransmitters, and improved motor functions in MPTP-intoxicated mice. Therefore, we conclude that attenuation of the chemokine-dependent adaptive immune response may be of therapeutic benefit for PD patients. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

  16. Reflectance confocal microscopy of tinea nigra: comparing images with dermoscopy and mycological examination results.

    PubMed

    Veasey, John Verrinder; Avila, Ricardo Bertozzi de; Ferreira, Marcus Antônio Maia de Olivas; Lazzarini, Rosana

    2017-01-01

    Tinea nigra is a superficial mycosis whose diagnosis is confirmed by isolating the infectious agent Hortae werneckii through mycological examinations. In vivo reflectance confocal microscopy, initially used in melanocytic dermatosis, has been used with skin infectious diseases to identify the parasite at the cellular level. We report, for the first time in the scientific literature, the use of reflectance confocal microscopy in a case of tinea nigra and compare its findings to dermoscopy and mycological examination results.

  17. Reflectance confocal microscopy of tinea nigra: comparing images with dermoscopy and mycological examination results*

    PubMed Central

    Veasey, John Verrinder; de Avila, Ricardo Bertozzi; Ferreira, Marcus Antônio Maia de Olivas; Lazzarini, Rosana

    2017-01-01

    Tinea nigra is a superficial mycosis whose diagnosis is confirmed by isolating the infectious agent Hortae werneckii through mycological examinations. In vivo reflectance confocal microscopy, initially used in melanocytic dermatosis, has been used with skin infectious diseases to identify the parasite at the cellular level. We report, for the first time in the scientific literature, the use of reflectance confocal microscopy in a case of tinea nigra and compare its findings to dermoscopy and mycological examination results. PMID:28954116

  18. Mechanism for Prenatal LPS-Induced DA Neuron Loss

    DTIC Science & Technology

    2005-03-01

    of 48.5% F 12, 485% high glucose DMEM (Life Science/Gibco), 2% B27 supplement, 1% Pen/Strep antibiotics, and epidermal growth factor (EGF) at 20 ng/ml...Itagaki S, Boyes BE, McGeer EG (1988) Reactive microglia are positive for HLA -DR in the substantia nigra of Parkinson’s and Alzheimer’s disease

  19. Wood identification of Dalbergia nigra (CITES Appendix I) using quantitative wood anatomy, principal components analysis and naive Bayes classification.

    PubMed

    Gasson, Peter; Miller, Regis; Stekel, Dov J; Whinder, Frances; Zieminska, Kasia

    2010-01-01

    Dalbergia nigra is one of the most valuable timber species of its genus, having been traded for over 300 years. Due to over-exploitation it is facing extinction and trade has been banned under CITES Appendix I since 1992. Current methods, primarily comparative wood anatomy, are inadequate for conclusive species identification. This study aims to find a set of anatomical characters that distinguish the wood of D. nigra from other commercially important species of Dalbergia from Latin America. Qualitative and quantitative wood anatomy, principal components analysis and naïve Bayes classification were conducted on 43 specimens of Dalbergia, eight D. nigra and 35 from six other Latin American species. Dalbergia cearensis and D. miscolobium can be distinguished from D. nigra on the basis of vessel frequency for the former, and ray frequency for the latter. Principal components analysis was unable to provide any further basis for separating the species. Naïve Bayes classification using the four characters: minimum vessel diameter; frequency of solitary vessels; mean ray width; and frequency of axially fused rays, classified all eight D. nigra correctly with no false negatives, but there was a false positive rate of 36.36 %. Wood anatomy alone cannot distinguish D. nigra from all other commercially important Dalbergia species likely to be encountered by customs officials, but can be used to reduce the number of specimens that would need further study.

  20. Genetic homogeneity in Juglans nigra(Juglanaceae) at nuclear microsatellites

    Treesearch

    Erin R. Victory; Jeffrey C. Glaubitz; Olin E., Jr. Rhodes; Keith E. Woeste

    2006-01-01

    Broad-scale studies of genetic structure and diversity are indicative of the recent evolutionary history of a species and are relevant to conservation efforts. We have estimated current levels of genetic diversity and population structure for black walnut (Juglans nigra L.), a highly valuable timber species, in the central hardwood region of the...

  1. Chemotaxonomic significance of the terpene composition in natural populations of Pinus nigra J.F.Arnold from Serbia.

    PubMed

    Sarac, Zorica; Bojović, Srdjan; Nikolić, Biljana; Tešević, Vele; Ethorđević, Iris; Marin, Petar D

    2013-08-01

    The essential-oil variability in seven native populations belonging to different infraspecific taxa of Pinus nigra (ssp. nigra, var. gocensis, ssp. pallasiana, and var. banatica) growing wild in Serbia was analyzed. In the needles of 195 trees from seven populations, 58 essential-oil components were identified. The major components were α-pinene (43.6%) and germacrene D (29.8%), comprising together 73.4% of the total oil composition. Based on the average chemical profile of the main terpene components (with contents >5%), the studied populations were found to be the most similar to populations from central Italy and Greece (ssp. nigra). Cluster analysis showed the division of the populations into three principal groups: the first group consisted of Populations I, II, III, IV, and V (considered as ssp. nigra group), the second of Population VI (ssp. pallasiana group), and the third of Population VII, which had the most distinct oil composition (ssp. banatica group). The taxonomic implications of the essential-oil profiles of the investigated taxa of this very complex species are discussed. Copyright © 2013 Verlag Helvetica Chimica Acta AG, Zürich.

  2. Assessment of black ash (Fraxinus nigra) decline in Minnesota

    Treesearch

    Kathleen Ward; Michael Ostry; Robert Venette; Brian Palik; Mark Hansen; Mark Hatfield

    2009-01-01

    Black ash (Fraxinus nigra) is an important component of wetland forests throughout the Upper Midwest and northeastern United States and is highly valued for paneling, furniture, and basketry. Decline of black ash has been noted with increasing frequency, although no detailed studies of the pattern of decline across the region have been done. From...

  3. Chemical composition and bioactivity studies of Alpinia nigra essential oils

    USDA-ARS?s Scientific Manuscript database

    Free radical scavenging, bactericidal and bitting deterrent properties of Alpinia nigra essential oils (EOs) were investigated in the present study. Chemical composition of the EOs were analyzed using GC-MS/GC-FID which revealed the presence of 63 constituents including ß-caryophyllene as major comp...

  4. Composition, diffusion, and antifungal activity of black mustard (Brassica nigra) essential oil when applied by direct addition or vapor phase contact.

    PubMed

    Mejía-Garibay, Beatriz; Palou, Enrique; López-Malo, Aurelio

    2015-04-01

    In this study, we characterized the essential oil (EO) of black mustard (Brassica nigra) and quantified its antimicrobial activity, when applied by direct contact into the liquid medium or by exposure in the vapor phase (in laboratory media or in a bread-type product), against the growth of Aspergillus niger, Aspergillus ochraceus, or Penicillium citrinum. Allyl-isothiocyanate (AITC) was identified as the major component of B. nigra EO with a concentration of 378.35 mg/ml. When B. nigra EO was applied by direct contact into the liquid medium, it inhibited the growth of A. ochraceus and P. citrinum when the concentration was 2 μl/ml of liquid medium (MIC), while for A. niger, a MIC of B. nigra EO was 4 μl/ml of liquid medium. Exposure of molds to B. nigra EO in vapor phase showed that 41.1 μl of B. nigra EO per liter of air delayed the growth of P. citrinum and A. niger by 10 days, while A. ochraceus growth was delayed for 20 days. Exposure to concentrations ≥ 47 μl of B. nigra EO per liter of air (MIC) inhibited the growth of tested molds by 30 days, and they were not able to recover after further incubation into an environment free of EO (fungicidal effect). Adsorbed AITC was quantified by exposing potato dextrose agar to B. nigra EO in a vapor phase, exhibiting that AITC was retained at least 5 days when testing EO at its MIC or with higher concentrations. Mustard EO MIC was also effective against the evaluated molds inhibiting their growth for 30 days in a bread-type product when exposed to EO by vapor contact, demonstrating its antifungal activity.

  5. Cortical-basal ganglionic degeneration.

    PubMed

    Riley, D E; Lang, A E; Lewis, A; Resch, L; Ashby, P; Hornykiewicz, O; Black, S

    1990-08-01

    We report our experience with 15 patients believed to have cortical-basal ganglionic degeneration. The clinical picture is distinctive, comprising features referable to both cortical and basal ganglionic dysfunction. Characteristic manifestations include cortical sensory loss, focal reflex myoclonus, "alien limb" phenomena, apraxia, rigidity and akinesia, a postural-action tremor, limb dystonia, hyperreflexia, and postural instability. The asymmetry of symptoms and signs is often striking. Brain imaging may demonstrate greater abnormalities contralateral to the more affected side. Postmortem studies in 2 patients revealed the characteristic pathologic features of swollen, poorly staining (achromatic) neurons and degeneration of cerebral cortex and substantia nigra. Biochemical analysis of 1 brain showed a severe, diffuse loss of dopamine in the striatum. This condition is more frequent than previously believed, and the diagnosis can be predicted during life on the basis of clinical findings. However, as with other "degenerative" diseases of the nervous system, a definitive diagnosis of cortical-basal ganglionic degeneration requires confirmation by autopsy.

  6. Neuropathologic findings in an aged albino gorilla.

    PubMed

    Márquez, M; Serafin, A; Fernández-Bellon, H; Serrat, S; Ferrer-Admetlla, A; Bertranpetit, J; Ferrer, I; Pumarola, M

    2008-07-01

    Pallido-nigral spheroids associated with iron deposition have been observed in some aged clinically normal nonhuman primates. In humans, similar findings are observed in neurodegeneration with brain iron accumulation diseases, which, in some cases, show associated mutations in pantothenate kinase 2 gene (PANK2). Here we present an aged gorilla, 40 years old, suffering during the last 2 years of life from progressive tetraparesis, nystagmus, and dyskinesia of the arms, hands, and neck, with accompanying abnormal behavior. The postmortem neuropathologic examination revealed, in addition to aging-associated changes in the brain, numerous corpora amylacea in some brain areas, especially the substantia nigra, and large numbers of axonal spheroids associated with iron accumulation in the internal globus pallidus. Sequencing of the gorilla PANK2 gene failed to detect any mutation. The clinical, neuropathologic, and genetic findings in this gorilla point to an age-related pallido-nigral degeneration that presented PKAN-like neurologic deficits.

  7. A clinical, dermoscopic, and histopathological study of Dermatosis Papulosa Nigra (DPN) - An Indian perspective.

    PubMed

    Bhat, Ramesh M; Patrao, Ninon; Monteiro, Rochelle; Sukumar, D

    2017-09-01

    Dermatosis papulosa nigra (DPN) is a benign cutaneous condition which commonly occurs in dark-skinned people, especially Asians and African Americans. Owing to its benign nature and rarity, very few studies have been conducted to date, and dermoscopic studies are practically nonexistent. To study the clinical and epidemiological characteristics of patients with dermatosis papulosa nigra (DPN) and to correlate the clinical findings with dermoscopic and histopathological findings in DPN. A total of 100 patients attending the Dermatology outpatient department at Father Muller Medical College, Mangalore, India, with clinically diagnosed dermatosis papulosa nigra were included in the study. Histopathology and dermoscopic evaluation of the lesions were done, and the characteristics seen were noted. Earlier onset of lesions was noted in our study, i.e. onset in the 4th decade as compared to the 6th decade in most other studies. A female preponderance, positive family history, history of sun exposure, and involvement of the head and neck were other significant associations. Histopathology revealed an acanthotic variant in all the lesions that were biopsied. The predominant dermoscopic finding was fissures and ridges of the cerebriform pattern followed by comedo-like openings. Dermatosis papulosa nigra is a benign unaesthetic condition seen in Fitzpatrick skin types IV-VI. The diagnosis is mainly clinical; however, in a few cases histopathology and dermoscopy aid in differentiating it from other benign and malignant tumors. Dermoscopy, in particular, being a noninvasive investigative moiety is a rapid and accurate diagnostic tool. © 2017 The International Society of Dermatology.

  8. The potential role of neuroinflammation and transcription factors in Parkinson disease

    PubMed Central

    Tiwari, Prafulla Chandra; Pal, Rishi

    2017-01-01

    Parkinson disease (PD) is a neurodegenerative disorder characterized by dopaminergic neurons affected by inflammatory processes. Post-mortem analyses of brain and cerebrospinal fluid from PD patients show the accumulation of proinflammatory cytokines, confirming an ongoing neuroinflammation in the affected brain regions. These inflammatory mediators may activate transcription factors—notably nuclear factor κB, Ying-Yang 1 (YY1), fibroblast growth factor 20 (FGF20), and mammalian target of rapamycin (mTOR)—which then regulate downstream signaling pathways that in turn promote death of dopaminergic neurons through death domain-containing receptors. Dopaminergic neurons are vulnerable to oxidative stress and inflammatory attack. An increased level of inducible nitric oxide synthase observed in the substantia nigra and striatum of PD patients suggests that both cytokine—and chemokine-induced toxicity and inflammation lead to oxidative stress that contributes to degeneration of dopaminergic neurons and to disease progression. Lipopolysaccharide activation of microglia in the proximity of dopaminergic neurons in the substantia nigra causes their degeneration, and this appears to be a selective vulnerability of dopaminergic neurons to inflammation. In this review, we will look at the role of various transcription factors and signaling pathways in the development of PD. PMID:28566949

  9. Ineffectiveness of saxagliptin as a neuroprotective drug in 6-OHDA-lesioned rats.

    PubMed

    Turnes, Joelle de Melo; Bassani, Taysa Bervian; Souza, Leonardo C; Vital, Maria A B F

    2018-05-16

    To determine whether the drug saxagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor which is utilized for the treatment of Diabetes Mellitus, has neuroprotective effects in the animal model of Parkinson's disease (PD) induced by 6-hydroxydopamine (6-OHDA) in rats. Male Wistar rats (weighing 280-300 g) received a bilateral infusion of 6-OHDA in the substantia nigra. Twenty-four hours later, they were treated with saxagliptin (1 mg/kg, p.o) once daily, for 21 days. The motor function was evaluated using the open field and rotarod (RT) tests. In addition, cognition was assessed with the novel object recognition test (ORT). After the evaluation of the behavioural tests, the animals were transcardially perfused to perform immunohistochemistry staining for tyrosine hydroxylase (TH) in the substantia nigra pars compacta (SNpc). Saxagliptin impaired the memory of animals in the sham group. Saxagliptin treatment did not exhibit neuroprotection and it did not improve the cognitive and motor deficits in the 6-OHDA model of PD. Interestingly, when saxagliptin was administered to the sham animals, a cognitive decline was observed. Therefore, this drug should be investigated as a possible treatment for PTSD. © 2018 Royal Pharmaceutical Society.

  10. [Motivation and Emotional States: Structural Systemic, Neurochemical, Molecular and Cellular Mechanisms].

    PubMed

    Bazyan, A S

    2016-01-01

    The structural, systemic, neurochemical, molecular and cellular mechanisms of organization and coding motivation and emotional states are describe. The GABA and glutamatergic synaptic systems of basal ganglia form a neural network and participate in the implementation of voluntary behavior. Neuropeptides, neurohormones and paracrine neuromodulators involved in the organization of motivation and emotional states, integrated with synaptic systems, controlled by neural networks and organizing goal-directed behavior. Structural centers for united and integrated of information in voluntary and goal-directed behavior are globus pallidus. Substantia nigra pars reticulata switches the information from corticobasal networks to thalamocortical networks, induces global dopaminergic (DA) signal and organize interaction of mesolimbic and nigostriatnoy DA systems controlled by prefrontal and motor cortex. Together with the motor cortex, substantia nigra displays information in the brainstem and spinal cord to implementation of behavior. Motivation states are formed in the interaction of neurohormonal and neuropeptide systems by monoaminergic systems of brain. Emotional states are formed by monoaminergic systems of the mid-brain, where the leading role belongs to the mesolimbic DA system. The emotional and motivation state of the encoded specific epigenetic molecular and chemical pattern of neuron.

  11. ASIC1a Deficient Mice Show Unaltered Neurodegeneration in the Subacute MPTP Model of Parkinson Disease.

    PubMed

    Komnig, Daniel; Imgrund, Silke; Reich, Arno; Gründer, Stefan; Falkenburger, Björn H

    2016-01-01

    Inflammation contributes to the death of dopaminergic neurons in Parkinson disease and can be accompanied by acidification of extracellular pH, which may activate acid-sensing ion channels (ASIC). Accordingly, amiloride, a non-selective inhibitor of ASIC, was protective in an acute 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson disease. To complement these findings we determined MPTP toxicity in mice deficient for ASIC1a, the most common ASIC isoform in neurons. MPTP was applied i.p. in doses of 30 mg per kg on five consecutive days. We determined the number of dopaminergic neurons in the substantia nigra, assayed by stereological counting 14 days after the last MPTP injection, the number of Nissl positive neurons in the substantia nigra, and the concentration of catecholamines in the striatum. There was no difference between ASIC1a-deficient mice and wildtype controls. We are therefore not able to confirm that ASIC1a are involved in MPTP toxicity. The difference might relate to the subacute MPTP model we used, which more closely resembles the pathogenesis of Parkinson disease, or to further targets of amiloride.

  12. DNA isolation protocol effects on nuclear DNA analysis by microarrays, droplet digital PCR, and whole genome sequencing, and on mitochondrial DNA copy number estimation.

    PubMed

    Nacheva, Elizabeth; Mokretar, Katya; Soenmez, Aynur; Pittman, Alan M; Grace, Colin; Valli, Roberto; Ejaz, Ayesha; Vattathil, Selina; Maserati, Emanuela; Houlden, Henry; Taanman, Jan-Willem; Schapira, Anthony H; Proukakis, Christos

    2017-01-01

    Potential bias introduced during DNA isolation is inadequately explored, although it could have significant impact on downstream analysis. To investigate this in human brain, we isolated DNA from cerebellum and frontal cortex using spin columns under different conditions, and salting-out. We first analysed DNA using array CGH, which revealed a striking wave pattern suggesting primarily GC-rich cerebellar losses, even against matched frontal cortex DNA, with a similar pattern on a SNP array. The aCGH changes varied with the isolation protocol. Droplet digital PCR of two genes also showed protocol-dependent losses. Whole genome sequencing showed GC-dependent variation in coverage with spin column isolation from cerebellum. We also extracted and sequenced DNA from substantia nigra using salting-out and phenol / chloroform. The mtDNA copy number, assessed by reads mapping to the mitochondrial genome, was higher in substantia nigra when using phenol / chloroform. We thus provide evidence for significant method-dependent bias in DNA isolation from human brain, as reported in rat tissues. This may contribute to array "waves", and could affect copy number determination, particularly if mosaicism is being sought, and sequencing coverage. Variations in isolation protocol may also affect apparent mtDNA abundance.

  13. Neurotensin receptor binding levels in basal ganglia are not altered in Huntington's chorea or schizophrenia

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Palacios, J.M.; Chinaglia, G.; Rigo, M.

    1991-02-01

    Autoradiographic techniques were used to examine the distribution and levels of neurotensin receptor binding sites in the basal ganglia and related regions of the human brain. Monoiodo ({sup 125}I-Tyr3)neurotensin was used as a ligand. High amounts of neurotensin receptor binding sites were found in the substantia nigra pars compacta. Lower but significant quantities of neurotensin receptor binding sites characterized the caudate, putamen, and nucleus accumbens, while very low quantities were seen in both medial and lateral segments of the globus pallidus. In Huntington's chorea, the levels of neurotensin receptor binding sites were found to be comparable to those of controlmore » cases. Only slight but not statistically significant decreases in amounts of receptor binding sites were detected in the dorsal part of the head and in the body of caudate nucleus. No alterations in the levels of neurotensin receptor binding sites were observed in the substantia nigra pars compacta and reticulata. These results suggest that a large proportion of neurotensin receptor binding sites in the basal ganglia are located on intrinsic neurons and on extrinsic afferent fibers that do not degenerate in Huntington's disease.« less

  14. Shake the Disease. Georges Marinesco, Paul Blocq and the Pathogenesis of Parkinsonism, 1893

    PubMed Central

    Hostiuc, Sorin; Drima, Eduard; Buda, Octavian

    2016-01-01

    James Parkinson, in his “Essay on the Shaking Palsy” from 1817 described for the first time the disease that later on carried his name. Its anatomical substrate remained controversial for over 100 years. The first case that suggested the association between Parkinson’s disease and substantia nigra was published in 1893 Blocq and Marinesco, two scientists who worked at Salpêtrière. The article described a 38 years-old man, with tuberculosis, who was admitted to the Charcot’s neurological ward because he also showed signs of unilateral Parkinsonism. During the autopsy, the investigators found a tubercle that destroyed the right substantia nigra. As the patient had overactive reflexes on the left side and the symptomatology matched exactly the localization of the tumor, Blocq and Marinesco suggested the Parkinsonism to be more likely a complication of tuberculosis and not an incidental finding. In this article, we will discuss the contribution of these two authors to the elucidation of the pathology of Parkinson’s disease, and highlight how even a single case report may play an essential role in the development of knowledge in biomedical sciences. PMID:27445712

  15. Shifted dynamic interactions between subcortical nuclei and inferior frontal gyri during response preparation in persistent developmental stuttering.

    PubMed

    Metzger, F Luise; Auer, Tibor; Helms, Gunther; Paulus, Walter; Frahm, Jens; Sommer, Martin; Neef, Nicole E

    2018-01-01

    Persistent developmental stuttering is associated with basal ganglia dysfunction or dopamine dysregulation. Here, we studied whole-brain functional connectivity to test how basal ganglia structures coordinate and reorganize sensorimotor brain networks in stuttering. To this end, adults who stutter and fluent speakers (control participants) performed a response anticipation paradigm in the MRI scanner. The preparation of a manual Go/No-Go response reliably produced activity in the basal ganglia and thalamus and particularly in the substantia nigra. Strikingly, in adults who stutter, substantia nigra activity correlated positively with stuttering severity. Furthermore, functional connectivity analyses yielded altered task-related network formations in adults who stutter compared to fluent speakers. Specifically, in adults who stutter, the globus pallidus and the thalamus showed increased network synchronization with the inferior frontal gyrus. This implies dynamic shifts in the response preparation-related network organization through the basal ganglia in the context of a non-speech motor task in stuttering. Here we discuss current findings in the traditional framework of how D1 and D2 receptor activity shapes focused movement selection, thereby suggesting a disproportional involvement of the direct and the indirect pathway in stuttering.

  16. Establishing a baseline phase behavior in magnetic resonance imaging to determine normal vs. abnormal iron content in the brain.

    PubMed

    Haacke, E Mark; Ayaz, Muhammad; Khan, Asadullah; Manova, Elena S; Krishnamurthy, Bharani; Gollapalli, Lakshman; Ciulla, Carlo; Kim, I; Petersen, Floyd; Kirsch, Wolff

    2007-08-01

    To establish a baseline of phase differences between tissues in a number of regions of the human brain as a means of detecting iron abnormalities using magnetic resonance imaging (MRI). A fully flow-compensated, three-dimensional (3D), high-resolution, gradient-echo (GRE) susceptibility-weighted imaging (SWI) sequence was used to collect magnitude and phase data at 1.5 T. The phase images were high-pass-filtered and processed region by region with hand-drawn areas. The regions evaluated included the motor cortex (MC), putamen (PUT), globus pallidus (GP), caudate nucleus (CN), substantia nigra (SN), and red nucleus (RN). A total of 75 subjects, ranging in age from 55 to 89 years, were analyzed. The phase was found to have a Gaussian-like distribution with a standard deviation (SD) of 0.046 radians on a pixel-by-pixel basis. Most regions of interest (ROIs) contained at least 100 pixels, giving a standard error of the mean (SEM) of 0.0046 radians or less. In the MC, phase differences were found to be roughly 0.273 radians between CSF and gray matter (GM), and 0.083 radians between CSF and white matter (WM). The difference between CSF and the GP was 0.201 radians, and between CSF and the CN (head) it was 0.213 radians. For CSF and the PUT (the lower outer part) the difference was 0.449 radians, and between CSF and the RN (third slice vascularized region) it was 0.353 radians. Finally, the phase difference between CSF and SN was 0.345 radians. The Gaussian-like distributions in phase make it possible to predict deviations from normal phase behavior for tissues in the brain. Using phase as an iron marker may be useful for studying absorption of iron in diseases such as Parkinson's, Huntington's, neurodegeneration with brain iron accumulation (NBIA), Alzheimer's, and multiple sclerosis (MS), and other iron-related diseases. The phases quoted here will serve as a baseline for future studies that look for changes in iron content. (c) 2007 Wiley-Liss, Inc.

  17. In vitro antimicrobial and antiprotozoal activities, phytochemical screening and heavy metals toxicity of different parts of Ballota nigra.

    PubMed

    Ullah, Najeeb; Ahmad, Ijaz; Ayaz, Sultan

    2014-01-01

    The study was done to assess the phytochemicals (flavonoids, terpenoids, saponins, tannin, alkaloids, and phenol) in different parts (root, stem, and leaves) of Ballota nigra and correlated it to inhibition of microbes (bacteria and fungi), protozoan (Leishmania), and heavy metals toxicity evaluation. In root and stem flavonoids, terpenes and phenols were present in ethanol, chloroform, and ethyl acetate soluble fraction; these were found to be the most active inhibiting fractions against all the tested strains of bacteria, fungi, and leishmania. While in leaves flavonoids, terpenes, and phenols were present in ethanol, chloroform, and n-butanol fractions which were the most active fractions against both types of microbes and protozoan (leishmania) in in vitro study. Ethanol and chloroform fractions show maximum inhibition against Escherichia coli (17 mm). The phytochemical and biological screenings were correlated with the presence of heavy metals in selected plant Ballota nigra. Cr was found above permissible value (above 1.5 mg/kg) in all parts of the plant. Ni was above WHO limit in B. nigra root and leaves (3.35 ± 1.20 mg/kg and 5.09 ± 0.47 mg/kg, respectively). Fe was above permissible value in all parts of B. nigra (above 20 mg/kg). Cd was above permissible value in all parts of the plant (above 0.3 mg/kg). Pb was above WHO limit (above 2 mg/kg) in all parts of Ballota nigra.

  18. In Vitro Antimicrobial and Antiprotozoal Activities, Phytochemical Screening and Heavy Metals Toxicity of Different Parts of Ballota nigra

    PubMed Central

    Ullah, Najeeb; Ahmad, Ijaz; Ayaz, Sultan

    2014-01-01

    The study was done to assess the phytochemicals (flavonoids, terpenoids, saponins, tannin, alkaloids, and phenol) in different parts (root, stem, and leaves) of Ballota nigra and correlated it to inhibition of microbes (bacteria and fungi), protozoan (Leishmania), and heavy metals toxicity evaluation. In root and stem flavonoids, terpenes and phenols were present in ethanol, chloroform, and ethyl acetate soluble fraction; these were found to be the most active inhibiting fractions against all the tested strains of bacteria, fungi, and leishmania. While in leaves flavonoids, terpenes, and phenols were present in ethanol, chloroform, and n-butanol fractions which were the most active fractions against both types of microbes and protozoan (leishmania) in in vitro study. Ethanol and chloroform fractions show maximum inhibition against Escherichia coli (17 mm). The phytochemical and biological screenings were correlated with the presence of heavy metals in selected plant Ballota nigra. Cr was found above permissible value (above 1.5 mg/kg) in all parts of the plant. Ni was above WHO limit in B. nigra root and leaves (3.35 ± 1.20 mg/kg and 5.09 ± 0.47 mg/kg, respectively). Fe was above permissible value in all parts of B. nigra (above 20 mg/kg). Cd was above permissible value in all parts of the plant (above 0.3 mg/kg). Pb was above WHO limit (above 2 mg/kg) in all parts of Ballota nigra. PMID:25054139

  19. Bilateral Tinea Nigra Plantaris with Good Response to Isoconazole Cream: A Case Report.

    PubMed

    Falcão, Eduardo Mastrangelo Marinho; Trope, Beatriz Moritz; Martins, Natália Regina Pinto Guedes; Barreiros, Maria da Glória Carvalho; Ramos-E-Silva, Marcia

    2015-01-01

    Tinea nigra is a superficial fungal infection caused by Hortaea werneckii. It typically affects young individuals as an asymptomatic unilateral macule, from light brown to black on the palms and soles, mainly in tropical and subtropical regions. In 1997, Gupta et al. [Br J Dermatol 1997;137:483-484] described the dermoscopic characteristics of tinea nigra. Topical antifungals with or without keratolytic agents can be used for the treatment. The authors report a case of a 47-year-old man with asymptomatic light brown macules bilaterally on the plantar regions. Dermoscopic examination revealed brownish spicules consistent with the pattern described in the literature. Treatment with isoconazole cream was effective with complete resolution.

  20. Mechanisms of Dopamine Release From Rat Striatum and Nucleus Accumbens Slices:The Role of Transporters, Receptors and Membrane Depolarization

    DTIC Science & Technology

    1992-07-21

    hydroxylase could represent pan of the biochemical basis of cocaine addiction and craving (Beitner-Johnson and Nestler, 1991). Although cocaine...in reinforcement , the mechanisms underlying the stimulant and reinforcing effects of addictive drugs such as D-amphetamine and cocaine remain... baclofen on neurons in the tar substantia nigra slice. Brai n Res. 332:337-340, 1984 Pitts , D.K. and Marwah, J.: Cocaine and central monoaminergic

  1. A receptor autoradiographic and in situ hybridization analysis of the distribution of the 5-ht7 receptor in rat brain.

    PubMed Central

    Gustafson, E. L.; Durkin, M. M.; Bard, J. A.; Zgombick, J.; Branchek, T. A.

    1996-01-01

    1. Receptor autoradiography and in situ hybridization histochemistry have been used to delineate the distribution of the 5-ht7 receptor and its mRNA in rat brain. Receptor autoradiographic studies were performed using [3H]-5-carboxamidotryptamine (5-CT) as the radioligand. The binding characteristics of the masking compounds were determined in Cos-7 cells transfected with a panel of 5-HT receptor subtype cDNAs, including the rat 5-ht7 cDNA. In situ hybridization studies were carried out with 35S-labelled oligonucleotide probes to the rat 5-ht7 mRNA. 2. Specific binding of [3H]-5-CT was observed in many areas of the rat brain. Following co-incubation with 1 microM ergotamine, this binding was completely eliminated. After addition of the masking ligands, [3H]-5-CT binding remained in layers 1-3 of cortex, septum, globus pallidus, thalamus, hypothalamus, centromedial amygdala, substantia nigra, periaquaductal gray, and superior colliculus. Addition of the antagonist, methiothepin, to the incubation regimen eliminated most of the remaining [3H]-5-CT binding in the brain, with the exception of the globus pallidus and substantia nigra. 3. The 5-ht7 mRNA was discretely localized in rat brain. The most intense hybridization signals were observed over the thalamus, the anterior hippocampal rudiment, and over the CA3 region of the hippocampus. Other regions containing hybridization signals included the septum, the hypothalamus, the centromedial amygdala and the periaquaductal gray. The regions exhibiting a modest receptor binding signal after methiothepin incubation, the globus pallidus and the substantia nigra, contained no 5-ht7 hybridization signals, suggesting a non-5-ht7 subtype in these two related structures. 4. The distribution of the 5-ht7 receptor and its mRNA is suggestive of multiple roles for this novel 5-HT receptor, within several brain systems. The limbic system (centromedial amygdala, anterior hippocampal rudiment, hypothalamus) is particularly well

  2. Wood identification of Dalbergia nigra (CITES Appendix I) using quantitative wood anatomy, principal components analysis and naïve Bayes classification

    PubMed Central

    Gasson, Peter; Miller, Regis; Stekel, Dov J.; Whinder, Frances; Ziemińska, Kasia

    2010-01-01

    Background and Aims Dalbergia nigra is one of the most valuable timber species of its genus, having been traded for over 300 years. Due to over-exploitation it is facing extinction and trade has been banned under CITES Appendix I since 1992. Current methods, primarily comparative wood anatomy, are inadequate for conclusive species identification. This study aims to find a set of anatomical characters that distinguish the wood of D. nigra from other commercially important species of Dalbergia from Latin America. Methods Qualitative and quantitative wood anatomy, principal components analysis and naïve Bayes classification were conducted on 43 specimens of Dalbergia, eight D. nigra and 35 from six other Latin American species. Key Results Dalbergia cearensis and D. miscolobium can be distinguished from D. nigra on the basis of vessel frequency for the former, and ray frequency for the latter. Principal components analysis was unable to provide any further basis for separating the species. Naïve Bayes classification using the four characters: minimum vessel diameter; frequency of solitary vessels; mean ray width; and frequency of axially fused rays, classified all eight D. nigra correctly with no false negatives, but there was a false positive rate of 36·36 %. Conclusions Wood anatomy alone cannot distinguish D. nigra from all other commercially important Dalbergia species likely to be encountered by customs officials, but can be used to reduce the number of specimens that would need further study. PMID:19884155

  3. Multi-modal Brain MRI in Subjects with PD and iRBD.

    PubMed

    Mangia, Silvia; Svatkova, Alena; Mascali, Daniele; Nissi, Mikko J; Burton, Philip C; Bednarik, Petr; Auerbach, Edward J; Giove, Federico; Eberly, Lynn E; Howell, Michael J; Nestrasil, Igor; Tuite, Paul J; Michaeli, Shalom

    2017-01-01

    Idiopathic rapid eye movement sleep behavior disorder (iRBD) is a condition that often evolves into Parkinson's disease (PD). Therefore, by monitoring iRBD it is possible to track the neurodegeneration of individuals who may progress to PD. Here we aimed at piloting the characterization of brain tissue properties in mid-brain subcortical regions of 10 healthy subjects, 8 iRBD, and 9 early-diagnosed PD. We used a battery of magnetic resonance imaging (MRI) contrasts at 3 T, including adiabatic and non-adiabatic rotating frame techniques developed by our group, along with diffusion tensor imaging (DTI) and resting-state fMRI. Adiabatic T 1ρ and T 2ρ , and non-adiabatic RAFF4 (Relaxation Along a Fictitious Field in the rotating frame of rank 4) were found to have lower coefficient of variations and higher sensitivity to detect group differences as compared to DTI parameters such as fractional anisotropy and mean diffusivity. Significantly longer T 1ρ were observed in the amygdala of PD subjects vs. controls, along with a trend of lower functional connectivity as measured by regional homogeneity, thereby supporting the notion that amygdalar dysfunction occurs in PD. Significant abnormalities in reward networks occurred in iRBD subjects, who manifested lower network strength of the accumbens. In agreement with previous studies, significantly longer T 1ρ occurred in the substantia nigra compacta of PD vs. controls, indicative of neuronal degeneration, while regional homogeneity was lower in the substantia nigra reticulata. Finally, other trend-level findings were observed, i.e., lower RAFF4 and T 2ρ in the midbrain of iRBD subjects vs. controls, possibly indicating changes in non-motor features as opposed to motor function in the iRBD group. We conclude that rotating frame relaxation methods along with functional connectivity measures are valuable to characterize iRBD and PD subjects, and with proper validation in larger cohorts may provide pathological signatures

  4. Effects of Sambucus nigra and Aronia melanocarpa extracts on immune system disorders within diabetes mellitus.

    PubMed

    Badescu, Magda; Badulescu, Oana; Badescu, Laurentiu; Ciocoiu, Manuela

    2015-04-01

    The fruits of Aronia melanocarpa Elliot (Rosaceae), (black chokeberry), and Sambucus nigra L. (Caprifoliaceae), elderberries are rich in anthocyanins. Many studies have reported that anthocyanins are beneficial in diabetes due to their capacity to stimulate insulin secretion and reduce oxidative stress. The purpose of this study is to prove the biologically active properties of polyphenols extracted from S. nigra and A. melanocarpa fruit. The study also details the influence of plant polyphenols on immune system imbalances within diabetes mellitus. Polyphenolic extract was administered to Wistar rats 0.040 g/kg body every 2 d for 16 weeks. The absorbencies of all the solutions were determined using a V-550 Able Jasco UV-VIS spectrophotometer. The immunomodulatory capacity of vegetal extracts was assessed by studying cytokines TNF-α and IFN-γ through the ELISA method and fibrinogen values. At 48 h, the anti-inflammatory effects of S. nigra and A. melanocarpa substances have been revealed by an increase of the TNF-α and IFN-γ levels in the diabetic group protected by these extracts. Seventy-two hours post-administration of both substances in the diabetic groups, the TNF-α level returns to the values read 24 h after substance administration. The vegetal extracts limit the production of fibrinogen in the diabetic rats under polyphenolic protection, the values being highly significant compared with the diabetic group. Natural polyphenols extracted from S. nigra and A. melanocarpa modulate specific and non-specific immune defenses in insulin-deficiency diabetes and reduce the inflammatory status and self-sustained pancreatic insulitis.

  5. Tinea nigra by Hortaea werneckii, a report of 22 cases from Mexico.

    PubMed

    Bonifaz, A; Badali, H; de Hoog, G S; Cruz, M; Araiza, J; Cruz, M A; Fierro, L; Ponce, R M

    2008-01-01

    Tinea nigra is a superficial mycosis caused by Hortaea werneckii. It is an infrequent asymptomatic infection that affects human palms and soles, and is mostly observed in tropical countries. We evaluate retrospectively twenty-two confirmed cases of tinea nigra from a total of eleven yr (1997-2007) and discuss the epidemiology, clinical features and treatment of this disease. In twelve cases, adults were involved, in 10, children. In nineteen cases the disorder was located on palms of hands and in three on soles of feet. In all cases, the obtained isolates were morphologically identified as Hortaea werneckii and the identification of ten isolates was retrospectively confirmed with the help of sequences of the internal transcribed spacer regions of the ribosomal DNA. The patients received topical treatment with Whitfield ointment, ketoconazole, bifonazole, or terbinafine. Treatment with keratolytic agents and topical antifungals was effective.

  6. Functional Analysis of Dopaminergic Systems in a DYT1 Knock-in Mouse Model of Dystonia

    PubMed Central

    Song, Chang-Hyun; Fan, Xueliang; Exeter, Cicely J.; Hess, Ellen J.; Jinnah, H. A.

    2012-01-01

    The dystonias are a group of disorders characterized by involuntary twisting movements and abnormal posturing. The most common of the inherited dystonias is DYT1 dystonia, which is due to deletion of a single GAG codon (ΔE) in the TOR1A gene that encodes torsinA. Since some forms of dystonia have been linked with dysfunction of brain dopamine pathways, the integrity of these pathways was explored in a knock-in mouse model of DYT1 dystonia. In DYT1(ΔE) knock-in mice, neurochemical measures revealed only small changes in the content of dopamine or its metabolites in tissue homogenates from caudoputamen or midbrain, but microdialysis studies revealed robust decreases in baseline and amphetamine-stimulated extracellular dopamine in the caudoputamen. Quantitative stereological methods revealed no evidence for striatal or midbrain atrophy, but substantia nigra neurons immunopositive for tyrosine hydroxylase were slightly reduced in numbers and enlarged in size. Behavioral studies revealed subtle abnormalities in gross motor activity and motor coordination without overt dystonia. Neuropharmacological challenges of dopamine systems revealed normal behavioral responses to amphetamine and a minor increase in sensitivity to haloperidol. These results demonstrate that this DYT1(ΔE) knock-in mouse model of dystonia harbors neurochemical and structural changes of the dopamine pathways, as well as motor abnormalities. PMID:22659308

  7. Midbrain dopamine function in schizophrenia and depression: a post-mortem and positron emission tomographic imaging study.

