Vascular endothelial growth factor is upregulated by l-dopa in the parkinsonian brain: implications for the development of dyskinesia

PubMed Central

Francardo, Veronica; Lindgren, Hanna S.; Sillivan, Stephanie E.; O’Sullivan, Sean S.; Luksik, Andrew S.; Vassoler, Fair M.; Lees, Andrew J.; Konradi, Christine

2011-01-01

Angiogenesis and increased permeability of the blood–brain barrier have been reported to occur in animal models of Parkinson’s disease and l-dopa-induced dyskinesia, but the significance of these phenomena has remained unclear. Using a validated rat model of l-dopa-induced dyskinesia, this study demonstrates that chronic treatment with l-dopa dose dependently induces the expression of vascular endothelial growth factor in the basal ganglia nuclei. Vascular endothelial growth factor was abundantly expressed in astrocytes and astrocytic processes in the proximity of blood vessels. When co-administered with l-dopa, a small molecule inhibitor of vascular endothelial growth factor signalling significantly attenuated the development of dyskinesia and completely blocked the angiogenic response and associated increase in blood–brain barrier permeability induced by the treatment. The occurrence of angiogenesis and vascular endothelial growth factor upregulation was verified in post-mortem basal ganglia tissue from patients with Parkinson’s disease with a history of dyskinesia, who exhibited increased microvascular density, microvascular nestin expression and an upregulation of vascular endothelial growth factor messenger ribonucleic acid. These congruent findings in the rat model and human patients indicate that vascular endothelial growth factor is implicated in the pathophysiology of l-dopa-induced dyskinesia and emphasize an involvement of the microvascular compartment in the adverse effects of l-dopa pharmacotherapy in Parkinson’s disease. PMID:21771855

Studies on the role of dopamine in the degeneration of 5-HT nerve endings in the brain of Dark Agouti rats following 3,4-methylenedioxymethamphetamine (MDMA or ‘ecstasy') administration

PubMed Central

Colado, M I; O'Shea, E; Granados, R; Esteban, B; Martín, A B; Green, A R

1999-01-01

We investigated whether dopamine plays a role in the neurodegeneration of 5-hydroxytryptamine (5-HT) nerve endings occurring in Dark Agouti rat brain after 3,4-methylenedioxymethamphetamine (MDMA or ‘ecstasy') administration. Haloperidol (2 mg kg−1 i.p.) injected 5 min prior and 55 min post MDMA (15 mg kg−1 i.p.) abolished the acute MDMA-induced hyperthermia and attenuated the neurotoxic loss of 5-HT 7 days later. When the rectal temperature of MDMA+haloperidol treated rats was kept elevated, this protective effect was marginal. MDMA (15 mg kg−1) increased the dopamine concentration in the dialysate from a striatal microdialysis probe by 800%. L-DOPA (25 mg kg−1 i.p., plus benserazide, 6.25 mg kg−1 i.p.) injected 2 h after MDMA (15 mg kg−1) enhanced the increase in dopamine in the dialysate, but subsequent neurodegeneration was unaltered. L-DOPA (25 mg kg−1) injected before a sub-toxic dose of MDMA (5 mg kg−1) failed to induce neurodegeneration. The MDMA-induced increase in free radical formation in the hippocampus (indicated by increased 2,3- and 2,5-dihydroxybenzoic acid in a microdialysis probe perfused with salicylic acid) was unaltered by L-DOPA. The neuroprotective drug clomethiazole (50 mg kg−1 i.p.) did not influence the MDMA-induced increase in extracellular dopamine. These data suggest that previous observations on the protective effect of haloperidol and potentiating effect of L-DOPA on MDMA-induced neurodegeneration may have resulted from effects on MDMA-induced hyperthermia. The increased extracellular dopamine concentration following MDMA may result from effects of MDMA on dopamine re-uptake, monoamine oxidase and 5-HT release rather than an ‘amphetamine-like' action on dopamine release, thus explaining why the drug does not induce degeneration of dopamine nerve endings. PMID:10193771

Single or combined treatment with L-DOPA and quinpirole differentially modulate expression and phosphorylation of key regulatory kinases in neuroblastoma cells.

PubMed

Fuzzati-Armentero, Marie Therese; Ghezzi, Cristina; Nisticò, Robert; Oda, Adriano; Blandini, Fabio

2013-09-27

In the past decades, the clinical use of dopamine agonists has expanded from adjunct therapy in patients with a deteriorating response to L-3,4-dihydroxyphenylalanine (L-DOPA) to monotherapy for the treatment of early PD. Dopamine agonists provide their antiparkinsonian benefit through stimulation of brain postsynaptic type 2 dopamine receptors that exert their effect through classical cAMP-dependent mechanisms, as well as cAMP-independent cellular signaling cascades, including the Akt/glycogen synthase kinase 3 (GSK3) pathway. Alterations of Akt/GSK3 have been observed and may contribute to the neurodegenerative processes and the development of L-DOPA-induced dyskinesia. The effects L-DOPA and quinpirole, a dopamine agonist, on the two key regulatory kinases, Akt and GSK3, were evaluated in neuroblastoma cell line. L-DOPA and dopamine agonist dose-dependently and differentially modulated Akt and GSK3 expression and phosphorylation when added alone or combined. The combined treatment inverted or potentiated the modulatory properties of the single compound. The drug- and concentration-dependent balance of dopamine receptor stimulation over auto-oxidation may distinctively modulate GSK3 isoforms and Akt. Our results indicate that particular attention must be given to drug concentration and combination when multiple therapies are applied for the clinical treatment of PD patients. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Dopaminergic modulation of hemodynamic signal variability and the functional connectome during cognitive performance.

PubMed

Alavash, Mohsen; Lim, Sung-Joo; Thiel, Christiane; Sehm, Bernhard; Deserno, Lorenz; Obleser, Jonas

2018-05-15

Dopamine underlies important aspects of cognition, and has been suggested to boost cognitive performance. However, how dopamine modulates the large-scale cortical dynamics during cognitive performance has remained elusive. Using functional MRI during a working memory task in healthy young human listeners, we investigated the effect of levodopa (l-dopa) on two aspects of cortical dynamics, blood oxygen-level-dependent (BOLD) signal variability and the functional connectome of large-scale cortical networks. We here show that enhanced dopaminergic signaling modulates the two potentially interrelated aspects of large-scale cortical dynamics during cognitive performance, and the degree of these modulations is able to explain inter-individual differences in l-dopa-induced behavioral benefits. Relative to placebo, l-dopa increased BOLD signal variability in task-relevant temporal, inferior frontal, parietal and cingulate regions. On the connectome level, however, l-dopa diminished functional integration across temporal and cingulo-opercular regions. This hypo-integration was expressed as a reduction in network efficiency and modularity in more than two thirds of the participants and to different degrees. Hypo-integration co-occurred with relative hyper-connectivity in paracentral lobule and precuneus, as well as posterior putamen. Both, l-dopa-induced BOLD signal variability modulation and functional connectome modulations proved predictive of an individual's l-dopa-induced benefits in behavioral performance, namely response speed and perceptual sensitivity. Lastly, l-dopa-induced modulations of BOLD signal variability were correlated with l-dopa-induced modulation of nodal connectivity and network efficiency. Our findings underline the role of dopamine in maintaining the dynamic range of, and communication between, cortical systems, and their explanatory power for inter-individual differences in benefits from dopamine during cognitive performance. Copyright © 2018 Elsevier Inc. All rights reserved.

Pathophysiology of L-dopa-induced motor and non-motor complications in Parkinson's disease.

PubMed

Bastide, Matthieu F; Meissner, Wassilios G; Picconi, Barbara; Fasano, Stefania; Fernagut, Pierre-Olivier; Feyder, Michael; Francardo, Veronica; Alcacer, Cristina; Ding, Yunmin; Brambilla, Riccardo; Fisone, Gilberto; Jon Stoessl, A; Bourdenx, Mathieu; Engeln, Michel; Navailles, Sylvia; De Deurwaerdère, Philippe; Ko, Wai Kin D; Simola, Nicola; Morelli, Micaela; Groc, Laurent; Rodriguez, Maria-Cruz; Gurevich, Eugenia V; Quik, Maryka; Morari, Michele; Mellone, Manuela; Gardoni, Fabrizio; Tronci, Elisabetta; Guehl, Dominique; Tison, François; Crossman, Alan R; Kang, Un Jung; Steece-Collier, Kathy; Fox, Susan; Carta, Manolo; Angela Cenci, M; Bézard, Erwan

2015-09-01

Involuntary movements, or dyskinesia, represent a debilitating complication of levodopa (L-dopa) therapy for Parkinson's disease (PD). L-dopa-induced dyskinesia (LID) are ultimately experienced by the vast majority of patients. In addition, psychiatric conditions often manifested as compulsive behaviours, are emerging as a serious problem in the management of L-dopa therapy. The present review attempts to provide an overview of our current understanding of dyskinesia and other L-dopa-induced dysfunctions, a field that dramatically evolved in the past twenty years. In view of the extensive literature on LID, there appeared a critical need to re-frame the concepts, to highlight the most suitable models, to review the central nervous system (CNS) circuitry that may be involved, and to propose a pathophysiological framework was timely and necessary. An updated review to clarify our understanding of LID and other L-dopa-related side effects was therefore timely and necessary. This review should help in the development of novel therapeutic strategies aimed at preventing the generation of dyskinetic symptoms. Copyright © 2015 Elsevier Ltd. All rights reserved.