    PubMed

    Howes, Oliver D; Williams, Matthew; Ibrahim, Kemal; Leung, Garret; Egerton, Alice; McGuire, Philip K; Turkheimer, Federico

    2013-11-01

    Elevated in vivo markers of presynaptic striatal dopamine activity have been a consistent finding in schizophrenia, and include a large effect size elevation in dopamine synthesis capacity. However, it is not known if the dopaminergic dysfunction is limited to the striatal terminals of dopamine neurons, or is also evident in the dopamine neuron cell bodies, which mostly originate in the substantia nigra. The aim of our studies was therefore to determine whether dopamine synthesis capacity is altered in the substantia nigra of people with schizophrenia, and how this relates to symptoms. In a post-mortem study, a semi-quantitative analysis of tyrosine hydroxylase staining was conducted in nigral dopaminergic cells from post-mortem tissue from patients with schizophrenia (n = 12), major depressive disorder (n = 13) and matched control subjects (n = 13). In an in vivo imaging study, nigral and striatal dopaminergic function was measured in patients with schizophrenia (n = 29) and matched healthy control subjects (n = 29) using (18)F-dihydroxyphenyl-L-alanine ((18)F-DOPA) positron emission tomography. In the post-mortem study we found that tyrosine hydroxylase staining was significantly increased in nigral dopaminergic neurons in schizophrenia compared with both control subjects (P < 0.001) and major depressive disorder (P < 0.001). There was no significant difference in tyrosine hydroxylase staining between control subjects and patients with major depressive disorder, indicating that the elevation in schizophrenia is not a non-specific indicator of psychiatric illness. In the in vivo imaging study we found that (18)F-dihydroxyphenyl-L-alanine uptake was elevated in both the substantia nigra and in the striatum of patients with schizophrenia (effect sizes = 0.85, P = 0.003 and 1.14, P < 0.0001, respectively) and, in the voxel-based analysis, was elevated in the right nigra (P < 0.05 corrected for family wise-error). Furthermore, nigral (18)F

  8. Canopy treatment influences growth of replacement tree species in Fraxinus nigra forests threatened by the emerald ash borer in Minnesota, USA

    Treesearch

    Christopher E. Looney; Anthony W. D' Amato; Brian J. Palik; Robert A. Slesak

    2017-01-01

    Fraxinus nigra Marsh. (black ash), a dominant tree species of wetland forests in northern Minnesota, USA, is imperiled by the invasive insect emerald ash borer (EAB; Agrilus planipennis Fairmaire, 1888). Regeneration of associated tree species is generally low in F. nigra forests and could be impacted...

  9. Engineering Devices to Treat Epilepsy: A Clinical Perspective

    DTIC Science & Technology

    2001-10-25

    Research over the next three decades reinforced the idea that seizures likely spread through discrete, functional neuronal networks [2]. Over the last...15 years, researchers have demonstrated that it is possible to modulate the activity of functional neuronal networks in animal models of epilepsy by...hypothalamus [5], mamillary bodies [6], cerebellum [7], basal ganglia [8], locus ceruleus [9] and the substantia nigra [10]. At the same time some

  10. Striatal dysfunction increases basal ganglia output during motor cortex activation in parkinsonian rats.

    PubMed

    Belluscio, Mariano A; Riquelme, Luis A; Murer, M Gustavo

    2007-05-01

    During movement, inhibitory neurons in the basal ganglia output nuclei show complex modulations of firing, which are presumptively driven by corticostriatal and corticosubthalamic input. Reductions in discharge should facilitate movement by disinhibiting thalamic and brain stem nuclei while increases would do the opposite. A proposal that nigrostriatal dopamine pathway degeneration disrupts trans-striatal pathways' balance resulting in sustained overactivity of basal ganglia output nuclei neurons and Parkinson's disease clinical signs is not fully supported by experimental evidence, which instead shows abnormal synchronous oscillatory activity in animal models and patients. Yet, the possibility that variation in motor cortex activity drives transient overactivity in output nuclei neurons in parkinsonism has not been explored. In Sprague-Dawley rats with 6-hydroxydopamine (6-OHDA)-induced nigrostriatal lesions, approximately 50% substantia nigra pars reticulata (SNpr) units show abnormal cortically driven slow oscillations of discharge. Moreover, these units selectively show abnormal responses to motor cortex stimulation consisting in augmented excitations of an odd latency, which overlapped that of inhibitory responses presumptively mediated by the trans-striatal direct pathway in control rats. Delivering D1 or D2 dopamine agonists into the striatum of parkinsonian rats by reverse microdialysis reduced these abnormal excitations but had no effect on pathological oscillations. The present study establishes that dopamine-deficiency related changes of striatal function contribute to producing abnormally augmented excitatory responses to motor cortex stimulation in the SNpr. If a similar transient overactivity of basal ganglia output were driven by motor cortex input during movement, it could contribute to impeding movement initiation or execution in Parkinson's disease.

  11. Influence of altitudinal variation on the content of phenolic compounds in wild populations of Calluna vulgaris, Sambucus nigra, and Vaccinium myrtillus.

    PubMed

    Rieger, Gudrun; Müller, Maria; Guttenberger, Helmut; Bucar, Franz

    2008-10-08

    This study deals with the effect of altitudinal variation on the content of phenolic compounds in three traditional herbal plants, which are also consumed as food in Central Europe. Herbs of Calluna vulgaris (L.) HULL, flowers and fruits of Sambucus nigra L., and berries of Vaccinium myrtillus L. collected in the Naturpark Solktaler (Austria) were extracted using accelerated solvent extraction (ASE). Identification and quantification of the constituents in the polar extracts (methanol 80%, v/v) were achieved by means of RP-HPLC-PDA and/or LC-PDA-MS analysis with external standards. 3,5- O-Dicaffeoylquinic acid was identified in flowers of S. nigra for the first time. Rising concentrations of flavonoids and especially flavonol-3- O-glycosides with adjacent hydroxyl groups in ring B in C. vulgaris and S. nigra with increasing altitude were observed. Anthocyanins from the berries of both S. nigra and V. myrtillus occurred in decreasing amounts with rising altitude. C. vulgaris showed the best radical scavenging capacity based on the DPPH assay.

  12. Tinea nigra by Hortaea werneckii, a report of 22 cases from Mexico

    PubMed Central

    Bonifaz, A.; Badali, H.; de Hoog, G.S.; Cruz, M.; Araiza, J.; Cruz, M.A.; Fierro, L.; Ponce, R.M.

    2008-01-01

    Tinea nigra is a superficial mycosis caused by Hortaea werneckii. It is an infrequent asymptomatic infection that affects human palms and soles, and is mostly observed in tropical countries. We evaluate retrospectively twenty-two confirmed cases of tinea nigra from a total of eleven yr (1997–2007) and discuss the epidemiology, clinical features and treatment of this disease. In twelve cases, adults were involved, in 10, children. In nineteen cases the disorder was located on palms of hands and in three on soles of feet. In all cases, the obtained isolates were morphologically identified as Hortaea werneckii and the identification of ten isolates was retrospectively confirmed with the help of sequences of the internal transcribed spacer regions of the ribosomal DNA. The patients received topical treatment with Whitfield ointment, ketoconazole, bifonazole, or terbinafine. Treatment with keratolytic agents and topical antifungals was effective. PMID:19287529

  13. Mimetic Muscles in a Despotic Macaque (Macaca mulatta) Differ from Those in a Closely Related Tolerant Macaque (M. nigra).

    PubMed

    Burrows, Anne M; Waller, Bridget M; Micheletta, Jérôme

    2016-10-01

    Facial displays (or expressions) are a primary means of visual communication among conspecifics in many mammalian orders. Macaques are an ideal model among primates for investigating the co-evolution of facial musculature, facial displays, and social group size/behavior under the umbrella of "ecomorphology". While all macaque species share some social behaviors, dietary, and ecological parameters, they display a range of social dominance styles from despotic to tolerant. A previous study found a larger repertoire of facial displays in tolerant macaque species relative to despotic species. The present study was designed to further explore this finding by comparing the gross morphological features of mimetic muscles between the Sulawesi macaque (Macaca nigra), a tolerant species, and the rhesus macaque (M. mulatta), a despotic species. Five adult M. nigra heads were dissected and mimetic musculature was compared to those from M. mulatta. Results showed that there was general similarity in muscle presence/absence between the species as well as muscle form except for musculature around the external ear. M. mulatta had more musculature around the external ear than M. nigra. In addition, M. nigra lacked a zygomaticus minor while M. mulatta is reported to have one. These morphological differences match behavioral observations documenting a limited range of ear movements used by M. nigra during facial displays. Future studies focusing on a wider phylogenetic range of macaques with varying dominance styles may further elucidate the roles of phylogeny, ecology, and social variables in the evolution of mimetic muscles within Macaca Anat Rec, 299:1317-1324, 2016. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  14. Rapid in vitro shoot multiplication of the recalcitrant species Juglans nigra L.

    Treesearch

    Micah E. Stevens; Paula M. Pijut

    2018-01-01

    Black walnut (Juglans nigra L.) has long been prized for its timber, leading to commercial cultivation and significant breeding efforts for improving marketable traits. Vegetative and in vitro black walnut propagation techniques, however, are variable and highly genotype dependent. Optimizing plant growth regulator type and...

  15. A Review of the Pedunculopontine Nucleus in Parkinson's Disease.

    PubMed

    French, Isobel T; Muthusamy, Kalai A

    2018-01-01

    The pedunculopontine nucleus (PPN) is situated in the upper pons in the dorsolateral portion of the ponto-mesencephalic tegmentum. Its main mass is positioned at the trochlear nucleus level, and is part of the mesenphalic locomotor region (MLR) in the upper brainstem. The human PPN is divided into two subnuclei, the pars compacta (PPNc) and pars dissipatus (PPNd), and constitutes both cholinergic and non-cholinergic neurons with afferent and efferent projections to the cerebral cortex, thalamus, basal ganglia (BG), cerebellum, and spinal cord. The BG controls locomotion and posture via GABAergic output of the substantia nigra pars reticulate (SNr). In PD patients, GABAergic BG output levels are abnormally increased, and gait disturbances are produced via abnormal increases in SNr-induced inhibition of the MLR. Since the PPN is vastly connected with the BG and the brainstem, dysfunction within these systems lead to advanced symptomatic progression in Parkinson's disease (PD), including sleep and cognitive issues. To date, the best treatment is to perform deep brain stimulation (DBS) on PD patients as outcomes have shown positive effects in ameliorating the debilitating symptoms of this disease by treating pathological circuitries within the parkinsonian brain. It is therefore important to address the challenges and develop this procedure to improve the quality of life of PD patients.

  16. A Review of the Pedunculopontine Nucleus in Parkinson's Disease

    PubMed Central

    French, Isobel T.; Muthusamy, Kalai A.

    2018-01-01

    The pedunculopontine nucleus (PPN) is situated in the upper pons in the dorsolateral portion of the ponto-mesencephalic tegmentum. Its main mass is positioned at the trochlear nucleus level, and is part of the mesenphalic locomotor region (MLR) in the upper brainstem. The human PPN is divided into two subnuclei, the pars compacta (PPNc) and pars dissipatus (PPNd), and constitutes both cholinergic and non-cholinergic neurons with afferent and efferent projections to the cerebral cortex, thalamus, basal ganglia (BG), cerebellum, and spinal cord. The BG controls locomotion and posture via GABAergic output of the substantia nigra pars reticulate (SNr). In PD patients, GABAergic BG output levels are abnormally increased, and gait disturbances are produced via abnormal increases in SNr-induced inhibition of the MLR. Since the PPN is vastly connected with the BG and the brainstem, dysfunction within these systems lead to advanced symptomatic progression in Parkinson's disease (PD), including sleep and cognitive issues. To date, the best treatment is to perform deep brain stimulation (DBS) on PD patients as outcomes have shown positive effects in ameliorating the debilitating symptoms of this disease by treating pathological circuitries within the parkinsonian brain. It is therefore important to address the challenges and develop this procedure to improve the quality of life of PD patients. PMID:29755338

  17. Neuroprotective and Therapeutic Strategies against Parkinson’s Disease: Recent Perspectives

    PubMed Central

    Sarkar, Sumit; Raymick, James; Imam, Syed

    2016-01-01

    Parkinsonism is a progressive motor disease that affects 1.5 million Americans and is the second most common neurodegenerative disease after Alzheimer’s. Typical neuropathological features of Parkinson’s disease (PD) include degeneration of dopaminergic neurons located in the pars compacta of the substantia nigra that project to the striatum (nigro-striatal pathway) and depositions of cytoplasmic fibrillary inclusions (Lewy bodies) which contain ubiquitin and α-synuclein. The cardinal motor signs of PD are tremors, rigidity, slow movement (bradykinesia), poor balance, and difficulty in walking (Parkinsonian gait). In addition to motor symptoms, non-motor symptoms that include autonomic and psychiatric as well as cognitive impairments are pressing issues that need to be addressed. Several different mechanisms play an important role in generation of Lewy bodies; endoplasmic reticulum (ER) stress induced unfolded proteins, neuroinflammation and eventual loss of dopaminergic neurons in the substantia nigra of mid brain in PD. Moreover, these diverse processes that result in PD make modeling of the disease and evaluation of therapeutics against this devastating disease difficult. Here, we will discuss diverse mechanisms that are involved in PD, neuroprotective and therapeutic strategies currently in clinical trial or in preclinical stages, and impart views about strategies that are promising to mitigate PD pathology. PMID:27338353

  18. Brain dopamine and kinematics of graphomotor functions.

    PubMed

    Lange, Klaus W; Mecklinger, Lara; Walitza, Susanne; Becker, Georg; Gerlach, Manfred; Naumann, Markus; Tucha, Oliver

    2006-10-01

    Three experiments were performed in an attempt to achieve a better understanding of the effect of dopamine on handwriting. In the first experiment, kinematic aspects of handwriting movements were compared between healthy participants and patients with Parkinson's disease (PD) on their usual dopaminergic treatment and following withdrawal of dopaminergic medication. In the second experiment, the writing performance of healthy participants with a hyperechogenicity of the substantia nigra as detected by transcranial sonography (TCS) was compared with the performance of healthy participants with low echogenicity of the substantia nigra. The third experiment examined the effect of central dopamine reduction on kinematic aspects of handwriting movements in healthy adults using acute phenylalanine and tyrosine depletion (APTD). A digitising tablet was used for the assessment of handwriting movements. Participants were asked to perform a simple writing task. Movement time, distance, velocity, acceleration and measures of fluency of handwriting movements were measured. The kinematic analysis of handwriting movements revealed that alterations of central dopaminergic neurotransmission adversely affect movement execution during handwriting. In comparison to the automatic processing of handwriting movements displayed by control participants, participants with an altered dopaminergic neurotransmission shifted from an automatic to a controlled processing of movement execution. Central dopamine appears to be of particular importance with regard to the automatic execution of well-learned movements.

  19. Chronic restraint stress triggers dopaminergic and noradrenergic neurodegeneration: Possible role of chronic stress in the onset of Parkinson's disease.

    PubMed

    Sugama, Shuei; Sekiyama, Kazunari; Kodama, Tohru; Takamatsu, Yoshiki; Takenouchi, Takato; Hashimoto, Makoto; Bruno, Conti; Kakinuma, Yoshihiko

    2016-01-01

    Parkinson's disease (PD) is a neurodegenerative disease characterized by the loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc) and, to a lesser extent, in the noradrenergic neurons of the locus coeruleus (LC). Most cases of PD are idiopathic and sporadic and are believed to be the result of both environmental and genetic factors. Here, to the best of our knowledge, we report the first evidence that chronic restraint stress (8h/day, 5days/week) substantially reduces nigral DA and LC noradrenergic neuronal cell numbers in rats. Loss of DA neurons in the SNpc was evident after 2weeks of stress and progressed in a time-dependent manner, reaching up to 61% at 16weeks. This reduction was accompanied by robust microglial activation and oxidative stress and was marked by nitrotyrosine in the SNpc and LC of the midbrain. These results indicate that chronic stress triggers DA and noradrenergic neurodegeneration by increasing oxidative stress, and that activated microglia in the substantia nigra and LC may play an important role in modulating the neurotoxic effects of oxidative stress. Taken together, these data suggest that exposure to chronic stress triggers DA and noradrenergic neurodegeneration, which is a cause of PD. Copyright © 2015 Elsevier Inc. All rights reserved.

  20. Treadmill exercise alleviates short-term memory impairment in 6-hydroxydopamine-induced Parkinson's rats.

    PubMed

    Cho, Han-Sam; Shin, Mal-Soon; Song, Wook; Jun, Tae-Won; Lim, Baek-Vin; Kim, Young-Pyo; Kim, Chang-Ju

    2013-01-01

    Progressive loss of dopaminergic neurons in substantia nigra is a key pathogenesis of Parkinson's disease. In the present study, we investigated the effects of treadmill exercise on short-term memory, apoptotic dopaminergic neuronal cell death and fiber loss in the nigrostriatum, and cell proliferation in the hippocampal dentate gyrus of Parkinson's rats. Parkinson's rats were made by injection of 6-hydroxydopamine (6-OHDA) into the striatum using stereotaxic instrument. Four weeks after 6-OHDA injection, the rats in the 6-OHDA-injection group exhibited significant rotational asymmetry following apomorphine challenge. The rats in the exercise groups were put on the treadmill to run for 30 min once a day for 14 consecutive days starting 4 weeks after 6-OHDA injection. In the present results, extensive degeneration of the dopaminergic neurons in the substantia nigra with loss of dopaminergic fibers in the striatum were produced in the rats without treadmill running, which resulted in short-term memory impairment. However, the rats performing treadmill running for 2 weeks alleviated nigrostriatal dopaminergic cell loss and alleviated short-term memory impairment with increasing cell proliferation in the hippocampal dentate gyrus of Parkinson's rats. The present results show that treadmill exercise may provide therapeutic value for the Parkinson's disease.

  1. Transcranial sonography of brainstem structures in panic disorder.

    PubMed

    Šilhán, Petr; Jelínková, Monika; Walter, Uwe; Pavlov Praško, Ján; Herzig, Roman; Langová, Kateřina; Školoudík, David

    2015-10-30

    Panic disorder has been associated with altered serotonin metabolism in the brainstem raphe. The aim of study was to evaluate the BR echogenicity on transcranial sonography (TCS) in panic disorder. A total of 96 healthy volunteers were enrolled in the "derivation" cohort, and 26 healthy volunteers and 26 panic disorder patients were enrolled in the "validation" cohort. TCS echogenicity of brainstem raphe and substantia nigra was assessed on anonymized images visually and by means of digitized image analysis. Significantly reduced brainstem raphe echogenicity was detected more frequently in panic disorder patients than in controls using both visual (68% vs. 31%) and digitized image analysis (52% vs. 12%). The optimal cut-off value of digitized brainstem raphe echogenicity indicated the diagnosis of panic disorder with a sensitivity of 64% and a specificity of 73%, and corresponded to the 30th percentile in the derivation cohort. Reduced brainstem raphe echogenicity was associated with shorter treatment duration, and, by trend, lower severity of anxiety. No relationship was found between echogenicity of brainstem raphe or substantia nigra and age, gender, severity of panic disorder, or severity of depression. Patients with panic disorder exhibit changes of brainstem raphe on TCS suggesting an alteration of the central serotonergic system. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  2. DNA isolation protocol effects on nuclear DNA analysis by microarrays, droplet digital PCR, and whole genome sequencing, and on mitochondrial DNA copy number estimation

    PubMed Central

    Nacheva, Elizabeth; Mokretar, Katya; Soenmez, Aynur; Pittman, Alan M.; Grace, Colin; Valli, Roberto; Ejaz, Ayesha; Vattathil, Selina; Maserati, Emanuela; Houlden, Henry; Taanman, Jan-Willem; Schapira, Anthony H.

    2017-01-01

    Potential bias introduced during DNA isolation is inadequately explored, although it could have significant impact on downstream analysis. To investigate this in human brain, we isolated DNA from cerebellum and frontal cortex using spin columns under different conditions, and salting-out. We first analysed DNA using array CGH, which revealed a striking wave pattern suggesting primarily GC-rich cerebellar losses, even against matched frontal cortex DNA, with a similar pattern on a SNP array. The aCGH changes varied with the isolation protocol. Droplet digital PCR of two genes also showed protocol-dependent losses. Whole genome sequencing showed GC-dependent variation in coverage with spin column isolation from cerebellum. We also extracted and sequenced DNA from substantia nigra using salting-out and phenol / chloroform. The mtDNA copy number, assessed by reads mapping to the mitochondrial genome, was higher in substantia nigra when using phenol / chloroform. We thus provide evidence for significant method-dependent bias in DNA isolation from human brain, as reported in rat tissues. This may contribute to array “waves”, and could affect copy number determination, particularly if mosaicism is being sought, and sequencing coverage. Variations in isolation protocol may also affect apparent mtDNA abundance. PMID:28683077

  3. Early Life Stress, Depression And Parkinson's Disease: A New Approach.

    PubMed

    Dallé, Ernest; Mabandla, Musa V

    2018-03-19

    This review aims to shed light on the relationship that involves exposure to early life stress, depression and Parkinson's disease (PD). A systematic literature search was conducted in Pubmed, MEDLINE, EBSCOHost and Google Scholar and relevant data were submitted to a meta-analysis . Early life stress may contribute to the development of depression and patients with depression are at risk of developing PD later in life. Depression is a common non-motor symptom preceding motor symptoms in PD. Stimulation of regions contiguous to the substantia nigra as well as dopamine (DA) agonists have been shown to be able to attenuate depression. Therefore, since PD causes depletion of dopaminergic neurons in the substantia nigra, depression, rather than being just a simple mood disorder, may be part of the pathophysiological process that leads to PD. It is plausible that the mesocortical and mesolimbic dopaminergic pathways that mediate mood, emotion, and/or cognitive function may also play a key role in depression associated with PD. Here, we propose that a medication designed to address a deficiency in serotonin is more likely to influence motor symptoms of PD associated with depression. This review highlights the effects of an antidepressant, Fluvoxamine maleate, in an animal model that combines depressive-like symptoms and Parkinsonism.

  4. Effects of Postnatal Enriched Environment in a Model of Parkinson's Disease in Adult Rats.

    PubMed

    Jungling, Adel; Reglodi, Dora; Karadi, Zsofia Nozomi; Horvath, Gabor; Farkas, Jozsef; Gaszner, Balazs; Tamas, Andrea

    2017-02-14

    Environmental enrichment is a widespread neuroprotective strategy during development and also in the mature nervous system. Several research groups have described that enriched environment in adult rats has an impact on the progression of Parkinson's disease (PD). The aim of our present study was to examine the effects of early, postnatal environmental enrichment after 6-hydroxydopamine-induced (6-OHDA) lesion of the substantia nigra in adulthood. Newborn Wistar rats were divided into control and enriched groups according to their environmental conditions. For environmental enrichment, during the first five postnatal weeks animals were placed in larger cages and exposed to intensive complex stimuli. Dopaminergic cell loss, and hypokinetic and asymmetrical signs were evaluated after inducing PD with unilateral injections of 6-OHDA in three-month-old animals. Treatment with 6-OHDA led to a significant cell loss in the substantia nigra of control animals, however, postnatal enriched circumstances could rescue the dopaminergic cells. Although there was no significant difference in the percentage of surviving cells between 6-OHDA-treated control and enriched groups, the slightly less dopaminergic cell loss in the enriched group compared to control animals resulted in less severe hypokinesia. Our investigation is the first to provide evidence for the neuroprotective effect of postnatal enriched environment in PD later in life.

  5. Brain iron chelation by deferiprone in a phase 2 randomised double-blinded placebo controlled clinical trial in Parkinson's disease.

    PubMed

    Martin-Bastida, Antonio; Ward, Roberta J; Newbould, Rexford; Piccini, Paola; Sharp, David; Kabba, Christina; Patel, Maneesh C; Spino, Michael; Connelly, John; Tricta, Fernando; Crichton, Robert R; Dexter, David T

    2017-05-03

    Parkinson's disease (PD) is associated with increased iron levels in the substantia nigra (SNc). This study evaluated whether the iron chelator, deferiprone, is well tolerated, able to chelate iron from various brain regions and improve PD symptomology. In a randomised double-blind, placebo controlled trial, 22 early onset PD patients, were administered deferiprone, 10 or 15 mg/kg BID or placebo, for 6 months. Patients were evaluated for PD severity, cognitive function, depression rating and quality of life. Iron concentrations were assessed in the substantia nigra (SNc), dentate and caudate nucleus, red nucleus, putamen and globus pallidus by T2* MRI at baseline and after 3 and 6 months of treatment. Deferiprone therapy was well tolerated and was associated with a reduced dentate and caudate nucleus iron content compared to placebo. Reductions in iron content of the SNc occurred in only 3 patients, with no changes being detected in the putamen or globus pallidus. Although 30 mg/kg deferiprone treated patients showed a trend for improvement in motor-UPDRS scores and quality of life, this did not reach significance. Cognitive function and mood were not adversely affected by deferiprone therapy. Such data supports more extensive clinical trials into the potential benefits of iron chelation in PD.

  6. Individual differences in schedule-induced polydipsia: neuroanatomical dopamine divergences.

    PubMed

    Pellón, Ricardo; Ruíz, Ana; Moreno, Margarita; Claro, Francisco; Ambrosio, Emilio; Flores, Pilar

    2011-02-02

    Autoradiography analysis of D1 and D2 dopamine receptors and c-Fos activity were performed in brain of rats classified as low drinkers (LD) and high drinkers (HD) according to schedule-induced polydipsia (SIP) performance. Previous studies have shown that groups selected according to their rate of drinking in SIP differ in behavioral response to dopaminergic drugs. This study reports differences between LD and HD rats in dopamine D1 and D2 receptor binding through different mesocorticolimbic brain areas. LD and HD rats showed opposite patterns of binding in dopamine D1 and D2 receptors in the nucleus accumbens, medial prefrontal cortex, amygdala, ventral tegmental area and substantia nigra. Whereas LD rats showed higher binding than HD rats for D1 receptors, HD rats showed higher binding than LD rats for D2 receptors (except in substantia nigra that were roughly similar). These neuroanatomical differences in dopamine receptor binding were also associated with an elevated c-Fos count in the medial prefrontal cortex of HD rats. In tandem with previous evidence, our results suggest a different dopaminergic function between LD and HD, and points to SIP as a behavioral model for distinguishing populations possibly vulnerable to dopaminergic function disorders. Copyright © 2010 Elsevier B.V. All rights reserved.

  7. Calcium Homeostatasis and Mitochondrial Dysfunction in Dopaminergic Neurons of the Substantia Nigra

    DTIC Science & Technology

    2010-03-01

    discovery that calcium entry through L-type channels during normal pacemaking elevates the sensitivity of SNc dopaminergic neurons to toxins; • the...discovery that L-type calcium channels participate in but are not necessary for pacemaking; • the discovery that serum concentration of the...FDA approved doses; • the discovery that calcium entry through L-type channels during pacemaking elevates mitochondrial oxidant stress and leads

  8. Assessment of Black Ash (Fraxinus nigra) Decline in Minnesota. Chapter 12

    Treesearch

    Brian J. Palik; Michael E. Ostry; Robert C. Venette; Kathleen T. Ward

    2012-01-01

    Black ash (Fraxinus nigra) is present throughout the upper Midwest and Northeastern United States and is often found in lowland hardwood forests. Black ash seed is an important food for birds and small mammals, and its twigs and foliage are used by ungulates. Black ash wood is valued for paneling and furniture as well as for Native American basketry...

  9. Reproductive characteristics of the Point Arena mountain beaver (Aplodontia rufa nigra)

    Treesearch

    William Zielinski; M. J. Mazurek

    2016-01-01

    Little is known about the ecology and life history of the federally endangered Point Arena mountain beaver (Aplodontia rufa nigra). The distribution of this primitive burrowing rodent is disjunct from the balance of the species’ range and occurs in a unique maritime environment of coastal grasslands and forests. Fundamental to protecting this taxon...

  10. Hydrogen Peroxide Response in Leaves of Poplar (Populus simonii × Populus nigra) Revealed from Physiological and Proteomic Analyses

    PubMed Central

    Jin, Xin; Sun, Xiaomei; Gao, Tianxiang; Chen, Xiaomei; She, Yimin; Jiang, Tingbo; Chen, Sixue; Dai, Shaojun

    2017-01-01

    Hydrogen peroxide (H2O2) is one of the most abundant reactive oxygen species (ROS), which plays dual roles as a toxic byproduct of cell metabolism and a regulatory signal molecule in plant development and stress response. Populus simonii × Populus nigra is an important cultivated forest species with resistance to cold, drought, insect and disease, and also a key model plant for forest genetic engineering. In this study, H2O2 response in P. simonii × P. nigra leaves was investigated using physiological and proteomics approaches. The seedlings of 50-day-old P. simonii × P. nigra under H2O2 stress exhibited stressful phenotypes, such as increase of in vivo H2O2 content, decrease of photosynthetic rate, elevated osmolytes, antioxidant accumulation, as well as increased activities of several ROS scavenging enzymes. Besides, 81 H2O2-responsive proteins were identified in the poplar leaves. The diverse abundant patterns of these proteins highlight the H2O2-responsive pathways in leaves, including 14-3-3 protein and nucleoside diphosphate kinase (NDPK)-mediated signaling, modulation of thylakoid membrane structure, enhancement of various ROS scavenging pathways, decrease of photosynthesis, dynamics of proteins conformation, and changes in carbohydrate and other metabolisms. This study provides valuable information for understanding H2O2-responsive mechanisms in leaves of P. simonii × P. nigra. PMID:28974034

  11. [Ultrastructure of the substantia spongiosa of the femur head and talus].

    PubMed

    Copf, F; Czarnetzki, A; Lierse, W

    1990-01-01

    The results of the SEM examination of the zone between the cartilage and the spongeous substances are described precisely. For the first time, W. Lierse examined the 'tensulae' of calcium-collagen lamellae by light microscopy. The examination of this zone was initiated by the fact that the hydrodynamic flow can take place in the calcified zone of the cartilage which is filled with synovial fluid and that the calcified zone adheres to the subchondral substantia corticalis. The subchondral corticalis is characterized by funnel-like indentations with a high number of calcium-collagen and chondrocyte 'tensulae' which are up to now uncounted. The special aim was to locate the separation of the space of adipose and arterial supplies.

  12. Samuel Thomas Soemmerring (1755-1830): The Naming of Cranial Nerves.

    PubMed

    Pearce, John M S

    2017-01-01

    Samuel Thomas Soemmerring was a Prussian polymathic doctor with remarkable achievements in anatomy, draftsmanship and inventions. His naming of 12 pairs of cranial nerves in his graduation thesis is of particular importance. He also gave original descriptions of the macula, sensory pathways and of the substantia nigra. His non-medical contributions were diverse and included criticism of the guillotine, invention of a telegraphic system, and discoveries in palaeontology. © 2017 S. Karger AG, Basel.

  13. Pre-Clinical Testing of New Hydroxybutyrate Analogues

    DTIC Science & Technology

    2011-07-01

    complex I and II sites. Several years ago, we evaluated the use of ketone bodies as secondary sources of energy for mitochondria compromised due to...hydroxybutyrate (DβHB), a ketone body normally produced by hepatocytes and astrocytes and infused via Alzet pump, protected the substantia nigra...crisis in the neurons . In an earlier study, bypassing this complex I deficiency using D-- hydroxybutyrate (DHB) in the MPTP (1-methyl-4-phenyl-1,2,3,6

  14. Stimulation of serotonin2C receptors elicits abnormal oral movements by acting on pathways other than the sensorimotor one in the rat basal ganglia.

    PubMed

    Beyeler, A; Kadiri, N; Navailles, S; Boujema, M Ben; Gonon, F; Moine, C Le; Gross, C; De Deurwaerdère, P

    2010-08-11

    Serotonin2C (5-HT(2C)) receptors act in the basal ganglia, a group of sub-cortical structures involved in motor behavior, where they are thought to modulate oral activity and participate in iatrogenic motor side-effects in Parkinson's disease and Schizophrenia. Whether abnormal movements initiated by 5-HT(2C) receptors are directly consequent to dysfunctions of the motor circuit is uncertain. In the present study, we combined behavioral, immunohistochemical and extracellular single-cell recordings approaches in rats to investigate the effect of the 5-HT(2C) agonist Ro-60-0175 respectively on orofacial dyskinesia, the expression of the marker of neuronal activity c-Fos in basal ganglia and the electrophysiological activity of substantia nigra pars reticulata (SNr) neuron connected to the orofacial motor cortex (OfMC) or the medial prefrontal cortex (mPFC). The results show that Ro-60-0175 (1 mg/kg) caused bouts of orofacial movements that were suppressed by the 5-HT(2C) antagonist SB-243213 (1 mg/kg). Ro-60-0175 (0.3, 1, 3 mg/kg) dose-dependently enhanced Fos expression in the striatum and the nucleus accumbens. At the highest dose, it enhanced Fos expression in the subthalamic nucleus, the SNr and the entopeduncular nucleus but not in the external globus pallidus. However, the effect of Ro-60-0175 was mainly associated with associative/limbic regions of basal ganglia whereas subregions of basal ganglia corresponding to sensorimotor territories were devoid of Fos labeling. Ro-60-0175 (1-3 mg/kg) did not affect the electrophysiological activity of SNr neurons connected to the OfMC nor their excitatory-inhibitory-excitatory responses to the OfMC electrical stimulation. Conversely, Ro-60-0175 (1 mg/kg) enhanced the late excitatory response of SNr neurons evoked by the mPFC electrical stimulation. These results suggest that oral dyskinesia induced by 5-HT(2C) agonists are not restricted to aberrant signalling in the orofacial motor circuit and demonstrate discrete

  15. Quantification of 18F-JNJ-42259152, a novel phosphodiesterase 10A PET tracer: kinetic modeling and test-retest study in human brain.

    PubMed

    Van Laere, Koen; Ahmad, Rawaha U; Hudyana, Hendra; Dubois, Kristof; Schmidt, Mark E; Celen, Sofie; Bormans, Guy; Koole, Michel

    2013-08-01

    Phosphodiesterase 10A (PDE10A) plays a central role in striatal signaling and is implicated in several neuropsychiatric disorders, such as movement disorders and schizophrenia. We performed initial brain kinetic modeling of the novel PDE10A tracer (18)F-JNJ-42259152 (2-[[4-[1-(2-(18)F-fluoroethyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]phenoxy]methyl]-3,5-dimethyl-pyridine) and studied test-retest reproducibility in healthy volunteers. Twelve healthy volunteers (5 men, 7 women; age range, 42-77 y) were scanned dynamically up to 135 min after bolus injection of 172.5 ± 10.3 MBq of (18)F-JNJ42259152. Four volunteers (2 men, 2 women) underwent retest scanning, with a mean interscan interval of 37 d. Input functions and tracer parent fractions were determined using arterial sampling and high-performance liquid chromatography analysis. Volumes of interest for the putamen, caudate nucleus, ventral striatum, substantia nigra, thalamus, frontal cortex, and cerebellum were delineated using individual volumetric T1 MR imaging scans. One-tissue (1T) and 2-tissue (2T) models were evaluated to calculate total distribution volume (VT). Simplified models were also tested to calculate binding potential (BPND), including the simplified reference tissue model (SRTM) and multilinear reference tissue model, using the frontal cortex as the optimal reference tissue. The stability of VT and BPND was assessed down to a 60-min scan time. The average intact tracer half-life in blood was 90 min. The 2T model VT values for the putamen, caudate nucleus, ventral striatum, substantia nigra, thalamus, frontal cortex, and cerebellum were 1.54 ± 0.37, 0.90 ± 0.24, 0.64 ± 0.18, 0.42 ± 0.09, 0.35 ± 0.09, 0.30 ± 0.07, and 0.36 ± 0.12, respectively. The 1T model provided significantly lower VT values, which were well correlated to the 2T VT. SRTM BPND values referenced to the frontal cortex were 3.45 ± 0.43, 1.78 ± 0.35, 1.10 ± 0.31, and 0.44 ± 0.09 for the respective target regions putamen

  16. Characterization of species-specific repeated DNA sequences from B. nigra.

    PubMed

    Gupta, V; Lakshmisita, G; Shaila, M S; Jagannathan, V; Lakshmikumaran, M S

    1992-07-01

    The construction and characterization of two genome-specific recombinant DNA clones from B. nigra are described. Southern analysis showed that the two clones belong to a dispersed repeat family. They differ from each other in their length, distribution and sequence, though the average GC content is nearly the same (45%). These B genome-specific repeats have been used to analyse the phylogenetic relationships between cultivated and wild species of the family Brassicaceae.

  17. Deep brain stimulation changes basal ganglia output nuclei firing pattern in the dystonic hamster.

    PubMed

    Leblois, Arthur; Reese, René; Labarre, David; Hamann, Melanie; Richter, Angelika; Boraud, Thomas; Meissner, Wassilios G

    2010-05-01

    Dystonia is a heterogeneous syndrome of movement disorders characterized by involuntary muscle contractions leading to abnormal movements and postures. While medical treatment is often ineffective, deep brain stimulation (DBS) of the internal pallidum improves dystonia. Here, we studied the impact of DBS in the entopeduncular nucleus (EP), the rodent equivalent of the human globus pallidus internus, on basal ganglia output in the dt(sz)-hamster, a well-characterized model of dystonia by extracellular recordings. Previous work has shown that EP-DBS improves dystonic symptoms in dt(sz)-hamsters. We report that EP-DBS changes firing pattern in the EP, most neurons switching to a less regular firing pattern during DBS. In contrast, EP-DBS did not change the average firing rate of EP neurons. EP neurons display multiphasic responses to each stimulation impulse, likely underlying the disruption of their firing rhythm. Finally, neurons in the substantia nigra pars reticulata display similar responses to EP-DBS, supporting the idea that EP-DBS affects basal ganglia output activity through the activation of common afferent fibers. Copyright 2010 Elsevier Inc. All rights reserved.

  18. Critical Involvement of the Motor Cortex in the Pathophysiology and Treatment of Parkinson’s Disease

    PubMed Central

    Lindenbach, David; Bishop, Christopher

    2013-01-01

    This review examines the involvement of the motor cortex in Parkinson’s disease (PD), a debilitating movement disorder typified by degeneration of dopamine cells of the substantia nigra. While much of PD research has focused on the caudate/putamen, many aspects of motor cortex function are abnormal in PD patients and in animal models of PD, implicating motor cortex involvement in disease symptoms and their treatment. Herein, we discuss several lines of evidence to support this hypothesis. Dopamine depletion alters regional metabolism in the motor cortex and also reduces interneuron activity, causing a breakdown in intracortical inhibition. This leads to functional reorganization of motor maps and excessive corticostriatal synchrony when movement is initiated. Recent work suggests that electrical stimulation of the motor cortex provides a clinical benefit for PD patients. Based on extant research, we identify a number of unanswered questions regarding the motor cortex in PD and argue that a better understanding of the contribution of the motor cortex to PD symptoms will facilitate the development of novel therapeutic approaches. PMID:24113323

  19. Magnetic Resonance Spectroscopy: An In Vivo Molecular Imaging Biomarker for Parkinson's Disease?

    PubMed Central

    Ciurleo, Rosella; Di Lorenzo, Giuseppe; Marino, Silvia

    2014-01-01

    Parkinson's disease (PD) is a neurodegenerative disorder caused by selective loss of dopaminergic neurons in the substantia nigra pars compacta which leads to dysfunction of cerebral pathways critical for the control of movements. The diagnosis of PD is based on motor symptoms, such as bradykinesia, akinesia, muscular rigidity, postural instability, and resting tremor, which are evident only after the degeneration of a significant number of dopaminergic neurons. Currently, a marker for early diagnosis of PD is still not available. Consequently, also the development of disease-modifying therapies is a challenge. Magnetic resonance spectroscopy is a quantitative imaging technique that allows in vivo measurement of certain neurometabolites and may produce biomarkers that reflect metabolic dysfunctions and irreversible neuronal damage. This review summarizes the abnormalities of cerebral metabolites found in MRS studies performed in patients with PD and other forms of parkinsonism. In addition, we discuss the potential role of MRS as in vivo molecular imaging biomarker for early diagnosis of PD and for monitoring the efficacy of therapeutic interventions. PMID:25302300

  20. Parkinsonism in a pair of monozygotic CADASIL twins sharing the R1006C mutation: a transcranial sonography study.

    PubMed

    Ragno, Michele; Sanguigni, Sandro; Manca, Antonio; Pianese, Luigi; Paci, Cristina; Berbellini, Alfonso; Cozzolino, Valeria; Gobbato, Roberto; Peluso, Silvio; De Michele, Giuseppe

    2016-06-01

    Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), the most common hereditary cerebral small vessel disease, is caused by mutations in the NOTCH3 gene on chromosome 19. Clinical manifestations of CADASIL include recurrent transient ischemic attacks, strokes, cognitive defects, epilepsy, migraine and psychiatric symptoms. Parkinsonian features have variably been reported in CADASIL patients, but only a few patients showed a clear parkinsonian syndrome. We studied two patients, a pair of monozygotic twins, carrying the R1006C mutation of the NOTCH3 gene and affected by a parkinsonian syndrome. For the first time in CADASIL patients, we used transcranial sonography (TCS) to assess basal ganglia abnormalities. TCS showed a bilateral hyperechogenic pattern of substantia nigra in one twin, and a right hyperechogenic pattern in the other. In both patients, lenticular nuclei showed a bilateral hyperechogenic pattern, and the width of the third ventricle was slightly increased. The TCS pattern found in our CADASIL patients is characteristic neither for Parkinson's disease, nor for vascular parkinsonism and seems to be specific and related to the disease-specific pathological features.

  1. Protective effects of Althaea officinalis L. extract in 6-hydroxydopamine-induced hemi-Parkinsonism model: behavioral, biochemical and histochemical evidence.

    PubMed

    Rezaei, Maryam; Alirezaei, Masoud

    2014-05-01

    It is well known that Parkinson's disease (PD) is the second most common neurodegenerative disorder in humans. In this regard, the neuroprotective effect of Althaea officinalis (AO) has already been reported. Therefore, this study examined whether administration of AO extract would improve behavioral, biochemical and structural abnormalities in an experimental animal model of PD in rats. For this purpose, we induced hemi-Parkinsonism by unilateral intranigral injection of 6-hydroxydopamine (6-OHDA, 8 μg/5 μl saline-ascorbate). The rats were pretreated i.p. with AO extract (10 mg/kg) started 6 days before surgery and continued until the 3rd day post-surgery. Regarding oxidative stress, brain MDA concentration (as a lipid peroxidation marker) increased significantly in the 6-OHDA-administered group in comparison with rats pretreated with AO extract. It was found that AO treatment attenuated rotational behavior in the 6-OHDA-administered group and protected the neurons of substantia nigra pars compacta against 6-OHDA toxicity. Overall, AO extract administration indicated neuroprotective effects against 6-OHDA-induced hemi-Parkinsonism in rats.

  2. Effect of UV radiation on habitat selection by Girella laevifrons and Graus nigra (Kyphosidae).

    PubMed

    Pulgar, J; Lagos, P; Maturana, D; Valdés, M; Aldana, M; Pulgar, V M

    2015-02-01

    The effect of UV radiation on habitat use of two species of intertidal fishes that inhabit the same pools but exhibit different activity levels and diets was measured: the highly active omnivorous Girella laevifrons and the cryptic carnivorous Graus nigra. Individuals of each species were acclimated to a tank divided in three sections with different illumination; no light (NL), ultraviolet light (UV) and white light (WL), and the time spent and number of visits to each section were recorded. Although both species preferred the NL section, G. laevifrons spent more time in UV and less time in WL compared with G. nigra; G. laevifrons also displayed higher number of visits to UV, suggesting a different tendency in space use in response to UV exposure in intertidal fishes. © 2015 The Fisheries Society of the British Isles.

  3. Alterations in striatal dopamine catabolism precede loss of substantia nigra neurons in a mouse model of Juvenile Neuronal Ceroid Lipofuscinosis

    PubMed Central

    Weimer, Jill M.; Benedict, Jared W.; Elshatory, Yasser M.; Short, Douglas W.; Ramirez-Montealegre, Denia; Ryan, Deborah A.; Alexander, Noreen A.; Federoff, Howard J.; Cooper, Jonathan D.; Pearce, David A.

    2016-01-01

    Batten disease, or juvenile neuronal ceroid lipofuscinosis (JNCL), results from mutations in the CLN3 gene. This disorder presents clinically around the age of five years with visual deficits progressing to include seizures, cognitive impairment, motor deterioration, hallucinations, and premature death by the third to forth decade of life. The motor deficits include coordination and gait abnormalities, myoclonic jerks, inability to initiate movements, and spasticity. Previous work from our laboratory has identified an early reduction in catechol-O-methyltransferase (COMT), an enzyme responsible for the efficient degradation of dopamine. Alterations in the kinetics of dopamine metabolism could cause the accumulation of undegraded or unsequestered dopamine leading to the formation of toxic dopamine intermediates. We report an imbalance in the catabolism of dopamine in three month Cln3-/- mice persisting through nine months of age that may be causal to oxidative damage within the striatum at nine months of age. Combined with the previously reported inflammatory changes and loss of post-synaptic D1α receptors, this could facilitate cell loss in striatal projection regions and underlie a general locomotion deficit that becomes apparent at twelve months of age in Cln3-/- mice. This study provides evidence for early changes in the kinetics of COMT in the Cln3-/- mouse striatum, affecting the turnover of dopamine, likely leading to neuron loss and motor deficits. These data provide novel insights into the basis of motor deficits in JNCL and how alterations in dopamine catabolism may result in oxidative damage and localized neuronal loss in this disorder. PMID:17617387

  4. Characterization of [11C]Lu AE92686 as a PET radioligand for phosphodiesterase 10A in the nonhuman primate brain.

    PubMed

    Yang, Kai-Chun; Stepanov, Vladimir; Amini, Nahid; Martinsson, Stefan; Takano, Akihiro; Nielsen, Jacob; Bundgaard, Christoffer; Bang-Andersen, Benny; Grimwood, Sarah; Halldin, Christer; Farde, Lars; Finnema, Sjoerd J

    2017-02-01

    [ 11 C]Lu AE92686 is a positron emission tomography (PET) radioligand that has recently been validated for examining phosphodiesterase 10A (PDE10A) in the human striatum. [ 11 C]Lu AE92686 has high affinity for PDE10A (IC 50  = 0.39 nM) and may also be suitable for examination of the substantia nigra, a region with low density of PDE10A. Here, we report characterization of regional [ 11 C]Lu AE92686 binding to PDE10A in the nonhuman primate (NHP) brain. A total of 11 PET measurements, seven baseline and four following pretreatment with unlabeled Lu AE92686 or the structurally unrelated PDE10A inhibitor MP-10, were performed in five NHPs using a high resolution research tomograph (HRRT). [ 11 C]Lu AE92686 binding was quantified using a radiometabolite-corrected arterial input function and compartmental and graphical modeling approaches. Regional time-activity curves were best described with the two-tissue compartment model (2TCM). However, the distribution volume (V T ) values for all regions were obtained by the Logan plot analysis, as reliable cerebellar V T values could not be derived by the 2TCM. For cerebellum, a proposed reference region, V T values increased by ∼30 % with increasing PET measurement duration from 63 to 123 min, while V T values in target regions remained stable. Both pretreatment drugs significantly decreased [ 11 C]Lu AE92686 binding in target regions, while no significant effect on cerebellum was observed. Binding potential (BP ND ) values, derived with the simplified reference tissue model (SRTM), were 13-17 in putamen and 3-5 in substantia nigra and correlated well to values from the Logan plot analysis. The method proposed for quantification of [ 11 C]Lu AE92686 binding in applied studies in NHP is based on 63 min PET data and SRTM with cerebellum as a reference region. The study supports that [ 11 C]Lu AE92686 can be used for PET examinations of PDE10A binding also in substantia nigra.

  5. Increased mitochondrial calcium sensitivity and abnormal expression of innate immunity genes precede dopaminergic defects in Pink1-deficient mice.

    PubMed

    Akundi, Ravi S; Huang, Zhenyu; Eason, Joshua; Pandya, Jignesh D; Zhi, Lianteng; Cass, Wayne A; Sullivan, Patrick G; Büeler, Hansruedi

    2011-01-13

    PTEN-induced kinase 1 (PINK1) is linked to recessive Parkinsonism (EOPD). Pink1 deletion results in impaired dopamine (DA) release and decreased mitochondrial respiration in the striatum of mice. To reveal additional mechanisms of Pink1-related dopaminergic dysfunction, we studied Ca²+ vulnerability of purified brain mitochondria, DA levels and metabolism and whether signaling pathways implicated in Parkinson's disease (PD) display altered activity in the nigrostriatal system of Pink1⁻/⁻ mice. Purified brain mitochondria of Pink1⁻/⁻ mice showed impaired Ca²+ storage capacity, resulting in increased Ca²+ induced mitochondrial permeability transition (mPT) that was rescued by cyclosporine A. A subpopulation of neurons in the substantia nigra of Pink1⁻/⁻ mice accumulated phospho-c-Jun, showing that Jun N-terminal kinase (JNK) activity is increased. Pink1⁻/⁻ mice 6 months and older displayed reduced DA levels associated with increased DA turnover. Moreover, Pink1⁻/⁻ mice had increased levels of IL-1β, IL-12 and IL-10 in the striatum after peripheral challenge with lipopolysaccharide (LPS), and Pink1⁻/⁻ embryonic fibroblasts showed decreased basal and inflammatory cytokine-induced nuclear factor kappa-β (NF-κB) activity. Quantitative transcriptional profiling in the striatum revealed that Pink1⁻/⁻ mice differentially express genes that (i) are upregulated in animals with experimentally induced dopaminergic lesions, (ii) regulate innate immune responses and/or apoptosis and (iii) promote axonal regeneration and sprouting. Increased mitochondrial Ca²+ sensitivity and JNK activity are early defects in Pink1⁻/⁻ mice that precede reduced DA levels and abnormal DA homeostasis and may contribute to neuronal dysfunction in familial PD. Differential gene expression in the nigrostriatal system of Pink1⁻/⁻ mice supports early dopaminergic dysfunction and shows that Pink1 deletion causes aberrant expression of genes that regulate innate

  6. Increased Mitochondrial Calcium Sensitivity and Abnormal Expression of Innate Immunity Genes Precede Dopaminergic Defects in Pink1-Deficient Mice

    PubMed Central

    Akundi, Ravi S.; Huang, Zhenyu; Eason, Joshua; Pandya, Jignesh D.; Zhi, Lianteng; Cass, Wayne A.; Sullivan, Patrick G.; Büeler, Hansruedi

    2011-01-01

    Background PTEN-induced kinase 1 (PINK1) is linked to recessive Parkinsonism (EOPD). Pink1 deletion results in impaired dopamine (DA) release and decreased mitochondrial respiration in the striatum of mice. To reveal additional mechanisms of Pink1-related dopaminergic dysfunction, we studied Ca2+ vulnerability of purified brain mitochondria, DA levels and metabolism and whether signaling pathways implicated in Parkinson's disease (PD) display altered activity in the nigrostriatal system of Pink1−/− mice. Methods and Findings Purified brain mitochondria of Pink1−/− mice showed impaired Ca2+ storage capacity, resulting in increased Ca2+ induced mitochondrial permeability transition (mPT) that was rescued by cyclosporine A. A subpopulation of neurons in the substantia nigra of Pink1−/− mice accumulated phospho-c-Jun, showing that Jun N-terminal kinase (JNK) activity is increased. Pink1−/− mice 6 months and older displayed reduced DA levels associated with increased DA turnover. Moreover, Pink1−/− mice had increased levels of IL-1β, IL-12 and IL-10 in the striatum after peripheral challenge with lipopolysaccharide (LPS), and Pink1−/− embryonic fibroblasts showed decreased basal and inflammatory cytokine-induced nuclear factor kappa-β (NF-κB) activity. Quantitative transcriptional profiling in the striatum revealed that Pink1−/− mice differentially express genes that (i) are upregulated in animals with experimentally induced dopaminergic lesions, (ii) regulate innate immune responses and/or apoptosis and (iii) promote axonal regeneration and sprouting. Conclusions Increased mitochondrial Ca2+ sensitivity and JNK activity are early defects in Pink1−/− mice that precede reduced DA levels and abnormal DA homeostasis and may contribute to neuronal dysfunction in familial PD. Differential gene expression in the nigrostriatal system of Pink1−/− mice supports early dopaminergic dysfunction and shows that Pink1 deletion causes aberrant

  7. Parkinsonism after glycine-derivate exposure.

    PubMed

    Barbosa, E R; Leiros da Costa, M D; Bacheschi, L A; Scaff, M; Leite, C C

    2001-05-01

    This 54-year-old man accidentally sprayed himself with the chemical agent glyphosate, a herbicide derived from the amino acid glycine. He developed disseminated skin lesions 6 hours after the accident. One month later, he developed a symmetrical parkinsonian syndrome. Two years after the initial exposure to glyphosate, magnetic resonance imaging revealed hyperintense signal in the globus pallidus and substantia nigra, bilaterally, on T2-weighted images. Levodopa/benserazide 500/125 mg daily provided satisfactory clinical outcome.

  8. Ultrasonic surface measurements at the Porta Nigra, Trier, and the Neptungrotte, Park Sanssouci Potsdam

    NASA Astrophysics Data System (ADS)

    Meier, Thomas; Auras, Michael; Fehr, Moritz; Köhn, Daniel

    2015-04-01

    Ultrasonic measurements along profiles at the surface of an object are well suited to characterize non-destructively weathering of natural stone near the surface. Ultrasonic waveforms of surface measurements in the frequency range between 10 kHz and 300 kHz are often dominated by the Rayleigh wave - a surface wave that is mainly sensitive to the velocity and attenuation of S-waves in the upper 0.3 cm to 3 cm. The frequency dependence of the Rayleigh wave velocity may be used to analyze variations of the material properties with depth. Applications of ultrasonic surface measurements are shown for two buildings: the Roman Porta Nigra in Trier from the 3rd century AD and the Neptungrotte at Park Sanssouci in Potsdam designed by von Knobelsdorff in the 18th century. Both buildings belong to the world cultural heritage and restorations are planned for the near future. It is interesting to compare measurements at these two buildings because they show the applicability of ultrasonic surface measurements to different natural stones. The Porta Nigra is made of local sandstones whereas the facades of the Neptungrotte are made of Carrara and Kauffunger marble. 71 and 46 surface measurements have been carried out, respectively. At both buildings, Rayleigh-wave group velocities show huge variations. At the Porta Nigra they vary between ca. 0.4 km/s and 1.8 km/s and at the Neptungrotte between ca. 0.7 km/s and 3.0 km/s pointing to alterations in the Rayleigh- and S-wave velocities of more than 50 % due to weathering. Note that velocities of elastic waves may increase e.g. because of the formation of black crusts like at the Porta Nigra or they may be strongly reduced due to weathering. The accuracy of the ultrasonic surface measurements, its reproducibility, and the influence of varying water saturation are discussed. Options for the analysis of ultrasonic waveforms are presented ranging from dispersion analysis to full waveform inversions for one-dimensional and two

  9. Boron accumulation and toxicity in hybrid poplar (Populus nigra × euramericana).

    PubMed

    Rees, Rainer; Robinson, Brett H; Menon, Manoj; Lehmann, Eberhard; Günthardt-Goerg, Madeleine S; Schulin, Rainer

    2011-12-15

    Poplars accumulate high B concentrations and are thus used for the phytomanagement of B contaminated soils. Here, we performed pot experiments in which Populus nigra × euramericana were grown on a substrate with B concentrations ranging from 13 to 280 mg kg(-1) as H(3)BO(3). Salix viminalis, Brassica juncea, and Lupinus albus were grown under some growing conditions for comparison. Poplar growth was unaffected at soil B treatment levels up to 93 mg kg(-1). Growth was progressively reduced at levels of 168 and 280 mg kg(-1). None of the other species survived at these substrate B levels. At leaf B concentrations <900 mg kg(-1) only <10% of the poplar leaf area showed signs of toxicity. Neutron radiography revealed that chlorotic leaf tissues had B concentrations of 1000-2000 mg kg(-1), while necrotic tissues had >2000 mg kg(-1). Average B concentrations of up to 3500 mg kg(-1) were found in leaves, while spots within leaves had concentrations >7000 mg kg(-1), showing that B accumulation in leaf tissue continued even after the onset of necrosis. The B accumulation ability of P. nigra × euramericana is associated with B hypertolerance in the living tissue and storage of B in dead leaf tissue.

  10. Copper and Copper Proteins in Parkinson's Disease

    PubMed Central

    Rivera-Mancia, Susana; Diaz-Ruiz, Araceli; Tristan-Lopez, Luis; Rios, Camilo

    2014-01-01

    Copper is a transition metal that has been linked to pathological and beneficial effects in neurodegenerative diseases. In Parkinson's disease, free copper is related to increased oxidative stress, alpha-synuclein oligomerization, and Lewy body formation. Decreased copper along with increased iron has been found in substantia nigra and caudate nucleus of Parkinson's disease patients. Copper influences iron content in the brain through ferroxidase ceruloplasmin activity; therefore decreased protein-bound copper in brain may enhance iron accumulation and the associated oxidative stress. The function of other copper-binding proteins such as Cu/Zn-SOD and metallothioneins is also beneficial to prevent neurodegeneration. Copper may regulate neurotransmission since it is released after neuronal stimulus and the metal is able to modulate the function of NMDA and GABA A receptors. Some of the proteins involved in copper transport are the transporters CTR1, ATP7A, and ATP7B and the chaperone ATOX1. There is limited information about the role of those biomolecules in the pathophysiology of Parkinson's disease; for instance, it is known that CTR1 is decreased in substantia nigra pars compacta in Parkinson's disease and that a mutation in ATP7B could be associated with Parkinson's disease. Regarding copper-related therapies, copper supplementation can represent a plausible alternative, while copper chelation may even aggravate the pathology. PMID:24672633

  11. Distribution of the messenger RNA for the small conductance calcium-activated potassium channel SK3 in the adult rat brain and correlation with immunoreactivity.

    PubMed

    Tacconi, S; Carletti, R; Bunnemann, B; Plumpton, C; Merlo Pich, E; Terstappen, G C

    2001-01-01

    Small conductance calcium-activated potassium channels are voltage independent potassium channels which modulate the firing patterns of neurons by activating the slow component of the afterhyperpolarization. The genes encoding a family of small conductance calcium-activated potassium channels have been cloned and up to now three known members have been described and named small conductance calcium-activated potassium channel type 1, small conductance calcium-activated potassium channel type 2 and small conductance calcium-activated potassium channel type 3; the distribution of their messenger RNA in the rat CNS has already been performed but only in a limited detail. The present study represents the first detailed analysis of small conductance calcium-activated potassium channel type 3 mRNA distribution in the adult rat brain and resulted in a strong to moderate expression of signal in medial habenular nucleus, substantia nigra compact part, suprachiasmatic nucleus, ventral tegmental area, lateral septum, dorsal raphe and locus coeruleus. Immunohistological experiments were also performed and confirmed the presence of small conductance calcium-activated potassium channel type 3 protein in medial habenular nucleus, locus coeruleus and dorsal raphe. Given the importance of dorsal raphe, locus coeruleus and substantia nigra/ventral tegmental area for serotonergic, noradrenergic and dopaminergic transmission respectively, our results pose the morphological basis for further studies on the action of small conductance calcium-activated potassium channel type 3 in serotonergic, noradrenergic and dopaminergic transmission.

  12. Overexpression of parkin in the rat nigrostriatal dopamine system protects against methamphetamine neurotoxicity.

    PubMed

    Liu, Bin; Traini, Roberta; Killinger, Bryan; Schneider, Bernard; Moszczynska, Anna

    2013-09-01

    Methamphetamine (METH) is a central nervous system psychostimulant with a high potential for abuse. At high doses, METH causes a selective degeneration of dopaminergic terminals in the striatum, sparing other striatal terminals and cell bodies. We previously detected a deficit in parkin after binge METH in rat striatal synaptosomes. Parkin is an ubiquitin-protein E3 ligase capable of protecting dopamine neurons from diverse cellular insults. Whether the deficit in parkin mediates the toxicity of METH and whether parkin can protect from toxicity of the drug is unknown. The present study investigated whether overexpression of parkin attenuates degeneration of striatal dopaminergic terminals exposed to binge METH. Parkin overexpression in rat nigrostriatal dopamine system was achieved by microinjection of adeno-associated viral transfer vector 2/6 encoding rat parkin (AAV2/6-parkin) into the substantia nigra pars compacta. The microinjections of AAV2/6-parkin dose-dependently increased parkin levels in both the substantia nigra pars compacta and striatum. The levels of dopamine synthesizing enzyme, tyrosine hydroxylase, remained at the control levels; therefore, tyrosine hydroxylase immunoreactivity was used as an index of dopaminergic terminal integrity. In METH-exposed rats, the increase in parkin levels attenuated METH-induced decreases in striatal tyrosine hydroxylase immunoreactivity in a dose-dependent manner, indicating that parkin can protect striatal dopaminergic terminals against METH neurotoxicity. Copyright © 2013 Elsevier Inc. All rights reserved.

  13. Overexpression of parkin in rat nigrostriatal dopamine system protects against methamphetamine neurotoxicity

    PubMed Central

    Liu, Bin; Traini, Roberta; Killinger, Bryan; Schneider, Bernard; Moszczynska, Anna

    2013-01-01

    Methamphetamine (METH) is a central nervous system psychostimulant with a high potential for abuse. At high doses, METH causes a selective degeneration of dopaminergic terminals in the striatum, sparing other striatal terminals and cell bodies. We previously detected a deficit in parkin after binge METH in rat striatal synaptosomes. Parkin is an ubiquitin-protein E3 ligase capable of protecting dopamine neurons from diverse cellular insults. Whether the deficit in parkin mediates the toxicity of METH and whether parkin can protect from toxicity of the drug is unknown. The present study investigated whether overexpression of parkin attenuates degeneration of striatal dopaminergic terminals exposed to binge METH. Parkin overexpression in rat nigrostriatal dopamine system was achieved by microinjection of adeno-associated viral transfer vector 2/6 encoding rat parkin (AAV2/6-parkin) into the substantia nigra pars compacta. The microinjections of AAV2/6-parkin dose-dependently increased parkin levels in both the substantia nigra pars compacta and striatum. The levels of dopamine synthesizing enzyme, tyrosine hydroxylase, remained at the control levels; therefore, tyrosine hydroxylase immunoreactivity was used as an index of dopaminergic terminal integrity. In METH-exposed rats, the increase in parkin levels attenuated METH-induced decreases in striatal tyrosine hydroxylase immunoreactivity in a dose-dependent manner, indicating that parkin can protect striatal dopaminergic terminals against METH neurotoxicity. PMID:23313192

  14. String Vessel Formation is Increased in the Brain of Parkinson Disease.

    PubMed

    Yang, Panzao; Pavlovic, Darja; Waldvogel, Henry; Dragunow, Mike; Synek, Beth; Turner, Clinton; Faull, Richard; Guan, Jian

    2015-01-01

    String vessels are collapsed basement membrane without endothelium and have no function in circulation. String vessel formation contributes to vascular degeneration in Alzheimer disease. By comparing to age-matched control cases we have recently reported endothelial degeneration in brain capillaries of human Parkinson disease (PD). Current study evaluated changes of basement membrane of capillaries, string vessel formation and their association with astrocytes, blood-brain-barrier integrity and neuronal degeneration in PD. Brain tissue from human cases of PD and age-matched controls was used. Immunohistochemical staining for collagen IV, GFAP, NeuN, tyrosine hydroxylase, fibrinogen and Factor VIII was evaluated by image analysis in the substantia nigra, caudate nucleus and middle frontal gyrus. While the basement-membrane-associated vessel density was similar between the two groups, the density of string vessels was significantly increased in the PD cases, particularly in the substantia nigra. Neuronal degeneration was found in all brain regions. Astrocytes and fibrinogen were increased in the caudate nuclei of PD cases compared with control cases. Endothelial degeneration and preservation of basement membrane result in an increase of string vessel formation in PD. The data may suggest a possible role for cerebral hypoperfusion in the neuronal degeneration characteristic of PD, which needs further investigation. Elevated astrocytosis in the caudate nucleus of PD cases could be associated with disruption of the blood-brain barrier in this brain region.

  15. Insulin resistance impairs nigrostriatal dopamine function.

    PubMed

    Morris, J K; Bomhoff, G L; Gorres, B K; Davis, V A; Kim, J; Lee, P-P; Brooks, W M; Gerhardt, G A; Geiger, P C; Stanford, J A

    2011-09-01

    Clinical studies have indicated a link between Parkinson's disease (PD) and Type 2 Diabetes. Although preclinical studies have examined the effect of high-fat feeding on dopamine function in brain reward pathways, the effect of diet on neurotransmission in the nigrostriatal pathway, which is affected in PD and parkinsonism, is less clear. We hypothesized that a high-fat diet, which models early-stage Type 2 Diabetes, would disrupt nigrostriatal dopamine function in young adult Fischer 344 rats. Rats were fed a high fat diet (60% calories from fat) or a normal chow diet for 12 weeks. High fat-fed animals were insulin resistant compared to chow-fed controls. Potassium-evoked dopamine release and dopamine clearance were measured in the striatum using in vivo electrochemistry. Dopamine release was attenuated and dopamine clearance was diminished in the high-fat diet group compared to chow-fed rats. Magnetic resonance imaging indicated increased iron deposition in the substantia nigra of the high fat group. This finding was supported by alterations in the expression of several proteins involved in iron metabolism in the substantia nigra in this group compared to chow-fed animals. The diet-induced systemic and basal ganglia-specific changes may play a role in the observed impairment of nigrostriatal dopamine function. Copyright © 2011 Elsevier Inc. All rights reserved.

  16. Facial dysmorphism in Leigh syndrome with SURF-1 mutation and COX deficiency.

    PubMed

    Yüksel, Adnan; Seven, Mehmet; Cetincelik, Umran; Yeşil, Gözde; Köksal, Vedat

    2006-06-01

    Leigh syndrome is an inherited, progressive neurodegenerative disorder of infancy and childhood. Mutations in the nuclear SURF-1 gene are specifically associated with cytochrome C oxidase-deficient Leigh syndrome. This report describes two patients with similar facial features. One of them was a 2(1/2)-year-old male, and the other was a 3-year-old male with a mutation in SURF-1 gene and facial dysmorphism including frontal bossing, brachycephaly, hypertrichosis, lateral displacement of inner canthi, esotropia, maxillary hypoplasia, hypertrophic gums, irregularly placed teeth, upturned nostril, low-set big ears, and retrognathi. The first patient's magnetic resonance imaging at 15 months of age indicated mild symmetric T2 prolongation involving the subthalamic nuclei. His second magnetic resonance imaging at 2 years old revealed a symmetric T2 prolongation involving the subthalamic nuclei, substantia nigra, and medulla lesions. In the second child, at the age of 2 the first magnetic resonance imaging documented heavy brainstem and subthalamic nuclei involvement. A second magnetic resonance imaging, performed when he was 3 years old, revealed diffuse involvement of the substantia nigra and hyperintense lesions of the central tegmental tract in addition to previous lesions. Facial dysmorphism and magnetic resonance imaging findings, observed in these cases, can be specific findings in Leigh syndrome patients with cytochrome C oxidase deficiency. SURF-1 gene mutations must be particularly reviewed in such patients.

  17. A novel dual GLP-1 and GIP incretin receptor agonist is neuroprotective in a mouse model of Parkinson's disease by reducing chronic inflammation in the brain.

    PubMed

    Cao, Lijun; Li, Dongfang; Feng, Peng; Li, Lin; Xue, Guo-Fang; Li, Guanglai; Hölscher, Christian

    2016-04-13

    The incretins glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are growth factors. GLP-1 mimetics are on the market as treatments for type 2 diabetes. Both GLP-1 and GIP mimetics have shown neuroprotective properties in previous studies. In addition, the GLP-1 mimetic exendin-4 has shown protective effects in a clinical trial in Parkinson's disease (PD) patients. Novel GLP-1/GIP dual-agonist peptides have been developed to treat diabetes. Here, we report the neuroprotective effects of a novel dual agonist (DA-JC1) in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. MPTP was injected once daily (20 mg/kg intraperitoneally) for 7 days and the dual agonist was coinjected once daily (50 nmol/kg intraperitoneally). We found that the drug reduced most of the MPTP-induced motor impairments in the rotarod, open-field locomotion, and muscle strength test. The number of tyrosine hydroxylase-positive neurons in the substantia nigra and striatum was reduced by MPTP and increased by DA-JC1. Synapse numbers (synaptophysin expression) were reduced in the substantia nigra and the striatum by MPTP and DA-JC1 reversed this effect. The activation of a chronic inflammation response by MPTP was considerably reduced by the dual agonist (DA) (astroglia and microglia activation). Therefore, dual agonists show promise as a novel treatment of PD.

  18. Basal Ganglia Neuronal Activity during Scanning Eye Movements in Parkinson’s Disease

    PubMed Central

    Sieger, Tomáš; Bonnet, Cecilia; Serranová, Tereza; Wild, Jiří; Novák, Daniel; Růžička, Filip; Urgošík, Dušan; Růžička, Evžen; Gaymard, Bertrand; Jech, Robert

    2013-01-01

    The oculomotor role of the basal ganglia has been supported by extensive evidence, although their role in scanning eye movements is poorly understood. Nineteen Parkinsońs disease patients, which underwent implantation of deep brain stimulation electrodes, were investigated with simultaneous intraoperative microelectrode recordings and single channel electrooculography in a scanning eye movement task by viewing a series of colored pictures selected from the International Affective Picture System. Four patients additionally underwent a visually guided saccade task. Microelectrode recordings were analyzed selectively from the subthalamic nucleus, substantia nigra pars reticulata and from the globus pallidus by the WaveClus program which allowed for detection and sorting of individual neurons. The relationship between neuronal firing rate and eye movements was studied by crosscorrelation analysis. Out of 183 neurons that were detected, 130 were found in the subthalamic nucleus, 30 in the substantia nigra and 23 in the globus pallidus. Twenty percent of the neurons in each of these structures showed eye movement-related activity. Neurons related to scanning eye movements were mostly unrelated to the visually guided saccades. We conclude that a relatively large number of basal ganglia neurons are involved in eye motion control. Surprisingly, neurons related to scanning eye movements differed from neurons activated during saccades suggesting functional specialization and segregation of both systems for eye movement control. PMID:24223158

  19. Structural analysis of the rDNA intergenic spacer of Brassica nigra: evolutionary divergence of the spacers of the three diploid Brassica species.

    PubMed

    Bhatia, S; Singh Negi, M; Lakshmikumaran, M

    1996-11-01

    EcoRI restriction of the B. nigra rDNA recombinants, isolated from a lambda genomic library, showed that the 3.9-kb fragment corresponded to the Intergenic Spacer (IGS), which was sequenced and found to be 3,928 bp in size. Sequence and dot-matrix analyses showed that the organization of the B. nigra rDNA IGS was typical of most rDNA spacers, consisting of a central repetitive region and flanking unique sequences on either side. The repetitive region was composed of two repeat families-RF 'A' and RF 'B.' The B. nigra RF 'A' consisted of a tandem array of three full-length copies of a 106-bp sequence element. RF 'B' was composed of 66 tandemly repeated elements. Each 'B' element was only 21-bp in size and this is the smallest repeat unit identified in plant rDNA to date. The putative transcription initiation site (TIS) was identified as nucleotide position 3,110. Based on the sequence analysis it was suggested that the present organization of the repeat families was generated by successive cycles of deletions and amplifications and was being maintained by homogenization processes such as gene conversion and crossing-over.A detailed comparison of the rDNA IGS sequences of the three diploid Brassica species-namely, B. nigra, B. campestris, and B. oleracea-was carried out. First, comparisons revealed that B. campestris and B. oleracea were close to each other as the repeat families in both showed high sequence homology between each other. Second, the repeat elements in both the species were organized in an interspersed manner. Third, a 52-bp sequence, present just downstream of the repeats in B. campestris, was found to be identical to the B. oleracea repeats, thereby suggesting a common progenitor. On the other hand, in B. nigra no interspersion pattern of organization of repeats was observed. Further, the B. nigra RF 'A' was identified as distinct from the repeat families of B. campestris and B. oleracea. Based on this analysis, it was suggested that during

  20. Tinea versicolor, tinea nigra, white piedra, and black piedra.

    PubMed

    Bonifaz, Alexandro; Gómez-Daza, Fernando; Paredes, Vanessa; Ponce, Rosa María

    2010-03-04

    Superficial mycoses are fungal infections limited to the stratum corneum and its adnexal structures. The most frequent types are dermatophytoses or tineas. Tinea versicolor involves the skin in the form of hypochromic or hyperchromic plaques, and tinea nigra affects the skin of the palms with dark plaques. White piedra and black piedra are parasitic infections of scalp hairs in the form of concretions caused by fungal growth. Diagnosis of these mycoses is made from mycologic studies, direct examination, stains, and isolation, and identification of the fungi. Treatment includes systemic antifungals, topical antifungals, and keratolytics. Copyright 2010 Elsevier Inc. All rights reserved.

  1. Striatal Cholinergic Interneurons Modulate Spike-Timing in Striosomes and Matrix by an Amphetamine-Sensitive Mechanism

    PubMed Central

    Crittenden, Jill R.; Lacey, Carolyn J.; Weng, Feng-Ju; Garrison, Catherine E.; Gibson, Daniel J.; Lin, Yingxi; Graybiel, Ann M.

    2017-01-01

    The striatum is key for action-selection and the motivation to move. Dopamine and acetylcholine release sites are enriched in the striatum and are cross-regulated, possibly to achieve optimal behavior. Drugs of abuse, which promote abnormally high dopamine release, disrupt normal action-selection and drive restricted, repetitive behaviors (stereotypies). Stereotypies occur in a variety of disorders including obsessive-compulsive disorder, autism, schizophrenia and Huntington's disease, as well as in addictive states. The severity of drug-induced stereotypy is correlated with induction of c-Fos expression in striosomes, a striatal compartment that is related to the limbic system and that directly projects to dopamine-producing neurons of the substantia nigra. These characteristics of striosomes contrast with the properties of the extra-striosomal matrix, which has strong sensorimotor and associative circuit inputs and outputs. Disruption of acetylcholine signaling in the striatum blocks the striosome-predominant c-Fos expression pattern induced by drugs of abuse and alters drug-induced stereotypy. The activity of striatal cholinergic interneurons is associated with behaviors related to sensory cues, and cortical inputs to striosomes can bias action-selection in the face of conflicting cues. The neurons and neuropil of striosomes and matrix neurons have observably separate distributions, both at the input level in the striatum and at the output level in the substantia nigra. Notably, cholinergic axons readily cross compartment borders, providing a potential route for local cross-compartment communication to maintain a balance between striosomal and matrix activity. We show here, by slice electrophysiology in transgenic mice, that repetitive evoked firing patterns in striosomal and matrix striatal projection neurons (SPNs) are interrupted by optogenetic activation of cholinergic interneurons either by the addition or the deletion of spikes. We demonstrate that this

  2. Tinea corporis, tinea cruris, tinea nigra, and piedra.

    PubMed

    Gupta, Aditya K; Chaudhry, Maria; Elewski, Boni

    2003-07-01

    Tinea infections are among the most common dermatologic conditions throughout the world. To avoid a misdiagnosis, identification of dermatophyte infections requires both a fungal culture on Sabouraud's agar media, and a light microscopic mycologic examination from skin scrapings. Topical antifungals may be sufficient for treatment of tinea corporis and cruris and tinea nigra, and the shaving of hair infected by piedra may also be beneficial. Systemic therapy, however, may be required when the infected areas are large, macerated with a secondary infection, or in immunocompromised individuals. Preventative measures of tinea infections include practicing good personal hygiene; keeping the skin dry and cool at all times; and avoiding sharing towels, clothing, or hair accessories with infected individuals.

  3. Phenolic acids in the flowers of Althaea rosea var. nigra.

    PubMed

    Dudek, Marlena; Matławska, Irena; Szkudlarek, Maurycy

    2006-01-01

    Distribution of phenolic acids in the flowers of Althaea rosea var. nigra has been studied by 2D-TLC and HPLC methods. The phenolic acids occurring in these fractions have been identified as ferulic, vanillic, syringic, p-coumaric, p-hydroxybenzoic, p-hydroxyphenylacetic and caffeic acids. By means of the HPLC methods the contents of major phenolic acids were estimated. From among the phenolic acids analyzed the syringic, p-hydroxybenzoic and p-coumaric acids are dominant. Total content of phenolic acids was determined by the Arnov's method.

  4. Tree regeneration in black ash (Fraxinus nigra) stands exhibiting crown dieback in Minnesota

    Treesearch

    Brian J. Palik; Michael E. Ostry; Robert C. Venette; Ebrahim. Abdela

    2012-01-01

    Crown dieback and mortality of black ash (Fraxinus nigra) has been noted across the range of the species in North America for several decades. Causes of dieback and mortality are not definitive, but may be related to spring drought or excessive moisture. Where black ash is the dominant tree species in the forest, continued dieback and mortality may...

  5. Electrical and Ca2+ signaling in dendritic spines of substantia nigra dopaminergic neurons

    PubMed Central

    Hage, Travis A; Sun, Yujie; Khaliq, Zayd M

    2016-01-01

    Little is known about the density and function of dendritic spines on midbrain dopamine neurons, or the relative contribution of spine and shaft synapses to excitability. Using Ca2+ imaging, glutamate uncaging, fluorescence recovery after photobleaching and transgenic mice expressing labeled PSD-95, we comparatively analyzed electrical and Ca2+ signaling in spines and shaft synapses of dopamine neurons. Dendritic spines were present on dopaminergic neurons at low densities in live and fixed tissue. Uncaging-evoked potential amplitudes correlated inversely with spine length but positively with the presence of PSD-95. Spine Ca2+ signals were less sensitive to hyperpolarization than shaft synapses, suggesting amplification of spine head voltages. Lastly, activating spines during pacemaking, we observed an unexpected enhancement of spine Ca2+ midway throughout the spike cycle, likely involving recruitment of NMDA receptors and voltage-gated conductances. These results demonstrate functionality of spines in dopamine neurons and reveal a novel modulation of spine Ca2+ signaling during pacemaking. DOI: http://dx.doi.org/10.7554/eLife.13905.001 PMID:27163179

  6. Effect of variety on content of bioactive phenolic compounds in common elder (Sambucus nigra L.).

    PubMed

    Vrchotová, Naděžda; Dadáková, Eva; Matějíček, Aleš; Tříska, Jan; Kaplan, Jiří

    2017-03-01

    The inflorescence of common elder (Sambucus nigra L., Adoxaceae) is known to be rich in phenolic compounds. The content of five selected phenolic compounds (rutin, chlorogenic acid, isoquercitrin, isorhamnetin-3-O- rutinoside and dicaffeoylquinic acid) was determined in methanolic extracts from flowers and floral stems by HPLC in samples obtained from 20 varieties of S. nigra cultivated in Czech Republic. In all samples, there were determined rutin (11-54 mg/g), chlorogenic acid (23-46 mg/g), isoquercitrin (0.6-18 mg/g), isorhamnetin-3-O-rutinoside (3-10 mg/g), calculated on air-dried material. The content of dicaffeoylquinic acid was 0-13 mg/g of air-dried material. The amount of the analysed compounds in floral stems was lower than the flowers. The results are a unique set of information on the content of main phenolics in the inflorescence of cultured elderberry varieties.

  7. Comparative Analysis of Growth and Photosynthetic Characteristics of (Populus simonii × P. nigra) × (P. nigra × P. simonii) Hybrid Clones of Different Ploidides

    PubMed Central

    Bian, Xiuyan; Liu, Mengran; Sun, Yanshuang; Jiang, Jing; Wang, Fuwei; Li, Shuchun; Cui, Yonghong; Liu, Guifeng; Yang, Chuanping

    2015-01-01

    To evaluate differences among poplar clones of various ploidies, 12 hybrid poplar clones (P. simonii × P. nigra) × (P. nigra × P. simonii) with different ploidies were used to study phenotypic variation in growth traits and photosynthetic characteristics. Analysis of variance showed remarkable differences for each of the investigated traits among these clones (P < 0.01). Coefficients of phenotypic variation (PCV) ranged from 2.38% to 56.71%, and repeatability ranged from 0.656 to 0.987. The Pn (photosynthetic rate) photosynthetic photon flux density (PPFD) curves of the 12 clones were S-shaped, but the Pn-ambient CO2 (Ca) curves were shaped like an inverted “V”. The stomatal conductance (Gs)-PPFD and transpiration rate (Tr)-PPFD curves had an upward tendency; however, with increasing PFFD, the intercellular CO2 concentration (Ci)-PPFD curves had a downward tendency in all of the clones. The Pn-PPFD and Pn-Ca curves followed the pattern of a quadratic equation. The average light saturation point and light compensation point of the triploid clones were the highest and lowest, respectively, among the three types of clones. For Pn-Ca curves, diploid clones had a higher average CO2 saturation point and average CO2 compensation point compared with triploid and tetraploid clones. Correlation analyses indicated that all investigated traits were strongly correlated with each other. In future studies, molecular methods should be used to analyze poplar clones of different ploidies to improve our understanding of the growth and development mechanisms of polyploidy. PMID:25867100

  8. A case of Tinea nigra associated to a bite from a European rabbit (Oryctolagus cuniculus, Leporidae): the role of dermoscopy in diagnosis.