Assessment of oxidative stress and activities of antioxidant enzymes depicts the negative systemic effect of iron-containing fertilizers and plant phenolic compounds in the desert locust.

PubMed

Renault, David; Dorrah, Moataza A; Mohamed, Amr A; Abdelfattah, Eman A; Bassal, Taha T M

2016-11-01

For herbivore insects, digesting can be somewhat challenging, as the defense mechanisms evolved by plants, including the release of phenolics like the non-protein amino acid L-3,4-dihydroxyphenylalanine (L-DOPA), can cause fitness costs. In addition, industrial and agricultural activities have elevated the amounts of iron that can be found in nature and more particularly FeSO 4 that is used as fertilizer. Traces of iron can enhance the auto-oxidation of L-DOPA, in turn, generating reactive oxygen species (ROS) and consequently oxidative stress in insects. We examined the effects of the ion Fe 2+ (as FeSO 4 ) and L-DOPA on fifth instars of the desert locust Schistocerca gregaria. We measured the level of oxidative damage occurring to macromolecules (proteins and lipids) from midgut and thoracic tissues and assessed the activities of responsive antioxidant enzymes. Injected L-DOPA and redox-active metal iron generated ROS which caused oxidative damages to proteins and lipids to S. gregaria. The protein carbonyls and lipid peroxides present in tissue homogenates were elevated in treated insects. No synergism was observed when L-DOPA was co-injected with Fe 2+ . K m values of superoxide dismutase (SOD), glutathione reductase (GR), and glutathione peroxidase (GPx) were 4.3, 2.6, and 4.0 mM in thoracic muscles and 5.00, 2.43, and 1.66 mM in whole midgut for SOD, GR, and GPx, respectively, and 8.3 and 3.43 M for catalase (CAT) in the two tissues, respectively. These results suggest higher affinities of GPx and CAT to H 2 O 2 in midgut than in muscles. The time-course changes in activities of antioxidant enzymes and amounts of protein carbonyls and lipid peroxides showed fluctuating patterns, suggesting complex interactions among macromolecules, L-DOPA and FeSO 4 , and their degradation products. Our results demonstrated the stressful effects of L-DOPA and FeSO 4 , proving that iron-containing fertilizers are pollutants that can strongly affect S. gregaria.

Nociceptive Response to L-DOPA-Induced Dyskinesia in Hemiparkinsonian Rats.

PubMed

Nascimento, G C; Bariotto-Dos-Santos, K; Leite-Panissi, C R A; Del-Bel, E A; Bortolanza, M

2018-04-02

Non-motor symptoms are increasingly identified to present clinical and diagnostic importance for Parkinson's disease (PD). The multifactorial origin of pain in PD makes this symptom of great complexity. The dopamine precursor, L-DOPA (L-3,4-dihydroxyphenylalanine), the classic therapy for PD, seems to be effective in pain threshold; however, there are no studies correlating L-DOPA-induced dyskinesia (LID) and nociception development in experimental Parkinsonism. Here, we first investigated nociceptive responses in a 6-hydroxydopamine (6-OHDA)-lesioned rat model of Parkinson's disease to a hind paw-induced persistent inflammation. Further, the effect of L-DOPA on nociception behavior at different times of treatment was investigated. Pain threshold was determined using von Frey and Hot Plate/Tail Flick tests. Dyskinesia was measured by abnormal involuntary movements (AIMs) induced by L-DOPA administration. This data is consistent to show that 6-OHDA-lesioned rats had reduced nociceptive thresholds compared to non-lesioned rats. Additionally, when these rats were exposed to a persistent inflammatory challenge, we observed increased hypernociceptive responses, namely hyperalgesia. L-DOPA treatment alleviated pain responses on days 1 and 7 of treatment, but not on day 15. During that period, we observed an inverse relationship between LID and nociception threshold in these rats, with a high LID rate corresponding to a reduced nociception threshold. Interestingly, pain responses resulting from CFA-induced inflammation were significantly enhanced during established dyskinesia. These data suggest a pro-algesic effect of L-DOPA-induced dyskinesia, which is confirmed by the correlation founded here between AIMs and nociceptive indexes. In conclusion, our results are consistent with the notion that central dopaminergic mechanism is directly involved in nociceptive responses in Parkinsonism condition.

Nicotine Reduces l-DOPA-Induced Dyskinesias by Acting at β2* Nicotinic Receptors

PubMed Central

Huang, Luping Z.; Grady, Sharon R.

2011-01-01

l-DOPA-induced dyskinesias or abnormal involuntary movements (AIMs) are a debilitating adverse complication associated with prolonged l-DOPA administration for Parkinson's disease. Few treatments are currently available for dyskinesias. Our recent data showed that nicotine reduced l-DOPA-induced AIMs in parkinsonian animal models. An important question is the nicotinic acetylcholine receptor (nAChR) subtypes through which nicotine exerts this beneficial effect, because such knowledge would allow for the development of drugs that target the relevant receptor population(s). To address this, we used β2 nAChR subunit knockout [β2(−/−)] mice because β2-containing nAChRs are key regulators of nigrostriatal dopaminergic function. All of the mice were lesioned by intracranial injection of 6-hydroxydopamine into the right medial forebrain bundle. Lesioning resulted in a similar degree of nigrostriatal damage and parkinsonism in β2(−/−) and wild-type mice. All of the mice then were injected with l-DOPA (3 mg/kg) plus benserazide (15 mg/kg) once daily for 4 weeks until AIMs were fully developed. l-DOPA-induced AIMs were approximately 40% less in the β2(−/−) mice compared with the wild-type mice. It is interesting to note that nicotine (300 μg/ml in drinking water) reduced l-DOPA-induced AIMs by 40% in wild-type mice but had no effect in β2(−/−) mice with partial nigrostriatal damage. The nicotine-mediated decline in AIMs was much less pronounced in wild-type mice with near-complete degeneration, suggesting that presynaptic nAChRs on dopaminergic terminals have a major influence. These data demonstrate an essential role for β2* nAChRs in the antidyskinetic effect of nicotine and suggest that drugs targeting these subtypes may be useful for the management of l-DOPA-induced dyskinesias in Parkinson's disease. PMID:21665941

Gypenosides attenuate the development of L-DOPA-induced dyskinesia in 6-hydroxydopamine-lesioned rat model of Parkinson's disease.

PubMed

Shin, Keon Sung; Zhao, Ting Ting; Park, Keun Hong; Park, Hyun Jin; Hwang, Bang Yeon; Lee, Chong Kil; Lee, Myung Koo

2015-04-21

Gypenosides (GPS) and ethanol extract of Gynostemma pentaphyllum (GP-EX) show anxiolytic effects on affective disorders in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned mouse model of Parkinson's disease (PD). Long-term administration of L-3,4-dihydroxyphenylalanine (L-DOPA) leads to the development of severe motor side effects such as L-DOPA-induced-dyskinesia (LID) in PD. The present study investigated the effects of GPS and GP-EX on LID in a 6-hydroxydopamine (6-OHDA)-lesioned rat model of PD. Daily administration of L-DOPA (25 mg/kg) in the 6-OHDA-lesioned rat model of PD for 22 days induced expression of LID, which was determined by the body and locomotive AIMs scores and contralateral rotational behaviors. However, co-treatments of GPS (25 and 50 mg/kg) or GP-EX (50 mg/kg) with L-DOPA significantly attenuated the development of LID without compromising the anti-parkinsonian effects of L-DOPA. In addition, the increases in ∆FosB expression and ERK1/2 phosphorylation in 6-OHDA-lesioned rats induced by L-DOPA administration were significantly reduced by co-treatment with GPS (25 and 50 mg/kg) or GP-EX (50 mg/kg). These results suggest that GPS (25 and 50 mg/kg) and GP-EX (50 mg/kg) effectively attenuate the development of LID by modulating the biomarker activities of ∆FosB expression and ERK1/2 phosphorylation in the 6-OHDA-lesioned rat model of PD. GPS and GP-EX will be useful adjuvant therapeutics for LID in PD.

In vivo evidence of D3 dopamine receptor sensitization in parkinsonian primates and rodents with L-DOPA-induced dyskinesias

PubMed Central

Sánchez-Pernaute, Rosario; Jenkins, Bruce G.; Choi, Ji-Kyung; Chen, Yin-Ching Iris; Isacson, Ole

2008-01-01

A growing body of evidence indicates a role for D3 receptors in L-DOPA-induced dyskinesias. This involvement could be amenable to non-invasive in vivo analysis using functional neuroimaging. With this goal, we examined the hemodynamic response to the dopamine D3-preferring agonist 7-hydroxy-N,N-di-n-propyl-2 aminotetralin (7-OHDPAT) in naïve, parkinsonian and L-DOPA-treated, dyskinetic rodents and primates using pharmacological MRI (phMRI) and relative cerebral blood volume (rCBV) mapping. Administration of 7-OHDPAT induced minor negative changes of rCBV in the basal ganglia in naïve and parkinsonian animals. Remarkably, the hemodynamic response was reversed (increased rCBV) in the striatum of parkinsonian animals rendered dyskinetic by repeated L-DOPA treatment. Such increase in rCBV is consistent with D1 receptor-like signaling occurring in response to D3 stimulation, demonstrates a dysregulation of dopamine receptor function in dyskinesia and provides a potentially novel means for the characterization and treatment of L-DOPA-induced dyskinesia in patients. PMID:17588764

Levodopa-induced plasticity: a double-edged sword in Parkinson's disease?