    PubMed

    Rossetto, André Luiz; Corrêa, Patricia Rossetto; Cruz, Rosana Cé Bella; Pereira, Eduardo Figueiredo; Haddad Filho, Vidal

    2014-01-01

    We report a case of Tinea nigra in an adolescent living in Itapema, Santa Catarina, Brazil, who presented a hyperchromic macule on the palm of the left hand, close to another erythematous macule caused by a rabbit bite. The patient received guidance on accidents and animal bites and evolved well treated with topical butenafine for the dermatomycosis. The authors also highlight the efficacy of the dermoscopic exam in diagnosing Tinea nigra with animal bite lesions and other traumas.

  9. Habitat characteristics at den sites of the Point Arena mountain beaver (Aplodontia rufa nigra)

    Treesearch

    William J. Zielinski; John E. Hunter; Robin Hamlin; Keith M. Slauson; M. J. Mazurek

    2010-01-01

    The Point Arena mountain beaver (Aplodontia rufa nigra) is a federally listed endangered species, but has been the subject of few studies. Mountain beavers use burrows that include a single subterranean den. Foremost among the information needs for this subspecies is a description of the above-ground habitat features associated with dens. Using...

  10. Culturable heterotrophic bacteria from the marine sponge Dendrilla nigra: isolation and phylogenetic diversity of actinobacteria

    NASA Astrophysics Data System (ADS)

    Selvin, Joseph; Gandhimathi, R.; Kiran, G. Seghal; Priya, S. Shanmugha; Ravji, T. Rajeetha; Hema, T. A.

    2009-09-01

    Culturable heterotrophic bacterial composition of marine sponge Dendrilla nigra was analysed using different enrichments. Five media compositions including without enrichment (control), enriched with sponge extract, with growth regulator (antibiotics), with autoinducers, and complete enrichment containing sponge extract, antibiotics, and autoinducers were developed. DNA hybridization assay was performed to explore host specific bacteria and ecotypes of culturable sponge-associated bacteria. Enrichment with selective inducers (AHLs and sponge extract) and regulators (antibiotics) considerably enhanced the cultivation potential of sponge-associated bacteria. It was found that Marinobacter (MSI032), Micromonospora (MSI033), Streptomyces (MSI051), and Pseudomonas (MSI057) were sponge-associated obligate symbionts. The present findings envisaged that “ Micromonospora-Saccharomonospora-Streptomyces” group was the major culturable actinobacteria in the marine sponge D. nigra. The DNA hybridization assay was a reliable method for the analysis of culturable bacterial community in marine sponges. Based on the culturable community structure, the sponge-associated bacteria can be grouped (ecotypes) as general symbionts, specific symbionts, habitat flora, and antagonists.

  11. A case of Tinea nigra associated to a bite from a European rabbit (Oryctolagus cuniculus, Leporidae): the role of dermoscopy in diagnosis*

    PubMed Central

    Rossetto, André Luiz; Corrêa, Patricia Rossetto; Cruz, Rosana Cé Bella; Pereira, Eduardo Figueiredo; Haddad Junior, Vidal

    2014-01-01

    We report a case of Tinea nigra in an adolescent living in Itapema, Santa Catarina, Brazil, who presented a hyperchromic macule on the palm of the left hand, close to another erythematous macule caused by a rabbit bite. The patient received guidance on accidents and animal bites and evolved well treated with topical butenafine for the dermatomycosis. The authors also highlight the efficacy of the dermoscopic exam in diagnosing Tinea nigra with animal bite lesions and other traumas. PMID:24626667

  12. Chalcone dimethylallyltransferase from Morus nigra cell cultures. Substrate specificity studies.

    PubMed

    Vitali, Alberto; Giardina, Bruno; Delle Monache, Giuliano; Rocca, Filippo; Silvestrini, Andrea; Tafi, Andrea; Botta, Bruno

    2004-01-16

    A new prenyltransferase (PT) enzyme derived from the microsomal fractions of cell cultures of Morus nigra was shown to be able to prenylate exclusively chalcones with a 2',4'-dihydroxy substitution and the isoflavone genistein. Computational studies were performed to shed some light on the relationship between the structure of the substrate and the enzymatic activity. PT requires divalent cations, particularly Mg(2+), to be effective. The apparent K(m) values for gamma,gamma-dimethylallyldiphosphate and 2',4'-dihydroxychalcone were 63 and 142 microM, respectively. The maximum activity of the enzyme was expressed during the first 10 days of cell growth.

  13. Selective increases in serotonin 5-HT1B/1D and 5-HT2A/2C binding sites in adult rat basal ganglia following lesions of serotonergic neurons.

    PubMed

    Compan, V; Segu, L; Buhot, M C; Daszuta, A

    1998-05-18

    Quantitative autoradiography was used to examine possible adaptive changes in serotonin 5-HT1B/1D and 5-HT2A/2C receptor binding sites in adult rat basal ganglia, after partial or severe lesions of serotonergic neurons produced by intraraphe injections of variable amounts of 5,7-dihydroxytryptamine. In controls, the 5-HT1B/1D sites labeled with S-CM-G[125I]TNH2 were evenly distributed in the core and the shell of the nucleus accumbens. The density of 5-HT1B/1D sites was higher in the ventral than dorsal part of the striatum and no regional differences were detected along the rostrocaudal axis of the structure. The 5-HT2A/2C sites labeled with [125I]DOI were preferentially distributed in the mediodorsal striatum and higher densities were detected in the shell than core of the nucleus accumbens. Following 5,7-dihydroxytryptamine injections, there were no changes in binding of either receptor subtype after partial lesions entailing 80-90% 5-HT depletions. After severe 5-HT depletions (over 95%), large increases in 5-HT1B/1D binding were observed in the substantia nigra (78%), but no changes took place in the globus pallidus. Increases in 5-HT1B/1D binding were also detected in the shell of the nucleus accumbens (27%). Similar sized increases in 5-HT2A/2C binding (22%) were restricted to the medial striatum. The present results suggest a preferential association between 5-HT1B/1D receptors and the striatonigral neurons containing substance P, as indicated by the striatal distribution of these receptors and their selective increases in the substantia nigra after severe 5-HT deprivation. We recently proposed a similar relationship between the 5-HT4 receptors and the striatopallidal neurons containing met-enkephalin. Moreover, the increases in 5-HT1B/1D binding in the substantia nigra and in the shell of the nucleus accumbens reinforce the view of an implication of this receptor subtype in motor functions. In contrast, the prominent increases in 5-HT2A/2C binding after

  14. Sigma-1 receptor deficiency reduces MPTP-induced parkinsonism and death of dopaminergic neurons

    PubMed Central

    Hong, J; Sha, S; Zhou, L; Wang, C; Yin, J; Chen, L

    2015-01-01

    Sigma-1 receptor (σ1R) has been reported to be decreased in nigrostriatal motor system of Parkinson's disease patients. Using heterozygous and homozygous σ1R knockout (σ1R+/− and σ1R−/−) mice, we investigated the influence of σ1R deficiency on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-impaired nigrostriatal motor system. The injection of MPTP for 5 weeks in wild-type mice (MPTP-WT mice), but not in σ1R+/− or σ1R−/− mice (MPTP-σ1R+/− or MPTP-σ1R−/− mice), caused motor deficits and ~40% death of dopaminergic neurons in substantia nigra pars compacta with an elevation of N-methyl-d-aspartate receptor (NMDAr) NR2B phosphorylation. The σ1R antagonist NE100 or the NR2B inhibitor Ro25-6981 could alleviate the motor deficits and the death of dopaminergic neurons in MPTP-WT mice. By contrast, MPTP-σ1R+/− mice treated with the σ1R agonist PRE084 or MPTP-σ1R−/− mice treated with the NMDAr agonist NMDA appeared to have similar motor deficits and loss of dopaminergic neurons as MPTP-WT mice. The pharmacological or genetic inactivation of σ1R suppressed the expression of dopamine transporter (DAT) in substantia nigra, which was corrected by NMDA. The activation of σ1R by PRE084 enhanced the DAT expression in WT mice or σ1R+/− mice. By contrast, the level of vesicular monoamine transporter 2 (VMAT2) in σ1R+/− mice or σ1R−/− mice had no difference from WT mice. Interestingly, MPTP-WT mice showed the reduction in the levels of DAT and VMAT2, but MPTP-σ1R−/− mice did not. The inactivation of σ1R by NE100 could prevent the reduction of VMAT2 in MPTP-WT mice. In addition, the activation of microglia cells in substantia nigra was equally enhanced in MPTP-WT mice and MPTP-σ1R−/− mice. The number of activated astrocytes in MPTP-σ1R−/− mice was less than that in MPTP-WT mice. The findings indicate that the σ1R deficiency through suppressing NMDAr function and DAT expression can reduce MPTP-induced death of

  15. Functional and ultrastructural neuroanatomy of interactive intratectal/tectonigral mesencephalic opioid inhibitory links and nigrotectal GABAergic pathways: involvement of GABAA and mu1-opioid receptors in the modulation of panic-like reactions elicited by electrical stimulation of the dorsal midbrain.

    PubMed

    Ribeiro, S J; Ciscato, J G; de Oliveira, R; de Oliveira, R C; D'Angelo-Dias, R; Carvalho, A D; Felippotti, T T; Rebouças, E C C; Castellan-Baldan, L; Hoffmann, A; Corrêa, S A L; Moreira, J E; Coimbra, N C

    2005-12-01

    In the present study, the functional neuroanatomy of nigrotectal-tectonigral pathways as well as the effects of central administration of opioid antagonists on aversive stimuli-induced responses elicited by electrical stimulation of the midbrain tectum were determined. Central microinjections of naloxonazine, a selective mu(1)-opiod receptor antagonist, in the mesencephalic tectum (MT) caused a significant increase in the escape thresholds elicited by local electrical stimulation. Furthermore, either naltrexone or naloxonazine microinjected in the substantia nigra, pars reticulata (SNpr), caused a significant increase in the defensive thresholds elicited by electrical stimulation of the continuum comprised by dorsolateral aspects of the periaqueductal gray matter (dlPAG) and deep layers of the superior colliculus (dlSC), as compared with controls. These findings suggest an opioid modulation of GABAergic inhibitory inputs controlling the defensive behavior elicited by MT stimulation, in cranial aspects. In fact, iontophoretic microinjections of the neurotracer biodextran into the SNpr, a mesencephalic structure rich in GABA-containing neurons, show outputs to neural substrate of the dlSC/dlPAG involved with the generation and organization of fear- and panic-like reactions. Neurochemical lesion of the nigrotectal pathways increased the sensitivity of the MT to electrical (at alertness, freezing and escape thresholds) and chemical (blockade of GABA(A) receptors) stimulation, suggesting a tonic modulatory effect of the nigrotectal GABAergic outputs on the neural networks of the MT involved with the organization of the defensive behavior and panic-like reactions. Labeled neurons of the midbrain tectum send inputs with varicosities to ipsi and contralateral dlSC/dlPAG and ipsilateral substantia nigra, pars reticulata and compacta, in which the anterograde and retrograde tracing from a single injection indicates that the substantia nigra has reciprocal connections with

  16. Comparative study on bioremediation of heavy metals by solitary ascidian, Phallusia nigra, between Thoothukudi and Vizhinjam ports of India.

    PubMed

    Abdul Jaffar Ali, H; Tamilselvi, M; Akram, A Soban; Kaleem Arshan, M L; Sivakumar, V

    2015-11-01

    Ascidians belonging to the sub-phylum Uro-chordata are used as potential model organisms in various parts of the world for biosorption of metals. The sedentary nature, filter feeding habits, presence of vanadocytes and the absence of kidneys cause them to accumulate metals. The present study was aimed to compare biosorption of metals such as cadmium, copper, lead, mercury and vanadium in test and mantle body of solitary ascidian Phallusia nigra between two ecologically significant stations such as Thoothukudi (Station 1) and Vizhinjam (Station 2) ports of India. Monthly samplings of water and P. nigra were done for a period of one year from September 2010 to August 2011 and subjected to analysis of metal accumulation. The average metal concentrations except mercury in the Thoothukudi water were found to be higher of comparable magnitudes than the Vizhinjam water. One-way ANOVA showed significant differences between the stations. A comparison of average metal concentrations in the test and mantle body of P. nigra between two stations showed that the enrichment of V, Cd, Pb, Cu and Hg in the Thoothukudi samples may be due to high bioaccumulation factors of these elements as compared to other species of ascidians. The bioaccumulation factors were in the order of V>Pb>Cd>Cu> Hg for the test and mantle body in stations 1 and 2. Application of one-way ANOVA for the concentration of these metals between test and mantle body showed significant differences in both stations. Similarly, ANOVA for biosorption of these trace metals by P. nigra showed significant difference between stations. Metal concentrations recorded in this ascidian could effectively be used as good reference material for monitoring metal contamination in Indian sea waters. Copyright © 2015 Elsevier Inc. All rights reserved.

  17. Cytotoxic activity of a methanol extract of Phallusia nigra (Tunicata, Ascidiacea).

    PubMed

    Costa, L V; Malpezzi, E L; Matsui, D H; Machado-Santelli, G M; Freitas, J C

    1996-03-01

    Tunicates have been reported to be a rich source of biologically active compounds. In this study, we demonstrate the presence of cytotoxic substances in Phallusia nigra, a common tunicate from Brazilian coastal waters. An extract of tunicate tissue was obtained by homogenizing the visceral organs from 50 specimens in methanol, followed by filtration and concentration in a rotary vacuum evaporator. Finally, the concentrate was partitioned with chloroform to remove lipids. The resulting extract possessed antimitotic and hemolytic activity. The former was demonstrated as a delay in the development of sea urchin eggs by partially inhibiting the process of cleavage (first cleavage, EC50 +/- SEM = 3.44 +/- 0.84 mg/ml). The < 500 molecular fraction of the extract obtained by ultrafiltration also inhibited cell proliferation (the number of viable cells was decreased by 68% with 500 micrograms/ml) and DNA synthesis of T47D cells derived from human breast carcinoma as measured by [3H]-thymidine incorporation (66% of the control value after 24-h incubation with 100 micrograms/ml). Dose-dependent hemolysis obtained with P. nigra extract on mouse erythrocytes had an EC50 +/- SEM = 1.12 +/- 0.02 mg/ml for a 0.5% erythrocyte suspension. Hemolysis could be reduced by pre-incubating the cells with choline-containing phospholipid. Sphingomyelin (40 micrograms/ml) increased the EC50 by two-fold to 2.86 +/- 0.04 mg/ml, but phosphatidylcholine (80 micrograms/ml) did not modify hemolysis.

  18. Property of lysosomal storage disease associated with midbrain pathology in the central nervous system of Lamp-2-deficient mice.

    PubMed

    Furuta, Akiko; Kikuchi, Hisae; Fujita, Hiromi; Yamada, Daisuke; Fujiwara, Yuuki; Kabuta, Tomohiro; Nishino, Ichizo; Wada, Keiji; Uchiyama, Yasuo

    2015-06-01

    Lysosome-associated membrane protein-2 (LAMP-2) is the gene responsible for Danon disease, which is characterized by cardiomyopathy, autophagic vacuolar myopathy, and variable mental retardation. To elucidate the function of LAMP-2 in the central nervous system, we investigated the neuropathological changes in Lamp-2-deficient mice. Immunohistochemical observations revealed that Lamp-1 and cathepsin D-positive lysosomal structures increased in the large neurons of the mouse brain. Ubiquitin-immunoreactive aggregates and concanavalin A-positive materials were detected in these neurons. By means of ultrastructural studies, we found various-shaped accumulations, including lipofuscin, glycolipid-like materials, and membranous structures, in the neurons and glial cells of Lamp-2-deficient brains. In deficient mice, glycogen granules accumulated in hepatocyte lysosomes but were not observed in neurons. These pathological features indicate lysosomal storage disease; however, the findings are unlikely a consequence of deficiency of a single lysosomal enzyme. Although previous study results have shown a large amount of autophagic vacuoles in parenchymal cells of the visceral organs, these findings were rarely detected in the brain tissue except for some axons in the substantia nigra, in which abundant activated microglial cells with increased lipid peroxidation were observed. Thus, LAMP-2 in the central nervous system has a possible role in the degradation of the various macromolecules in lysosomes and an additional function concerning protection from oxidative stress, especially in the substantia nigra. Copyright © 2015 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

  19. Altered Mitochondrial DNA Methylation Pattern in Alzheimer Disease-Related Pathology and in Parkinson Disease.

    PubMed

    Blanch, Marta; Mosquera, Jose Luis; Ansoleaga, Belén; Ferrer, Isidre; Barrachina, Marta

    2016-02-01

    Mitochondrial dysfunction is linked with the etiopathogenesis of Alzheimer disease and Parkinson disease. Mitochondria are intracellular organelles essential for cell viability and are characterized by the presence of the mitochondrial (mt)DNA. DNA methylation is a well-known epigenetic mechanism that regulates nuclear gene transcription. However, mtDNA methylation is not the subject of the same research attention. The present study shows the presence of mitochondrial 5-methylcytosine in CpG and non-CpG sites in the entorhinal cortex and substantia nigra of control human postmortem brains, using the 454 GS FLX Titanium pyrosequencer. Moreover, increased mitochondrial 5-methylcytosine levels are found in the D-loop region of mtDNA in the entorhinal cortex in brain samples with Alzheimer disease-related pathology (stages I to II and stages III to IV of Braak and Braak; n = 8) with respect to control cases. Interestingly, this region shows a dynamic pattern in the content of mitochondrial 5-methylcytosine in amyloid precursor protein/presenilin 1 mice along with Alzheimer disease pathology progression (3, 6, and 12 months of age). Finally, a loss of mitochondrial 5-methylcytosine levels in the D-loop region is found in the substantia nigra in Parkinson disease (n = 10) with respect to control cases. In summary, the present findings suggest mtDNA epigenetic modulation in human brain is vulnerable to neurodegenerative disease states. Copyright © 2016 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

  20. Nimodipine, an L-type calcium channel blocker attenuates mitochondrial dysfunctions to protect against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced Parkinsonism in mice.

    PubMed

    Singh, Alpana; Verma, Poonam; Balaji, Gillela; Samantaray, Supriti; Mohanakumar, Kochupurackal P

    2016-10-01

    Parkinson's disease (PD), the most common progressive neurodegenerative movement disorder, results from loss of dopaminergic neurons of substantia nigra pars compacta. These neurons exhibit Cav1.3 channel-dependent pacemaking activity. Epidemiological studies suggest reduced risk for PD in population under long-term antihypertensive therapy with L-type calcium channel antagonists. These prompted us to investigate nimodipine, an L-type calcium channel blocker for neuroprotective effect in cellular and animal models of PD. Nimodipine (0.1-10 μM) significantly attenuated 1-methyl-4-phenyl pyridinium ion-induced loss in mitochondrial morphology, mitochondrial membrane potential and increases in intracellular calcium levels in SH-SY5Y neuroblastoma cell line as measured respectively employing Mitotracker green staining, TMRM, and Fura-2 fluorescence, but only a feeble neuroprotective effect was observed in MTT assay. Nimodipine dose-dependently reduced 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced parkinsonian syndromes (akinesia and catalepsy) and loss in swimming ability in Balb/c mice. It attenuated MPTP-induced loss of dopaminergic tyrosine hydroxylase positive neurons in substantia nigra, improved mitochondrial oxygen consumption and inhibited reactive oxygen species production in the striatal mitochondria measured using dichlorodihydrofluorescein fluorescence, but failed to block striatal dopamine depletion. These results point to an involvement of L-type calcium channels in MPTP-induced dopaminergic neuronal death in experimental parkinsonism and more importantly provide evidences for nimodipine to improve mitochondrial integrity and function. Copyright © 2016 Elsevier Ltd. All rights reserved.

  1. Synergistic effects of influenza and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) can be eliminated by the use of influenza therapeutics: experimental evidence for the multi-hit hypothesis.

    PubMed

    Sadasivan, Shankar; Sharp, Bridgett; Schultz-Cherry, Stacey; Smeyne, Richard Jay

    2017-01-01

    Central Nervous System inflammation has been implicated in neurodegenerative disorders including Parkinson's disease (Ransohoff, Science 353: 777-783, 2016; Kannarkat et al. J. Parkinsons Dis. 3: 493-514, 2013). Here, we examined if the H1N1 influenza virus (Studahl et al. Drugs 73: 131-158, 2013) could synergize with the parkinsonian toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (Jackson-Lewis et al. in Mark LeDoux (ed) Movement Disorders: Genetics and Models : 287-306, Elsevier, 2015) to induce a greater microglial activation and loss of substantia nigra pars compacta dopaminergic neurons than either insult alone. H1N1-infected animals administered 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine exhibit a 20% greater loss of substantia nigra pars compacta dopaminergic neurons than occurs from the additive effects of H1N1 or 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine alone ( p  < 0.001). No synergistic effects were found in microglial activation. The synergistic dopaminergic neuron loss is eliminated by influenza vaccination or treatment with oseltamivir carboxylate. This work shows that multiple insults can induce synergistic effects; and even these small changes can be significant as it might allow one to cross a phenotypic disease threshold that would not occur from individual non-interacting exposures. Our observations also have important implications for public health, providing impetus for influenza vaccination or prompt treatment with anti-viral medications upon influenza diagnosis.

  2. Representation of spontaneous movement by dopaminergic neurons is cell-type selective and disrupted in parkinsonism

    PubMed Central

    Dreyer, Jakob K.; Jennings, Katie A.; Syed, Emilie C. J.; Wade-Martins, Richard; Cragg, Stephanie J.; Bolam, J. Paul; Magill, Peter J.

    2016-01-01

    Midbrain dopaminergic neurons are essential for appropriate voluntary movement, as epitomized by the cardinal motor impairments arising in Parkinson’s disease. Understanding the basis of such motor control requires understanding how the firing of different types of dopaminergic neuron relates to movement and how this activity is deciphered in target structures such as the striatum. By recording and labeling individual neurons in behaving mice, we show that the representation of brief spontaneous movements in the firing of identified midbrain dopaminergic neurons is cell-type selective. Most dopaminergic neurons in the substantia nigra pars compacta (SNc), but not in ventral tegmental area or substantia nigra pars lateralis, consistently represented the onset of spontaneous movements with a pause in their firing. Computational modeling revealed that the movement-related firing of these dopaminergic neurons can manifest as rapid and robust fluctuations in striatal dopamine concentration and receptor activity. The exact nature of the movement-related signaling in the striatum depended on the type of dopaminergic neuron providing inputs, the striatal region innervated, and the type of dopamine receptor expressed by striatal neurons. Importantly, in aged mice harboring a genetic burden relevant for human Parkinson’s disease, the precise movement-related firing of SNc dopaminergic neurons and the resultant striatal dopamine signaling were lost. These data show that distinct dopaminergic cell types differentially encode spontaneous movement and elucidate how dysregulation of their firing in early Parkinsonism can impair their effector circuits. PMID:27001837

  3. Treatment of Parkinson's disease in rats by Nrf2 transfection using MRI-guided focused ultrasound delivery of nanomicrobubbles

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Long, Ling; Cai, Xiaodong; Guo, Ruomi

    Parkinson's disease (PD) is a very common neurological disorder. However, effective therapy is lacking. Although the blood-brain-barrier (BBB) protects the brain, it prevents the delivery of about 90% of drugs and nucleotides into the brain, thereby hindering the development of gene therapy for PD. Magnetic resonance imaging (MRI)-guided focused ultrasound delivery of microbubbles enhances the delivery of gene therapy vectors across the BBB and improves transfection efficiency. In the present study, we delivered nuclear factor E2-related factor 2 (Nrf2, NFE2L2) contained in nanomicrobubbles into the substantia nigra of PD rats by MRI-guided focused ultrasound, and we examined the effect ofmore » Nrf2 over-expression in this animal model of PD. The rat model of PD was established by injecting 6-OHDA in the right substantia nigra stereotactically. Plasmids (pDC315 or pDC315/Nrf2) were loaded onto nanomicrobubbles, and then injected through the tail vein with the assistance of MRI-guided focused ultrasound. MRI-guided focused ultrasound delivery of nanomicrobubbles increased gene transfection efficiency. Furthermore, Nrf2 gene transfection reduced reactive oxygen species levels, thereby protecting neurons in the target region. - Highlights: • MRI-guided focused ultrasound enhances gene transfection into the brain of rats. • Increased Nrf2 expression protects neurons in the rat model of PD. • Nrf2 protects neurons in PD by inhibiting ROS production.« less

  4. Non-Motor Symptom Burdens Are Not Associated with Iron Accumulation in Early Parkinson's Disease: a Quantitative Susceptibility Mapping Study.

    PubMed

    Shin, Chaewon; Lee, Seon; Lee, Jee Young; Rhim, Jung Hyo; Park, Sun Won

    2018-03-26

    Quantitative susceptibility mapping (QSM) has been used to measure iron accumulation in the deep nuclei of patients with Parkinson's disease (PD). This study examined the relationship between non-motor symptoms (NMSs) and iron accumulation in the deep nuclei of patients with PD. The QSM data were acquired from 3-Tesla magnetic resonance imaging (MRI) in 29 patients with early PD and 19 normal controls. The Korean version of the NMS scale (K-NMSS) was used for evaluation of NMSs in patients. The patients were divided into high NMS and low NMS groups. The region-of-interest analyses were performed in the following deep nuclei: red nucleus, substantia nigra pars compacta, substantia nigra pars reticulata, dentate nucleus, globus pallidus, putamen, and head of the caudate nucleus. Thirteen patients had high NMS scores (total K-NMSS score, mean = 32.1), and 16 had low NMS scores (10.6). The QSM values in the deep were not different among the patients with high NMS scores, low NMS scores, and controls. The QSM values were not correlated linearly with K-NMSS total score after adjusting the age at acquisition of brain MRI. The study demonstrated that the NMS burdens are not associated with iron accumulation in the deep nuclei of patients with PD. These results suggest that future neuroimaging studies on the pathology of NMSs in PD should use more specific and detailed clinical tools and recruit PD patients with severe NMSs. © 2018 The Korean Academy of Medical Sciences.

  5. Diadenosine tetraphosphate reduces toxicity caused by high-dose methamphetamine administration.

    PubMed

    Harvey, Brandon K; Chou, Jenny; Shen, Hui; Hoffer, Barry J; Wang, Yun

    2009-05-01

    Diadenosine tetraphosphate (AP(4)A), two adenosine moieties bridged by four phosphates, is an endogenous purinergic ligand found in brain. Previous studies have shown that AP(4)A reduced neurodegeneration caused by the dopaminergic neurotoxin 6-hydroxydopamine in rat striatum and substantia nigra. The purpose of this study was to determine whether AP(4)A is protective against methamphetamine (MA)-mediated toxicity. Primary neuronal cultures were prepared from rat embryonic (E14-E15) ventral mesencephalic tissue. Cultures treated with 2mM MA exhibited decreased tyrosine hydroxylase (TH) immunoreactivity and increased cleaved caspase-3 immunoreactivity and TUNEL labeling. All these changes were lessened by pretreatment with AP(4)A. The protective effect of AP(4)A was also found in vivo. Adult Sprague-Dawley rats were injected with AP(4)A (25 microg/20 microl) or vehicle intracerebroventricularly followed by 4 doses of MA (5 or 10 mg/kg), given subcutaneously every 2h. Administration of MA reduced locomotor activity 1 day after injection, which was significantly antagonized by the pretreatment with AP(4)A. Using immunohistochemical analysis, TH fiber density at the substantia nigra pars reticulata was found reduced while cleaved caspase-3 immunoreactivity in striatum was increased after MA treatment; these responses were also significantly antagonized by AP(4)A. Taken together, our data show that AP(4)A has protective effects against MA-mediated toxicity both in vitro and in vivo. The mechanism of action involves suppression of MA-induced apoptosis.

  6. Early Activation of Ventral Hippocampus and Subiculum during Spontaneous Seizures in a Rat Model of Temporal Lobe Epilepsy

    PubMed Central

    Toyoda, Izumi; Bower, Mark R.; Leyva, Fernando

    2013-01-01

    Temporal lobe epilepsy is the most common form of epilepsy in adults. The pilocarpine-treated rat model is used frequently to investigate temporal lobe epilepsy. The validity of the pilocarpine model has been challenged based largely on concerns that seizures might initiate in different brain regions in rats than in patients. The present study used 32 recording electrodes per rat to evaluate spontaneous seizures in various brain regions including the septum, dorsomedial thalamus, amygdala, olfactory cortex, dorsal and ventral hippocampus, substantia nigra, entorhinal cortex, and ventral subiculum. Compared with published results from patients, seizures in rats tended to be shorter, spread faster and more extensively, generate behavioral manifestations more quickly, and produce generalized convulsions more frequently. Similarities to patients included electrographic waveform patterns at seizure onset, variability in sites of earliest seizure activity within individuals, and variability in patterns of seizure spread. Like patients, the earliest seizure activity in rats was recorded most frequently within the hippocampal formation. The ventral hippocampus and ventral subiculum displayed the earliest seizure activity. Amygdala, olfactory cortex, and septum occasionally displayed early seizure latencies, but not above chance levels. Substantia nigra and dorsomedial thalamus demonstrated consistently late seizure onsets, suggesting their unlikely involvement in seizure initiation. The results of the present study reveal similarities in onset sites of spontaneous seizures in patients with temporal lobe epilepsy and pilocarpine-treated rats that support the model's validity. PMID:23825415

  7. Valeriana officinalis ameliorates vacuous chewing movements induced by reserpine in rats.

    PubMed

    Pereira, Romaiana Picada; Fachinetto, Roselei; de Souza Prestes, Alessandro; Wagner, Caroline; Sudati, Jéssie Haigert; Boligon, Aline Augusti; Athayde, Margareth Linde; Morsch, Vera Maria; Rocha, João Batista Teixeira

    2011-11-01

    Oral movements are associated with important neuropathologies as Parkinson's disease and tardive dyskinesia. However, until this time, there has been no known efficacious treatment, without side effects, for these disorders. Thus, the aim of the present study was to investigate the possible preventive effects of V. officinalis, a phytotherapic that has GABAergic and antioxidant properties, in vacuous chewing movements (VCMs) induced by reserpine in rats. Adult male rats were treated with reserpine (1 mg/kg, s.c.) and/or with V. officinalis (in the drinking water, starting 15 days before the administration of the reserpine). VCMs, locomotor activity and oxidative stress measurements were evaluated. Furthermore, we carried out the identification of valeric acid and gallic acid by HPLC in the V. officinalis tincture. Our findings demonstrated that reserpine caused a marked increase on VCMs and the co-treatment with V. officinalis was able to reduce the intensity of VCM. Reserpine did not induce oxidative stress in cerebral structures (cortex, hippocampus, striatum and substantia nigra). However, a significant positive correlation between DCF-oxidation (an estimation of oxidative stress) in the cortex and VCMs (p < 0.05) was observed. Moreover, a negative correlation between Na(+)K(+)-ATPase activity in substantia nigra and the number of VCMs was observed (p < 0.05). In conclusion, V. officinalis had behavioral protective effect against reserpine-induced VCMs in rats; however, the exact mechanisms that contributed to this effect have not been completely understood.

  8. Presymptomatic detection of Parkinson's disease.

    PubMed

    Jenner, P

    1993-01-01

    Presymptomatic detection of Parkinson's disease is necessary if neuroprotective therapies are to be utilized in its treatment. Various methods (PET, electrophysiology, enzyme assays, olfactory function) may be applicable but none has been rigorously evaluated. Other possible approaches are now considered. Plasma HVA levels (pHVA) in the presence of debrisoquine may reflect cerebral dopamine function. However, there are no detectable differences in pHVA between newly diagnosed and untreated parkinsonian patients and control subjects. Compensatory increases in dopamine turnover may mask a decrease in pHVA in the early stages of the disease. So, at present this technique could not be used as a diagnostic tool. Post-mortem studies of brain in Parkinson's disease may provide clues to biochemical markers indicative of nigral pathology. Mitochondrial complex I activity is reduced in substantia nigra in Parkinson's disease and it was reported also to be markedly reduced in blood platelets. However, subsequent studies suggest that the difference in platelet complex I activity is too small to be diagnostic of Parkinson's disease. There are also selective reductions in brain glutathione levels in Parkinson's disease restricted to substantia nigra, which do not occur in other neurodegenerative disorders and are not due to drug treatment. Importantly, in incidental Lewy body disease (preclinical Parkinson's disease) nigral glutathione levels are reduced to the same degree as in advanced Parkinson's disease. So, some peripheral index of altered glutathione function may be valuable in the early detection of the disease process.

  9. Efficacy and Safety of Pedunculopontine Nuclei (PPN) Deep Brain Stimulation in the Treatment of Gait Disorders: A Meta-Analysis of Clinical Studies.

    PubMed

    Golestanirad, Laleh; Elahi, Behzad; Graham, Simon J; Das, Sunit; Wald, Lawrence L

    2016-01-01

    Pedunculopontine nucleus (PPN) has complex reciprocal connections with basal ganglia, especially with internal globus pallidus and substantia nigra, and it has been postulated that PPN stimulation may improve gait instability and freezing of gait. In this meta-analysis, we will assess the evidence for PPN deep brain stimulation in treatment of gait and motor abnormalities especially focusing on Parkinson disease patients. PubMed and Scopus electronic databases were searched for related studies published before February 2014. Medline (1966-2014), Embase (1974-2010), CINAHL, Web of Science, Scopus bibliographic, and Google Scholar databases (1960-2014) were also searched for studies investigating effect of PPN deep brain stimulation in treatment of postural and postural instability and total of ten studies met the inclusion criteria for this analysis. Our findings showed a significant improvement in postural instability (p<0.001) and motor symptoms of Parkinson disease on and off medications (p<0.05), but failed to show improvement in freezing of gait. Despite significant improvement in postural instability observed in included studies, evidence from current literature is not sufficient to generalize these findings to the majority of patients.

  10. Generation and characterisation of a parkin-Pacrg knockout mouse line and a Pacrg knockout mouse line.

    PubMed

    Stephenson, Sarah E M; Aumann, Timothy D; Taylor, Juliet M; Riseley, Jessica R; Li, Ruili; Mann, Jeffrey R; Tomas, Doris; Lockhart, Paul J

    2018-05-14

    Mutations in PARK2 (parkin) can result in Parkinson's disease (PD). Parkin shares a bidirectional promoter with parkin coregulated gene (PACRG) and the transcriptional start sites are separated by only ~200 bp. Bidirectionally regulated genes have been shown to function in common biological pathways. Mice lacking parkin have largely failed to recapitulate the dopaminergic neuronal loss and movement impairments seen in individuals with parkin-mediated PD. We aimed to investigate the function of PACRG and test the hypothesis that parkin and PACRG function in a common pathway by generating and characterizing two novel knockout mouse lines harbouring loss of both parkin and Pacrg or Pacrg alone. Successful modification of the targeted allele was confirmed at the genomic, transcriptional and steady state protein levels for both genes. At 18-20 months of age, there were no significant differences in the behaviour of parental and mutant lines when assessed by openfield, rotarod and balance beam. Subsequent neuropathological examination suggested there was no gross abnormality of the dopaminergic system in the substantia nigra and no significant difference in the number of dopaminergic neurons in either knockout model compared to wildtype mice.

  11. Progressive nonfluent aphasia: a rare clinical subtype of FTLD-TDP in Japan.

    PubMed

    Aoki, Naoya; Tsuchiya, Kuniaki; Kobayashi, Zen; Arai, Tetsuaki; Togo, Takashi; Miyazaki, Hiroshi; Kondo, Hiromi; Ishizu, Hideki; Uchikado, Hirotake; Katsuse, Omi; Hirayasu, Yoshio; Akiyama, Haruhiko

    2012-06-01

    Progressive nonfluent aphasia (PNFA) is a clinical subtype of frontotemporal lobar degeneration (FTLD). FTLD with tau accumulation (FTLD-tau) and FTLD with TDP-43 accumulation (FTLD-TDP) both cause PNFA. We reviewed clinical records of 29 FTLD-TDP cases in the brain archive of our institute and found only one case of PNFA. The patient was an 81-year-old male at death. There was no family history of dementia or aphasia. He presented with slow, labored and nonfluent speech at age 75. Behavioral abnormality and movement disorders were absent. MRI at age 76 demonstrated atrophy of the perisylvian regions, including the inferior frontal gyrus, insular gyrus and superior temporal gyrus. The atrophy was more severe in the left hemisphere than the right. On post mortem examinations, neuronal loss was evident in these regions as well as in the substantia nigra. There were abundant TDP-43-immunoreactive neuronal cytoplasmic inclusions and round or irregular-shaped structures in the affected cerebral cortices. A few dystrophic neurites and neuronal intranuclear inclusions were also seen. FTLD-TDP showing PNFA seems to be rare but does exist in Japan, similar to that in other countries. © 2011 Japanese Society of Neuropathology.

  12. Locomotor differences in mice expressing wild-type human α-synuclein.

    PubMed

    Giraldo, Genesys; Brooks, Mieu; Giasson, Benoit I; Janus, Christopher

    2018-05-01

    Parkinson's disease manifests as a progressive movement disorder with underlying degeneration of dopaminergic neurons in the substantia nigra, consequent depletion of dopamine levels, and the accumulation of Lewy bodies in the brain. Because α-synuclein (α-Syn) protein is the major component of Lewy bodies, mouse models expressing wild-type or mutant SNCA/α-Syn genes provide a useful tool to investigate canonical characteristics of the disease. We evaluated a mouse model (denoted M20) that expresses human wild-type SNCA gene. The M20 mice showed abnormal locomotor behavior and reduced species-specific home cage activity. However, the direction of behavioral changes was task specific. In comparison with their control littermates, the M20 mice exhibited shorter grip endurance, and longer times to traverse elevated beams, but they descended the vertical pole faster and stayed longer on the accelerated rod than the control mice. The M20 mice were also impaired in burrowing and nest building activities. These results indicate a possible role of α-Syn in motor coordination and the motivation to perform species-specific behaviors in the presymptomatic model of synucleinopathy. Published by Elsevier Inc.

  13. Development and characterization of microsatellite markers in the Point Arena mountain beaver Aplodontia rufa nigra

    Treesearch

    Kristine L. Pilgrim; William J. Zielinski; Mary J. Mazurek; Frederick V. Schlexer; Michael K. Schwartz

    2006-01-01

    The Point Arena mountain beaver (Aplodontia rufa nigra) is an endangered subspecies. Efforts to recover this sub-species will be aided by advances in molecular genetics, specifically the ability to estimate population size using noninvasive genetic sampling. Here we report on the development of nine polymorphic loci for the Point Arena mountain...

  14. Effects of photooxidation on membrane integrity in Salix nigra seeds

    PubMed Central

    Roqueiro, Gonzalo; Facorro, Graciela B.; Huarte, Mónica G.; Rubín de Celis, Emilio; García, Fernando; Maldonado, Sara; Maroder, Horacio

    2010-01-01

    Background and Aims Salix nigra seeds are desiccation-tolerant, as are orthodox seeds, although in contrast to other orthodox seeds they lose viability in a few weeks at room temperature. They also differ in that the chloroplasts of the embryo tissues conserve their chlorophyll and endomembranes. The aim of this paper was to investigate the role of chlorophyll in seed deterioration. Methods Seeds were aged at different light intensities and atmospheric conditions. Mean germination time and normal and total germination were evaluated. The formation of free radicals was assessed using electronic spin resonance spectroscopy, and changes in the fatty acid composition from phospholipids, galactolipids and triglycerides using gas–liquid chromatography. Membrane integrity was studied with electronic spin resonance spin probe techniques, electrolyte leakage and transmission electron microscopy. Key Results Light and oxygen played an important role in free-radical generation, causing a decrease in normal germination and an increase in mean germination time. Both indices were associated with a decrease in polyunsaturated fatty acids derived from membrane lipids as phospholipids and galactolipids. The detection of damage in thylakoid membranes and an increase in plasmalemma permeability were consistent with the decrease in both types of lipids. Triglycerides remained unchanged. Light-induced damage began in outermost tissues and spread inwards, decreasing normal germination. Conclusions Salix nigra seeds were very susceptible to photooxidation. The thylakoid membranes appeared to be the first target of the photooxidative process since there were large decreases in galactolipids and both these lipids and the activated chlorophyll are contiguous in the structure of that membrane. Changes in normal germination and mean germination time could be explained by the deteriorative effects of oxidation. PMID:20338949

  15. Clinical and neuropathological findings of acute carbon monoxide toxicity in chihuahuas following smoke inhalation.

    PubMed

    Kent, Marc; Creevy, Kate E; Delahunta, Alexander

    2010-01-01

    Three adult Chihuahuas were presented for evaluation after smoke inhalation during a house fire. All three dogs received supportive care and supplemental oxygen. After initial improvement, the dogs developed seizures. Despite anticonvulsant therapy and supportive care, the dogs died. The brains of two dogs were examined. Lesions were identified that were compatible with acute carbon monoxide (CO) toxicity. Lesions were confined to the caudate nucleus, the globus pallidus, and the substantia nigra bilaterally, as well as the cerebellum, cerebral cortex, and dorsal thalamus. This case report describes the clinicopathological sequelae in acute CO toxicity.

  16. Midbrain and spinal cord magnetic resonance imaging (MRI) changes in poliomyelitis.

    PubMed

    Choudhary, Anita; Sharma, Suvasini; Sankhyan, Naveen; Gulati, Sheffali; Kalra, Veena; Banerjee, Bidisha; Kumar, Atin

    2010-04-01

    Poliomyelitis, though eradicated from most parts of the world, continues to occur in India. There is paucity of data on the magnetic resonance imaging (MRI) changes in poliomyelitis. We report a 3(1/2)-year-old boy who presented with subacute onset flaccid paralysis and altered sensorium. Stool culture was positive for wild polio virus type 3. Magnetic resonance imaging revealed signal changes in bilateral substantia nigra and anterior horns of the spinal cord. These MRI changes may be of potential diagnostic significance in a child with poliomyelitis.

  17. Winter variation in physiological status of cold stored and freshly lifted semi-evergreen quercus nigra seedlings

    Treesearch

    Rosa C. Goodman; Douglass F. Jacobs; Kent G. Apostol; Barrett C. Wilson; Emile S. Gardiner

    2009-01-01

    Water oak (Quercus nigra L.) is a tardily deciduous species commonly planted in afforestation projects in the Lower Mississippi River Alluvial Valley, USA. Field performance is often marked by low survival rates and top dieback, which may be associated with poor physiological quality of planting stock.

  18. The adhesion of Pseudomonas aeruginosa to high molecular weight human tear film species corresponds to glycoproteins reactive with Sambucus nigra lectin.

    PubMed

    Aristoteli, Lina Panayiota; Willcox, Mark D P

    2006-11-01

    Pseudomonas aeruginosa is a pathogen gaining prevalence in contact lens-related corneal ulcers. Tear outflow protects the ocular surface, where high molecular weight tear glycoproteins bind bacteria for removal from the eye. The purpose of the present study was to identify glycoproteins in human tears involved in the adhesion of ocular P. aeruginosa isolates. Basal human tears were applied to a bacterial adhesion assay involving electrophoretic separation of tear components, transfer to nitrocellulose and incubation with biotin-labelled bacteria. Glycoproteins were further characterised using lectin profiling. The results showed large-dimension agarose gels were imperative for the detection of at least four glycoproteins with a migration >200 kDa, including species not previously identified. P. aeruginosa 6294 preferentially bound to a well-defined glycoprotein near the origin of the gel that, unlike other glycoproteins >200 kDa, reacted with Sambucus nigra lectin (sialic acid alpha2-6) but not WGA lectin (N-acetylglucosamine, sialic acid alpha2-3). Adhesion did not involve free biotin label or hydrophobic interactions. Also, the pre-incubation of separated tear glycoproteins with S. nigra lectin increased subsequent adhesion of 6294 to this tear glycoprotein. The less virulent Paer1 strain showed diffuse adhesion in the S. nigra-reactive region at the gel origin. In conclusion, an overlay adhesion assay was developed that identified slow-migrating sialylated glycoprotein species in human tears preferentially bound by P. aeruginosa ocular strains, and S. nigra lectin seemed to enhance the interaction. The study provides a basis for direct investigation of bacterial adhesion to glycoproteins with an apparent migration >200 kDa in tear fluid.

  19. Dense genetic linkage maps of three Populus species (Populus deltoides, P. nigra and P. trichocarpa) based on AFLP and microsatellite markers.

    PubMed

    Cervera, M T; Storme, V; Ivens, B; Gusmão, J; Liu, B H; Hostyn, V; Van Slycken, J; Van Montagu, M; Boerjan, W

    2001-06-01

    Populus deltoides, P. nigra, and P. trichocarpa are the most important species for poplar breeding programs worldwide. In addition, Populus has become a model for fundamental research on trees. Linkage maps were constructed for these three species by analyzing progeny of two controlled crosses sharing the same female parent, Populus deltoides cv. S9-2 x P. nigra cv. Ghoy and P. deltoides cv. S9-2 x P. trichocarpa cv. V24. The two-way pseudotestcross mapping strategy was used to construct the maps. Amplified fragment length polymorphism (AFLP) markers that segregated 1:1 were used to form the four parental maps. Microsatellites and sequence-tagged sites were used to align homoeologous groups between the maps and to merge linkage groups within the individual maps. Linkage analysis and alignment of the homoeologous groups resulted in 566 markers distributed over 19 groups for P. deltoides covering 86% of the genome, 339 markers distributed over 19 groups for P. trichocarpa covering 73%, and 369 markers distributed over 28 groups for P. nigra covering 61%. Several tests for randomness showed that the AFLP markers were randomly distributed over the genome.

  20. Dense genetic linkage maps of three Populus species (Populus deltoides, P. nigra and P. trichocarpa) based on AFLP and microsatellite markers.

    PubMed Central

    Cervera, M T; Storme, V; Ivens, B; Gusmão, J; Liu, B H; Hostyn, V; Van Slycken, J; Van Montagu, M; Boerjan, W

    2001-01-01

    Populus deltoides, P. nigra, and P. trichocarpa are the most important species for poplar breeding programs worldwide. In addition, Populus has become a model for fundamental research on trees. Linkage maps were constructed for these three species by analyzing progeny of two controlled crosses sharing the same female parent, Populus deltoides cv. S9-2 x P. nigra cv. Ghoy and P. deltoides cv. S9-2 x P. trichocarpa cv. V24. The two-way pseudotestcross mapping strategy was used to construct the maps. Amplified fragment length polymorphism (AFLP) markers that segregated 1:1 were used to form the four parental maps. Microsatellites and sequence-tagged sites were used to align homoeologous groups between the maps and to merge linkage groups within the individual maps. Linkage analysis and alignment of the homoeologous groups resulted in 566 markers distributed over 19 groups for P. deltoides covering 86% of the genome, 339 markers distributed over 19 groups for P. trichocarpa covering 73%, and 369 markers distributed over 28 groups for P. nigra covering 61%. Several tests for randomness showed that the AFLP markers were randomly distributed over the genome. PMID:11404342

  1. Chemical Composition of Ballota macedonica Vandas and Ballota nigra L. ssp. foetida (Vis.) Hayek Essential Oils - The Chemotaxonomic Approach.

    PubMed

    Đorđević, Aleksandra S; Jovanović, Olga P; Zlatković, Bojan K; Stojanović, Gordana S

    2016-06-01

    The essential oils isolated from fresh aerial parts of Ballota macedonica (two populations) and Ballota nigra ssp. foetida were analyzed by GC and GC/MS. Eighty five components were identified in total; 60 components in B. macedonica oil (population from the Former Yugoslav Republic of Macedonia), 34 components in B. macedonica oil (population from the Republic of Serbia), and 33 components in the oil of B. nigra ssp. foetida accounting for 93.9%, 98.4%, and 95.8% of the total oils, respectively. The most abundant components in B. macedonica oils were carotol (13.7 - 52.1%), germacrene D (8.6 - 24.6%), and (E)-caryophyllene (6.5 - 16.5%), while B. nigra ssp. foetida oil was dominated by (E)-phytol (56.9%), germacrene D (10.0%), and (E)-caryophyllene (4.7%). Multivariate statistical analyses (agglomerative hierarchical cluster analysis and principal component analysis) were used to compare and discuss relationships among Ballota species examined so far based on their volatile profiles. The chemical compositions of B. macedonica essential oils are reported for the first time. © 2016 Verlag Helvetica Chimica Acta AG, Zürich.

  2. NORADRENERGIC CONTROL OF CORTICO-STRIATO-THALAMIC AND MESOLIMBIC CROSS-STRUCTURAL SYNCHRONY

    PubMed Central

    Dzirasa, Kafui; Phillips, H. Westley; Sotnikova, Tatyana D.; Salahpour, Ali; Kumar, Sunil; Gainetdinov, Raul R.; Caron, Marc G.; Nicolelis, Miguel A. L.

    2010-01-01

    While normal dopaminergic tone has been shown to be essential for the induction of cortico-striatal and mesolimbic theta oscillatory activity, the influence of norepinephrine on these brain networks remains relatively unknown. To address this question, we simultaneously recorded local field potentials (LFPs) and single neuron activity across ten interconnected brain areas (ventral striatum, frontal association cortex hippocampus, primary motor cortex, orbital frontal cortex, prelimbic cortex, dorsal lateral striatum, medial dorsal nucleus of thalamus, substantia nigra pars reticularis, and ventral tegmental area) in a combined genetically and pharmacologically induced mouse model of hyponoradrenergia. Our results show that norepinephrine (NE) depletion induces a novel state in male mice characterized by a profound disruption of coherence across multiple cortico-striatal circuits, and an increase in mesolimbic cross-structural coherence. Moreover, this brain state is accompanied by a complex behavioral phenotype consisting of transient hyperactivity, stereotypic behaviors, and an acute twelve-fold increase in grooming. Notably, treatment with a norepinephrine precursors (L-DOPA 100mg/kg or L-DOPS 5mg/kg), or a selective serotonin reuptake inhibitor (fluoxetine 20mg/kg) attenuates the abnormal behaviors and selectively reverses the circuit changes observed in NE depleted mice. Together, our results demonstrate that norepinephrine modulates the dynamic tuning of coherence across cortico-striatal-thalamic circuits, and they suggest that changes in coherence across these circuits mediate the abnormal generation of hyperactivity and repetitive behaviors. PMID:20445065

  3. Noradrenergic control of cortico-striato-thalamic and mesolimbic cross-structural synchrony.

    PubMed

    Dzirasa, Kafui; Phillips, H Westley; Sotnikova, Tatyana D; Salahpour, Ali; Kumar, Sunil; Gainetdinov, Raul R; Caron, Marc G; Nicolelis, Miguel A L

    2010-05-05

    Although normal dopaminergic tone has been shown to be essential for the induction of cortico-striatal and mesolimbic theta oscillatory activity, the influence of norepinephrine on these brain networks remains relatively unknown. To address this question, we simultaneously recorded local field potentials and single-neuron activity across 10 interconnected brain areas (ventral striatum, frontal association cortex, hippocampus, primary motor cortex, orbital frontal cortex, prelimbic cortex, dorsal lateral striatum, medial dorsal nucleus of thalamus, substantia nigra pars reticularis, and ventral tegmental area) in a combined genetically and pharmacologically induced mouse model of hyponoradrenergia. Our results show that norepinephrine (NE) depletion induces a novel state in male mice characterized by a profound disruption of coherence across multiple cortico-striatal circuits and an increase in mesolimbic cross-structural coherence. Moreover, this brain state is accompanied by a complex behavioral phenotype consisting of transient hyperactivity, stereotypic behaviors, and an acute 12-fold increase in grooming. Notably, treatment with a norepinephrine precursors (l-3,4-dihydroxyphenylalanine at 100 mg/kg or l-threo-dihydroxyphenylserine at 5 mg/kg) or a selective serotonin reuptake inhibitor (fluoxetine at 20 mg/kg) attenuates the abnormal behaviors and selectively reverses the circuit changes observed in NE-depleted mice. Together, our results demonstrate that norepinephrine modulates the dynamic tuning of coherence across cortico-striato-thalamic circuits, and they suggest that changes in coherence across these circuits mediate the abnormal generation of hyperactivity and repetitive behaviors.

  4. Mucuna pruriens seed extract reduces oxidative stress in nigrostriatal tissue and improves neurobehavioral activity in paraquat-induced Parkinsonian mouse model.

    PubMed

    Yadav, Satyndra Kumar; Prakash, Jay; Chouhan, Shikha; Singh, Surya Pratap

    2013-06-01

    Parkinson's disease (PD) is a neurodegenerative disease which causes rigidity, resting tremor and postural instability. Treatment for this disease is still under investigation. Mucuna pruriens (L.), is a traditional herbal medicine, used in India since 1500 B.C., as a neuroprotective agent. In this present study, we evaluated the therapeutic effects of aqueous extract of M. pruriens (Mp) seed in Parkinsonian mouse model developed by chronic exposure to paraquat (PQ). Results of our study revealed that the nigrostriatal portion of Parkinsonian mouse brain showed significantly increased levels of nitrite, malondialdehyde (MDA) and reduced levels of catalase compared to the control. In the Parkinsonian mice hanging time was decreased, whereas narrow beam walk time and foot printing errors were increased. Treatment with aqueous seed extract of Mp significantly increased the catalase activity and decreased the MDA and nitrite level, compared to untreated Parkinsonian mouse brain. Mp treatment also improved the behavioral abnormalities. It increased hanging time, whereas it decreased narrow beam walk time and foot printing error compared to untreated Parkinsonian mouse brain. Furthermore, we observed a significant reduction in tyrosine hydroxylase (TH) immunoreactivity in the substantia nigra (SN) and striatum region of the brain, after treatment with PQ which was considerably restored by the use of Mp seed extract. Our result suggested that Mp seed extract treatment significantly reduced the PQ induced neurotoxicity as evident by decrease in oxidative damage, physiological abnormalities and immunohistochemical changes in the Parkinsonian mouse. Copyright © 2013 Elsevier Ltd. All rights reserved.

  5. Cultivar identification and genetic relatedness among 25 black walnut (Juglans nigra) clones based on microsatellite markers

    Treesearch

    Kejia Pang; Keith Woeste; Charles Michler

    2017-01-01

    A set of eight microsatellite markers was used to genotype 25 black walnut (Juglans nigra L.) clones within the Purdue University germplasm repository. The identities of 212 ramets were verified using the same eight microsatellite markers. Some trees were mislabeled and corrected as to clone using analysis of microsatellite markers. A genetic...

  6. First report of Geosmithia morbida on ambrosia beetles emerged from thousand cankers-diseased Juglans nigra in Ohio

    Treesearch

    Jennifer Juzwik; M. McDermott-Kubeczko; T. J. Stewart; M. D. Ginzel

    2016-01-01

    Eastern black walnut (Juglans nigra) is a highly-valued species for timber and nut production in the eastern United States. Thousand cankers disease (TCD), caused by the interaction of the walnut twig beetle (Pityophthorus juglandis) and the canker fungus Geosmithia morbida (Tisserat et al. 2009), was first...

  7. Noninvasive PK11195-PET Image Analysis Techniques Can Detect Abnormal Cerebral Microglial Activation in Parkinson's Disease.

    PubMed

    Kang, Yeona; Mozley, P David; Verma, Ajay; Schlyer, David; Henchcliffe, Claire; Gauthier, Susan A; Chiao, Ping C; He, Bin; Nikolopoulou, Anastasia; Logan, Jean; Sullivan, Jenna M; Pryor, Kane O; Hesterman, Jacob; Kothari, Paresh J; Vallabhajosula, Shankar

    2018-05-04

    Neuroinflammation has been implicated in the pathophysiology of Parkinson's disease (PD), which might be influenced by successful neuroprotective drugs. The uptake of [ 11 C](R)-PK11195 (PK) is often considered to be a proxy for neuroinflammation, and can be quantified using the Logan graphical method with an image-derived blood input function, or the Logan reference tissue model using automated reference region extraction. The purposes of this study were (1) to assess whether these noninvasive image analysis methods can discriminate between patients with PD and healthy volunteers (HVs), and (2) to establish the effect size that would be required to distinguish true drug-induced changes from system variance in longitudinal trials. The sample consisted of 20 participants with PD and 19 HVs. Two independent teams analyzed the data to compare the volume of distribution calculated using image-derived input functions (IDIFs), and binding potentials calculated using the Logan reference region model. With all methods, the higher signal-to-background in patients resulted in lower variability and better repeatability than in controls. We were able to use noninvasive techniques showing significantly increased uptake of PK in multiple brain regions of participants with PD compared to HVs. Although not necessarily reflecting absolute values, these noninvasive image analysis methods can discriminate between PD patients and HVs. We see a difference of 24% in the substantia nigra between PD and HV with a repeatability coefficient of 13%, showing that it will be possible to estimate responses in longitudinal, within subject trials of novel neuroprotective drugs. © 2018 The Authors. Journal of Neuroimaging published by Wiley Periodicals, Inc. on behalf of American Society of Neuroimaging.

  8. A well-refined in vitro model derived from human embryonic stem cell for screening phytochemicals with midbrain dopaminergic differentiation-boosting potential for improving Parkinson's disease.

    PubMed

    Hsieh, Wen-Ting; Chiang, Been-Huang

    2014-07-09

    Stimulation of endogenous neurogenesis is a potential approach to compensate for loss of dopaminergic neurons of substantia nigra compacta nigra (SNpc) in patients with Parkinson's disease (PD). This objective was to establish an in vitro model by differentiating pluripotent human embryonic stem cells (hESCs) into midbrain dopaminergic (mDA) neurons for screening phytochemicals with mDA neurogenesis-boosting potentials. Consequently, a five-stage differentiation process was developed. The derived cells expressed many mDA markers including tyrosine hydroxylase (TH), β-III tubulin, and dopamine transporter (DAT). The voltage-gated ion channels and dopamine release were also examined for verifying neuron function, and the dopamine receptor agonists bromocriptine and 7-hydroxy-2-(dipropylamino)tetralin (7-OH-DPAT) were used to validate our model. Then, several potential phytochemicals including green tea catechins and ginsenosides were tested using the model. Finally, ginsenoside Rb1 was identified as the most potent phytochemical which is capable of upregulating neurotrophin expression and inducing mDA differentiation.

  9. Dopamine induces soluble α-synuclein oligomers and nigrostriatal degeneration

    PubMed Central

    Mor, Danielle E.; Tsika, Elpida; Mazzulli, Joseph R.; Gould, Neal S.; Kim, Hanna; Daniels, Malcolm J.; Doshi, Shachee; Gupta, Preetika; Grossman, Jennifer L.; Tan, Victor X.; Kalb, Robert G.; Caldwell, Kim A.; Caldwell, Guy A.; Wolfe, John H.; Ischiropoulos, Harry

    2018-01-01

    Parkinson’s disease is defined by the loss of dopaminergic neurons in the substantia nigra and formation of Lewy body inclusions containing aggregated α-synuclein. Efforts to explain dopamine neuron vulnerability are hindered by the lack of dopaminergic cell death in α-synuclein transgenic mice. To address this, we manipulated dopamine levels in addition to α-synuclein expression. Nigra-targeted expression of mutant tyrosine hydroxylase with enhanced catalytic activity increased dopamine without damaging neurons in non-transgenic mice. In contrast, raising dopamine in mice expressing human A53T mutant α-synuclein induced progressive nigrostriatal degeneration and reduced locomotion. Dopamine elevation in A53T mice increased levels of potentially toxic α-synuclein oligomers, resulting in conformationally and functionally modified species. Moreover, in genetically tractable C. elegans models expression of α-synuclein mutated at the site of interaction with dopamine prevented dopamine-induced toxicity. The data suggest a unique mechanism linking two cardinal features of Parkinson’s disease, dopaminergic cell death and α-synuclein aggregation. PMID:28920936

  10. Examination of correlation between histidine and nickel absorption by Morus L., Robinia pseudoacacia L. and Populus nigra L. using HPLC-MS and ICP-MS.

    PubMed

    Ozen, Sukran Akkus; Yaman, Mehmet

    2016-08-02

    In this study, HPLC-MS and ICP-MS methods were used for the determination of histidine and nickel in Morus L., Robinia pseudoacacia L., and Populus nigra L. leaves taken from industrial areas including Gaziantep and Bursa cities. In the determination of histidine by HPLC-MS, all of the system parameters such as flow rate of mobile phase, fragmentor potential, injection volume and column temperature were optimized and found to be 0.2 mL min(-1), 70 V, 15 µL, and 20°C, respectively. Under the optimum conditions, histidine was extracted from plant sample by distilled water at 90°C for 30 min. Concentrations of histidine as mg kg(-1) were found to be between 2-9 for Morus L., 6-13 for Robinia pseudoacacia L., and 2-10 for Populus nigra L. Concentrations of nickel were in the ranges of 5-10 mg kg(-1) for Morus L., 3-10 mg kg(-1) for Robinia pseudoacacia L., and 0.6-4 mg kg(-1) for Populus nigra L. A significant linear correlation (r = 0.78) between histidine and Ni was observed for Populus nigra L., whereas insignificant linear correlation for Robinia pseudoacacia L. (r = 0.22) were seen. Limits of detection (LOD) and quantitation (LOQ) were found to be 0.025 mg Ni L(-1) and 0.075 mg Ni L(-1), respectively.

  11. Developing new microsatellite markers in walnut (Juglans regia L.) from Juglans nigra genomic GA enriched library

    Treesearch

    Hayat Topcu; Nergiz Coban; Keith Woeste; Mehmet Sutyemez; Salih Kafkas

    2015-01-01

    We attempted to develop new polymorphic SSR primer pairs in walnut using sequences derived from Juglans nigra L. genomic enriched library with GA repeat. The designed 94 SSR primer pairs were subjected to gradient PCR in 12 walnut cultivars to determine their optimum annealing temperatures and to determine whether they produce bands. Then, the...

  12. Brazilian Morus nigra Attenuated Hyperglycemia, Dyslipidemia, and Prooxidant Status in Alloxan-Induced Diabetic Rats

    PubMed Central

    Júnior, Ivanildo I. da S.; Barbosa, Humberto de Moura; Carvalho, Débora C. R.; Barros, Ruideglan de Alencar; Albuquerque, Flávia Peixoto; da Silva, Dionísio Henrique Amaral; Souza, Grasielly R.; Souza, Nathália A. C.; Silva, Flaviane M. M.; Duarte, Glória I. B. P.; de Oliveira Júnior, Flávio Monteiro; Gomes, Dayane A.

    2017-01-01

    Morus nigra has been used popularly for several proposes, including diabetic. In an attempt to support medicinal value, the acute hypoglycemic, hypolipidemic, and antioxidant effects of the ethanolic extract of Morus nigra (EEMn 200 or 400 mg/kg b.w.) were evaluated in normal and alloxan-induced diabetic treated for 14 days. Serum biochemical and antioxidant analysis were performed at the end of experiment. Oral glucose tolerance test was performed at 10th and 15th days. Chromatographic analysis by HPLC-DAD of EEMn was performed. Insulin was used as positive control to glycemic metabolism as well as fenofibrate to lipid metabolism. EEMn (400 mg/kg/day) reduced fasting and postprandial glycaemia, improved oral glucose tolerance, and reduced lipolysis and proteolysis in diabetic rats. EEMn decreased the blood levels of total cholesterol and increased HDL level when compared to the diabetic control rats. At higher levels, EEMn reduced triglycerides and VLDL levels in diabetic rats. Also, EEMn reduced malondialdehyde and increased the reduced glutathione levels in liver of diabetic rats. Chromatographic analysis identified the presence of the flavonoids rutin, isoquercetin, and kaempferitrin. Acute EEMn treatment reduced hyperglycemia, improved oral glucose tolerance, and minimized dyslipidemia and oxidative stress leading to a reduction in atherogenic index in alloxan-induced diabetic rats. PMID:28567440

  13. Acyl spermidines in inflorescence extracts of elder (Sambucus nigra L., Adoxaceae) and elderflower drinks.

    PubMed

    Kite, Geoffrey C; Larsson, Sonny; Veitch, Nigel C; Porter, Elaine A; Ding, Ning; Simmonds, Monique S J

    2013-04-10

    LC-UV-MS analyses of inflorescence extracts of Sambucus nigra L. (elder, Adoxaceae) revealed the presence of numerous acyl spermidines, with isomers of N,N-diferuloylspermidine and N-acetyl-N,N-diferuloylspermidine being most abundant. Pollen was the main source of the acyl spermidines in the inflorescence. Three of the major acyl spermidines were isolated and their structures determined by NMR spectroscopy as N⁵,N¹⁰-di-(E,E)-feruloylspermidine and the new compounds N¹-acetyl-N⁵,N¹⁰-di-(Z,E)-feruloylspermidine and N¹-acetyl-N⁵,N¹⁰-di-(E,E)-feruloylspermidine. An isomer of N,N,N-triferuloylspermidine was also obtained and identified as N¹,N⁵,N¹⁰-tri-(E,E,E)-feruloylspermidine. In addition to stereoisomers of the isolated acyl spermidines, other acyl spermidines detected by the positive ion LC-UV-MS were isomers of N-caffeoyl-N,N-diferuloylspermidine, N-coumaroyl-N,N-diferuloylspermidine, N-caffeoyl-N-feruloylspermidine, N-coumaroyl-N-feruloylspermidine, N-acetyl-N-caffeoyl-N-feruloylspermidine, and N-acetyl-N-coumaroyl-N-feruloylspermidine. Analysis of commercial elderflower drinks showed that acyl spermidines were persistent in these processed elderflower products. Examination of inflorescence extracts from Sambucus canadensis L. (American elder) revealed the presence of acyl spermidines that were different from those of S. nigra.

  14. Vegetation responses to simulated emerald ash borer infestation in Fraxinus nigra dominated wetlands of Upper Michigan, USA

    Treesearch

    Joshua C. Davis; Joseph P. Shannon; Nicholas W. Bolton; Randall K. Kolka; Thomas G. Pypker

    2017-01-01

    The invasive emerald ash borer (EAB) (Agrilus planipennis Fairmaire (Coleoptera: Buprestidae)) is a significant threat to biodiversity and ecosystem processes in North American forests. Of particular concern is the fate of Fraxinus nigra (black ash), which is frequently a dominant canopy species across much of its range. To...

  15. Nutritional pattern and eco-physiology of Hortaea werneckii, agent of human tinea nigra.

    PubMed

    de Hoog, G S; Gerrits van den Ende, A H

    1992-11-01

    The life cycle of Hortaea werneckii includes yeast-like, hyphal and meristematic growth. The preponderance of each form of propagation can be influenced by environmental conditions. The clinical entity 'tinea nigra' is explained by ecological similarities between supposed natural niches and human hyperhydrotic skin. The species is recognizable by assimilation of lactose, nitrate and nitrite, no or little growth with L-lysine, cadaverine, creatine and creatinine, and tolerance of 10% NaCl. It generally does not grow at 36 degrees C.

  16. DOE Office of Scientific and Technical Information (OSTI.GOV)

    Dilts, R.P.; Kalivas, P.W.

    The enkephalin analog (2-D-penicillamine, 5-D-penicillamine)enkephalin was radioiodinated (125I-DPDPE) and shown to retain a pharmacological selectivity characteristic of the delta opioid receptor in in vitro binding studies. The distributions of 125I-DPDPE binding, using in vitro autoradiographic techniques, were similar to those previously reported for the delta opioid receptor. The nucleus accumbens, striatum, and medial prefrontal cortex contain dense gradients of 125I-DPDPE binding in regions known to receive dopaminergic afferents emanating from the mesencephalic tegmentum. Selective chemical lesions of the ventral tegmental area and substantia nigra were employed to deduce the location of the 125I-DPDPE binding within particular regions of the mesocorticolimbicmore » dopamine system. Unilateral lesions of dopamine perikarya (A9 and A10) within the ventral tegmental area and substantia nigra produced by mesencephalic injection of 6-hydroxydopamine resulted in significant (20-30%) increases in 125I-DPDPE binding contralateral to the lesion within the striatum and nucleus accumbens. Lesions of the perikarya (dopaminergic and nondopaminergic) of the ventral tegmental area, induced by quinolinic acid injections, caused increases of less magnitude within these same nuclei. No significant alterations in 125I-DPDPE binding were observed within the mesencephalon as a result of either treatment. The specificity of the lesions was confirmed by immunocytochemistry for tyrosine hydroxylase. These results suggest that the enkephalins and opioid agonists acting through delta opioid receptors do not directly modulate dopaminergic afferents but do regulate postsynaptic targets of the mesocorticolimbic dopamine system.« less

  17. Pigmented Creatine Deposits in Amyotrophic Lateral Sclerosis Central Nervous System Tissues Identified by Synchrotron Fourier Transform Infrared Microspectroscopy and X-ray Fluorescence Spectromicroscopy

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Kastyak, M.; Szczerbowska-Boruchowska, M; Adamek, D

    2010-01-01

    Amyotrophic Lateral Sclerosis (ALS) is an untreatable, neurodegenerative disease of motor neurons characterized by progressive muscle atrophy, limb paralysis, dysarthria, dysphagia, dyspnae and finally death. Large motor neurons in ventral horns of spinal cord and motor nuclei in brainstem, large pyramidal neurons of motor cortex and/or large myelinated axons of corticospinal tracts are affected. In recent synchrotron Fourier Transform Infrared microspectroscopy (sFTIR) studies of ALS CNS autopsy tissue, we discovered a small deposit of crystalline creatine, which has a crucial role in energy metabolism. We have now examined unfixed, snap frozen, post-autopsy tissue sections of motor cortex, brain stem, spinalmore » cord, hippocampus and substantia nigra from six ALS and three non-degenerated cases with FTIR and micro-X-ray fluorescence (XRF). Heterogeneous pigmented deposits were discovered in spinal cord, brain stem and motor neuron cortex of two ALS cases. The FTIR signature of creatine has been identified in these deposits and in numerous large, non-pigmented deposits in four of the ALS cases. Comparable pigmentation and creatine deposits were not found in controls or in ALS hippocampus and substantia nigra. Ca, K, Fe, Cu and Zn, as determined by XRF, were not correlated with the pigmented deposits; however, there was a higher incidence of hot spots (Ca, Zn, Fe and Cu) in the ALS cases. The identity of the pigmented deposits remains unknown, although the absence of Fe argues against both erythrocytes and neuromelanin. We conclude that elevated creatine deposits may be indicators of dysfunctional oxidative processes in some ALS cases.« less

  18. Expanding Lipidome Coverage Using LC-MS/MS Data-Dependent Acquisition with Automated Exclusion List Generation

    NASA Astrophysics Data System (ADS)

    Koelmel, Jeremy P.; Kroeger, Nicholas M.; Gill, Emily L.; Ulmer, Candice Z.; Bowden, John A.; Patterson, Rainey E.; Yost, Richard A.; Garrett, Timothy J.

    2017-05-01

    Untargeted omics analyses aim to comprehensively characterize biomolecules within a biological system. Changes in the presence or quantity of these biomolecules can indicate important biological perturbations, such as those caused by disease. With current technological advancements, the entire genome can now be sequenced; however, in the burgeoning fields of lipidomics, only a subset of lipids can be identified. The recent emergence of high resolution tandem mass spectrometry (HR-MS/MS), in combination with ultra-high performance liquid chromatography, has resulted in an increased coverage of the lipidome. Nevertheless, identifications from MS/MS are generally limited by the number of precursors that can be selected for fragmentation during chromatographic elution. Therefore, we developed the software IE-Omics to automate iterative exclusion (IE), where selected precursors using data-dependent topN analyses are excluded in sequential injections. In each sequential injection, unique precursors are fragmented until HR-MS/MS spectra of all ions above a user-defined intensity threshold are acquired. IE-Omics was applied to lipidomic analyses in Red Cross plasma and substantia nigra tissue. Coverage of the lipidome was drastically improved using IE. When applying IE-Omics to Red Cross plasma and substantia nigra lipid extracts in positive ion mode, 69% and 40% more molecular identifications were obtained, respectively. In addition, applying IE-Omics to a lipidomics workflow increased the coverage of trace species, including odd-chained and short-chained diacylglycerides and oxidized lipid species. By increasing the coverage of the lipidome, applying IE to a lipidomics workflow increases the probability of finding biomarkers and provides additional information for determining etiology of disease.

  19. Linking Inflammation and Parkinson Disease: Hypochlorous Acid Generates Parkinsonian Poisons

    PubMed Central

    Jeitner, Thomas M.; Kalogiannis, Mike; Krasnikov, Boris F.; Gomlin, Irving; Peltier, Morgan R.; Moran, Graham R.

    2016-01-01

    Inflammation is a common feature of Parkinson Disease and other neurodegenerative disorders. Hypochlorous acid (HOCl) is a reactive oxygen species formed by neutrophils and other myeloperoxidase-containing cells during inflammation. HOCl chlorinates the amine and catechol moieties of dopamine to produce chlorinated derivatives collectively termed chlorodopamine. Here, we report that chlorodopamine is toxic to dopaminergic neurons both in vivo and in vitro. Intrastriatal administration of 90 nmol chlorodopamine to mice resulted in loss of dopaminergic neurons from the substantia nigra and decreased ambulation-results that were comparable to those produced by the same dose of the parkinsonian poison, 1-methyl-4-phenylpyridinium (MPP+). Chlorodopamine was also more toxic to differentiated SH SY5Y cells than HOCl. The basis of this selective toxicity is likely mediated by chlorodopamine uptake through the dopamine transporter, as expression of this transporter in COS-7 cells conferred sensitivity to chlorodopamine toxicity. Pharmacological blockade of the dopamine transporter also mitigated the deleterious effects of chlorodopamine in vivo. The cellular actions of chlorodopamine included inactivation of the α-ketoglutarate dehydrogenase complex, as well as inhibition of mitochondrial respiration. The latter effect is consistent with inhibition of cytochrome c oxidase. Illumination at 670 nm, which stimulates cytochrome c oxidase, reversed the effects of chlorodopamine. The observed changes in mitochondrial biochemistry were also accompanied by the swelling of these organelles. Overall, our findings suggest that chlorination of dopamine by HOCl generates toxins that selectively kill dopaminergic neurons in the substantia nigra in a manner comparable to MPP+. PMID:27026709

  20. The PPARgamma agonist pioglitazone is effective in the MPTP mouse model of Parkinson's disease through inhibition of monoamine oxidase B.

    PubMed

    Quinn, L P; Crook, B; Hows, M E; Vidgeon-Hart, M; Chapman, H; Upton, N; Medhurst, A D; Virley, D J

    2008-05-01

    The peroxisome proliferator-activated receptor-gamma (PPARgamma) agonist pioglitazone has previously been shown to attenuate dopaminergic cell loss in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson's disease, an effect attributed to its anti-inflammatory properties. In the present investigation, we provide evidence that pioglitazone is effective in the MPTP mouse model, not via an anti-inflammatory action, but through inhibition of MAO-B, the enzyme required to biotransform MPTP to its active neurotoxic metabolite 1-methyl-4-phenylpyridinium (MPP+). Mice were treated with pioglitazone (20 mg kg(-1) b.i.d. (twice a day), p.o., for 7 days), prior and post or post-MPTP (30 mg kg(-1) s.c.) treatment. Mice were then assessed for motor impairments on a beam-walking apparatus and for reductions in TH immunoreactivity in the substantia nigra and depletions in striatal dopamine. The effects of pioglitazone on striatal MPP+ levels and MAO-B activity were also assessed. Mice treated with MPTP showed deficits in motor performance, marked depletions in striatal dopamine levels and a concomitant reduction in TH immunoreactivity in the substantia nigra. Pretreatment with pioglitazone completely prevented these effects of MPTP. However, pretreatment with pioglitazone also significantly inhibited the MPTP-induced production of striatal MPP+ and the activity of MAO-B in the striatum. The neuroprotection observed with pioglitazone pretreatment in the MPTP mouse model was due to the blockade of the conversion of MPTP to its active toxic metabolite MPP+, via inhibition of MAO-B.

  1. Alterations in cortical and extrastriatal subcortical dopamine function in schizophrenia: systematic review and meta-analysis of imaging studies.

    PubMed

    Kambeitz, Joseph; Abi-Dargham, Anissa; Kapur, Shitij; Howes, Oliver D

    2014-06-01

    The hypothesis that cortical dopaminergic alterations underlie aspects of schizophrenia has been highly influential. To bring together and evaluate the imaging evidence for dopaminergic alterations in cortical and other extrastriatal regions in schizophrenia. Electronic databases were searched for in vivo molecular studies of extrastriatal dopaminergic function in schizophrenia. Twenty-three studies (278 patients and 265 controls) were identified. Clinicodemographic and imaging variables were extracted and effect sizes determined for the dopaminergic measures. There were sufficient data to permit meta-analyses for the temporal cortex, thalamus and substantia nigra but not for other regions. The meta-analysis of dopamine D2/D3 receptor availability found summary effect sizes of d = -0.32 (95% CI -0.68 to 0.03) for the thalamus, d = -0.23 (95% CI -0.54 to 0.07) for the temporal cortex and d = 0.04 (95% CI -0.92 to 0.99) for the substantia nigra. Confidence intervals were wide and all included no difference between groups. Evidence for other measures/regions is limited because of the small number of studies and in some instances inconsistent findings, although significant differences were reported for D2/D3 receptors in the cingulate and uncus, for D1 receptors in the prefrontal cortex and for dopamine transporter availability in the thalamus. There is a relative paucity of direct evidence for cortical dopaminergic alterations in schizophrenia, and findings are inconclusive. This is surprising given the wide influence of the hypothesis. Large, well-controlled studies in drug-naive patients are warranted to definitively test this hypothesis. Royal College of Psychiatrists.

  2. Piracetam and vinpocetine ameliorate rotenone-induced Parkinsonism in rats

    PubMed Central

    Zaitone, Sawsan A.; Abo-Elmatty, Dina M.; Elshazly, Shimaa M.

    2012-01-01

    Objective: To evaluate the neuroprotective effect of the nootropic drugs, piracetam (PIR) and vinpocetine (VIN), in rotenone-induced Parkinsonism in rats. Materials and Methods: Sixty male rats were divided into 6 groups of 10 rats each. The groups were administered vehicle, control (rotenone, 1.5 mg/kg/48 h/6 doses, s.c.), PIR (100 and 200 mg/kg/day, p.o.) and VIN (3 and 6 mg/kg/day, p.o.). The motor performance of the rats was evaluated by the open field and pole test. Striatal dopamine level, malondialdehyde (MDA), reduced glutathione (GSH) and tumor necrosis factor-α (TNF-α) were assayed. Histopathological study of the substantia nigra was also done. Results: Results showed that rotenone-treated rats exhibited bradykinesia and motor impairment in the open-field test. In addition, GSH level was decreased whereas MDA and TNF-α increased in striata of rotenone-treated rats as compared to vehicle-treated rats. Marked degeneration of the substantia nigra pars compacta (SNpc) neurons and depletion of striatal dopamine was also observed in the rotenone-treated rats. Treatment with PIR or VIN significantly reversed the locomotor deficits and increased striatal dopamine level. Treatment with VIN significantly (P < 0.05) reduced the striatal level of MDA and GSH in comparison to rotenone group whereas TNF-α production was found to be significantly decreased in PIR group (P < 0.05). Conclusion: VIN and PIR exhibit neuroprotective activity in rotenone-induced Parkinsonism. Hence, these nootropic agents may be considered as possible candidates in the treatment of Parkinson's disease. PMID:23248410

  3. Locus Coeruleus Neuron Density and Parkinsonism in Older Adults without Parkinson’s Disease

    PubMed Central

    Buchman, Aron S.; Nag, Sukriti; Shulman, Joshua M.; Lim, Andrew S.P.; VanderHorst, Veronique G.J.M.; Leurgans, Sue E.; Schneider, Julie A.; Bennett, David A.