PubMed Central

Calabresi, Paolo; Ghiglieri, Veronica; Mazzocchetti, Petra; Corbelli, Ilenia; Picconi, Barbara

2015-01-01

The long-term replacement therapy with the dopamine (DA) precursor 3,4-dihydroxy-l-phenylalanine (L-DOPA) is a milestone in the treatment of Parkinson's disease (PD). Although this drug precursor can be metabolized into the active neurotransmitter DA throughout the brain, its therapeutic benefit is due to restoring extracellular DA levels within the dorsal striatum, which lacks endogenous DA as a consequence of the neurodegenerative process induced by the disease. In the early phases of PD, L-DOPA treatment is able to restore both long-term depression (LTD) and long-term potentiation (LTP), two major forms of corticostriatal synaptic plasticity that are altered by dopaminergic denervation. However, unlike physiological DA transmission, this therapeutic approach in the advanced phase of the disease leads to abnormal peaks of DA, non-synaptically released, which are supposed to trigger behavioural sensitization, namely L-DOPA-induced dyskinesia. This condition is characterized by a loss of synaptic depotentiation, an inability to reverse previously induced LTP. In the advanced stages of PD, L-DOPA can also induce non-motor fluctuations with cognitive dysfunction and neuropsychiatric symptoms such as compulsive behaviours and impulse control disorders. Although the mechanisms underlying the role of L-DOPA in both motor and behavioural symptoms are still incompletely understood, recent data from electrophysiological and imaging studies have increased our understanding of the function of the brain areas involved and of the mechanisms implicated in both therapeutic and adverse actions of L-DOPA in PD patients. PMID:26009763

Assessment of symptomatic and neuroprotective efficacy of Mucuna pruriens seed extract in rodent model of Parkinson's disease.

PubMed

Kasture, Sanjay; Pontis, Silvia; Pinna, Annalisa; Schintu, Nicoletta; Spina, Liliana; Longoni, Rosanna; Simola, Nicola; Ballero, Mauro; Morelli, Micaela

2009-02-01

Mucuna pruriens (MP) has long been used in Indian traditional medicine as support in the treatment of Parkinson's disease. However, no systematic preclinical studies that aimed at evaluating the efficacy of this substance are available to date. This study undertook an extensive evaluation of the antiparkinsonian effects of an extract of MP seeds known to contain, among other components, 12.5% L: -dihydroxyphenylalanine (L: -DOPA), as compared to equivalent doses of L: -DOPA. Moreover, the neuroprotective efficacy of MP and its potential rewarding effects were evaluated. The results obtained reveal how an acute administration of MP extract at a dose of 16 mg/kg (containing 2 mg/kg of L: -DOPA) consistently antagonized the deficit in latency of step initiation and adjusting step induced by a unilateral 6-hydroxydopamine lesion, whereas L: -DOPA was equally effective only at the doses of 6 mg/kg. At the same dosage, MP significantly improved the placement of the forelimb in vibrissae-evoked forelimb placing, suggesting a significant antagonistic activity on both motor and sensory-motor deficits. The effects of MP extract were moreover investigated by means of the turning behavior test and in the induction of abnormal involuntary movements (AIMs) after either acute or subchronic administration. MP extract acutely induced a significantly higher contralateral turning behavior than L: -DOPA (6 mg/kg) when administered at a dose of 48 mg/kg containing 6 mg/kg of L: -DOPA. On subchronic administration, both MP extract (48 mg/kg) and L: -DOPA (6 mg/kg) induced sensitization of contralateral turning behavior; however, L: -DOPA alone induced a concomitant sensitization in AIMs suggesting that the dyskinetic potential of MP is lower than that of L: -DOPA. MP (48 mg/kg) was also effective in antagonizing tremulous jaw movements induced by tacrine, a validated test reproducing parkinsonian tremor. Furthermore, MP induced no compartment preference in the place preference test, indicating the lack of components characterized by rewarding effects in the extract. Finally, in a subchronic mice model of 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine hydrochloride (MPTP)-induced dopamine neuron degeneration, MP extract did not prove capable of preventing either tyrosine hydroxylase decrease induced by MPTP or astroglial or microglial activation as assessed by means of GFAP and CD11b immunohistochemistry, supporting the absence of neuroprotective effects by MP. Characterization MP extract strongly supports its antiparkinsonian activity.

Dopamine drives Drosophila sechellia adaptation to its toxic host

PubMed Central

Lavista-Llanos, Sofía; Svatoš, Aleš; Kai, Marco; Riemensperger, Thomas; Birman, Serge; Stensmyr, Marcus C; Hansson, Bill S

2014-01-01

Many insect species are host-obligate specialists. The evolutionary mechanism driving the adaptation of a species to a toxic host is, however, intriguing. We analyzed the tight association of Drosophila sechellia to its sole host, the fruit of Morinda citrifolia, which is toxic to other members of the melanogaster species group. Molecular polymorphisms in the dopamine regulatory protein Catsup cause infertility in D. sechellia due to maternal arrest of oogenesis. In its natural host, the fruit compensates for the impaired maternal dopamine metabolism with the precursor l-DOPA, resuming oogenesis and stimulating egg production. l-DOPA present in morinda additionally increases the size of D. sechellia eggs, what in turn enhances early fitness. We argue that the need of l-DOPA for successful reproduction has driven D. sechellia to become an M. citrifolia obligate specialist. This study illustrates how an insect's dopaminergic system can sustain ecological adaptations by modulating ontogenesis and development. DOI: http://dx.doi.org/10.7554/eLife.03785.001 PMID:25487989

Singlet oxygen generation during the oxidation of L-tyrosine and L-dopa with mushroom tyrosinase.

PubMed

Miyaji, Akimitsu; Kohno, Masahiro; Inoue, Yoshihiro; Baba, Toshihide

2016-03-18

The generation of singlet oxygen during the oxidation of tyrosine and L-dopa using mushroom tyrosinase in a phosphate buffer (pH 7.4), the model of melanin synthesis in melanocytes, was examined. The reaction was performed in the presence of 2,2,6,6-tetramethyl-4-piperidone (4-oxo-TEMP), an acceptor of singlet oxygen and the electron spin resonance (ESR) of the spin adduct, 4-oxo-2,2,6,6-tetramethyl-1-piperidinyloxy (4-oxo-TEMPO), was measured. An increase in the ESR signal attributable to 4-oxo-TEMPO was observed during the oxidation of tyrosine and L-dopa with tyrosinase, indicating the generation of singlet oxygen. The results suggest that (1)O2 generation via tyrosinase-catalyzed melanin synthesis occurs in melanocyte. Copyright © 2016 Elsevier Inc. All rights reserved.

Levodopa/Benserazide Loaded Microspheres Alleviate L-dopa Induced Dyskinesia through Preventing the Over-Expression of D1R/Shp-2/ERK1/2 Signaling Pathway in a Rat Model of Parkinson's Disease

PubMed Central

Wan, Ying; Wu, Na; Song, Lu; Wang, Xijin; Liu, Zhenguo; Yuan, Weien; Gan, Jing

2017-01-01

Background: The long-term intermittent Levodopa (L-dopa) stimulation contributes to an aberrant activation of D1 receptor (D1R) mediated extracellular signal-regulated kinases1/2 (ERK1/2) in the striatal medium spiny neurons, resulting in the occurrence of L-dopa induced dyskinesia (LID). Recently, a novel signaling pathway, D1R/Shp-2/ERK1/2, was proposed to be required for the occurrence of LID. Here we designed the study in which two different methods of L-dopa delivery [continuous dopamine stimulation (CDS) vs. intermittent dopamine stimulation] were used to further identify: (1) the role of D1R/Shp-2/ERK1/2 signaling pathway in the occurrence of LID; (2) whether CDS alleviated LID though preventing the over-expression of the D1R/Shp-2/ERK1/2 signaling pathway. Methods: 6-OHDA-lesioned rat models of Parkinson's disease (PD) were randomly divided into two groups to receive intermittent L-dopa stimulation (L-dopa/benserazide standard group, LS group) or CDS (L-dopa/benserazide loaded microspheres, LBM group) for 21 days. Dyskinesia and anti-parkinsonian effect were compared between the two groups through the AIMs assessment and cylinder test. The critical protein changes in the D1R/Shp-2/ERK1/2 signaling pathway were compared between the two groups through Western blotting. Results: Intermittent L-dopa administration induced serious dyskinetic movements in the 6-OHDA-lesioned rats, and the anti-parkinsonian effect of L-dopa was gradually counteracted by the occurrence of dyskinesia. Intermittent L-dopa administration enhanced the expression of membrane D1R, and induced a robust increase of phosphorylation of Shp-2, Src, DARPP-32, and ERK1/2 in the 6-OHDA-lesioned striatum. In contrast, CDS played a dose-dependent anti-parkinsonian role, without inducing such apparent dyskinetic movements. Moreover, CDS induced no change of membrane D1R expression or phosphorylation of Shp-2, Src, DARPP-32, and ERK1/2 in the 6-OHDA-lesioned striatum. Conclusion: The aberrant activation of D1R/Shp-2 complex was evidenced to be required for the D1R mediating ERK1/2 phosphorylation and the occurrence of LID. CDS effectively prevented the overexpression of D1R/Shp-2/ERK1/2 signaling pathway, resulting in the reduction of LID in 6-OHDA-lesioned rats model of PD. PMID:29093677

Preparation of rotigotine-loaded microspheres and their combination use with L-DOPA to modify dyskinesias in 6-OHDA-lesioned rats.

PubMed

Wang, Aiping; Wang, Lexi; Sun, Kaoxiang; Liu, Wanhui; Sha, Chunjie; Li, Youxin

2012-09-01

To prepare rotigotine loaded microspheres (RoMS) to achieve continuous dopaminergic stimulation (CDS) for the treatment of Parkinson's disease (PD) and investigate both the therapeutic benefit and inducibility of AIMs of administration of RoMS combination with L-DOPA in 6-OHDA-leisioned rats. Rotigotine was encapsulated into poly(lactic-co-glycolic acid) (PLGA) microspheres by an oil-in-water emulsion solvent evaporation technique. In vitro characteristics and in vivo pharmacokinetics of RoMS either in rat blood or brain (by microdialysis) were investigated. Contraversive rotations and AIMs were observed to investigate the therapeutic benefit and the propensity to induce dyskinesia of RoMS or RoMS combination with L-DOPA in 6-OHDA-lesioned rats. RoMS displayed continuous-release characteristics of rotigotine in animals and exhibited a steady efficacy lasted for 2 weeks in 6-OHDA-lesioned rats. No significant difference of the therapeutic benefit between the treatment of RoMS and pulsatile L-DOPA combination and mono L-DOPA was found. While the dyskinesia was significantly decreased with the treatment of RoMS and pulsatile L-DOPA combination compared to mono L-DOPA. RoMS could supply an alternative of CDS for the treatment of PD and the study indicates a potential advantage of RoMS for the treatment of mild and advanced PD patient in combination with L-DOPA.

Low doses of sarizotan reduce dyskinesias and maintain antiparkinsonian efficacy of L-Dopa in parkinsonian monkeys.

PubMed

Grégoire, Laurent; Samadi, Pershia; Graham, Julie; Bédard, Paul J; Bartoszyk, Gerd D; Di Paolo, Thérèse

2009-07-01

Dyskinesia is an important complication of treatment in Parkinson's disease (PD). Sarizotan, a 5-HT(1A) agonist with high affinity for D3 and D4 receptors was investigated on L-Dopa-induced dyskinesia (LID) in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) animal model of PD. Five MPTP female cynomolgus monkeys (Macaca fascicularis) with a moderate to severe parkinsonian syndrome and LID were used. Sarizotan 0.2, 1, and 2 mg/kg administered alone did not worsen parkinsonian symptoms; there were no effect on locomotor counts or on normal behavior of the monkeys. Sarizotan 0.2, 1, and 2 mg/kg administered 30 min before a fixed dose of L-Dopa (25-30 mg/kg s.c.) + benserazide (50 mg) did not affect the antiparkinsonian response to L-Dopa. However, mean dyskinetic scores were significantly reduced with sarizotan 1 and 2 mg/kg but not at 0.2 mg/kg. Higher doses of sarizotan (4 and 8 mg/kg, administered immediately before L-Dopa) reduced L-Dopa-induced locomotor response in all monkeys. A pharmacokinetic investigation in these monkeys showed a dose-dependent increase in mean plasma sarizotan concentrations with similar mean plasma concentrations for sarizotan 1 mg/kg alone or with L-Dopa, indicating a lack of sarizotan/L-Dopa interaction. The time course of plasma sarizotan concentrations was associated with time of maximal reduction of dyskinesias. When administered daily for two weeks in combination with L-Dopa in the same MPTP monkeys, sarizotan 1 mg/kg had a sustained antidyskinetic effect while maintaining the antiparkinsonian and locomotor effect of L-Dopa. This detailed sarizotan investigation in MPTP monkeys supports the antidyskinetic activity of this drug and for 5-HT(1A) agonists.

Relationship between L-DOPA-induced reduction in motor and exploratory activity and degree of DAT binding in the rat

PubMed Central

Nikolaus, Susanne; Beu, Markus; De Souza Silva, Angelica Maria; Huston, Joseph P.; Hautzel, Hubertus; Chao, Owen Y.; Antke, Christina; Müller, Hans-Wilhelm

2014-01-01

Purpose: The present study assessed the influence of L-DOPA administration on neostriatal dopamine (DA) transporter (DAT) binding in relation to motor and exploratory behaviors in the rat. Methods: Rats received injections of 5 mg/kg L-DOPA, 10 mg/kg L-DOPA or vehicle. Motor and exploratory behaviors were assessed for 30 min in an open field prior to administration of [123I]FP-CIT. Dopamine transporter binding was measured with small animal single-photon emission computed tomography (SPECT) 2 h after radioligand administration for 60 min. Results: Both L-DOPA doses significantly reduced DAT binding and led to significantly less head-shoulder motility and more sitting relative to vehicle. Moreover, 10 mg/kg L-DOPA induced less distance traveled and ambulation than 5 mg/kg L-DOPA. Analysis of time-behavior (t-b) curves showed that L-DOPA-treated animals relative to vehicle exhibited (1) a faster rate of increase in duration of sitting; (2) a slower rate of increase in duration of head-shoulder motility; and (3) a slower rate of decrease in frequency of head-shoulder motility. Conclusions: The reductions of striatal DAT binding after L-DOPA challenges reflected elevated concentrations of synaptic DA. L-DOPA-treated animals showed less head-shoulder motility and more sitting than vehicle-treated animals, indicating an association between less behavioral activity and increased availability of striatal DA. The faster increase of sitting duration to a higher final level and the slower increase of head-shoulder motility to a lower final level relative to controls may be interpreted in terms on behavioral habituation to a novel environment. PMID:25566000

Specific induction of PAG608 in cranial and spinal motor neurons of L-DOPA-treated parkinsonian rats.

PubMed

Shimizu, Masako; Miyazaki, Ikuko; Higashi, Youichirou; Eslava-Alva, Maria J; Diaz-Corrales, Francisco J; Asanuma, Masato; Ogawa, Norio

2008-04-01

We identified p53-activated gene 608 (PAG608) as a specifically induced gene in striatal tissue of L-DOPA (100mg/kg)-injected hemi-parkinsonian rats using differential display assay. In the present study, we further examined morphological distribution of PAG608 in the central nervous system of L-DOPA-treated hemi-parkinsonian rats. PAG608 expression was markedly induced in fibers and neuronal cells of the lateral globus pallidus and reticular thalamic nucleus adjacent to internal capsule, specifically in the parkinsonian side of L-DOPA-treated models. The protein was also constitutively expressed in motor neurons specifically in either side of the pontine nucleus and motor nuclei of trigeminal and facial nerves. Furthermore, L-DOPA-induced PAG608 expression on motor neurons in the contralateral side of the ventral horn of the spinal cord and the lateral corticospinal tract without cell loss. The specific induction of PAG608 6-48h after L-DOPA injection in the extrapyramidal tracts, pyramidal tracts and corresponding lower motor neurons of the spinal cords suggests its involvement in molecular events in stimulated motor neurons. Taken together with the constitutive expression of PAG608 in the motor nuclei of cranial nerves, PAG608 may be a useful marker of stressed or activated lower motor neurons.

Electrochemically reduced graphene oxide/Poly-Glycine composite modified electrode for sensitive determination of l-dopa.

PubMed

Palakollu, Venkata Narayana; Thapliyal, Neeta; Chiwunze, Tirivashe E; Karpoormath, Rajshekhar; Karunanidhi, Sivanandhan; Cherukupalli, Srinivasulu

2017-08-01

A facile preparation strategy based on electrochemical technique for the fabrication of glycine (Poly-Gly) and electrochemically reduced graphene oxide (ERGO) composite modified electrode was developed. The morphology of the developed composite (ERGO/Poly-Gly) was investigated using field emission scanning electron microscope (FE-SEM). The composite modified glassy carbon electrode (GCE) was characterized using fourier transform-infrared (FT-IR) spectroscopy, electrochemical impedance spectroscopy (EIS) and cyclic voltammetry (CV). The electrochemical characterization results revealed that ERGO/Poly-Gly modified GCE has excellent electrocatalytic activity. Further, it was employed for sensing of l-dopa in pH5.5. Differential pulse voltammetry (DPV) was used for the quantification of l-dopa as well as for the simultaneous resolution of l-dopa and uric acid (UA). The LOD (S/N=3) was found to be 0.15μM at the proposed composite modified electrode. Determination of l-dopa could also be achieved in the presence of potentially interfering substances. The sensor showed high sensitivity and selectivity with appreciable reliability and precision. The proposed sensor was also successfully applied for real sample analysis. Copyright © 2017 Elsevier B.V. All rights reserved.