    2013-01-01

    Objective Prior work has showed that nigral neuron density is related to the severity of parkinsonism proximate to death in older persons without a clinical diagnosis of Parkinson’s disease (PD). We tested the hypothesis that neuron density in other brainstem aminergic nuclei is also related to the severity of parkinsonism. Design We studied brain autopsies from 125 deceased older adults without PD enrolled in the Memory and Aging Project, a clinical-pathologic investigation. Parkinsonism was assessed with a modified version of the Unified Parkinson’s Disease Rating Scale (UPDRS). We measured neuron density in the substantia nigra, ventral tegmental area, locus coeruleus and dorsal raphe; and postmortem indices of Lewy body Alzheimer’s disease and cerebrovascular pathologies. Results Mean age at death was 88.0 and global parkinsonism was 14.8 (SD=9.50). In a series of regression models which controlled for demographics and neuron density in the substantia nigra, neuron density in the locus coeruleus (Estimate, −0.261, S.E., 0.117, p=0.028) but not in the ventral tegmental area or dorsal raphe was associated with the severity of global parkinsonism proximate to death. These findings were unchanged in models which controlled for post-mortem interval, whole brain weight and other common neuropathologies including Alzheimer’s disease and Lewy body pathology and cerebrovascular vascular pathologies. Conclusion In older adults without a clinical diagnosis of PD, neuron density in locus coeruleus nuclei is associated with the severity of parkinsonism and may contribute to late-life motor impairments. PMID:23038629

  4. Diadenosine Tetraphosphate Reduces Toxicity caused by High-Dose Methamphetamine Administration

    PubMed Central

    Harvey, Brandon K.; Chou, Jenny; Shen, Hui; Hoffer, Barry J.; Wang, Yun

    2009-01-01

    Diadenosine tetraphosphate (AP4A), two adenosine moieties bridged by four phosphates, is an endogenous purinergic ligand found in brain. Previous studies have shown that AP4A reduced neurodegeneration caused by the dopaminergic neurotoxin 6-hydroxydopamine in rat striatum and substantia nigra. The purpose of this study was to determine whether AP4A is protective against methamphetamine (MA) –mediated toxicity. Primary neuronal cultures were prepared from rat embryonic (E14- E15) ventral mesencephalic tissue. Cultures treated with 2 mM MA exhibited decreased tyrosine hydroxylase (TH) immunoreactivity and increased cleaved caspase-3 immunoreactivity and TUNEL labeling. All these changes were lessened by pretreatment with AP4A. The protective effect of AP4A was also found in vivo. Adult Sprague-Dawley rats were injected with AP4A (25 μg/ 20 μl) or vehicle intracerebroventricularly followed by 4 doses of MA (5 or 10 mg/ kg), given subcutaneously every two hours. Administration of MA reduced locomotor activity one day after injection, which was significantly antagonized by the pretreatment with AP4A. Using immunohistochemical analysis, TH fiber density at the substantia nigra pars reticulata was found reduced while cleaved caspase-3 immunoreactivity in striatum was increased after MA treatment; these responses were also significantly antagonized by AP4A. Taken together, our data show that AP4A has protective effects against MA-mediated toxicity both in vitro and in vivo. The mechanism of action involves suppression of MA -induced apoptosis. PMID:19442829

  5. Tectonigral Projections in the Primate: A Pathway for Pre-Attentive Sensory Input to Midbrain Dopaminergic Neurons

    PubMed Central

    May, Paul J.; McHaffie, John G.; Stanford, Terrence R.; Jiang, Huai; Costello, M. Gabriela; Coizet, Veronique; Hayes, Lauren M.; Haber, Suzanne N.; Redgrave, Peter

    2010-01-01

    Much of the evidence linking the short-latency phasic signaling of midbrain dopaminergic neurons with reward-prediction errors used in learning and habit formation comes from recording the visual responses of monkey dopaminergic neurons. However, the information encoded by dopaminergic neuron activity is constrained by the qualities of the afferent visual signals made available to these cells. Recent evidence from rats and cats indicates the primary source of this visual input originates subcortically, via a direct tectonigral projection. The present anatomical study sought to establish whether a direct tectonigral projection is a significant feature of the primate brain. Injections of anterograde tracers into the superior colliculus of macaque monkeys labelled terminal arbors throughout the substantia nigra, with the densest terminations in the dorsal tier. Labelled boutons were found in close association (possibly indicative of synaptic contact) with ventral midbrain neurons staining positively for the dopaminergic marker tyrosine hydroxylase. Injections of retrograde tracer confined to the macaque substantia nigra retrogradely labelled small to medium sized neurons in the intermediate and deep layers of the superior colliculus. Together, these data indicate that a direct tectonigral projection is also a feature of the monkey brain, and therefore likely to have been conserved throughout mammalian evolution. Insofar as the superior colliculus is configured to detect unpredicted, biologically salient, sensory events, it may be safer to regard the phasic responses of midbrain dopaminergic neurons as ‘sensory prediction errors’ rather than ‘reward prediction errors’, in which case, dopamine-based theories of reinforcement learning will require revision. PMID:19175405

  6. Piracetam and vinpocetine ameliorate rotenone-induced Parkinsonism in rats.

    PubMed

    Zaitone, Sawsan A; Abo-Elmatty, Dina M; Elshazly, Shimaa M

    2012-01-01

    To evaluate the neuroprotective effect of the nootropic drugs, piracetam (PIR) and vinpocetine (VIN), in rotenone-induced Parkinsonism in rats. Sixty male rats were divided into 6 groups of 10 rats each. The groups were administered vehicle, control (rotenone, 1.5 mg/kg/48 h/6 doses, s.c.), PIR (100 and 200 mg/kg/day, p.o.) and VIN (3 and 6 mg/kg/day, p.o.). The motor performance of the rats was evaluated by the open field and pole test. Striatal dopamine level, malondialdehyde (MDA), reduced glutathione (GSH) and tumor necrosis factor-α (TNF-α) were assayed. Histopathological study of the substantia nigra was also done. Results showed that rotenone-treated rats exhibited bradykinesia and motor impairment in the open-field test. In addition, GSH level was decreased whereas MDA and TNF-α increased in striata of rotenone-treated rats as compared to vehicle-treated rats. Marked degeneration of the substantia nigra pars compacta (SNpc) neurons and depletion of striatal dopamine was also observed in the rotenone-treated rats. Treatment with PIR or VIN significantly reversed the locomotor deficits and increased striatal dopamine level. Treatment with VIN significantly (P<0.05) reduced the striatal level of MDA and GSH in comparison to rotenone group whereas TNF-α production was found to be significantly decreased in PIR group (P<0.05). VIN and PIR exhibit neuroprotective activity in rotenone-induced Parkinsonism. Hence, these nootropic agents may be considered as possible candidates in the treatment of Parkinson's disease.

  7. Dopaminergic Neuron-Specific Deletion of p53 Gene Attenuates Methamphetamine Neurotoxicity.

    PubMed

    Lu, Tao; Kim, Paul P; Greig, Nigel H; Luo, Yu

    2017-08-01

    p53 plays an essential role in the regulation of cell death in dopaminergic (DA) neurons and its activation has been implicated in the neurotoxic effects of methamphetamine (MA). However, how p53 mediates MA neurotoxicity remains largely unknown. In this study, we examined the effect of DA-specific p53 gene deletion in DAT-p53KO mice. Whereas in vivo MA binge exposure reduced locomotor activity in wild-type (WT) mice, this was significantly attenuated in DAT-p53KO mice and associated with significant differences in the levels of the p53 target genes BAX and p21 between WT and DAT-p53KO. Notably, DA-specific deletion of p53 provided protection of substantia nigra pars reticulata (SNpr) tyrosine hydroxylase (TH) positive fibers following binge MA, with DAT-p53KO mice having less decline of TH protein levels in striatum versus WT mice. Whereas DAT-p53KO mice demonstrated a consistently higher density of TH fibers in striatum compared to WT mice at 10 days after MA exposure, DA neuron counts within the substantia nigra pars compacta (SNpc) were similar. Finally, supportive of these results, administration of a p53-specific inhibitor (PFT-α) provided a similarly protective effect on MA binge-induced behavioral deficits. Neither DA specific p53 deletion nor p53 pharmacological inhibition affected hyperthermia induced by MA binge. These findings demonstrate a specific contribution of p53 activation in behavioral deficits and DA neuronal terminal loss by MA binge exposure.

  8. A local circuit model of learned striatal and dopamine cell responses under probabilistic schedules of reward.

    PubMed

    Tan, Can Ozan; Bullock, Daniel

    2008-10-01

    Recently, dopamine (DA) neurons of the substantia nigra pars compacta (SNc) were found to exhibit sustained responses related to reward uncertainty, in addition to the phasic responses related to reward-prediction errors (RPEs). Thus, cue-dependent anticipations of the timing, magnitude, and uncertainty of rewards are learned and reflected in components of DA signals. Here we simulate a local circuit model to show how learned uncertainty responses are generated, along with phasic RPE responses, on single trials. Both types of simulated DA responses exhibit the empirically observed dependencies on conditional probability, expected value of reward, and time since onset of the reward-predicting cue. The model's three major pathways compute expected values of cues, timed predictions of reward magnitudes, and uncertainties associated with these predictions. The first two pathways' computations refine those modeled by Brown et al. (1999). The third, newly modeled, pathway involves medium spiny projection neurons (MSPNs) of the striatal matrix, whose axons corelease GABA and substance P, both at synapses with GABAergic neurons in the substantia nigra pars reticulata (SNr) and with distal dendrites (in SNr) of DA neurons whose somas are located in ventral SNc. Corelease enables efficient computation of uncertainty responses that are a nonmonotonic function of the conditional probability of reward, and variability in striatal cholinergic transmission can explain observed individual differences in the amplitudes of uncertainty responses. The involvement of matricial MSPNs and cholinergic transmission within the striatum implies a relation between uncertainty in cue-reward contingencies and action-selection functions of the basal ganglia.

  9. Degenerative pontine lesions in patients with familial narcolepsy.

    PubMed

    Stepień, Adam; Staszewski, Jacek; Domzał, Teofan M; Tomczykiewicz, Kazimierz; Skrobowska, Ewa; Durka-Kesy, Marta

    2010-01-01

    Narcolepsy is characterized by chronic excessive daytime sleepiness with episodic sleep attacks. There are several associated symptoms of narcolepsy: cataplexy (bilateral muscle weakness without loss of consciousness provoked by an emotional trigger, e.g. laughter), sleep paralysis and hypnagogic-hypnopompic hallucinations. Most cases are sporadic; familial narcolepsy contributes to only 1-5% of all cases. While most cases of narcolepsy are idiopathic and are not associated with clinical or radiographic evidence of brain pathology, symptomatic or secondary narcolepsy may occur occasionally in association with lesions caused by tumours, demyelination or strokes of the diencephalon, midbrain, and pons. There are some examples of non-specific brainstem lesions found in magnetic resonance imaging (MRI) in patients with idiopathic narcolepsy. The authors present eleven patients from a five-generation family with many members who suffer from episodic excessive daytime sleepiness. Narcolepsy was diagnosed in 9 patients. Sleepiness was frequently associated with cataplexy, hypnagogic-hypnopompic hallucinations and sleep paralysis. Improvement in their clinical state was observed during the treatment with modafinil. All probands had MRI of the brain, routine blood tests, EEG, polysomnography, examination of the level of hypocretin in cerebrospinal fluid and evaluation by means of Epworth and Stanford Sleepiness Scales. In 9 patients with narcolepsy, decreased thickness of the substantia nigra was found and in six of them degenerative lesions in the pontine substantia nigra were also noticed. The significance of these changes remains unclear. No data have been published until now concerning the presence of any brain lesions in patients with familial narcolepsy.

  10. Responses of the extrapyramidal and limbic substance P systems to ibogaine and cocaine treatments.

    PubMed

    Alburges, M E; Ramos, B P; Bush, L; Hanson, G R

    2000-02-25

    Ibogaine is an indolamine found in the West Africa shrub, Tabernanthe iboga, and has been proposed for the treatment of addiction to central nervous system (CNS) stimulants such as cocaine and amphetamine. The mechanism of ibogaine action and its suitability as a treatment for drug addiction still remains unclear. Since previous studies demonstrated differential effects of stimulants of abuse (amphetamines) on neuropeptide systems such as substance P, we examined the impact of ibogaine and cocaine on extrapyramidal (striatum and substantia nigra) and limbic (nucleus accumbens and frontal cortex) substance P-like immunoreactivity. Ibogaine and cocaine treatments altered substance P systems by increasing striatal and nigral substance P-like immunoreactivity concentration 12 h after the last drug treatment. However, substance P-like immunoreactivity content was not significantly increased in nucleus accumbens after treatment with either drug. The ibogaine- and cocaine-induced increases in substance P-like immunoreactivity in striatum and substantia nigra were blocked by coadministration of selective dopamine D(1) receptor antagonist (SCH 23390; R(+)-7-Chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4, 5-tetrahydro-1H-3-benzazepine hydrochloride) or dopamine D(2) receptor antagonist (eticlopride; S(-)-3-Chloro-5-ethyl-N-[(1-ethyl-2-pyrrolidinyl)methyl]-6-hydroxy-2- methoxy-benzamide hydrochloride). Most of the responses by substance P systems to ibogaine administration resembled those caused by cocaine, except in cortical tissue where multiple administration of cocaine, but not ibogaine increased substance P-like immunoreactivity. These data suggest that substance P systems may contribute to the effects of ibogaine and cocaine treatment.

  11. Species verification of Dalbergia nigra and Dalbergia spruceana samples in the wood collection of the Forest Products Laboratory

    Treesearch

    Michael C. Wiemann; Edgard O. Espinoza

    2017-01-01

    To evade endangered timber species laws, unscrupulous importers sometimes attempt to pass protected Dalbergia nigra as look-alike but unprotected, Dalbergia Spruceana. Wood density and fluorescence properties are sometimes used to identify the species. Although these properties are useful and do not require special equipment,...

  12. Assessment of extracts of Helichrysum arenarium, Crataegus monogyna, Sambucus nigra in photoprotective UVA and UVB; photostability in cosmetic emulsions.

    PubMed

    Jarzycka, Anna; Lewińska, Agnieszka; Gancarz, Roman; Wilk, Kazimiera A

    2013-11-05

    The aim of our study was to investigate the photoprotective activity and photostability efficacy of sunscreen formulations containing Helichrysum arenarium, Sambucus nigra, Crataegus monogyna extracts and their combination. UV transmission of the emulsion films was performed by using diffuse transmittance measurements coupling to an integrating sphere. In vitro photoprotection and photostability efficacy were evaluated according to the following parameters: sun protection factor (SPF), UVA protection factor (PF-UVA), UVA/UVB ratio and critical wavelength (λc) before and after UV irradiation. The results obtained show that the formulations containing polyphenols fulfill the official requirements for sunscreen products due to their broad spectrum of UV protection combined with their high photostability and remarkable antioxidant properties. Therefore H. arenarium, S. nigra, C. monogyna extracts represent useful additives for cosmetic formulation. Copyright © 2013 Elsevier B.V. All rights reserved.

  13. Comparative analysis of Sambucus nigra and Sambucus australis flowers: development and validation of an HPLC method for raw material quantification and preliminary stability study.

    PubMed

    Scopel, Marina; Mentz, Lílian Auler; Henriques, Amélia Teresinha

    2010-07-01

    This work was designed to develop a simple, effective, and reliable LC system to identify a chemical marker and compare Sambucus nigra L. and Sambucus australis Cham. et Schltdl. flower extracts (American and European elder). Rutin was the main constituent of both species. The developed method showed a linear response in the range of 10 to 45 microg x mL(-1) for rutin and 1.75 to 3.25 microg x mL(-1) for samples of the Sambucus species. Precision was determined and the relative standard deviations were 1.75 % for HSN and 1.28 % for HSA for intraday precision and 1.28 % and 1.51 % for inter-day precision, respectively, while accuracy was 97.9 % for HSN and 99.41 % for HSA. Quantification and detection limits as well as robustness were determined, presenting adequate results. The LC method showed an adequate performance for the separation of flavonoid glycosides in S. nigra and S. australis extracts, since the presence of interference had been previously evaluated. The analysis of thirty different samples of S. NIGRA and S. australis of different origins did not show significant variability among them. An accelerated stability study revealed a significant decrease in the first 30 days reaching 57 % in 90 days for S. australis samples and a total decrease of 25 % in 90 days for S. nigra samples, considering rutin as the chemical marker. These results will contribute to quality control analysis routines of these raw materials in pharmaceutical production facilities. Georg Thieme Verlag KG Stuttgart.New York.

  14. Callus induction of leaf explant Piper betle L. Var Nigra with combination of plant growth regulators indole-3-acetic acid (IAA), benzyl amino purin (BAP) and kinetin

    NASA Astrophysics Data System (ADS)

    Junairiah, Zuraidassanaaz, Nabilah Istighfari; Izdihar, Fairuz Nabil; Manuhara, Yosephine Sri Wulan

    2017-09-01

    The purpose of this research was to determine the combination of plant growth regulators IAA, BAP and kinetin towards callus induction and growth of leaf explants Piper betle L. VarNigra. Explants from leaf of Piper betle L. VarNigra was cultured on MS medium with 24 treatment combinations of plant growth regulators IAA and BAP and 24 treatment combinations of plant growth regulators IAA and kinetin with 0.0;0.5;1.0;1.5;2.0 mg/L concentration respectively, the observed variable were the length of time the formation of callus, callus morphology, fresh and dry weight of callus. The results of this research showed that the combination of growth regulators IAA with BAP and kinetin had effects on leaf growth of Piper betle L. VarNigra. During 8 weeks observation, it indicated that the combination of concentration IAA 0.5 mg/L and BAP 2.0 mg/L showed fastest callus formation at 8.5 days. Combination of concentration IAA 1.0 mg/L and BAP 1.5 mg/L showed the highest of fresh weight at 0.6596 grams, and the highest dry weight was obtained from the combination of concentration IAA 0.5 mg/L and BAP 0.5 mg/L at 0.0727 grams. Combination of concentration IAA 1.0 mg/L and kinetin 1.5 mg/L had the highest of fresh weight at 0.2972 grams and the highest dry weight at 0.1660 grams. Callus of Piper betle L. VarNigra had two textures, that were compact and friable, and also showed various kind of colors, like white, greenish white, yellowish white, tanned white, brown and black. Based on this research, that concentration IAA 1.0 mg/L and 1.5 mg/L kinetin was the best combination for induction of callus from leaf of Piper betle L. Var Nigra.

  15. Nonsaponifiable lipid components of the pollen of elder (Sambucus nigra L.).

    PubMed

    Stránsky, K; Valterová, I; Fiedler, P

    2001-11-30

    Pollen of the elder (Sambucus nigra L.) was extracted with chloroform-methanol. The extract was separated by column chromatography into the following groups of compounds: hydrocarbons (8.7%). polycyclic aromatic hydrocarbons (0.2%), complex esters (5.2%), triglycerides (18.7%), hydroxy esters (27.9%), free fatty acids and alcohols (16.8%), free sterols (6.8%), and triterpenic alcohols (4.0%). The nonsaponifiable components (hydrocarbons, fatty acids, alcohols, and sterols) were examined in detail using spectroscopic and chromatographic methods (IR spectroscopy, GC, and GC-MS). The identified compounds were characterized by their mass spectra and Kováts retention indices. The double bond positions and their configurations in unsaturated compounds are also reported.

  16. Bidirectional control of absence seizures by the basal ganglia: a computational evidence.

    PubMed

    Chen, Mingming; Guo, Daqing; Wang, Tiebin; Jing, Wei; Xia, Yang; Xu, Peng; Luo, Cheng; Valdes-Sosa, Pedro A; Yao, Dezhong

    2014-03-01

    Absence epilepsy is believed to be associated with the abnormal interactions between the cerebral cortex and thalamus. Besides the direct coupling, anatomical evidence indicates that the cerebral cortex and thalamus also communicate indirectly through an important intermediate bridge-basal ganglia. It has been thus postulated that the basal ganglia might play key roles in the modulation of absence seizures, but the relevant biophysical mechanisms are still not completely established. Using a biophysically based model, we demonstrate here that the typical absence seizure activities can be controlled and modulated by the direct GABAergic projections from the substantia nigra pars reticulata (SNr) to either the thalamic reticular nucleus (TRN) or the specific relay nuclei (SRN) of thalamus, through different biophysical mechanisms. Under certain conditions, these two types of seizure control are observed to coexist in the same network. More importantly, due to the competition between the inhibitory SNr-TRN and SNr-SRN pathways, we find that both decreasing and increasing the activation of SNr neurons from the normal level may considerably suppress the generation of spike-and-slow wave discharges in the coexistence region. Overall, these results highlight the bidirectional functional roles of basal ganglia in controlling and modulating absence seizures, and might provide novel insights into the therapeutic treatments of this brain disorder.

  17. Transcranial sonography in movement disorders: an interesting tool for diagnostic perspectives.

    PubMed

    Sanzaro, E; Iemolo, F

    2016-03-01

    Transcranial sonography has become an important tool for the diagnosis of various movement disorders. In most patients with idiopathic Parkinson disease, a markedly hyperechogenic substantia nigra (SN) was detected on at least one side. We have highlighted the sonographic features that might help the differential diagnosis of PD and other movement disorders. Our investigation involved 30 patients (age 45-85 years) with idiopathic Parkinson disease, 2 multiple system atrophy, 3 progressive supranuclear palsy and 2 patients with restless legs syndrome. In accordance with several previous studies, we detected hyperechogenicity of the SN by TCS in 90% of patients with idiopathic Parkinson disease. Subjects with a marked severity disease had a larger extent of the hyperechogenic SN signal. All progressive supranuclear palsy patients had an enlarged third ventricle and, in two cases, we observed the presence of hyperechoic areas in the lentiform nucleus. This last ultrasonographic feature was also seen in our patients with multiple system atrophy. TCS abnormalities of the SN, midbrain raphe and basal ganglia are characteristics of several movement and affective disorders. These features are less easily detected by other techniques, such as CT and MRI, which enable the exclusion of structural lesions, such as tumours and multi-infarct disease, because the physical principle differs from other imaging methods.

  18. Can a Positive Allosteric Modulation of GABAergic Receptors Improve Motor Symptoms in Patients with Parkinson's Disease? The Potential Role of Zolpidem in the Treatment of Parkinson's Disease

    PubMed Central

    Daniele, Antonio; Panza, Francesco; Greco, Antonio; Logroscino, Giancarlo; Seripa, Davide

    2016-01-01

    At present, patients with advanced Parkinson's disease (PD) are unsatisfactorily controlled by currently used anti-Parkinsonian dopaminergic drugs. Various studies suggest that therapeutic strategies based on nondopaminergic drugs might be helpful in PD. Zolpidem, an imidazopyridine widely used as sleep inducer, shows high affinity only for GABAA receptors containing the α-1 subunit and facilitates GABAergic neurotransmission through a positive allosteric modulation of GABAA receptors. Various observations, although preliminary, consistently suggest that in PD patients zolpidem may induce beneficial (and sometimes remarkable) effects on motor symptoms even after single doses and may also improve dyskinesias. Since a high density of zolpidem binding sites is in the two main output structures of the basal ganglia which are abnormally overactive in PD (internal globus pallidus, GPi, and substantia nigra pars reticulata, SNr), it was hypothesized that in PD patients zolpidem may induce through GABAA receptors an inhibition of GPi and SNr (and, possibly, of the subthalamic nucleus also), resulting in an increased activity of motor cortical areas (such as supplementary motor area), which may give rise to improvement of motor symptoms of PD. Randomized clinical trials are needed in order to assess the efficacy, safety, and tolerability of zolpidem in treating motor symptoms of PD. PMID:27293955

  19. Endoplasmic reticulum and mitochondria interplay mediates apoptotic cell death: relevance to Parkinson's disease.

    PubMed

    Arduíno, Daniela Moniz; Esteves, A Raquel; Cardoso, Sandra M; Oliveira, Catarina R

    2009-09-01

    Sporadic Parkinson's disease (PD) is a progressive neurodegenerative disease characterized by a loss of dopaminergic neurons in the substantia nigra pars compacta. Many cellular mechanisms are thought to be involved in the death of these specific neurons in PD, including oxidative stress, changes of intracellular calcium homeostasis, and mitochondrial dysfunction. Since recent studies have revealed that also endoplasmic reticulum (ER) stress in conjunction with abnormal protein degradation can contribute to the PD pathophysiology, we investigated here the molecular mechanisms underlying the interplay between ER and mitochondria and its relevance in the control of neuronal cell death in PD. We observed that MPP+ induced changes in the mitochondrial function, affecting mitochondrial membrane potential and electron transport chain function. Likewise, it was also evident the unfolded protein response activation by an overexpression of GRP78 protein. Moreover, stress stimuli caused the release of Ca2+ from the ER that consistently induced mitochondrial Ca2+ uptake, with a rise of mitochondrial matrix free Ca2+. Besides, Ca2+ release inhibition prevented MPP+ mediated mitochondria-dependent caspases activation. Our findings show that ER and mitochondria are in a close communication, establishing a dynamic ER-Ca2+-mitochondria interconnection that can play a prominent role in the neuronal cell death induction under particular stressful circumstances of PD pathology.

  20. Trace element mapping in Parkinsonian brain by quantitative ion beam microscopy

    NASA Astrophysics Data System (ADS)

    Barapatre, Nirav; Morawski, Markus; Butz, Tilman; Reinert, Tilo

    2010-06-01

    The role of iron in the pathogenesis of the Parkinson's disease (PD) is a current subject of research in Neurochemistry, since an abnormal increase in iron is reported in the substantia nigra (SN) of Parkinsonian patients. A severe loss of the cells containing dopamine in the SN in the PD has also drawn attention towards the function of a browny-black pigment called neuromelanin, which accumulates predominantly in these dopaminergic neurons. The neuromelanin has an ability to chelate metal ions, which, in free state, may cause considerable damage to cells by reacting with their lipid-rich membranes. However, it could also potentiate free radical production if it releases the bound metal ions. The highly sensitive and non-destructive micro-PIXE method suits best to quantify and map the trace elements in the SN. The accuracy in charge measurement for such microanalysis studies is of utmost importance for quantitative analysis. Since a Faraday cup is usually placed behind the thin biological sample to measure the charge, the primary and the secondary electrons, knocked out from the sample by traversing ion beam, hamper an exact charge determination. Hence, a new non-interceptive technique was developed for precise charge measurement and for continuous monitoring of beam current.

  1. Genetic disruption of the nuclear receptor Nur77 (Nr4a1) in rat reduces dopamine cell loss and l-Dopa-induced dyskinesia in experimental Parkinson's disease.

    PubMed

    Rouillard, Claude; Baillargeon, Joanie; Paquet, Brigitte; St-Hilaire, Michel; Maheux, Jérôme; Lévesque, Catherine; Darlix, Noémie; Majeur, Simon; Lévesque, Daniel

    2018-06-01

    Parkinson's disease (PD) is an idiopathic progressive neurodegenerative disorder characterized by the loss of midbrain dopamine neurons. Levodopa (l-dopa) is the main pharmacological approach to relieve PD motor symptoms. However, chronic treatment with l-Dopa is inevitably associated with the generation of abnormal involuntary movements (l-Dopa-induced dyskinesia). We have previously shown that Nr4a1 (Nur77), a transcription factor of the nuclear receptor family, is closely associated with dopamine neurotransmission in the mature brain. However, the role of Nr4a1 in the etiology of PD and its treatment remain elusive. We report here that the neurotoxin 6-hydroxydopamine in rat lead to a rapid up-regulation of Nr4a1 in the substantia nigra. Genetic disruption of Nr4a1 in rat reduced neurotoxin-induced dopamine cell loss and l-Dopa-induced dyskinesia, whereas virally-driven striatal overexpression of Nr4a1 enhanced or partially restored involuntary movements induced by chronic l-Dopa in wild type and Nr4a1-deficient rats, respectively. Collectively, these results suggest that Nr4a1 is involved in dopamine cell loss and l-Dopa-induced dyskinesia in experimental PD. Copyright © 2018 Elsevier Inc. All rights reserved.

  2. Bidirectional Control of Absence Seizures by the Basal Ganglia: A Computational Evidence

    PubMed Central

    Wang, Tiebin; Jing, Wei; Xia, Yang; Xu, Peng; Luo, Cheng; Valdes-Sosa, Pedro A.; Yao, Dezhong

    2014-01-01

    Absence epilepsy is believed to be associated with the abnormal interactions between the cerebral cortex and thalamus. Besides the direct coupling, anatomical evidence indicates that the cerebral cortex and thalamus also communicate indirectly through an important intermediate bridge–basal ganglia. It has been thus postulated that the basal ganglia might play key roles in the modulation of absence seizures, but the relevant biophysical mechanisms are still not completely established. Using a biophysically based model, we demonstrate here that the typical absence seizure activities can be controlled and modulated by the direct GABAergic projections from the substantia nigra pars reticulata (SNr) to either the thalamic reticular nucleus (TRN) or the specific relay nuclei (SRN) of thalamus, through different biophysical mechanisms. Under certain conditions, these two types of seizure control are observed to coexist in the same network. More importantly, due to the competition between the inhibitory SNr-TRN and SNr-SRN pathways, we find that both decreasing and increasing the activation of SNr neurons from the normal level may considerably suppress the generation of spike-and-slow wave discharges in the coexistence region. Overall, these results highlight the bidirectional functional roles of basal ganglia in controlling and modulating absence seizures, and might provide novel insights into the therapeutic treatments of this brain disorder. PMID:24626189

  3. Low dopamine activity in Lesch Nyhan Disease. An 18-fluorodopa PET study

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Ernst, M.; Zametkin, A.; Matochik, J.

    1996-05-01

    Lesch-Nyhan Disease (LND) is a rare devastating X-linked recessive disorder characterized by the virtual absence of hypoxanthine guanine phosphoribosyl transferase (HPRT), a major enzyme of the salvage pathway of purine metabolism. The clinical presentation includes hyperuricemia choreoathetosis, dystonia, aggression and self-injurious behavior. The genetic and biochemical abnormalities are fully identified. However, the neuropathophysiological process by which the lack of HPRT produces the neuropsychiatric syndrome of LND in unclear. Presynaptic uptake of 18-Fluorodopa (FD) in basal ganglia, substantia nigra, and frontal and occipital cortices was measured by PET in 12 patients with LND, 10 to 20 years old, and 15 healthmore » controls, 12 to 23 years old. Radioactive counts (mCi/cc), recorded between 90 and 130 minutes after tracer injection, were measured in regions of interest by a rater blind to subjects` identities. Results were expressed as ratios of FD uptake in specific to non-specific (occipital cortex) brain areas. Presynaptic dopamine activity was significantly lower by 69% in putamen (p<0.0001), 61% in caudate (p<0.0001), 56% in frontal cortex (p=0.003) and 43% in substantiat nigra (p<0.016) in LND patients than in control subjects. Absolute FD measures in occipital regions did not differ between the two groups. Activity of FD in the basal ganglia was stable over time in the LND group and tended to increase in the control group (r=0.50, n=15, p=0.060). In the LND group, aggressive behavior was worse as FD activity was higher (r=0.60, n=12, p=0.40). LND is associated with a striking reduction of presynaptic dopamine activity that is not region-specific. The temporal stability of FD measures and of the severity of LND symptomatology is consistent with a developmental rather than degenerative process.« less

  4. The effect of Sambucus nigra L. extract and phytosinthesized gold nanoparticles on diabetic rats.

    PubMed

    Opris, Razvan; Tatomir, Corina; Olteanu, Diana; Moldovan, Remus; Moldovan, Bianca; David, Luminita; Nagy, Andras; Decea, Nicoleta; Kiss, Mihai Ludovic; Filip, Gabriela Adriana

    2017-02-01

    Nanomaterials such as gold nanoparticles (NPs) conjugated with natural products have shown good results in lowering the glycated hemoglobin and have an anti-inflamatory effect. The aim of our study is to evaluate the antidiabetic effect of NPs functionalized with Sambucus nigra L. (SN) extract on experimental model of diabetes in rats. Diabetes was induced to 18 Wistar male rats (n=6) by a single intramuscular injection of streptozotocin (30mg/kg body weight - b.w.). SN extract (15mg/kg b.w.), NPs (0.3mg/kg b.w.) and vehicle (normal saline) were administered by gavage once a day, every morning, for 2 weeks. Other 18 animals were used as control groups and were treated with the same compounds, at the same time. Afterwards, blood, liver and muscle samples were taken to assess the oxidant/antioxidant status and the liver for the evaluation of metalloproteinases (MMP)-2 and 9 activities, COX-2 and NFKB expressions and for immunohistochemistry. Serum glycemia, cholesterol, alanine aminotransferase (ALAT), aspartate aminotransferase (ASAT) were also measured. The administration of NPs extract increased the muscle and systemic GSH/GSSG ratio in the diabetic group vs. diabetic (p<0.03) or non-diabetic groups treated with vehicle (p<0.05) and decreased MDA levels compared to non-diabetic group (p<0.05). COX-2 expression (p<0.0001) and proMMP-2 activity (p<0.05) decreased after pretreatment with NPs in parallel with the reduction of Kupffer cells percent (<0.001). No morphological abnormalities were detected in histopathology. NPs present a great potential for further usage as adjuvants in the diabetic therapy due to the increase of antioxidant defence and reduction of MMPs activity and inflammation in liver tissue. Copyright © 2016 Elsevier B.V. All rights reserved.

  5. A range-wide occupancy estimate and habitat model for the endangered Point Arena mountain beaver (Aplodontia rufa nigra)

    Treesearch

    William J. Zielinski; Fredrick V. Schlexer; Jeffrey R. Dunk; Matthew J. Lau; James J. Graham

    2015-01-01

    The mountain beaver (Aplodontia rufa) is notably the most primitive North American rodent with a restricted distribution in the Pacific Northwest based on its physiological limits to heat stress and water needs. The Point Arena subspecies (A. r. nigra) is federally listed as endangered and is 1 of 2 subspecies that have extremely...

  6. Glutamate spillover drives endocannabinoid production and inhibits GABAergic transmission in the Substantia Nigra pars compacta.

    PubMed

    Freestone, Peter S; Guatteo, Ezia; Piscitelli, Fabiana; di Marzo, Vincenzo; Lipski, Janusz; Mercuri, Nicola B

    2014-04-01

    Endocannabinoids (eCBs) modulate synaptic transmission in the brain, but little is known of their regulatory role in nigral dopaminergic neurons, and whether transmission to these neurons is tonically inhibited by eCBs as seen in some other brain regions. Using whole-cell recording in midbrain slices, we observed potentiation of evoked IPSCs (eIPSCs) in these neurons after blocking CB1 receptors with rimonabant or LY-320,135, indicating the presence of an eCB tone reducing inhibitory synaptic transmission. Increased postsynaptic calcium buffering and block of mGluR1 or postsynaptic G-protein coupled receptors prevented this potentiation. Increasing spillover of endogenous glutamate by inhibiting uptake attenuated eIPSC amplitude, while enhancing the potentiation by rimonabant. Group I mGluR activation transiently inhibited eIPSCs, which could be prevented by GDP-β-S, increased calcium buffering or rimonabant. We explored the possibility that the dopamine-derived eCB N-arachidonoyl dopamine (NADA) is involved. The eCB tone was abolished by preventing dopamine synthesis, and enhanced by l-DOPA. It was not detected in adjacent non-dopaminergic neurons. Preventing 2-AG synthesis did not affect the tone, while inhibition of NADA production abolished it. Quantification of ventral midbrain NADA suggested a basal level that increased following prolonged depolarization or mGluR activation. Since block of the tone was not always accompanied by attenuation of depolarization-induced suppression of inhibition (DSI) and vice versa, our results indicate DSI and the eCB tone are mediated by distinct eCBs. This study provides evidence that dopamine modulates the activity of SNc neurons not only by conventional dopamine receptors, but also by CB1 receptors, potentially via NADA. Copyright © 2013 Elsevier Ltd. All rights reserved.

  7. The Central Amygdala Projection to the Substantia Nigra Reflects Prediction Error Information in Appetitive Conditioning

    ERIC Educational Resources Information Center

    Lee, Hongjoo J.; Gallagher, Michela; Holland, Peter C.

    2010-01-01

    The central amygdala nucleus (CeA) plays a critical role in cognitive processes beyond fear conditioning. For example, intact CeA function is essential for enhancing attention to conditioned stimuli (CSs). Furthermore, this enhanced attention depends on the CeA's connections to the nigrostriatal system. In the current study, we examined the role…

  8. An evidence-based systematic review of elderberry and elderflower (Sambucus nigra) by the Natural Standard Research Collaboration.

    PubMed

    Ulbricht, Catherine; Basch, Ethan; Cheung, Lisa; Goldberg, Harley; Hammerness, Paul; Isaac, Richard; Khalsa, Karta Purkh Singh; Romm, Aviva; Rychlik, Idalia; Varghese, Minney; Weissner, Wendy; Windsor, Regina C; Wortley, Jayme

    2014-03-01

    An evidence-based systematic review of elderberry and elderflower (Sambucus nigra) by the Natural Standard Research Collaboration consolidates the safety and efficacy data available in the scientific literature using a validated, reproducible grading rationale. This article includes written and statistical analysis of clinical trials, plus a compilation of expert opinion, folkloric precedent, history, pharmacology, kinetics/dynamics, interactions, adverse effects, toxicology, and dosing.

  9. Adaptive traits to fluvial systems of native tree European black Poplar (Populus nigra L.) population in Southern Italy

    NASA Astrophysics Data System (ADS)

    Saulino, Luigi; Pasquino, Vittorio; Todaro, Luigi; Rita, Angelo; Villani, Paolo; Battista Chirico, Giovanni; Saracino, Antonio

    2015-04-01

    This work focuses on the morphological and biomechanical traits developed by the European black poplar (Populus nigra) to cope with the hydraulic force and prolonged submersion periods during floods. Two riverine environments of the Cilento sub-region (Southern Italy) have been selected for this experimental study. The two sites have the same climatic and hydrological regimes. The first site is located along the Ripiti stream, characterized by a braided channel with longitudinal and transverse bars and eroding banks. The second site is located along the Badolato stream, an entrenched meandering riffle/pool channel, with low gradients and high width/depth. P. nigra mixed with Salix alba and along the Badolato stream also Platanus orientalis, is the dominant wooden riparian vegetation in both sites. Cuttings from adult P. nigra trees originated by seeds were collected and planted in the 'Azienda Sperimentale Regionale Improsta' (Eboli-Salerno, Campania region). The experimental plantation was managed according to a multi-stem short rotation coppice with low external energy input and high disturbance regime generated by a 3 years rotation coppicing. The two sample stool sets exhibit statistically similar morphological traits, but different values of Young elasticity module of the shoots. A functional evaluation of the biomechanical differences was performed by measuring the bending of the individual stems under the hypothesis of complete submergence within a flow of different mean velocities, using a numerical model that predicts the bending of woody vegetation beams allowing for large deflections. The results suggest that plants with the same gene pool but coming from morphologically different riverine environments, may reflect different dominant biomechanical properties, which might be relevant for designing local sustainable management and restoration plans of rivers and riparian systems.

  10. Small geographic range but not panmictic: how forests structure the endangered Point Arena mountain beaver (Aplodontia rufa nigra)

    Treesearch

    William J. Zielinski; Fredrick V. Schlexer; Sean A. Parks; Kristine L. Pilgrim; Michael K. Schwartz

    2012-01-01

    The landscape genetics framework is typically applied to broad regions that occupy only small portions of a species' range. Rarely is the entire range of a taxon the subject of study. We examined the landscape genetic structure of the endangered Point Arena mountain beaver (Aplodontia rufa nigra), whose isolated geographic range is found in a...

  11. White piedra, black piedra, tinea versicolor, and tinea nigra: contribution to the diagnosis of superficial mycosis.

    PubMed

    Veasey, John Verrinder; Avila, Ricardo Bertozzi de; Miguel, Barbara Arruda Fraletti; Muramatu, Laura Hitomi

    2017-01-01

    Superficial mycoses are fungal infections restricted to the stratum corneum and to the hair shafts, with no penetration in the epidermis; they are: white piedra, black piedra, tinea versicolor, and tinea nigra. This study presents images of mycological tests performed in the laboratory, as well as exams performed at the authors office, in order to improve the dermatologist's knowledge about the diagnosis of these dermatoses, which are common in many countries.