Fast-scan cyclic voltammetry reveals that L-Dopa produces regionally selective, bimodal influences on striatal dopamine kinetics in vivo

PubMed Central

Harun, R; Munoz, M; Grassi, C; Hare, K; Brough, E; Torres, GE; Grace, AA; Wagner, AK

2016-01-01

Parkinson’s disease (PD) is a debilitating condition that is caused by a relatively specific degeneration of dopaminergic (DAergic) neurons of the substantia nigra pars compacta. Levodopa (L-Dopa) was introduced as a viable treatment option for PD over 40 years ago and still remains the most common and effective therapy for PD. Though the effects of L-Dopa to augment striatal DA production are well known, little is actually known about how L-Dopa alters the kinetics of DA neurotransmission that contribute to its beneficial and adverse effects. In this study, we examined the effects of L-Dopa administration (100mg/kg carbidopa/250mg/kg L-Dopa) on regional electrically stimulated DA response kinetics using fast-scan cyclic voltammetry (FSCV) in anesthetized rats. We demonstrate that L-Dopa enhances DA release in both the dorsal striatum (D-STR) and nucleus accumbens (NAc), but surprisingly causes a delayed inhibition of release in the D-STR, a finding that may be related to high-dose L-Dopa effects. In both regions, L-Dopa progressively attenuated reuptake kinetics through a decrease in Vmax and an increase in Km. This finding is consistent with recent clinical studies suggesting that L-Dopa chronically down-regulates the DA transporter (DAT), which may relate to the common development of L-Dopa induced dyskinesias (LID) in PD subjects. PMID:26611352

Establishing contact between cell-laden hydrogels and metallic implants with a biomimetic adhesive for cell therapy supported implants.

PubMed

Barthes, Julien; Mutschler, Angela; Dollinger, Camille; Gaudinat, Guillaume; Lavalle, Philippe; Le Houerou, Vincent; Brian McGuinness, Garrett; Engin Vrana, Nihal

2017-12-15

For in-dwelling implants, controlling the biological interface is a crucial parameter to promote tissue integration and prevent implant failure. For this purpose, one possibility is to facilitate the establishment of the interface with cell-laden hydrogels fixed to the implant. However, for proper functioning, the stability of the hydrogel on the implant should be ensured. Modification of implant surfaces with an adhesive represents a promising strategy to promote the adhesion of a cell-laden hydrogel on an implant. Herein, we developed a peptidic adhesive based on mussel foot protein (L-DOPA-L-lysine) 2 -L-DOPA that can be applied directly on the surface of an implant. At physiological pH, unoxidized (L-DOPA-L-lysine) 2 -L-DOPA was supposed to strongly adhere to metallic surfaces but it only formed a very thin coating (less than 1 nm). Once oxidized at physiological pH, (L-DOPA-L-lysine) 2 -L-DOPA forms an adhesive coating about 20 nm thick. In oxidized conditions, L-lysine can adhere to metallic substrates via electrostatic interaction. Oxidized L-DOPA allows the formation of a coating through self-polymerization and can react with amines so that this adhesive can be used to fix extra-cellular matrix based materials on implant surfaces through the reaction of quinones with amino groups. Hence, a stable interface between a soft gelatin hydrogel and metallic surfaces was achieved and the strength of adhesion was investigated. We have shown that the adhesive is non-cytotoxic to encapsulated cells and enabled the adhesion of gelatin soft hydrogels for 21 days on metallic substrates in liquid conditions. The adhesion properties of this anchoring peptide was quantified by a 180° peeling test with a more than 60% increase in peel strength in the presence of the adhesive. We demonstrated that by using a biomimetic adhesive, for the application of cell-laden hydrogels to metallic implant surfaces, the hydrogel/implant interface can be ensured without relying on the properties of the deposited biomaterials.

Differential effects of gaseous versus injectable anesthetics on changes in regional cerebral blood flow and metabolism induced by l-DOPA in a rat model of Parkinson's disease.

PubMed

Bimpisidis, Zisis; Öberg, Carl M; Maslava, Natallia; Cenci, M Angela; Lundblad, Cornelia

2017-06-01

Preclinical imaging of brain activity requires the use of anesthesia. In this study, we have compared the effects of two widely used anesthetics, inhaled isoflurane and ketamine/xylazine cocktail, on cerebral blood flow and metabolism in a rat model of Parkinson's disease and l-DOPA-induced dyskinesia. Specific tracers were used to estimate regional cerebral blood flow (rCBF - [ 14 C]-iodoantipyrine) and regional cerebral metabolic rate (rCMR - [ 14 C]-2-deoxyglucose) with a highly sensitive autoradiographic method. The two types of anesthetics had quite distinct effects on l-DOPA-induced changes in rCBF and rCMR. Isoflurane did not affect either the absolute rCBF values or the increases in rCBF in the basal ganglia after l-DOPA administration. On the contrary, rats anesthetized with ketamine/xylazine showed lower absolute rCBF values, and the rCBF increases induced by l-DOPA were masked. We developed a novel improved model to calculate rCMR, and found lower metabolic activities in rats anesthetized with isoflurane compared to animals anesthetized with ketamine/xylazine. Both anesthetics prevented changes in rCMR upon l-DOPA administration. Pharmacological challenges in isoflurane-anesthetized rats indicated that drugs mimicking the actions of ketamine/xylazine on adrenergic or glutamate receptors reproduced distinct effects of the injectable anesthetics on rCBF and rCMR. Our results highlight the importance of anesthesia in studies of cerebral flow and metabolism, and provide novel insights into mechanisms mediating abnormal neurovascular responses to l-DOPA in Parkinson's disease. Copyright © 2017 Elsevier Inc. All rights reserved.

Enhanced Neuroprotective Effects of Coadministration of Tetrandrine with Glutathione in Preclinical Model of Parkinson's Disease

PubMed Central

Li, Xiang-Yun; Mei, Guang-Hai; Dong, Qiang; Zhang, Yu; Guo, Zhuang-Li; Su, Jing-Jing; Tang, Yu-Ping; Jin, Xue-Hong; Zhou, Hou-Guang; Huang, Yan-Yan

2015-01-01

Aim. In this study we examined the influence of tetrandrine (Tet) on the neuroprotective effects of glutathione (GSH) in the 6-hydroxydopamine- (6-OHDA-) lesioned rat model of Parkinson's disease (PD). Methods. Levels in the redox system, dopamine (DA) metabolism, dopaminergic neuronal survival, and apoptosis of the substantia nigra (SN) and striatum, as well as the rotational behavior of animals were examined after a 50-day administration of GSH + Tet (or GSH) and/or L-3,4-dihydroxyphenylalanine (L-dopa) to PD rats. Ethics Committee of Huashan Hospital, Fudan University approved the protocol (number SYXK2009-0082). Results. Administration of GSH or Tet alone did not show any significant effects on the factors evaluated in the PD rats. However, in the GSH + Tet group, we observed markedly decreased oxidative damage, inhibition of DA metabolism and enhanced DA synthesis, increased tyrosine hydroxylase- (TH-) immunopositive neuronal survival, and delayed apoptosis of dopaminergic neurons in the SN. Animal rotational behavior was improved in the GSH + Tet group. Additionally, coadministration of GSH + Tet appeared to offset the possible oxidative neurotoxicity induced by L-dopa. Conclusion. In this study, we demonstrated that tetrandrine allowed occurrence of the neuroprotective effect of glutathione probably due to inhibition of P-glycoprotein on 6-hydroxydopamine-lesioned rat models of Parkinson's disease, including rats undergoing long-term L-dopa treatment. PMID:26664824

Fast-scan cyclic voltammetry demonstrates that L-DOPA produces dose-dependent regionally selective, bimodal effects on striatal dopamine kinetics in vivo.

PubMed

Harun, R; Hare, K M; Brough, M E; Munoz, M J; Grassi, C M; Torres, G E; Grace, A A; Wagner, A K

2015-11-27

Parkinson's disease (PD) is a debilitating condition that is caused by a relatively specific degeneration of dopaminergic (DAergic) neurons of the substantia nigra pars compacta. Levodopa (L-DOPA) was introduced as a viable treatment option for PD over 40 years ago and still remains the most common and effective therapy for PD. Though the effects of L-DOPA to augment striatal DA production are well known, little is actually known about how L-DOPA alters the kinetics of DA neurotransmission that contribute to its beneficial and adverse effects. In this study, we examined the effects of L-DOPA administration (50mg/kg carbidopa + 0, 100, and 250mg/kg L-DOPA) on regional electrically stimulated DA response kinetics using fast-scan cyclic voltammetry (FSCV) in anesthetized rats. We demonstrate that L-DOPA enhances DA release in both the dorsal striatum (D-STR) and nucleus accumbens (NAc), but surprisingly causes a delayed inhibition of release in the D-STR. In both regions, L-DOPA progressively attenuated reuptake kinetics, predominantly through a decrease in Vmax. These findings have important implications on understanding the pharmacodynamics of L-DOPA, which can be informative for understand its therapeutic effects and also common side effects like L-DOPA induced dyskinesias (LID). This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Eltoprazine counteracts l-DOPA-induced dyskinesias in Parkinson’s disease: a dose-finding study

PubMed Central

Rosenblad, Carl; af Edholm Arvidsson, Karolina; Wictorin, Klas; Keywood, Charlotte; Shankar, Bavani; Lowe, David A.; Björklund, Anders; Widner, Håkan

2015-01-01

In advanced stages of Parkinson’s disease, serotonergic terminals take up l-DOPA and convert it to dopamine. Abnormally released dopamine may participate in the development of l-DOPA-induced dyskinesias. Simultaneous activation of 5-HT1A and 5-HT1B receptors effectively blocks l-DOPA-induced dyskinesias in animal models of dopamine depletion, justifying a clinical study with eltoprazine, a 5-HT1A/B receptor agonist, against l-DOPA-induced dyskinesias in patients with Parkinson’s disease. A double-blind, randomized, placebo-controlled and dose-finding phase I/IIa study was conducted. Single oral treatment with placebo or eltoprazine, at 2.5, 5 and 7.5 mg, was tested in combination with a suprathreshold dose of l-DOPA (Sinemet®) in 22 patients with Parkinson’s disease (16 male/six female; 66.6 ± 8.8 years old) with l-DOPA-induced dyskinesias. A Wilcoxon Signed Ranked Test was used to compare each eltoprazine dose level to paired randomized placebo on the prespecified primary efficacy variables; area under the curve scores on Clinical Dyskinesia Rating Scale for 3 h post-dose and maximum change of Unified Parkinson’s Disease Rating Scale part III for 3 h post-dose. Secondary objectives included effects on maximum Clinical Dyskinesia Rating Scale score, area under the curve of Rush Dyskinesia Rating Scale score for 3 h post-dose, mood parameters measured by Hospital Anxiety Depression Scale and Montgomery Asberg Depression Rating Scale along with the pharmacokinetics, safety and tolerability profile of eltoprazine. A mixed model repeated measures was used for post hoc analyses of the area under the curve and peak Clinical Dyskinesia Rating Scale scores. It was found that serum concentrations of eltoprazine increased in a dose-proportional manner. Following levodopa challenge, 5 mg eltoprazine caused a significant reduction of l-DOPA-induced dyskinesias on area under the curves of Clinical Dyskinesia Rating Scale [–1.02(1.49); P = 0.004] and Rush Dyskinesia Rating Scale [–0.15(0.23); P = 0.003]; and maximum Clinical Dyskinesia Rating Scale score [–1.14(1.59); P = 0.005]. The post hoc analysis confirmed these results and also showed an antidyskinetic effect of 7.5 mg eltoprazine. Unified Parkinson’s Disease Rating Scale part III scores did not differ between the placebo and eltoprazine treatments. The most frequent adverse effects after eltoprazine were nausea and dizziness. It can be concluded that a single dose, oral treatment with eltoprazine has beneficial antidyskinetic effects without altering normal motor responses to l-DOPA. All doses of eltoprazine were well tolerated, with no major adverse effects. Eltoprazine has a favourable risk-benefit and pharmacokinetic profile in patients with Parkinson’s disease. The data support further clinical studies with chronic oral eltoprazine to treat l-DOPA-induced-dyskinesias. PMID:25669730

The Role of Primary Motor Cortex (M1) Glutamate and GABA Signaling in l-DOPA-Induced Dyskinesia in Parkinsonian Rats

PubMed Central

Conti, Melissa M.; Ostock, Corinne Y.; George, Jessica A.; Goldenberg, Adam A.; Melikhov-Sosin, Mitchell; Nuss, Emily E.

2016-01-01

Long-term treatment of Parkinson's disease with l-DOPA almost always leads to the development of involuntary movements termed l-DOPA-induced dyskinesia. Whereas hyperdopaminergic signaling in the basal ganglia is thought to cause dyskinesia, alterations in primary motor cortex (M1) activity are also prominent during dyskinesia, suggesting that the cortex may represent a therapeutic target. The present study used the rat unilateral 6-hydroxydopamine lesion model of Parkinson's disease to characterize in vivo changes in GABA and glutamate neurotransmission within M1 and determine their contribution to behavioral output. 6-Hydroxydopamine lesion led to parkinsonian motor impairment that was partially reversed by l-DOPA. Among sham-lesioned rats, l-DOPA did not change glutamate or GABA efflux. Likewise, 6-hydroxydopamine lesion did not impact GABA or glutamate among rats chronically treated with saline. However, we observed an interaction of lesion and treatment whereby, among lesioned rats, l-DOPA given acutely (1 d) or chronically (14–16 d) reduced glutamate efflux and enhanced GABA efflux. Site-specific microinjections into M1 demonstrated that l-DOPA-induced dyskinesia was reduced by M1 infusion of a D1 antagonist, an AMPA antagonist, or a GABAA agonist. Overall, the present study demonstrates that l-DOPA-induced dyskinesia is associated with increased M1 inhibition and that exogenously enhancing M1 inhibition may attenuate dyskinesia, findings that are in agreement with functional imaging and transcranial magnetic stimulation studies in human Parkinson's disease patients. Together, our study suggests that increasing M1 inhibitory tone is an endogenous compensatory response designed to limit dyskinesia severity and that potentiating this response is a viable therapeutic strategy. SIGNIFICANCE STATEMENT Most Parkinson's disease patients will receive l-DOPA and eventually develop hyperkinetic involuntary movements termed dyskinesia. Such symptoms can be as debilitating as the disease itself. Although dyskinesia is associated with dynamic changes in primary motor cortex physiology, to date, there are no published studies investigating in vivo neurotransmitter release in M1 during dyskinesia. In parkinsonian rats, l-DOPA administration reduced M1 glutamate efflux and enhanced GABA efflux, coincident with the emergence of dyskinetic behaviors. Dyskinesia could be reduced by local M1 modulation of D1, AMPA, and GABAA receptors, providing preclinical support for the notion that exogenously blunting M1 signaling (pharmacologically or with cortical stimulation) is a therapeutic approach to the treatment of debilitating dyskinesias. PMID:27656025

The Role of Primary Motor Cortex (M1) Glutamate and GABA Signaling in l-DOPA-Induced Dyskinesia in Parkinsonian Rats.

PubMed

Lindenbach, David; Conti, Melissa M; Ostock, Corinne Y; George, Jessica A; Goldenberg, Adam A; Melikhov-Sosin, Mitchell; Nuss, Emily E; Bishop, Christopher

2016-09-21

Long-term treatment of Parkinson's disease with l-DOPA almost always leads to the development of involuntary movements termed l-DOPA-induced dyskinesia. Whereas hyperdopaminergic signaling in the basal ganglia is thought to cause dyskinesia, alterations in primary motor cortex (M1) activity are also prominent during dyskinesia, suggesting that the cortex may represent a therapeutic target. The present study used the rat unilateral 6-hydroxydopamine lesion model of Parkinson's disease to characterize in vivo changes in GABA and glutamate neurotransmission within M1 and determine their contribution to behavioral output. 6-Hydroxydopamine lesion led to parkinsonian motor impairment that was partially reversed by l-DOPA. Among sham-lesioned rats, l-DOPA did not change glutamate or GABA efflux. Likewise, 6-hydroxydopamine lesion did not impact GABA or glutamate among rats chronically treated with saline. However, we observed an interaction of lesion and treatment whereby, among lesioned rats, l-DOPA given acutely (1 d) or chronically (14-16 d) reduced glutamate efflux and enhanced GABA efflux. Site-specific microinjections into M1 demonstrated that l-DOPA-induced dyskinesia was reduced by M1 infusion of a D1 antagonist, an AMPA antagonist, or a GABAA agonist. Overall, the present study demonstrates that l-DOPA-induced dyskinesia is associated with increased M1 inhibition and that exogenously enhancing M1 inhibition may attenuate dyskinesia, findings that are in agreement with functional imaging and transcranial magnetic stimulation studies in human Parkinson's disease patients. Together, our study suggests that increasing M1 inhibitory tone is an endogenous compensatory response designed to limit dyskinesia severity and that potentiating this response is a viable therapeutic strategy. Most Parkinson's disease patients will receive l-DOPA and eventually develop hyperkinetic involuntary movements termed dyskinesia. Such symptoms can be as debilitating as the disease itself. Although dyskinesia is associated with dynamic changes in primary motor cortex physiology, to date, there are no published studies investigating in vivo neurotransmitter release in M1 during dyskinesia. In parkinsonian rats, l-DOPA administration reduced M1 glutamate efflux and enhanced GABA efflux, coincident with the emergence of dyskinetic behaviors. Dyskinesia could be reduced by local M1 modulation of D1, AMPA, and GABAA receptors, providing preclinical support for the notion that exogenously blunting M1 signaling (pharmacologically or with cortical stimulation) is a therapeutic approach to the treatment of debilitating dyskinesias. Copyright © 2016 the authors 0270-6474/16/369873-15$15.00/0.

Pupillometry as an indicator of L-DOPA dosages in Parkinson's disease patients.