  12. Traumatic Brain Injury in Adult Rats Causes Progressive Nigrostriatal Dopaminergic Cell Loss and Enhanced Vulnerability to the Pesticide Paraquat

    PubMed Central

    Hutson, Che Brown; Lazo, Carlos R.; Mortazavi, Farzad; Giza, Christopher C.; Hovda, David

    2011-01-01

    Abstract Parkinson's disease (PD) is a neurodegenerative disorder characterized by the loss of nigrostriatal dopaminergic neurons and the accumulation of alpha-synuclein. Both traumatic brain injury (TBI) and pesticides are risk factors for PD, but whether TBI causes nigrostriatal dopaminergic cell loss in experimental models and whether it acts synergistically with pesticides is unknown. We have examined the acute and long-term effects of TBI and exposure to low doses of the pesticide paraquat, separately and in combination, on nigrostriatal dopaminergic neurons in adult male rats. In an acute study, rats received moderate TBI by lateral fluid percussion (LFP) injury, were injected with saline or paraquat (10 mg/kg IP) 3 and 6 days after LFP, were sacrificed 5 days later, and their brains processed for immunohistochemistry. TBI alone increased microglial activation in the substantia nigra, and caused a 15% loss of dopaminergic neurons ipsilaterally. Paraquat increased the TBI effect, causing a 30% bilateral loss of dopaminergic neurons, reduced striatal tyrosine hydroxylase (TH) immunoreactivity more than TBI alone, and induced alpha-synuclein accumulation in the substantia nigra pars compacta. In a long-term study, rats received moderate LFP, were injected with saline or paraquat at 21 and 22 weeks post-injury, and were sacrificed 4 weeks later. At 26 weeks post injury, TBI alone induced a 30% bilateral loss of dopaminergic neurons that was not exacerbated by paraquat. These data suggest that TBI is sufficient to induce a progressive degeneration of nigrostriatal dopaminergic neurons. Furthermore, TBI and pesticide exposure, when occurring within a defined time frame, could combine to increase the PD risk. PMID:21644813

  13. Human neural stem cells survive long term in the midbrain of dopamine-depleted monkeys after GDNF overexpression and project neurites toward an appropriate target.

    PubMed

    Wakeman, Dustin R; Redmond, D Eugene; Dodiya, Hemraj B; Sladek, John R; Leranth, Csaba; Teng, Yang D; Samulski, R Jude; Snyder, Evan Y

    2014-06-01

    Transplanted multipotent human fetal neural stem cells (hfNSCs) significantly improved the function of parkinsonian monkeys in a prior study primarily by neuroprotection, with only 3%-5% of cells expressing a dopamine (DA) phenotype. In this paper, we sought to determine whether further manipulation of the neural microenvironment by overexpression of a developmentally critical molecule, glial cell-derived neurotrophic factor (GDNF), in the host striatum could enhance DA differentiation of hfNSCs injected into the substantia nigra and elicit growth of their axons to the GDNF-expressing target. hfNSCs were transplanted into the midbrain of 10 green monkeys exposed to 1-methyl-4-phenyl-1,2,3,6-tetrahydro-pyridine. GDNF was delivered concomitantly to the striatum via an adeno-associated virus serotype 5 vector, and the fate of grafted cells was assessed after 11 months. Donor cells remained predominantly within the midbrain at the injection site and sprouted numerous neurofilament-immunoreactive fibers that appeared to course rostrally toward the striatum in parallel with tyrosine hydroxylase-immunoreactive fibers from the host substantia nigra but did not mature into DA neurons. This work suggests that hfNSCs can generate neurons that project long fibers in the adult primate brain. However, in the absence of region-specific signals and despite GDNF overexpression, hfNSCs did not differentiate into mature DA neurons in large numbers. It is encouraging, however, that the adult primate brain appeared to retain axonal guidance cues. We believe that transplantation of stem cells, specifically instructed ex vivo to yield DA neurons, could lead to reconstruction of some portion of the nigrostriatal pathway and prove beneficial for the parkinsonian condition. ©AlphaMed Press.

  14. Astrocyte-specific DJ-1 overexpression protects against rotenone-induced neurotoxicity in a rat model of Parkinson's disease.

    PubMed

    De Miranda, Briana R; Rocha, Emily M; Bai, Qing; El Ayadi, Amina; Hinkle, David; Burton, Edward A; Timothy Greenamyre, J

    2018-07-01

    DJ-1 is a redox-sensitive protein with several putative functions important in mitochondrial physiology, protein transcription, proteasome regulation, and chaperone activity. High levels of DJ-1 immunoreactivity are reported in astrocytes surrounding pathology associated with idiopathic Parkinson's disease, possibly reflecting the glial response to oxidative damage. Previous studies showed that astrocytic over-expression of DJ-1 in vitro prevented oxidative stress and mitochondrial dysfunction in primary neurons. Based on these observations, we developed a pseudotyped lentiviral gene transfer vector with specific tropism for CNS astrocytes in vivo to overexpress human DJ-1 protein in astroglial cells. Following vector delivery to the substantia nigra and striatum of adult Lewis rats, the DJ-1 transgene was expressed robustly and specifically within astrocytes. There was no observable transgene expression in neurons or other glial cell types. Three weeks after vector infusion, animals were exposed to rotenone to induce Parkinson's disease-like pathology, including loss of dopaminergic neurons, accumulation of endogenous α-synuclein, and neuroinflammation. Animals over-expressing hDJ-1 in astrocytes were protected from rotenone-induced neurodegeneration, and displayed a marked reduction in neuronal oxidative stress and microglial activation. In addition, α-synuclein accumulation and phosphorylation were decreased within substantia nigra dopaminergic neurons in DJ-1-transduced animals, and expression of LAMP-2A, a marker of chaperone mediated autophagy, was increased. Together, these data indicate that astrocyte-specific overexpression of hDJ-1 protects neighboring neurons against multiple pathologic features of Parkinson's disease and provides the first direct evidence in vivo of a cell non-autonomous neuroprotective function of astroglial DJ-1. Copyright © 2018 Elsevier Inc. All rights reserved.

  15. Bee Venom Alleviates Motor Deficits and Modulates the Transfer of Cortical Information through the Basal Ganglia in Rat Models of Parkinson's Disease.

    PubMed

    Maurice, Nicolas; Deltheil, Thierry; Melon, Christophe; Degos, Bertrand; Mourre, Christiane; Amalric, Marianne; Kerkerian-Le Goff, Lydia

    2015-01-01

    Recent evidence points to a neuroprotective action of bee venom on nigral dopamine neurons in animal models of Parkinson's disease (PD). Here we examined whether bee venom also displays a symptomatic action by acting on the pathological functioning of the basal ganglia in rat PD models. Bee venom effects were assessed by combining motor behavior analyses and in vivo electrophysiological recordings in the substantia nigra pars reticulata (SNr, basal ganglia output structure) in pharmacological (neuroleptic treatment) and lesional (unilateral intranigral 6-hydroxydopamine injection) PD models. In the hemi-parkinsonian 6-hydroxydopamine lesion model, subchronic bee venom treatment significantly alleviates contralateral forelimb akinesia and apomorphine-induced rotations. Moreover, a single injection of bee venom reverses haloperidol-induced catalepsy, a pharmacological model reminiscent of parkinsonian akinetic deficit. This effect is mimicked by apamin, a blocker of small conductance Ca2+-activated K+ (SK) channels, and blocked by CyPPA, a positive modulator of these channels, suggesting the involvement of SK channels in the bee venom antiparkinsonian action. In vivo electrophysiological recordings in the substantia nigra pars reticulata (basal ganglia output structure) showed no significant effect of BV on the mean neuronal discharge frequency or pathological bursting activity. In contrast, analyses of the neuronal responses evoked by motor cortex stimulation show that bee venom reverses the 6-OHDA- and neuroleptic-induced biases in the influence exerted by the direct inhibitory and indirect excitatory striatonigral circuits. These data provide the first evidence for a beneficial action of bee venom on the pathological functioning of the cortico-basal ganglia circuits underlying motor PD symptoms with potential relevance to the symptomatic treatment of this disease.

  16. Glutathione S-transferase pi mediates MPTP-induced c-Jun N-terminal kinase activation in the nigrostriatal pathway.

    PubMed

    Castro-Caldas, Margarida; Carvalho, Andreia Neves; Rodrigues, Elsa; Henderson, Colin; Wolf, C Roland; Gama, Maria João

    2012-06-01

    Parkinson's disease (PD) is a progressive movement disorder resulting from the death of dopaminergic neurons in the substantia nigra. Neurotoxin-based models of PD using 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) recapitulate the neurological features of the disease, triggering a cascade of deleterious events through the activation of the c-Jun N-terminal kinase (JNK). The molecular mechanisms underlying the regulation of JNK activity under cellular stress conditions involve the activation of several upstream kinases along with the fine-tuning of different endogenous JNK repressors. Glutathione S-transferase pi (GSTP), a phase II detoxifying enzyme, has been shown to inhibit JNK-activated signaling by protein-protein interactions, preventing c-Jun phosphorylation and the subsequent trigger of the cell death cascade. Here, we use C57BL/6 wild-type and GSTP knockout mice treated with MPTP to evaluate the regulation of JNK signaling by GSTP in both the substantia nigra and the striatum. The results presented herein show that GSTP knockout mice are more susceptible to the neurotoxic effects of MPTP than their wild-type counterparts. Indeed, the administration of MPTP induces a progressive demise of nigral dopaminergic neurons together with the degeneration of striatal fibers at an earlier time-point in the GSTP knockout mice when compared to the wild-type mice. Also, MPTP treatment leads to increased p-JNK levels and JNK catalytic activity in both wild-type and GSTP knockout mice midbrain and striatum. Moreover, our results demonstrate that in vivo GSTP acts as an endogenous regulator of the MPTP-induced cellular stress response by controlling JNK activity through protein-protein interactions.

  17. Multi-modal and targeted imaging improves automated mid-brain segmentation

    NASA Astrophysics Data System (ADS)

    Plassard, Andrew J.; D'Haese, Pierre F.; Pallavaram, Srivatsan; Newton, Allen T.; Claassen, Daniel O.; Dawant, Benoit M.; Landman, Bennett A.

    2017-02-01

    The basal ganglia and limbic system, particularly the thalamus, putamen, internal and external globus pallidus, substantia nigra, and sub-thalamic nucleus, comprise a clinically relevant signal network for Parkinson's disease. In order to manually trace these structures, a combination of high-resolution and specialized sequences at 7T are used, but it is not feasible to scan clinical patients in those scanners. Targeted imaging sequences at 3T such as F-GATIR, and other optimized inversion recovery sequences, have been presented which enhance contrast in a select group of these structures. In this work, we show that a series of atlases generated at 7T can be used to accurately segment these structures at 3T using a combination of standard and optimized imaging sequences, though no one approach provided the best result across all structures. In the thalamus and putamen, a median Dice coefficient over 0.88 and a mean surface distance less than 1.0mm was achieved using a combination of T1 and an optimized inversion recovery imaging sequences. In the internal and external globus pallidus a Dice over 0.75 and a mean surface distance less than 1.2mm was achieved using a combination of T1 and FGATIR imaging sequences. In the substantia nigra and sub-thalamic nucleus a Dice coefficient of over 0.6 and a mean surface distance of less than 1.0mm was achieved using the optimized inversion recovery imaging sequence. On average, using T1 and optimized inversion recovery together produced significantly improved segmentation results than any individual modality (p<0.05 wilcox sign-rank test).

  18. β-Propeller protein-associated neurodegeneration: a new X-linked dominant disorder with brain iron accumulation.

    PubMed

    Hayflick, Susan J; Kruer, Michael C; Gregory, Allison; Haack, Tobias B; Kurian, Manju A; Houlden, Henry H; Anderson, James; Boddaert, Nathalie; Sanford, Lynn; Harik, Sami I; Dandu, Vasuki H; Nardocci, Nardo; Zorzi, Giovanna; Dunaway, Todd; Tarnopolsky, Mark; Skinner, Steven; Holden, Kenton R; Frucht, Steven; Hanspal, Era; Schrander-Stumpel, Connie; Mignot, Cyril; Héron, Delphine; Saunders, Dawn E; Kaminska, Margaret; Lin, Jean-Pierre; Lascelles, Karine; Cuno, Stephan M; Meyer, Esther; Garavaglia, Barbara; Bhatia, Kailash; de Silva, Rajith; Crisp, Sarah; Lunt, Peter; Carey, Martyn; Hardy, John; Meitinger, Thomas; Prokisch, Holger; Hogarth, Penelope

    2013-06-01

    Neurodegenerative disorders with high iron in the basal ganglia encompass an expanding collection of single gene disorders collectively known as neurodegeneration with brain iron accumulation. These disorders can largely be distinguished from one another by their associated clinical and neuroimaging features. The aim of this study was to define the phenotype that is associated with mutations in WDR45, a new causative gene for neurodegeneration with brain iron accumulation located on the X chromosome. The study subjects consisted of WDR45 mutation-positive individuals identified after screening a large international cohort of patients with idiopathic neurodegeneration with brain iron accumulation. Their records were reviewed, including longitudinal clinical, laboratory and imaging data. Twenty-three mutation-positive subjects were identified (20 females). The natural history of their disease was remarkably uniform: global developmental delay in childhood and further regression in early adulthood with progressive dystonia, parkinsonism and dementia. Common early comorbidities included seizures, spasticity and disordered sleep. The symptoms of parkinsonism improved with l-DOPA; however, nearly all patients experienced early motor fluctuations that quickly progressed to disabling dyskinesias, warranting discontinuation of l-DOPA. Brain magnetic resonance imaging showed iron in the substantia nigra and globus pallidus, with a 'halo' of T1 hyperintense signal in the substantia nigra. All patients harboured de novo mutations in WDR45, encoding a beta-propeller protein postulated to play a role in autophagy. Beta-propeller protein-associated neurodegeneration, the only X-linked disorder of neurodegeneration with brain iron accumulation, is associated with de novo mutations in WDR45 and is recognizable by a unique combination of clinical, natural history and neuroimaging features.

  19. Bee Venom Alleviates Motor Deficits and Modulates the Transfer of Cortical Information through the Basal Ganglia in Rat Models of Parkinson’s Disease

    PubMed Central

    Maurice, Nicolas; Deltheil, Thierry; Melon, Christophe; Degos, Bertrand; Mourre, Christiane

    2015-01-01

    Recent evidence points to a neuroprotective action of bee venom on nigral dopamine neurons in animal models of Parkinson’s disease (PD). Here we examined whether bee venom also displays a symptomatic action by acting on the pathological functioning of the basal ganglia in rat PD models. Bee venom effects were assessed by combining motor behavior analyses and in vivo electrophysiological recordings in the substantia nigra pars reticulata (SNr, basal ganglia output structure) in pharmacological (neuroleptic treatment) and lesional (unilateral intranigral 6-hydroxydopamine injection) PD models. In the hemi-parkinsonian 6-hydroxydopamine lesion model, subchronic bee venom treatment significantly alleviates contralateral forelimb akinesia and apomorphine-induced rotations. Moreover, a single injection of bee venom reverses haloperidol-induced catalepsy, a pharmacological model reminiscent of parkinsonian akinetic deficit. This effect is mimicked by apamin, a blocker of small conductance Ca2+-activated K+ (SK) channels, and blocked by CyPPA, a positive modulator of these channels, suggesting the involvement of SK channels in the bee venom antiparkinsonian action. In vivo electrophysiological recordings in the substantia nigra pars reticulata (basal ganglia output structure) showed no significant effect of BV on the mean neuronal discharge frequency or pathological bursting activity. In contrast, analyses of the neuronal responses evoked by motor cortex stimulation show that bee venom reverses the 6-OHDA- and neuroleptic-induced biases in the influence exerted by the direct inhibitory and indirect excitatory striatonigral circuits. These data provide the first evidence for a beneficial action of bee venom on the pathological functioning of the cortico-basal ganglia circuits underlying motor PD symptoms with potential relevance to the symptomatic treatment of this disease. PMID:26571268

  20. Decreased synaptic plasticity in the medial prefrontal cortex underlies short-term memory deficits in 6-OHDA-lesioned rats.

    PubMed

    Matheus, Filipe C; Rial, Daniel; Real, Joana I; Lemos, Cristina; Ben, Juliana; Guaita, Gisele O; Pita, Inês R; Sequeira, Ana C; Pereira, Frederico C; Walz, Roger; Takahashi, Reinaldo N; Bertoglio, Leandro J; Da Cunha, Cláudio; Cunha, Rodrigo A; Prediger, Rui D

    2016-03-15

    Parkinson's disease (PD) is characterized by motor dysfunction associated with dopaminergic degeneration in the dorsolateral striatum (DLS). However, motor symptoms in PD are often preceded by short-term memory deficits, which have been argued to involve deregulation of medial prefrontal cortex (mPFC). We now used a 6-hydroxydopamine (6-OHDA) rat PD model to explore if alterations of synaptic plasticity in DLS and mPFC underlie short-term memory impairments in PD prodrome. The bilateral injection of 6-OHDA (20μg/hemisphere) in the DLS caused a marked loss of dopaminergic neurons in the substantia nigra (>80%) and decreased monoamine levels in the striatum and PFC, accompanied by motor deficits evaluated after 21 days in the open field and accelerated rotarod. A lower dose of 6-OHDA (10μg/hemisphere) only induced a partial degeneration (about 60%) of dopaminergic neurons in the substantia nigra with no gross motor impairments, thus mimicking an early premotor stage of PD. Notably, 6-OHDA (10μg)-lesioned rats displayed decreased monoamine levels in the PFC as well as short-term memory deficits evaluated in the novel object discrimination and in the modified Y-maze tasks; this was accompanied by a selective decrease in the amplitude of long-term potentiation in the mPFC, but not in DLS, without changes of synaptic transmission in either brain regions. These results indicate that the short-term memory dysfunction predating the motor alterations in the 6-OHDA model of PD is associated with selective changes of information processing in PFC circuits, typified by persistent changes of synaptic plasticity. Copyright © 2015 Elsevier B.V. All rights reserved.

  1. Brain deposition and neurotoxicity of manganese in adult mice exposed via the drinking water

    PubMed Central

    Saritha, Krishna; Celia, Dodd A.; Shahryar, Hekmatyar K.; Nikolay, Filipov M.

    2013-01-01

    Natural leaching processes and/or anthropogenic contamination can result in ground water concentrations of the essential metal manganese (Mn) that far exceed the current regulatory standards. Neurological consequences of Mn drinking water (DW) overexposure to experimental animals, i.e. mice, including its brain deposition/distribution and behavioral effects are understudied. Adult male C57BL/6 mice were exposed to Mn via the DW for 8 weeks. After 5 weeks of Mn exposure, magnetic resonance imaging revealed significant Mn deposition in all examined brain regions; the degree of Mn deposition did not increase further a week later. Behaviorally, early hyperactivity and more time spent in the center of the arenas in an open field test, decreased forelimb grip strength and less time swimming in a forced swim test were observed after 6 weeks of Mn DW exposure. Eight-week Mn DW exposure did not alter striatal dopamine, its metabolites, or the expression of key dopamine homeostatic proteins, but it significantly increased striatal 5-hydroxyindoleacetic acid (a serotonin metabolite) level, without affecting the levels of serotonin itself. Increased expression (mRNA) of glial fibrillary acidic protein (GFAP, an astrocyte activation marker), heme oxygenase-1 and inducible nitric oxide synthase (oxidative and nitrosative stress markers, respectively) were observed 8 weeks post Mn DW exposure in the substantia nigra. Besides mRNA increases, GFAP protein expression was increased in the substantia nigra pars reticulata. In summary, the neurobehavioral deficits, characterized by locomotor and emotional perturbations, and nigral glial activation associated with significant brain Mn deposition are among the early signs of Mn neurotoxicity caused by DW overexposure. PMID:23832297

  2. Neurorestoration induced by the HDAC inhibitor sodium valproate in the lactacystin model of Parkinson’s is associated with histone acetylation and up-regulation of neurotrophic factors

    PubMed Central

    Harrison, Ian F; Crum, William R; Vernon, Anthony C; Dexter, David T

    2015-01-01

    Background and Purpose Histone hypoacetylation is associated with Parkinson's disease (PD), due possibly to an imbalance in the activities of enzymes responsible for histone (de)acetylation; correction of which may be neuroprotective/neurorestorative. This hypothesis was tested using the anti-epileptic drug sodium valproate, a known histone deacetylase inhibitor (HDACI), utilizing a delayed-start study design in the lactacystin rat model of PD. Experimental Approach The irreversible proteasome inhibitor lactacystin was unilaterally injected into the substantia nigra of Sprague–Dawley rats that subsequently received valproate for 28 days starting 7 days after lactacystin lesioning. Longitudinal motor behavioural testing, structural MRI and post-mortem assessment of nigrostriatal integrity were used to track changes in this model of PD and quantify neuroprotection/restoration. Subsequent cellular and molecular analyses were performed to elucidate the mechanisms underlying valproate's effects. Key Results Despite producing a distinct pattern of structural re-modelling in the healthy and lactacystin-lesioned brain, delayed-start valproate administration induced dose-dependent neuroprotection/restoration against lactacystin neurotoxicity, characterized by motor deficit alleviation, attenuation of morphological brain changes and restoration of dopaminergic neurons in the substantia nigra. Molecular analyses revealed that valproate alleviated lactacystin-induced histone hypoacetylation and induced up-regulation of brain neurotrophic/neuroprotective factors. Conclusions and Implications The histone acetylation and up-regulation of neurotrophic/neuroprotective factors associated with valproate treatment culminate in a neuroprotective and neurorestorative phenotype in this animal model of PD. As valproate induced structural re-modelling of the brain, further research is required to determine whether valproate represents a viable candidate for disease treatment; however

  3. Linking Inflammation and Parkinson Disease: Hypochlorous Acid Generates Parkinsonian Poisons.

    PubMed

    Jeitner, Thomas M; Kalogiannis, Mike; Krasnikov, Boris F; Gomolin, Irving; Peltier, Morgan R; Moran, Graham R

    2016-06-01

    Inflammation is a common feature of Parkinson Disease and other neurodegenerative disorders. Hypochlorous acid (HOCl) is a reactive oxygen species formed by neutrophils and other myeloperoxidase-containing cells during inflammation. HOCl chlorinates the amine and catechol moieties of dopamine to produce chlorinated derivatives collectively termed chlorodopamine. Here, we report that chlorodopamine is toxic to dopaminergic neurons both in vivo and in vitro Intrastriatal administration of 90 nmol chlorodopamine to mice resulted in loss of dopaminergic neurons from the substantia nigra and decreased ambulation-results that were comparable to those produced by the same dose of the parkinsonian poison, 1-methyl-4-phenylpyridinium (MPP+). Chlorodopamine was also more toxic to differentiated SH SY5Y cells than HOCl. The basis of this selective toxicity is likely mediated by chlorodopamine uptake through the dopamine transporter, as expression of this transporter in COS-7 cells conferred sensitivity to chlorodopamine toxicity. Pharmacological blockade of the dopamine transporter also mitigated the deleterious effects of chlorodopamine in vivo The cellular actions of chlorodopamine included inactivation of the α-ketoglutarate dehydrogenase complex, as well as inhibition of mitochondrial respiration. The latter effect is consistent with inhibition of cytochrome c oxidase. Illumination at 670 nm, which stimulates cytochrome c oxidase, reversed the effects of chlorodopamine. The observed changes in mitochondrial biochemistry were also accompanied by the swelling of these organelles. Overall, our findings suggest that chlorination of dopamine by HOCl generates toxins that selectively kill dopaminergic neurons in the substantia nigra in a manner comparable to MPP+. © The Author 2016. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  4. Early life exposure to permethrin: a progressive animal model of Parkinson's disease.

    PubMed

    Nasuti, Cinzia; Brunori, Gloria; Eusepi, Piera; Marinelli, Lisa; Ciccocioppo, Roberto; Gabbianelli, Rosita

    Oxidative stress, alpha-synuclein changes, mitochondrial complex I defects and dopamine loss, observed in the striatum of rats exposed to the pesticide permethrin in early life, could represent neuropathological hallmarks of Parkinson's disease (PD). Nevertheless, an animal model of PD should also fulfill criteria of face and predictive validities. This study was designed to: 1) verify dopaminergic status in the striatum and substantia nigra pars compacta; 2) recognize non-motor symptoms; 3) investigate the time-course development of motor disabilities; 4) assess L-Dopa effectiveness on motor symptoms in rats previously exposed to permethrin in early life. The permethrin-treated group received 34mg/kg daily of permethrin from postnatal day 6 to 21, whereas the age-matched control group was administered with the vehicle only. At adolescent age, the permethrin-treated group showed decreased levels of dopamine in the striatum, loss of dopaminergic neurons in the substantia nigra pars compacta and cognitive impairments. Motor coordination defects appeared at adult age (150days old) in permethrin-treated rats on rotarod and beam walking tasks, whereas no differences between the treated and control groups were detected on the foot print task. Predictive validity was evaluated by testing the ability of L-Dopa (5, 10 or 15mg/kg, os) to restore the postural instability in permethrin-treated rats (150days old) tested in a beam walking task. The results revealed full reversal of motor deficits starting from 10mg/kg of L-Dopa. The overall results indicate that this animal model replicates the progressive, time-dependent nature of the neurodegenerative process in Parkinson's disease. Copyright © 2016 Elsevier Inc. All rights reserved.

  5. Neonatal exposure to estradiol valerate increases dopamine content in nigrostriatal pathway during adulthood in the rat.

    PubMed

    Cruz, G; Riquelme, R; Espinosa, P; Jara, P; Dagnino-Subiabre, A; Renard, G M; Sotomayor-Zárate, R

    2014-05-01

    Research in programming has focused in the study of stimuli that affect sensitive periods of development such as prenatal and neonatal stage. We previously showed that exposure to estradiol valerate to female rats during the first 12 h of life increased catecholamine content in ventromedial-arcuatus hypothalamus of the adult rat. However, changes in others dopaminergic circuits have not been studied. The purpose of this work was to determine the neurotransmitters changes induced by neonatal estradiol valerate (0.1 mg/50 μl s. c. per rat) administration on nigrostriatal pathway of adult female rats. Sesame oil (50 μl s. c. per rat) was administered in a control parallel group. EV-1 adult rats presented effective markers of long-term estrogenization as decreased serum levels of progesterone and a reduction in the size of estrogen-sensitive organs. In the brain, neonatal estradiol valerate administration led to a significant increase in dopamine content in striatum, substantia nigra and ventral tegmental area. With respect to the contents of dopamine metabolites, only 3-methoxytyramine content increased in substantia nigra and ventral tegmental area. In addition, the content of noradrenaline increased only in striatum. Interestingly, estrogenized rats lacked locomotor activity induced by acute dose of amphetamine (1 mg/kg i. p.). Altogether, these results show that neonatal exposure to estradiol valerate permanently modified the content of monoamine neurotransmitters in nigrostriatal pathway and amphetamine-induced locomotor activity of adult female rats. This might imply that estrogenized rats could have changes in the expression of key proteins in dopaminergic regulation, as tyrosine hydroxylase and dopamine transporter. © Georg Thieme Verlag KG Stuttgart · New York.

  6. Defective functional connectivity between posterior hypothalamus and regions of the diencephalic-mesencephalic junction in chronic cluster headache.

    PubMed

    Ferraro, Stefania; Nigri, Anna; Bruzzone, Maria Grazia; Brivio, Luca; Proietti Cecchini, Alberto; Verri, Mattia; Chiapparini, Luisa; Leone, Massimo

    2018-01-01

    Objective We tested the hypothesis of a defective functional connectivity between the posterior hypothalamus and diencephalic-mesencephalic regions in chronic cluster headache based on: a) clinical and neuro-endocrinological findings in cluster headache patients; b) neuroimaging findings during cluster headache attacks; c) neuroimaging findings in drug-refractory chronic cluster headache patients improved after successful deep brain stimulation. Methods Resting state functional magnetic resonance imaging, associated with a seed-based approach, was employed to investigate the functional connectivity of the posterior hypothalamus in chronic cluster headache patients (n = 17) compared to age and sex-matched healthy subjects (n = 16). Random-effect analyses were performed to study differences between patients and controls in ipsilateral and contralateral-to-the-pain posterior hypothalamus functional connectivity. Results Cluster headache patients showed an increased functional connectivity between the ipsilateral posterior hypothalamus and a number of diencephalic-mesencephalic structures, comprising ventral tegmental area, dorsal nuclei of raphe, and bilateral substantia nigra, sub-thalamic nucleus, and red nucleus ( p < 0.005 FDR-corrected vs . control group). No difference between patients and controls was found comparing the contralateral hypothalami. Conclusions The observed deranged functional connectivity between the posterior ipsilateral hypothalamus and diencephalic-mesencephalic regions in chronic cluster headache patients mainly involves structures that are part of (i.e. ventral tegmental area, substantia nigra) or modulate (dorsal nuclei of raphe, sub-thalamic nucleus) the midbrain dopaminergic systems. The midbrain dopaminergic systems could play a role in cluster headache pathophysiology and in particular in the chronicization process. Future studies are needed to better clarify if this finding is specific to cluster headache or if it

  7. A decision tree for differentiating multiple system atrophy from Parkinson's disease using 3-T MR imaging.

    PubMed

    Nair, Shalini Rajandran; Tan, Li Kuo; Mohd Ramli, Norlisah; Lim, Shen Yang; Rahmat, Kartini; Mohd Nor, Hazman

    2013-06-01

    To develop a decision tree based on standard magnetic resonance imaging (MRI) and diffusion tensor imaging to differentiate multiple system atrophy (MSA) from Parkinson's disease (PD). 3-T brain MRI and DTI (diffusion tensor imaging) were performed on 26 PD and 13 MSA patients. Regions of interest (ROIs) were the putamen, substantia nigra, pons, middle cerebellar peduncles (MCP) and cerebellum. Linear, volumetry and DTI (fractional anisotropy and mean diffusivity) were measured. A three-node decision tree was formulated, with design goals being 100 % specificity at node 1, 100 % sensitivity at node 2 and highest combined sensitivity and specificity at node 3. Nine parameters (mean width, fractional anisotropy (FA) and mean diffusivity (MD) of MCP; anteroposterior diameter of pons; cerebellar FA and volume; pons and mean putamen volume; mean FA substantia nigra compacta-rostral) showed statistically significant (P < 0.05) differences between MSA and PD with mean MCP width, anteroposterior diameter of pons and mean FA MCP chosen for the decision tree. Threshold values were 14.6 mm, 21.8 mm and 0.55, respectively. Overall performance of the decision tree was 92 % sensitivity, 96 % specificity, 92 % PPV and 96 % NPV. Twelve out of 13 MSA patients were accurately classified. Formation of the decision tree using these parameters was both descriptive and predictive in differentiating between MSA and PD. • Parkinson's disease and multiple system atrophy can be distinguished on MR imaging. • Combined conventional MRI and diffusion tensor imaging improves the accuracy of diagnosis. • A decision tree is descriptive and predictive in differentiating between clinical entities. • A decision tree can reliably differentiate Parkinson's disease from multiple system atrophy.

  8. Brilliant Blue G, but not Fenofibrate, Treatment Reverts Hemiparkinsonian Behavior and Restores Dopamine Levels in an Animal Model of Parkinson's Disease

    PubMed Central

    Ferrazoli, Enéas G.; De Souza, Héllio D.N.; Nascimento, Isis C.; Oliveira-Giacomelli, Ágatha; Schwindt, Telma T.; Britto, Luiz R.; Ulrich, Henning

    2017-01-01

    Parkinson's disease (PD) is a neurodegenerative disorder, characterized by the loss of dopaminergic neurons in the substantia nigra and their projections to the striatum. Several processes have been described as potential inducers of the dopaminergic neuron death, such as inflammation, oxidative stress, and mitochondrial dysfunction. However, the death of dopaminergic neurons seems to be multifactorial, and its cause remains unclear. ATP-activating purinergic receptors influence various physiological functions in the CNS, including neurotransmission. Purinergic signaling is also involved in pathological scenarios, where ATP is extensively released and promotes sustained purinergic P2X7 receptor (P2X7R) activation and consequent induction of cell death. This effect occurs, among other factors, by oxidative stress and during the inflammatory response. On the other hand, peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α) is involved in energy metabolism and mitochondrial biogenesis. Expression and activity upregulation of this protein has been related with reduction of oxidative stress and neuroprotection. Therefore, P2X7R and PGC-1α are potential targets in the treatment of PD. Here hemiparkinsonism was induced by unilateral stereotactic injection of 6-OHDA in a rat model. After 7 days, the establishment of PD was confirmed and followed by treatment with the P2X7R antagonist Brilliant Blue G (BBG) or PGC-1α agonist fenofibrate. BBG, but not fenofibrate, reverted hemiparkinsonian behavior accompanied by an increase in tyrosine hydroxylase immunoreactivity in the substantia nigra. Our results suggest that the P2X7R may be a therapeutic target in Parkinson's disease. PMID:28403913

  9. Raclopride or high-frequency stimulation of the subthalamic nucleus stops cocaine-induced motor stereotypy and restores related alterations in prefrontal basal ganglia circuits.

    PubMed

    Aliane, Verena; Pérez, Sylvie; Deniau, Jean-Michel; Kemel, Marie-Louise

    2012-11-01

    Motor stereotypy is a key symptom of various neurological or neuropsychiatric disorders. Neuroleptics or the promising treatment using deep brain stimulation stops stereotypies but the mechanisms underlying their actions are unclear. In rat, motor stereotypies are linked to an imbalance between prefrontal and sensorimotor cortico-basal ganglia circuits. Indeed, cortico-nigral transmission was reduced in the prefrontal but not sensorimotor basal ganglia circuits and dopamine and acetylcholine release was altered in the prefrontal but not sensorimotor territory of the dorsal striatum. Furthermore, cholinergic transmission in the prefrontal territory of the dorsal striatum plays a crucial role in the arrest of motor stereotypy. Here we found that, as previously observed for raclopride, high-frequency stimulation of the subthalamic nucleus (HFS STN) rapidly stopped cocaine-induced motor stereotypies in rat. Importantly, raclopride and HFS STN exerted a strong effect on cocaine-induced alterations in prefrontal basal ganglia circuits. Raclopride restored the cholinergic transmission in the prefrontal territory of the dorsal striatum and the cortico-nigral information transmissions in the prefrontal basal ganglia circuits. HFS STN also restored the N-methyl-d-aspartic-acid-evoked release of acetylcholine and dopamine in the prefrontal territory of the dorsal striatum. However, in contrast to raclopride, HFS STN did not restore the cortico-substantia nigra pars reticulata transmissions but exerted strong inhibitory and excitatory effects on neuronal activity in the prefrontal subdivision of the substantia nigra pars reticulata. Thus, both raclopride and HFS STN stop cocaine-induced motor stereotypy, but exert different effects on the related alterations in the prefrontal basal ganglia circuits. © 2012 The Authors. European Journal of Neuroscience © 2012 Federation of European Neuroscience Societies and Blackwell Publishing Ltd.

  10. Mapping Dopamine Function in Primates Using Pharmacologic Magnetic Resonance Imaging

    PubMed Central

    Sanchez-Pernaute, Rosario; Brownell, Anna-Liisa; Chen, Yin-Ching Iris; Isacson, Ole

    2008-01-01

    Dopamine (DA) receptors play a central role in such diverse pathologies as Parkinson's disease, schizophrenia, and drug abuse. We used an amphetamine challenge combined with pharmacologic magnetic resonance imaging (phMRI) to map DA-associated circuitry in nonhuman primates with high sensitivity and spatial resolution. Seven control cynomolgous monkeys and 10 MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine)-treated parkinsonian primates were studied longitudinally using both positron emission tomography (PET) and phMRI. Amphetamine challenge (2.5 mg/kg, i.v.) in control monkeys increased relative cerebral blood volume (rCBV) in a number of brain regions not described previously, such as parafascicular thalamus, precentral gyrus, and dentate nucleus of the cerebellum. With the high spatial resolution, we were also able to readily identify changes in rCBV in the anterior cingulate, substantia nigra, ventral tegmental area, caudate (tail and head), putamen, and nucleus accumbens. Amphetamine induced decreases in rCBV in occipital and posterior parietal cortices. Parkinsonian primates had a prominent loss of response to amphetamine, with relative sparing of the nucleus accumbens and parafascicular thalamus. There was a significant correlation between rCBV loss in the substantia nigra and both PET imaging of dopamine transporters and behavioral measures. Monkeys with partial lesions as defined by 2β-carbomethoxy-3β-(4-fluorophenyl) tropane binding to dopamine transporters showed recruitment of premotor and motor cortex after amphetamine stimulus similar to what has been noted in Parkinson's patients during motor tasks. These data indicate that phMRI is a powerful tool for assessment of dynamic changes associated with normal and dysfunctional DA brain circuitry in primates. PMID:15509742

  11. Novel Food Supplement "CP1" Improves Motor Deficit, Cognitive Function, and Neurodegeneration in Animal Model of Parkinson's Disease.

    PubMed

    Wattanathorn, Jintanaporn; Sutalangka, Chatchada

    2016-08-01

    Based on pivotal roles of oxidative stress, dopaminergic and cholinergic systems on the pathophysiology of Parkinson's disease (PD), the searching for functional food for patients attacked with PD from Cyperus rotundus and Zingiber officinale, the substances possessing antioxidant activity, and the suppression effects on monoamine oxidase B (MAO-B) and acetylcholinesterase (AChE) have been considered. In this study, we aimed to determine the effect of the combined extract of C. rotundus and Z. officinale (CP1) to improve motor and memory deficits, neurodegeneration, oxidative stress, and functions of both cholinergic and dopaminergic systems in the animal model of PD induced by 6-hydroxydopamine hydrochloride (6-OHDA). Male Wistar rats, weighing 180-220 g, were induced unilateral lesion at right substantia nigra by 6-OHDA and were orally given CP1 at doses of 100, 200, and 300 mg/kg body weight for 14 days after 6-OHDA injection. The results showed that the 6-OHDA rats treated with CP1 increased spatial memory, but decreased neurodegeneration, malondialdehyde level, and AChE activity in hippocampus. The decreased motor disorder and neurodegeneration in substantia nigra together with the enhanced catalase activity, but decreased MAO-B activity in striatum, were also observed. The memory enhancing effect of CP1 might occur through the improved oxidative stress and the enhanced cholinergic function, whereas the effect to improve motor disorder of CP1 might occur through the enhanced dopaminergic function in striatum by decreasing the degeneration of dopaminergic neurons and the suppression of MAO-B. Therefore, CP1 is the potential functional food against PD. However, further researches in clinical trial and drug interactions are essential.

  12. Brain deposition and neurotoxicity of manganese in adult mice exposed via the drinking water.

    PubMed

    Krishna, Saritha; Dodd, Celia A; Hekmatyar, Shahryar K; Filipov, Nikolay M

    2014-01-01

    Natural leaching processes and/or anthropogenic contamination can result in ground water concentrations of the essential metal manganese (Mn) that far exceed the current regulatory standards. Neurological consequences of Mn drinking water (DW) overexposure to experimental animals, i.e., mice, including its brain deposition/distribution and behavioral effects are understudied. Adult male C57BL/6 mice were exposed to Mn via the DW for 8 weeks. After 5 weeks of Mn exposure, magnetic resonance imaging revealed significant Mn deposition in all examined brain regions; the degree of Mn deposition did not increase further a week later. Behaviorally, early hyperactivity and more time spent in the center of the arenas in an open field test, decreased forelimb grip strength and less time swimming in a forced swim test were observed after 6 weeks of Mn DW exposure. Eight-week Mn DW exposure did not alter striatal dopamine, its metabolites, or the expression of key dopamine homeostatic proteins, but it significantly increased striatal 5-hydroxyindoleacetic acid (a serotonin metabolite) levels, without affecting the levels of serotonin itself. Increased expression (mRNA) of glial fibrillary acidic protein (GFAP, an astrocyte activation marker), heme oxygenase-1 and inducible nitric oxide synthase (oxidative and nitrosative stress markers, respectively) were observed 8 weeks post-Mn DW exposure in the substantia nigra. Besides mRNA increases, GFAP protein expression was increased in the substantia nigra pars reticulata. In summary, the neurobehavioral deficits, characterized by locomotor and emotional perturbations, and nigral glial activation associated with significant brain Mn deposition are among the early signs of Mn neurotoxicity caused by DW overexposure.

  13. Small effect of dopamine release and no effect of dopamine depletion on [18F]fallypride binding in healthy humans.

    PubMed

    Cropley, Vanessa L; Innis, Robert B; Nathan, Pradeep J; Brown, Amira K; Sangare, Janet L; Lerner, Alicja; Ryu, Yong Hoon; Sprague, Kelly E; Pike, Victor W; Fujita, Masahiro

    2008-06-01

    Molecular imaging has been used to estimate both drug-induced and tonic dopamine release in the striatum and most recently extrastriatal areas of healthy humans. However, to date, studies of drug-induced and tonic dopamine release have not been performed in the same subjects. This study performed positron emission tomography (PET) with [18F]fallypride in healthy subjects to assess (1) the reproducibility of [18F]fallypride and (2) both D-amphetamine-induced and alpha-methyl-p-tyrosine (AMPT)-induced changes in dopamin release on [(18)F]fallypride binding in striatal and extrastriatal areas. Subjects underwent [18F]fallypride PET studies at baseline and following oral D-amphetamine administration (0.5 mg/kg) and oral AMPT administration (3 g/70 kg/day over 44 h). Binding potential (BP) (BP(ND)) of [18F]fallypride was calculated in striatal and extrastriatal areas using a reference region method. Percent change in regional BP(ND) was computed and correlated with change in cognition and mood. Test-retest variability of [18F]fallypride was low in both striatal and extrastriatal regions. D-Amphetamine significantly decreased BP(ND) by 8-14% in striatal subdivisions, caudate, putamen, substantia nigra, medial orbitofrontal cortex, and medial temporal cortex. Correlation between change in BP(ND) and verbal fluency was seen in the thalamus and substantia nigra. In contrast, depletion of endogenous dopamine with AMPT did not effect [18F]fallypride BP(ND) in both striatum and extrastriatal regions. These findings indicate that [18F]fallypride is useful for measuring amphetamine-induced dopamine release, but may be unreliable for estimating tonic dopamine levels, in striatum and extrastriatal regions of healthy humans.