PubMed

Bartošová, O; Bonnet, C; Ulmanová, O; Šíma, M; Perlík, F; Růžička, E; Slanař, O

2018-04-01

Dopamine was shown to induce mydriasis by excitation of alpha-adrenergic receptors at the dilator pupillae muscle. Pupilla diameter may thus serve as an indirect measure of peripheral pharmacokinetics of L-DOPA and dopamine. The aim of this study is to evaluate the effect of L-DOPA dosage on pupillometric parameters in Parkinson's disease (PD) patients. Sixteen PD patients and 14 healthy control subjects (CS) were studied. The statistical analysis revealed significant differences between CS and PD patients for the mean maximum and minimum pupil diameters (p = 0.017, p = 0.028, respectively), with higher values found in PD. Moreover, a significant dose-response relationship was found between the maximum pupil diameter and both the morning L-DOPA dose (R 2  = 0.78) and the total daily L-DOPA dose (R 2  = 0.93). A sigmoid-shaped curve best describes the dose-response relationship, with a ceiling effect at about 400 mg L-DOPA daily dose. In conclusion, measuring pupillometric parameters represents a sensitive tool for non-invasive evaluation of the peripheral effect of L-DOPA, especially with daily doses below 400 mg L-DOPA.

Correlation between dopamine receptor D2 expression and presence of abnormal involuntary movements in Wistar rats with hemiparkinsonism and dyskinesia.

PubMed

Caro Aponte, P A; Otálora, C A; Guzmán, J C; Turner, L F; Alcázar, J P; Mayorga, E L

2018-03-07

Parkinson's disease (PD) is characterised by motor alterations, which are commonly treated with L-DOPA. However, long-term L-DOPA use may cause dyskinesia. Although the pathogenic mechanism of L-DOPA-induced dyskinesia is unclear, the condition has been associated with alterations in dopamine receptors, among which D2 receptors (D2R) have received little attention. This study aims to: (i)develop and standardise an experimental model of L-DOPA-induced dyskinesia in rats with hemiparkinsonism; and (ii)evaluate the correlation between D2R expression and presence of abnormal involuntary movements (AIM). We allocated 21 male Wistar rats into 3 groups: intact controls, lesioned rats (with neurotoxin 6-OHDA), and dyskinetic rats (injected with L-DOPA for 19 days). Sensorimotor impairment was assessed with behavioural tests. Dyskinetic rats gradually developed AIMs during the treatment period; front leg AIMs were more severe and locomotor AIMs less severe (P<.05). All AIMs were significantly evident from day 5 and persisted until the last day of injection. D2R density was greater in the striatum and the medial anterior brain of the lesioned and dyskinetic rats than in those of controls. Our results suggest an association between D2R expression and locomotor AIMs. We conclude that RD2 is involved in L-DOPA-induced dyskinesia. Copyright © 2018 Sociedad Española de Neurología. Publicado por Elsevier España, S.L.U. All rights reserved.

Levodopa/benserazide microsphere (LBM) prevents L-dopa induced dyskinesia by inactivation of the DR1/PKA/P-tau pathway in 6-OHDA-lesioned Parkinson's rats

PubMed Central

Xie, Cheng-long; Wang, Wen-Wen; Zhang, Su-fang; Yuan, Ming-Lu; Che, Jun-Yi; Gan, Jing; Song, Lu; Yuan, Wei-En; Liu, Zhen-Guo

2014-01-01

L-3, 4-dihydroxyphenylalanine (L-dopa) is the gold standard for symptomatic treatment of Parkinson's disease (PD), but long-term therapy is associated with the emergence of L-dopa-induced dyskinesia (LID). In the present study, L-dopa and benserazide were loaded by poly (lactic-co-glycolic acid) microspheres (LBM), which can release levodopa and benserazide in a sustained manner in order to continuous stimulate dopaminergic receptors. We investigated the role of striatal DR1/PKA/P-tau signal transduction in the molecular event underlying LID in the 6-OHDA-lesioned rat model of PD. We found that animals rendered dyskinetic by L-dopa treatment, administration of LBM prevented the severity of AIM score, as well as improvement in motor function. Moreover, we also showed L-dopa elicits profound alterations in the activity of three LID molecular markers, namely DR1/PKA/P-tau (ser396). These modifications are totally prevented by LBM treatment, a similar way to achieve continuous dopaminergic delivery (CDD). In conclusion, our experiments provided evidence that intermittent administration of L-dopa, but not continuous delivery, and DR1/PKA/p-tau (ser396) activation played a critical role in the molecular and behavioural induction of LID in 6-OHDA-lesioned rats. In addition, LBM treatment prevented the development of LID by inhibiting the expression of DR1/PKA/p-tau, as well as PPEB mRNA in dyskintic rats. PMID:25511986

Levodopa/benserazide microsphere (LBM) prevents L-dopa induced dyskinesia by inactivation of the DR1/PKA/P-tau pathway in 6-OHDA-lesioned Parkinson's rats.

PubMed

Xie, Cheng-long; Wang, Wen-Wen; Zhang, Su-fang; Yuan, Ming-Lu; Che, Jun-Yi; Gan, Jing; Song, Lu; Yuan, Wei-En; Liu, Zhen-Guo

2014-12-16

L-3, 4-dihydroxyphenylalanine (L-dopa) is the gold standard for symptomatic treatment of Parkinson's disease (PD), but long-term therapy is associated with the emergence of L-dopa-induced dyskinesia (LID). In the present study, L-dopa and benserazide were loaded by poly (lactic-co-glycolic acid) microspheres (LBM), which can release levodopa and benserazide in a sustained manner in order to continuous stimulate dopaminergic receptors. We investigated the role of striatal DR1/PKA/P-tau signal transduction in the molecular event underlying LID in the 6-OHDA-lesioned rat model of PD. We found that animals rendered dyskinetic by L-dopa treatment, administration of LBM prevented the severity of AIM score, as well as improvement in motor function. Moreover, we also showed L-dopa elicits profound alterations in the activity of three LID molecular markers, namely DR1/PKA/P-tau (ser396). These modifications are totally prevented by LBM treatment, a similar way to achieve continuous dopaminergic delivery (CDD). In conclusion, our experiments provided evidence that intermittent administration of L-dopa, but not continuous delivery, and DR1/PKA/p-tau (ser396) activation played a critical role in the molecular and behavioural induction of LID in 6-OHDA-lesioned rats. In addition, LBM treatment prevented the development of LID by inhibiting the expression of DR1/PKA/p-tau, as well as PPEB mRNA in dyskintic rats.

The effects of BMY-14802 against L-DOPA- and dopamine agonist-induced dyskinesia in the hemiparkinsonian rat

PubMed Central

Bhide, Nirmal; Lindenbach, David; Surrena, Margaret A.; Goldenberg, Adam A.; Bishop, Christopher; Berger, S. Paul; Paquette, Melanie A.

2013-01-01

Rationale L-DOPA continues to be the primary treatment for patients with Parkinson’s disease; however, the benefits of long-term treatment are often accompanied by debilitating side effects known as dyskinesias. In recent years, several 5-HT1A receptor agonists have been found to reduce dyskinesia in clinical and experimental models of PD. The purported sigma-1 antagonist, BMY-14802 has been previously demonstrated to reduce L-DOPA induced dyskinesia in a 5-HT1A receptor dependent manner. Objective In the present study, we extend these findings by examining the anti-dyskinetic potential of BMY-14802 against L-DOPA, the D1 receptor agonist SKF81297 and the D2 receptor agonist, Quinpirole, in the hemi-parkinsonian rat model. In addition, the receptor specificity of BMY-14802’s effects was evaluated using WAY-100635, a 5-HT1A receptor antagonist. Results Results confirmed the dose-dependent (20>10>5 mg/kg) anti-dyskinetic effects of BMY-14802 against L-DOPA with preservation of antiparkinsonian efficacy at 10 mg/kg. BMY-14802 at 10 and 20 mg/kg also reduced dyskinesia induced by both D1 and D2 receptor agonists. Additionally, BMY-14802’s anti-dyskinetic effects against L-DOPA, but not SKF81297 or Quinpirole, were reversed by WAY-100635 (0.5 mg/kg). Conclusion Collectively, these findings demonstrate that BMY-14802 provides anti-dyskinetic relief against L-DOPA and direct DA agonist in a preclinical model of PD, acting via multiple receptor systems and supports the utility of such compounds for the improved treatment of PD. PMID:23389756

cAMP Response Element-Binding Protein Is Required for Dopamine-Dependent Gene Expression in the Intact But Not the Dopamine-Denervated Striatum

PubMed Central

Andersson, Malin; Konradi, Christine; Cenci, M. Angela

2014-01-01

The cAMP response element-binding protein (CREB) is believed to play a pivotal role in dopamine (DA) receptor-mediated nuclear signaling and neuroplasticity. Here we demonstrate that the significance of CREB for gene expression depends on the experimental paradigm. We compared the role of CREB in two different but related models: L-DOPA administration to unilaterally 6-hydroxydopamine lesioned rats, and cocaine administration to neurologically intact animals. Antisense technology was used to produce a local knockdown of CREB in the lateral caudate–putamen, a region that mediates the dyskinetic or stereotypic manifestations associated with L-DOPA or cocaine treatment, respectively. In intact rats, CREB antisense reduced both basal and cocaine-induced expression of c-Fos, FosB/ΔFosB, and prodynorphin mRNA. In the DA-denervated striatum, CREB was not required for L-DOPA to induce these gene products, nor did CREB contribute considerably to DNA binding activity at cAMP responsive elements (CREs) and CRE-like enhancers. ΔFosB-related proteins and JunD were the main contributors to both CRE and AP-1 DNA–protein complexes in L-DOPA-treated animals. In behavioral studies, intrastriatal CREB knockdown caused enhanced activity scores in intact control animals and exacerbated the dyskinetic effects of acute L-DOPA treatment in 6-OHDA-lesioned animals. These data demonstrate that CREB is not required for the development of L-DOPA-induced dyskinesia in hemiparkinsonian rats. Moreover, our results reveal an unexpected alteration of nuclear signaling mechanisms in the parkinsonian striatum treated with L-DOPA, where AP-1 transcription factors appear to supersede CREB in the activation of CRE-containing genes. PMID:11739600

Systemic administration of dizocilpine maleate (MK-801) or L-dopa reverses the increases in GAD65 and GAD67 mRNA expression in the globus pallidus in a rat hemiparkinsonian model.