  14. [Lectins from Sambucus nigra L inflorescences: isolation and investigation of biological activity using procaryotic test-systems].

    PubMed

    Karpova, I S; Korets'ka, N V; Pal'chykovs'ka, L H; Nehruts'ka, V V

    2007-01-01

    Isolation of lectins from extracts of the Sambucus nigra inflorescences and of pollen material have been performed using isoelectric focusing without carrier ampholytes (autofocusing). Fractions active in agglutination tests with different carbohydrate specificity were subjected to SDS-PAGE. The major lectin found in whole inflores-cences was GalNAc specific and is proposed to be a heterotetramer with subunits of about 30 and 33 kDa. It was called SNAflu-I. At least two other lectins were present in the pollen material and supposed to consist of identical subunits. Major positively charged lectin was Glc/Man specific with subunit of 26 kDa and called SNApol-I. Other pollen component (SNApol-II) was Gal specific with subunit of about 20 kDa. In order to elucidate cell targets sensitive for the S. nigra lectin's activity the combined effects of the lectins and transcriptional of phenazine origin on B. subtilis cells growth have been studied. Only SNApol-I demonstrated the antagonistic activity against these inhibitors in vivo. This lectin but not the SNAflu-I can also inhibit transcription in vitro. It is supposed that lectins from the same source may act in different directions on cell metabolism. Particularly one of the common targets may be the DNA-dependent synthesis of RNA.

  15. DOE Office of Scientific and Technical Information (OSTI.GOV)

    Merwe, Celia van der, E-mail: celiavdm@sun.ac.za; Loos, Ben; Swart, Chrisna

    Highlights: • Mitochondrial dysfunction observed in patients with parkin-null mutations. • Mitochondrial ATP levels were decreased. • Electron-dense vacuoles were observed in the patients. • Mitochondria from muscle biopsies appeared within normal limits. • One patient did not show these defects possibly due to compensatory mechanisms. - Abstract: Parkinson’s disease (PD), defined as a neurodegenerative disorder, is characterized by the loss of dopaminergic neurons in the substantia nigra in the midbrain. Loss-of-function mutations in the parkin gene are a major cause of autosomal recessive, early-onset PD. Parkin has been implicated in the maintenance of healthy mitochondria, although previous studies showmore » conflicting findings regarding mitochondrial abnormalities in fibroblasts from patients harboring parkin-null mutations. The aim of the present study was to determine whether South African PD patients with parkin mutations exhibit evidence for mitochondrial dysfunction. Fibroblasts were cultured from skin biopsies obtained from three patients with homozygous parkin-null mutations, two heterozygous mutation carriers and two wild-type controls. Muscle biopsies were obtained from two of the patients. The muscle fibers showed subtle abnormalities such as slightly swollen mitochondria in focal areas of the fibers and some folding of the sarcolemma. Although no differences in the degree of mitochondrial network branching were found in the fibroblasts, ultrastructural abnormalities were observed including the presence of electron-dense vacuoles. Moreover, decreased ATP levels which are consistent with mitochondrial dysfunction were observed in the patients’ fibroblasts compared to controls. Remarkably, these defects did not manifest in one patient, which may be due to possible compensatory mechanisms. These results suggest that parkin-null patients exhibit features of mitochondrial dysfunction. Involvement of mitochondria as a key role player in

  16. White piedra, black piedra, tinea versicolor, and tinea nigra: contribution to the diagnosis of superficial mycosis*

    PubMed Central

    Veasey, John Verrinder; de Avila, Ricardo Bertozzi; Miguel, Barbara Arruda Fraletti; Muramatu, Laura Hitomi

    2017-01-01

    Superficial mycoses are fungal infections restricted to the stratum corneum and to the hair shafts, with no penetration in the epidermis; they are: white piedra, black piedra, tinea versicolor, and tinea nigra. This study presents images of mycological tests performed in the laboratory, as well as exams performed at the authors office, in order to improve the dermatologist's knowledge about the diagnosis of these dermatoses, which are common in many countries. PMID:29186263

  17. Self-amplification of nigral degeneration in Parkinson's disease: a hypothesis.

    PubMed

    Ionov, Ilya D

    2008-12-01

    This review analyzes current evidence regarding possible mechanisms of nigral damage in idiopathic Parkinson's disease (iPD). In normal brain, a specific interplay among the blood-brain barrier (BBB), substantia nigra (SN), and locus coeruleus (LC) creates the condition for a self-accelerating damage to the SN. Three vicious circles involving SN-BBB, LC-SN-BBB, and histamine-BBB-SN interactions are described. In iPD, a self-accelerating loss of nigral cells can be triggered by brain hypoperfusion and by an increased blood histamine level. iPD-associated factors such as decreased CSF levels of substance P, somatostatin, and glutamate can aggravate the vicious-circle-induced damage to the SN.

  18. A neuropathological survey of brains submitted under the Bovine Spongiform Encephalopathy Orders in Scotland.

    PubMed

    Jeffrey, M

    1992-10-10

    Bovine spongiform encephalopathy was not confirmed histologically in 225 of 829 bovine brains submitted for diagnosis. Several previously described disorders of the central nervous system were observed in these brains as well as disorders not previously recognised in Britain, including bilateral vacuolation of the substantia nigra, hippocampal sclerosis with brainstem neuronal chromatolysis and necrosis, focal symmetrical encephalomalacia and meningio-angiomatosis. Severe cerebellar dysplasia consistent with pre-natal bovine viral diarrhoea--mucosal disease virus infection or mineralisation of the blood vessels of the basal ganglia were interpreted respectively as congenital changes or changes due to ageing and were considered to be of no clinical significance.

  19. The Role of Dopamine and Its Dysfunction as a Consequence of Oxidative Stress

    PubMed Central

    Juárez Olguín, Hugo; Calderón Guzmán, David; Hernández García, Ernestina; Barragán Mejía, Gerardo

    2016-01-01

    Dopamine is a neurotransmitter that is produced in the substantia nigra, ventral tegmental area, and hypothalamus of the brain. Dysfunction of the dopamine system has been implicated in different nervous system diseases. The level of dopamine transmission increases in response to any type of reward and by a large number of strongly additive drugs. The role of dopamine dysfunction as a consequence of oxidative stress is involved in health and disease. Introduce new potential targets for the development of therapeutic interventions based on antioxidant compounds. The present review focuses on the therapeutic potential of antioxidant compounds as a coadjuvant treatment to conventional neurological disorders is discussed. PMID:26770661

  20. West Nile virus encephalomyelitis with polio-like paralysis & nigral degeneration.

    PubMed

    Schafernak, Kristian T; Bigio, Eileen H

    2006-11-01

    Patients infected with West Nile virus (WNV) may develop acute neurologic disease, which can be severe or even fatal, including WNV meningitis, encephalitis, and an irreversible acute flaccid paralysis or poliomyelitis-like syndrome. Movement disorders have also been described. We report combined neuronal loss, gliosis, and neurofibrillary tangle formation in the substantia nigra of a 41-year-old man with a history of WNV encephalomyelitis and poliomyelitis-like paralysis. Clinically our patient did not display parkinsonism, however, it is interesting to speculate whether, in the absence of the residual subacute poliomyelitis-like syndrome, the neuropathologic findings could have eventually evolved clinically into WNV-associated postencephalitic parkinsonism.

  1. Extracts of Morus nigra L. Leaves Standardized in Chlorogenic Acid, Rutin and Isoquercitrin: Tyrosinase Inhibition and Cytotoxicity

    PubMed Central

    Fontes, Pedro Ribeiro; Souza, Paula Monteiro; William Fagg, Christopher; Neves Silva Guerra, Eliete; de Medeiros Nóbrega, Yanna Karla; Silveira, Damaris; Fonseca-Bazzo, Yris; Simeoni, Luiz Alberto; Homem-de-Mello, Maurício; Oliveira Magalhães, Pérola

    2016-01-01

    Melanogenesis is a process responsible for melanin production, which is stored in melanocytes containing tyrosinase. Inhibition of this enzyme is a target in the cosmetics industry, since it controls undesirable skin conditions such as hyperpigmentation due to the overproduction of melanin. Species of the Morus genus are known for the beneficial uses offered in different parts of its plants, including tyrosinase inhibition. Thus, this project aimed to study the inhibitory activity of tyrosinase by extracts from Morus nigra leaves as well as the characterization of its chromatographic profile and cytotoxicity in order to become a new therapeutic option from a natural source. M. nigra leaves were collected, pulverized, equally divided into five batches and the standardized extract was obtained by passive maceration. There was no significant difference between batches for total solids content, yield and moisture content, which shows good reproducibility of the extraction process. Tyrosinase enzymatic activity was determined for each batch, providing the percentage of enzyme inhibition and IC50 values obtained by constructing dose-response curves and compared to kojic acid, a well-known tyrosinase inhibitor. High inhibition of tyrosinase activity was observed (above 90% at 15.625 μg/mL). The obtained IC50 values ranged from 5.00 μg/mL ± 0.23 to 8.49 μg/mL ± 0.59 and were compared to kojic acid (3.37 μg/mL ± 0.65). High Performance Liquid Chromatography analysis revealed the presence of chlorogenic acid, rutin and, its major compound, isoquercitrin. The chromatographic method employed was validated according to ICH guidelines and the extract was standardized using these polyphenols as markers. Cytotoxicity, assessed by MTT assay, was not observed on murine melanomas, human keratinocytes and mouse fibroblasts in tyrosinase IC50 values. This study demonstrated the potential of M. nigra leaf extract as a promising whitening agent of natural source against skin

  2. Origin of adventitious roots in black walnut (Juglans nigra) softwood cuttings rooted under optimized conditions in a fog chamber

    Treesearch

    Micah E. Stevens; Paula M. Pijut

    2017-01-01

    High-quality black walnut (Juglans nigra L.) logs are of great economic value and are used in the manufacture of high-end products. Indigenous to the central hardwood region, black walnut has been commercially cultivated for many years, and genetic improvement and selections have resulted in superior timber genotypes. The recalcitrance of black...

  3. Antimalarial activity of 80 % methanolic extract of Brassica nigra (L.) Koch. (Brassicaceae) seeds against Plasmodium berghei infection in mice.

    PubMed

    Muluye, Abrham Belachew; Melese, Eshetie; Adinew, Getnet Mequanint

    2015-10-15

    Resistances to currently available drugs and insecticides, significant drug toxicities and costs and lack of vaccines currently complicated the treatment of malaria. A continued search for safe, effective and affordable plant-based antimalarial agents thus becomes crucial and vital in the face of these difficulties. The aim of the study was to evaluate the antimalarial activity of 80 % methanolic extract of the seeds of Brassica nigra against Plasmodium berghei infection in mice. Chloroquine sensitive Plasmodium berghei (ANKA strain) was used to test the antimalarial activity of the extract. In suppressive and prophylactic models, Swiss albino male mice were randomly grouped into five groups of five mice each. Group I mice were treated with the vehicle, group II, III and IV were treated with 100, 200, and 400 mg/kg of the extract, respectively and the last group (V) mice were treated with chloroquine (10 mg/kg). The level of parasitemia, survival time and variation in weight of mice were used to determine the antimalarial activity of the extract. Chemosuppressive activities produced by the extract of the seeds of Brassica nigra were 21.88, 50.00 (P < 0.01) and 53.13 % (P < 0.01), while the chemoprophylactic activities were 17.42, 21.21 and 53.79 % (P < 0.05) at 100, 200 and 400 mg/kg of the extract, respectively as compared to the negative control. Mice treated with 200 and 400 mg/kg extract were significantly (P < 0.05) lived longer and gained weight as compared to negative control in 4-day suppressive test. From this study, it can be concluded that the seed extract of Brassica nigra showed good chemosuppressive and moderate chemoprophylactic activities and the plant may contain biologically active principles which are relevant in the treatment and prophylaxis of malaria, thus supporting further studies of the plant for its active components.

  4. Functional analysis of embolism induced by air injection in Acer rubrum and Salix nigra

    PubMed Central

    Melcher, Peter J.; Zwieniecki, Maciej A.

    2013-01-01

    The goal of this study was to assess the effect of induced embolism with air injection treatments on the function of xylem in Acer rubrum L. and Salix nigra Marsh. Measurements made on mature trees of A. rubrum showed that pneumatic pressurization treatments that created a pressure gradient of 5.5 MPa across pit membranes (ΔPpit) had no effect on stomatal conductance or on branch-level sap flow. The same air injection treatments made on 3-year-old potted A. rubrum plants also had no effect on whole plant transpiration. A separate study made on mature A. rubrum trees showed that 3.0 and 5.5 MPa of ΔPpit values resulted in an immediate 100% loss in hydraulic conductance (PLC) in petioles. However, the observed change in PLC was short lived, and significant hydraulic recovery occurred within 5–10 min post air-pressurization treatments. Similar experiments conducted on S. nigra plants exposed to ΔPpit of 3 MPa resulted in a rapid decline in whole plant transpiration followed by leaf wilting and eventual plant death, showing that this species lacks the ability to recover from induced embolism. A survey that measured the effect of air-pressurization treatments on seven other species showed that some species are very sensitive to induction of embolism resulting in leaf wilting and branch death while others show minimal to no effect despite that in each case, the applied ΔPpit of 5.5 MPa significantly exceeded any native stress that these plants would experience naturally. PMID:24069025

  5. Functional analysis of embolism induced by air injection in Acer rubrum and Salix nigra.

    PubMed

    Melcher, Peter J; Zwieniecki, Maciej A

    2013-01-01

    The goal of this study was to assess the effect of induced embolism with air injection treatments on the function of xylem in Acer rubrum L. and Salix nigra Marsh. Measurements made on mature trees of A. rubrum showed that pneumatic pressurization treatments that created a pressure gradient of 5.5 MPa across pit membranes (ΔP pit) had no effect on stomatal conductance or on branch-level sap flow. The same air injection treatments made on 3-year-old potted A. rubrum plants also had no effect on whole plant transpiration. A separate study made on mature A. rubrum trees showed that 3.0 and 5.5 MPa of ΔP pit values resulted in an immediate 100% loss in hydraulic conductance (PLC) in petioles. However, the observed change in PLC was short lived, and significant hydraulic recovery occurred within 5-10 min post air-pressurization treatments. Similar experiments conducted on S. nigra plants exposed to ΔP pit of 3 MPa resulted in a rapid decline in whole plant transpiration followed by leaf wilting and eventual plant death, showing that this species lacks the ability to recover from induced embolism. A survey that measured the effect of air-pressurization treatments on seven other species showed that some species are very sensitive to induction of embolism resulting in leaf wilting and branch death while others show minimal to no effect despite that in each case, the applied ΔP pit of 5.5 MPa significantly exceeded any native stress that these plants would experience naturally.

  6. Nigrothalamic projections in the monkey demonstrated by autoradiographic technics.

    PubMed

    Carpenter, M B; Nakano, K; Kim, R

    1976-02-15

    In spite of repeated demonstrations by degeneration technics, nigrothalamic fibers have been regarded with some skepticism. Attempts were made to trace nigral efferent projections in the monkey by autoradiographic technics. Tritiated amino acids (L-leucine, L-lysine and L-proline), injected into portions of the substantia nigra (SN), labeled cells in four regions, designated as, (1) rostrolateral, (2) caudolateral, (3) rostromedial and (4) central. Rostrolateral nigral neurons transported radioactive label preferentially and abundantly to thalamic nuclei; localized isotope was found in parts of three thalamic nuclei, the medial part of the ventral lateral nucleus (VLm), the magnocellular part of the ventral anterior nucleus (VAmc), and the paralaminar part of the dorsomedial nucleus (DMpl)9 Lateral neurons in the caudal half of the SN transmitted radioactive label to the same thalamic nuclei as rostrolateral nigral neuron. Isotope transported to portions of the striatum was modest and localized. Radioactive label taken up by large cells in the caudal third of the SN was transported to portions of the striatum, but not to thalamic nuclei. Labeled nigral neurons in the medial two-thirds of the rostral half of the SN, and in the middle third of the central part of the SN, transported the label mainly to parts of the caudate nucleus and putamen. In these animals modest radioactive label was seen in VLm and VAmc, but not in other thalamic nuclei. There was no evidence that nigral neurons project to the subthalamic nucleus. No radioactive transport from nigral neurons was detected in the superior colliculus, the midbrain tegmentum, or the red nucleus, and none was transported to more caudal brain stem nuclei. Nigrothalamic fibers arise particularly from cells in rostral and lateral parts of the substantia nigra. While some cells in other parts of the nigra project to thalamic nuclei, these appear scattered and less numerous. Large cells in caudal parts of the SN do not

  7. Sapflow of hybrid poplar (Populus nigra L. x P. maximowiczii A. Henry 'NM6') during phytoremediation of landfill leachate

    Treesearch

    Ronald S., Jr. Zalesny; Adam H. Wiese; Edmund O. Bauer; Don E. Riemenschneider

    2006-01-01

    Poplars are ideal for phytoremediation because of their high water usage, fast growth, and deep root systems. We measured in 2002 and 2003 the sapflow of hybrid poplars (Populus nigra L. x P. maximowiczii A. Henry 'NM6') planted in 1999 for phytoremediation of a landfill in Rhinelander, WI, USA (45.6?N, 89.4?W).

  8. Mesencephalic Dopamine Neuron Number and Tyrosine Hydroxylase Content: Genetic Control and Candidate Genes

    PubMed Central

    Vadasz, Csaba; Smiley, John F.; Figarsky, Khadija; Saito, Mariko; Toth, Reka; Gyetvai, Beatrix M.; Oros, Melinda; Kovacs, Krisztina K.; Mohan, Panaiyur; Wang, Ray

    2007-01-01

    The mesotelencephalic dopamine system shows substantial genetic variation which fundamentally affects normal and pathological behaviors related to motor function, motivation, and learning. Our earlier radioenzyme assay studies demonstrated significantly higher activity of tyrosine hydroxylase (TH), the first and rate limiting enzyme in the biosynthesis of catecholamine neurotransmitters, in the substantia nigra – ventral tegmental area of BALB/cJ mice in comparison with that of C57BL/6ByJ mice. Here, using quantitative immunoblotting and immunocytochemistry, we tested the hypothesis that mesencephalic TH protein content and number of nigral TH-positive neurons show strain-dependent differences in C57BL/6ByJ and BALB/cJ parallel to those observed in the TH activity studies. Immunoblotting experiments detected significantly higher mesencephalic TH protein content in BALB/cJ in comparison to C57BL/6ByJ (p<0.05). Immunocytochemical studies demonstrated that the number of TH-positive cells in substantia nigra was 31.3% higher in BALB/cJ than that in C57BL/6ByJ (p<0.01), while the average dopamine neuron volume was not significantly different. In a search for candidate genes that modulate TH content and the size of mesencephalic dopamine neuron populations we also studied near-isogenic mouse sublines derived from the C57BL/6ByJ and BALB/cJ progenitor strains. A whole-genome scan with 768 single nucleotide polymorphism markers indicated that two sublines, C4A6/N and C4A6/B, were genetically very similar (98.3%). We found significantly higher mesencephalic tyrosine hydroxylase (TH) protein content in C4A6/B in comparison to C4A6/N (p=0.01), and a tendency for higher number of dopamine neurons in the substantia nigra in C4A6/B in comparison to C4A6/N, which, however, did not reach statistical significance. To identify the genetic source of the TH content difference we analyzed the SNP genotype data of the whole-genome scan, and detected two small differential chromosome

  9. Potential species replacements for black ash (Fraxinus nigra) at the confluence of two threats: Emerald ash borer and a changing climate

    Treesearch

    Louis Iverson; Kathleen S. Knight; Anantha Prasad; Daniel A. Herms; Stephen Matthews; Matthew Peters; Annemarie Smith; Diane M. Hartzler; Robert Long; John Almendinger

    2015-01-01

    The emerald ash borer (Agrilus planipennis; EAB) is causing widespread mortality of ash (Fraxinus spp.) and climate change is altering habitats of tree species throughout large portions of North America. Black ash (F. nigra), a moist-soil species common in the Northwoods of Minnesota, Wisconsin, and...

  10. Long-term population survey of the Sulawesi black macaques (Macaca nigra) at Tangkoko Nature Reserve, North Sulawesi, Indonesia.

    PubMed

    Kyes, Randall C; Iskandar, Entang; Onibala, Jane; Paputungan, Umar; Laatung, Sylvia; Huettmann, Falk

    2013-01-01

    The Sulawesi black macaque (Macaca nigra) population at Tangkoko Nature Reserve in North Sulawesi, Indonesia has been the focus of periodic study for over 30 years. The population has shown considerable decline during much of that time. Here we present the results of a long-term population survey of the Tangkoko M. nigra, conducted over the past decade, to provide updated information and on-going assessment of the population. Line-transect sampling was conducted annually from 1999 to 2002 and 2005 to 2011 along the same transect during a 2- to 3-week survey period. Although further decline in the population was observed at the outset of the survey, over the subsequent 12-year period we have seen stability in the population parameters with evidence of modest increases in both group and population density. During the 1999-2002 survey periods, there was a mean group density of 3.6 groups/km(2) and a mean population density of 39.8 individuals/km(2) . During 2005-2011, mean group density increased to 3.8 groups/km(2) and mean population density was 51.4 individuals/km(2) . The 2011 survey data indicated an estimated group density of 4.3 groups/km(2) and a population density of 61.5 individuals/km(2) . Given that our transect was located in the core of the Tangkoko reserve, our density estimates should be limited to that area of the reserve. One explanation for the apparent stabilization of the population may be tied to the increasing and sustained number of training and research programs being conducted at the reserve. This collective effort by local and international groups may be helping to reduce illegal activity in the reserve (i.e., hunting and habitat destruction) and generate greater awareness of this critically endangered species. Without the continued vigilance afforded by the existing research and training programs and the support and involvement of the local people, the M. nigra at the Tangkoko Nature Reserve will likely face further decline. © 2012 Wiley

  11. Seasonal Fluctuations of Lectins in Barks of Elderberry (Sambucus nigra) and Black Locust (Robinia pseudoacacia) 1

    PubMed Central

    Nsimba-Lubaki, Makuta; Peumans, Willy J.

    1986-01-01

    Elderberry (Sambucus nigra) and black locust (Robinia pseudoacacia) agglutinins, which are abundantly present in the bark of both species, display seasonal fluctuations with regard to their content in this tissue. These seasonal changes result apparently from a circa-annual rhythm of lectin accumulation and depletion during autumn and spring, respectively. Because the bark of trees can be considered as a type of vegetative storage tissue, the results suggest that bark lectins behave as typical storage proteins. Images Fig. 4 PMID:16664696

  12. Conserved microstructure of the Brassica B Genome of Brassica nigra in relation to homologous regions of Arabidopsis thaliana, B. rapa and B. oleracea

    PubMed Central

    2013-01-01

    Background The Brassica B genome is known to carry several important traits, yet there has been limited analyses of its underlying genome structure, especially in comparison to the closely related A and C genomes. A bacterial artificial chromosome (BAC) library of Brassica nigra was developed and screened with 17 genes from a 222 kb region of A. thaliana that had been well characterised in both the Brassica A and C genomes. Results Fingerprinting of 483 apparently non-redundant clones defined physical contigs for the corresponding regions in B. nigra. The target region is duplicated in A. thaliana and six homologous contigs were found in B. nigra resulting from the whole genome triplication event shared by the Brassiceae tribe. BACs representative of each region were sequenced to elucidate the level of microscale rearrangements across the Brassica species divide. Conclusions Although the B genome species separated from the A/C lineage some 6 Mya, comparisons between the three paleopolyploid Brassica genomes revealed extensive conservation of gene content and sequence identity. The level of fractionation or gene loss varied across genomes and genomic regions; however, the greatest loss of genes was observed to be common to all three genomes. One large-scale chromosomal rearrangement differentiated the B genome suggesting such events could contribute to the lack of recombination observed between B genome species and those of the closely related A/C lineage. PMID:23586706

  13. Short-term effects of prescribed burning on litterfall biomass in mixed stands of Pinus nigra and Pinus pinaster and pure stands of Pinus nigra in the Cuenca Mountains (Central-Eastern Spain).

    PubMed

    Espinosa, J; Madrigal, J; De La Cruz, A C; Guijarro, M; Jimenez, E; Hernando, C

    2018-03-15

    Fire severity, defined as the magnitude of fire effects in an ecosystem, is a key factor to consider in planning management strategies for protecting forests against fire. Although prescribed burning has been used as a fuel reduction tool in forest ecosystems, it is quite limited in the Mediterranean region. Furthermore, little is known about how tree crowns are affected by prescribed underburning aimed at reducing fire severity in conifer stands. As part of an ongoing study to assess the effects of prescribed burning on the tree canopy, litterfall is currently being monitored in a network of experimental plots located in mixed (Pinus nigra and Pinus pinaster) and pure (P. nigra) conifer stands in the Cuenca Mountains (Castilla La Mancha, Spain). A total of 12 study plots (30m×30m) were established in a completely randomized experimental design to determine the effect of burning, with 2 treatments: no burning (control) and burning (i.e. with three replicate plots for each treatment and site). Burning was conducted in May 2016. In each plot, 8 litterfall collectors were installed at regular intervals, according to international protocols (ICP Forests), and all biomass falling into the collectors is being monitored monthly. The specific objective of this study is to assess how prescribed burning affects the rate of generation of foliar and non-foliar litterfall biomass due to the fire. In addition, the Leaf Area Index was estimated before burning and one year later to verify possible changes in the structure of the stands. This information could be used to help minimize the negative impacts of prescribed underburning on litterfall. To our knowledge, this study represents the first attempt to evaluate the effect of prescribed burning on litterfall biomass in Europe. Copyright © 2017 Elsevier B.V. All rights reserved.

  14. SLP-2 interacts with Parkin in mitochondria and prevents mitochondrial dysfunction in Parkin-deficient human iPSC-derived neurons and Drosophila.

    PubMed

    Zanon, Alessandra; Kalvakuri, Sreehari; Rakovic, Aleksandar; Foco, Luisa; Guida, Marianna; Schwienbacher, Christine; Serafin, Alice; Rudolph, Franziska; Trilck, Michaela; Grünewald, Anne; Stanslowsky, Nancy; Wegner, Florian; Giorgio, Valentina; Lavdas, Alexandros A; Bodmer, Rolf; Pramstaller, Peter P; Klein, Christine; Hicks, Andrew A; Pichler, Irene; Seibler, Philip

    2017-07-01

    Mutations in the Parkin gene (PARK2) have been linked to a recessive form of Parkinson's disease (PD) characterized by the loss of dopaminergic neurons in the substantia nigra. Deficiencies of mitochondrial respiratory chain complex I activity have been observed in the substantia nigra of PD patients, and loss of Parkin results in the reduction of complex I activity shown in various cell and animal models. Using co-immunoprecipitation and proximity ligation assays on endogenous proteins, we demonstrate that Parkin interacts with mitochondrial Stomatin-like protein 2 (SLP-2), which also binds the mitochondrial lipid cardiolipin and functions in the assembly of respiratory chain proteins. SH-SY5Y cells with a stable knockdown of Parkin or SLP-2, as well as induced pluripotent stem cell-derived neurons from Parkin mutation carriers, showed decreased complex I activity and altered mitochondrial network morphology. Importantly, induced expression of SLP-2 corrected for these mitochondrial alterations caused by reduced Parkin function in these cells. In-vivo Drosophila studies showed a genetic interaction of Parkin and SLP-2, and further, tissue-specific or global overexpression of SLP-2 transgenes rescued parkin mutant phenotypes, in particular loss of dopaminergic neurons, mitochondrial network structure, reduced ATP production, and flight and motor dysfunction. The physical and genetic interaction between Parkin and SLP-2 and the compensatory potential of SLP-2 suggest a functional epistatic relationship to Parkin and a protective role of SLP-2 in neurons. This finding places further emphasis on the significance of Parkin for the maintenance of mitochondrial function in neurons and provides a novel target for therapeutic strategies. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  15. A preliminary investigation of Stroop-related intrinsic connectivity in cocaine dependence: Associations with treatment outcomes

    PubMed Central

    Mitchell, Marci R.; Balodis, Iris M.; DeVito, Elise E.; Lacadie, Cheryl M.; Yeston, Jon; Scheinost, Dustin; Constable, R. Todd; Carroll, Kathleen M.; Potenza, Marc N.

    2013-01-01

    Background Cocaine-dependent individuals demonstrate neural and behavioral differences compared to healthy comparison subjects when performing the Stroop color-word inference test. Stroop measures also relate to treatment outcome for cocaine dependence. Intrinsic connectivity analyses assess the extent to which task-related regional brain activations are related to each other in the absence of defining a priori regions-of-interest. Objective This study examined: 1) the extent to which cocaine-dependent and non-addicted individuals differed on measures of intrinsic connectivity during fMRI Stroop performance; and, 2) the relationships between fMRI Stroop intrinsic connectivity and treatment outcome in cocaine dependence. Methods Sixteen treatment-seeking cocaine-dependent patients and matched non-addicted comparison subjects completed an fMRI Stroop task. Between-group differences in intrinsic connectivity were assessed and related to self-reported and urine-toxicology-based cocaine-abstinence measures. Results Cocaine-dependent patients vs. comparison subjects showed less intrinsic connectivity in cortical and sub-cortical regions. When adjusting for individual degree of intrinsic connectivity, cocaine-dependent vs. comparison subjects showed relatively greater intrinsic connectivity in the ventral striatum, putamen, inferior frontal gyrus, anterior insula, thalamus, and substantia nigra. Non-mean-adjusted intrinsic-connectivity measures in the midbrain, thalamus, ventral striatum, substantia nigra, insula, and hippocampus negatively correlated with measures of cocaine abstinence. Conclusion The diminished intrinsic connectivity in cocaine-dependent vs. comparison subjects suggests poorer communication across brain regions during cognitive-control processes. In mean-adjusted analyses, the cocaine-dependent group displayed relatively greater Stroop-related connectivity in regions implicated in motivational processes in addictions. The relationships between treatment

  16. Spatiotemporal expression of MANF in the developing rat brain.

    PubMed

    Wang, Haiping; Ke, Zunji; Alimov, Alexander; Xu, Mei; Frank, Jacqueline A; Fang, Shengyun; Luo, Jia

    2014-01-01

    Mesencephalic astrocyte-derived neurotrophic factor (MANF) is an evolutionarily conserved neurotrophic factor which exhibited neuroprotective properties. Recent studies suggested that MANF may play a role in the neural development of Drosophila and zebra fishes. In this study, we investigated the spatiotemporal expression of MANF in the brain of postnatal and adult rats. MANF expression appeared wide spread and mainly localized in neurons. In the cerebral cortex, neurons in layer IV and VI displayed particularly strong MANF immunoreactivity. In the hippocampus, intensive MANF expression was observed throughout the subfields of Cornu Amonis (CA1, CA2, and CA3) and the granular layer of the dentate gyrus (DG). In the substantia nigra, high MANF expression was shown in the substantia nigra pars compacta (SNpc). In the thalamus, the anterodorsal thalamic nucleus (ADTN) exhibited the highest MANF immunoreactivity. In the hypothalamus, intensive MANF immunoreactivity was shown in the supraoptic nucleus (SON) and tuberomammillary nucleus (TMN). In the cerebellum, MANF was localized in the external germinal layer (EGL), Purkinje cell layer (PCL), internal granule layer (IGL) and the deep cerebellar nuclei (DCN). We examined the developmental expression of MANF on postnatal day (PD) 3, 5, 7, 9, 15, 21, 30 and adulthood. In general, the levels of MANF were high in the early PDs (PD3 and PD5), and declined gradually as the brain matured; MANF expression in the adult brain was the lowest among all time points examined. However, in some structures, such as PCL, IGL, SON, TMN and locus coeruleus (LC), high expression of MANF sustained throughout the postnatal period and persisted into adulthood. Our results indicated that MANF was developmentally regulated and may play a role in the maturation of the central nervous system (CNS).

  17. Multi-Atlas Based Segmentation of Brainstem Nuclei from MR Images by Deep Hyper-Graph Learning.

    PubMed

    Dong, Pei; Guo, Yangrong; Gao, Yue; Liang, Peipeng; Shi, Yonghong; Wang, Qian; Shen, Dinggang; Wu, Guorong

    2016-10-01

    Accurate segmentation of brainstem nuclei (red nucleus and substantia nigra) is very important in various neuroimaging applications such as deep brain stimulation and the investigation of imaging biomarkers for Parkinson's disease (PD). Due to iron deposition during aging, image contrast in the brainstem is very low in Magnetic Resonance (MR) images. Hence, the ambiguity of patch-wise similarity makes the recently successful multi-atlas patch-based label fusion methods have difficulty to perform as competitive as segmenting cortical and sub-cortical regions from MR images. To address this challenge, we propose a novel multi-atlas brainstem nuclei segmentation method using deep hyper-graph learning. Specifically, we achieve this goal in three-fold. First , we employ hyper-graph to combine the advantage of maintaining spatial coherence from graph-based segmentation approaches and the benefit of harnessing population priors from multi-atlas based framework. Second , besides using low-level image appearance, we also extract high-level context features to measure the complex patch-wise relationship. Since the context features are calculated on a tentatively estimated label probability map, we eventually turn our hyper-graph learning based label propagation into a deep and self-refining model. Third , since anatomical labels on some voxels (usually located in uniform regions) can be identified much more reliably than other voxels (usually located at the boundary between two regions), we allow these reliable voxels to propagate their labels to the nearby difficult-to-label voxels. Such hierarchical strategy makes our proposed label fusion method deep and dynamic. We evaluate our proposed label fusion method in segmenting substantia nigra (SN) and red nucleus (RN) from 3.0 T MR images, where our proposed method achieves significant improvement over the state-of-the-art label fusion methods.

  18. Spatiotemporal Expression of MANF in the Developing Rat Brain

    PubMed Central

    Wang, Haiping; Ke, Zunji; Alimov, Alexander; Xu, Mei; Frank, Jacqueline A.; Fang, Shengyun; Luo, Jia

    2014-01-01

    Mesencephalic astrocyte-derived neurotrophic factor (MANF) is an evolutionarily conserved neurotrophic factor which exhibited neuroprotective properties. Recent studies suggested that MANF may play a role in the neural development of Drosophila and zebra fishes. In this study, we investigated the spatiotemporal expression of MANF in the brain of postnatal and adult rats. MANF expression appeared wide spread and mainly localized in neurons. In the cerebral cortex, neurons in layer IV and VI displayed particularly strong MANF immunoreactivity. In the hippocampus, intensive MANF expression was observed throughout the subfields of Cornu Amonis (CA1, CA2, and CA3) and the granular layer of the dentate gyrus (DG). In the substantia nigra, high MANF expression was shown in the substantia nigra pars compacta (SNpc). In the thalamus, the anterodorsal thalamic nucleus (ADTN) exhibited the highest MANF immunoreactivity. In the hypothalamus, intensive MANF immunoreactivity was shown in the supraoptic nucleus (SON) and tuberomammillary nucleus (TMN). In the cerebellum, MANF was localized in the external germinal layer (EGL), Purkinje cell layer (PCL), internal granule layer (IGL) and the deep cerebellar nuclei (DCN). We examined the developmental expression of MANF on postnatal day (PD) 3, 5, 7, 9, 15, 21, 30 and adulthood. In general, the levels of MANF were high in the early PDs (PD3 and PD5), and declined gradually as the brain matured; MANF expression in the adult brain was the lowest among all time points examined. However, in some structures, such as PCL, IGL, SON, TMN and locus coeruleus (LC), high expression of MANF sustained throughout the postnatal period and persisted into adulthood. Our results indicated that MANF was developmentally regulated and may play a role in the maturation of the central nervous system (CNS). PMID:24587361

  19. Down-regulation of natural resistance-associated macrophage protein-1 (Nramp1) is associated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)/1-methyl-4-phenylpyridinium (MPP+ )-induced α-synuclein accumulation and neurotoxicity.

    PubMed

    Wu, K-C; Liou, H-H; Lee, C-Y; Lin, C-J

    2018-04-21

    The accumulation of α-synuclein is a hallmark in the pathogenesis of Parkinson's disease (PD). Natural resistance-associated macrophage protein-1 (Nramp1) was previously shown to contribute to the degradation of extracellular α-synuclein in microglia under conditions of iron overload. This study was aimed at investigating the role of Nramp1 in α-synuclein pathology in the neurone under 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)/1-methyl-4-phenylpyridinium (MPP + ) treatment. The expression of Nramp1 and pathological features (including iron and α-synuclein accumulation) were examined in the dopaminergic neurones of humans (with and without PD) and of mice [with and without receiving chronic MPTP intoxication]. The effects of Nramp1 expression on low-dose MPP + -induced α-synuclein expression and neurotoxicity were determined in human dopaminergic neuroblastoma SH-SY5Y cells. Similar to the findings in the substantia nigra of human PD, lower expression of Nramp1 but higher levels of iron and α-synuclein were identified in the dopaminergic neurones of mice receiving chronic MPTP intoxication, compared to controls. In parallel to the loss of dopaminergic neurones, the numbers of glial fibrillary acidic protein- and ionized calcium-binding adapter molecule-1-positive cells were significantly increased in the substantia nigra of MPTP-treated mice. Likewise, in human neuroblastoma SH-SY5Y cells exposed to low-dose MPP + , Nramp1 expression and cathepsin D activity were decreased, along with an increase in α-synuclein protein expression and aggregation. Overexpression of functional Nramp1 restored cathepsin D activity and attenuated α-synuclein up-regulation and neuronal cell death caused by MPP + treatment. These data suggest that the neuronal expression of Nramp1 is important for protecting against the development of MPTP/MPP + -induced α-synuclein pathology and neurotoxicity. © 2018 British Neuropathological Society.

  20. Design and evaluation of mucoadhesive microemulsion for neuroprotective effect of ibuprofen following intranasal route in the MPTP mice model.

    PubMed

    Mandal, Surjyanarayan; Mandal, Snigdha Das; Chuttani, Krishna; Sawant, Krutika K; Subudhi, Bharat Bhushan

    2016-08-01

    The present study is to investigate the neuroprotective effect of ibuprofen by intranasal administration of mucoadhesive microemulsion (MMEI) against inflammation-mediated by dopaminergic neurodegeneration in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of Parkinson's disease (PD). Ibuprofen-loaded polycarbophil-based MMEI was developed by using response surface methodology (RSM). Ibuprofen with dose of 2.86 mg/kg/day was administered intranasally to male C57BL/6 mice for two consecutive weeks which were pre-treated with four intraperitoneal injections of MPTP (20 mg/kg of body weight) at 2 h intervals. Immunohistochemistry was performed. Optimal MMEI was stable and non-ciliotoxic with 66.29 ± 4.15 nm as average globule size and -20.9 ± 3.98 mV as zeta potential. PDI value and transmission electron microscopy result showed the narrow globule size distribution of MMEI. The result showed that all three independent variables had a significant effect (p < 0.05) on the responses. Rota-rod and open-field test findings revealed the significant improvement in motor performance and gross behavioral activity of the mice. The results from in vivo study and immunohistochemistry showed that nasal administration of Ibuprofen significantly reduced the MPTP-mediated dopamine depletion. Furthermore TH neurons count in the substantia nigra and the density of striatal dopaminergic nerve terminals were found to be significant higher for ibuprofen treated groups. Findings of the investigation revealed that Ibuprofen through developed MMEI was shown to protect neurons against MPTP-induced injury in the Substantia nigra pars compacta (SNpc) and striatum and hence, could be a promising approach for brain targeting of Ibuprofen through intranasal route to treat PD.