PubMed

Bacci, Jean-Jacques; Salin, Pascal; Kerkerian-Le Goff, Lydia

2002-12-15

This study examined the consequences of systemic treatment with either L-dopa or MK-801 on the levels of mRNAs encoding the 65 and 67 kDa isoforms of glutamate decarboxylase (GAD65 and GAD67) in the striatum and globus pallidus (GP) of rats rendered hemiparkinsonian by intranigral 6-hydroxydopamine injection. GADs mRNA levels were assessed by means of in situ hybridization histochemistry. In the striatum, dopamine denervation resulted in increased GAD67 mRNA levels at the rostral and caudal levels, whereas GAD65 showed selective increase at the caudal level. L-dopa and MK-801 treatments showed differential effects on the two GAD isoform levels in rats with 6-hydroxydopamine lesion. The lesion-induced increases in GAD67 transcripts were potentiated by L-dopa but unaffected by MK-801, whereas the increases in GAD65 were suppressed by MK-801 but unaffected by L-dopa. These data suggest a heterogeneity of glutamate-dopamine interaction in the anteroposterior extent of the striatum and show that NMDA-mediated mechanisms are involved in the 6-hydroxydopamine lesion-induced transcriptional changes in striatal GAD65 but not GAD67. In GP, the 6-OHDA lesion elicited increases in both GAD65 and GAD67 mRNA levels. L-dopa or MK-801 treatment suppressed the lesion-induced augmentations in the two GADs mRNA levels. These results indicate that dopamine denervation-induced changes in the functional activity of GP neurons involve both dopamine and glutamate NMDA receptor-mediated mechanisms. Comparison between the effects of L-dopa and MK-801 treatments on markers of the activity of striatal and pallidal GABA neurons further suggest that the impact of these treatments at the GP level do not depend solely on the striatopallidal input. Copyright 2002 Wiley-Liss, Inc.

Contribution of dopamine to mitochondrial complex I inhibition and dopaminergic deficits caused by methylenedioxymethamphetamine in mice.

PubMed

Barros-Miñones, L; Goñi-Allo, B; Suquia, V; Beitia, G; Aguirre, N; Puerta, E

2015-06-01

Methylenedioxymethamphetamine (MDMA) causes a persistent loss of dopaminergic cell bodies in the substantia nigra of mice. Current evidence indicates that MDMA-induced neurotoxicity is mediated by oxidative stress probably due to the inhibition of mitochondrial complex I activity. In this study we investigated the contribution of dopamine (DA) to such effects. For this, we modulated the dopaminergic system of mice at the synthesis, uptake or metabolism levels. Striatal mitochondrial complex I activity was decreased 1 h after MDMA; an effect not observed in the striatum of DA depleted mice or in the hippocampus, a dopamine spare region. The DA precursor, L-dopa, caused a significant reduction of mitochondrial complex I activity by itself and exacerbated the dopaminergic deficits when combined with systemic MDMA. By contrast, no damage was observed when L-dopa was combined with intrastriatal injections of MDMA. On the other hand, dopamine uptake blockade using GBR 12909, inhibited both, the acute inhibition of complex I activity and the long-term dopaminergic toxicity caused by MDMA. Moreover, the inhibition of DA metabolism with the monoamine oxidase (MAO) inhibitor, pargyline, afforded a significant protection against MDMA-induced complex I inhibition and neurotoxicity. Taken together, these findings point to the formation of hydrogen peroxide subsequent to DA metabolism by MAO, rather than a direct DA-mediated mitochondrial complex I inhibition, and the contribution of a peripheral metabolite of MDMA, as the key steps in the chain of biochemical events leading to DA neurotoxicity caused by MDMA in mice. Copyright © 2015 Elsevier Ltd. All rights reserved.

Linagliptin potentiates the effect of l-dopa on the behavioural, biochemical and immunohistochemical changes in experimentally-induced Parkinsonism: Role of toll-like receptor 4, TGF-β1, NF-κB and glucagon-like peptide 1.

PubMed

Kabel, Ahmed M; Omar, Mohamed S; Alhadhrami, A; Alharthi, Salman S; Alrobaian, Majed M

2018-05-01

Our aim was to assess the effect of different doses of linagliptin with or without l-dopa/Carbidopa on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced parkinsonism in mice. Eighty Balb/c mice were divided into 8 equal groups: Control; MPTP; MPTP + l-dopa/Carbidopa; MPTP + linagliptin 3 mg/kg/day; MPTP + linagliptin 10 mg/kg/day; MPTP + Carboxymethyl cellulose; MPTP + l-dopa/Carbidopa + linagliptin 3 mg/kg/day and MPTP + l-dopa/Carbidopa + linagliptin 10 mg/kg/day. Striatal dopamine, tumor necrosis factor alpha (TNF-α), interleukin 10 (IL-10), transforming growth factor beta 1 (TGF-β1), toll-like receptor 4 (TLR4), antioxidant enzymes, adenosine triphosphate (ATP), glucagon-like peptide-1 (GLP-1), receptors of advanced glycation end products (RAGE), nuclear factor (erythroid-derived 2)-like 2 (Nrf2), heme oxygenase-1 (HO-1), mitochondrial complex I activity, catalepsy and total swim scores were measured. Also, the substantia nigra was subjected to immunohistochemical examination. The combination of l-dopa/Carbidopa and linagliptin in a dose-dependent manner resulted in significant improvement of the behavioural changes, striatal dopamine, antioxidant parameters, Nrf2/HO-1 content, GLP-1, ATP and mitochondrial complex I activity with significant decrease in striatal RAGE, TGF-β1, TNF-α, IL-10, TLR4 and alleviated the immunohistochemical changes better than the groups that received either l-dopa/Carbidopa or linagliptin alone. The combination of l-dopa/Carbidopa and linagliptin might represent a promising therapeutic modality for management of parkinsonism. Copyright © 2018 Elsevier Inc. All rights reserved.

Enkephalin and dynorphin neuropeptides are differently correlated with locomotor hypersensitivity and levodopa-induced dyskinesia in parkinsonian rats.

PubMed

Sgroi, Stefania; Capper-Loup, Christine; Paganetti, Paolo; Kaelin-Lang, Alain

2016-06-01

The opioidergic neuropeptides dynorphin (DYN) and enkephalin (ENK) and the D1 and D2 dopaminergic receptors (D1R, D2R) are involved in the striatal control of motor and behavioral function. In Parkinson's disease, motor disturbances such as "on-off" motor fluctuations and involuntary movements (dyskinesia) are severe complications that often arise after chronic l-dihydroxyphenylalanine (l-DOPA) treatment. Changes in the striatal expression of preproENK (PPENK), proDYN (PDYN), D1R, and D2R mRNA have been observed in parkinsonian animals treated with l-DOPA. Enhanced opioidergic transmission has been found in association with l-DOPA-induced dyskinesia, but the connection of PPENK, PDYN, D1R, and D2R mRNA expression with locomotor activity remains unclear. In this study, we measured PPENK, PDYN, D1R and D2R mRNA levels by in situ hybridization in the striatum of 6-OHDA hemi-parkinsonian rats treated with l-DOPA (PD+l-DOPA group), along with two control groups (PD+saline and naive+l-DOPA). We found different levels of expression of PPENK, PDYN, D1R and D2R mRNA across the experimental groups and correlated the changes in mRNA expression with dyskinesia and locomotor variables assessed by open field test during several phases of l-DOPA treatment. Both PDYN and PPENK mRNA levels were correlated with the severity of dyskinesia, while PPENK mRNA levels were also correlated with the frequency of contralateral rotational movements and with locomotor variables. Moreover, a strong correlation was found between D1R mRNA expression and D2R mRNA expression in the PD+l-DOPA group. These findings suggest that, in parkinsonian animals treated with l-DOPA, high levels of PPENK are a prerequisite for a locomotor sensitization to l-DOPA treatment, while PDYN overexpression is responsible only for the development of dyskinesia. Copyright © 2016 Elsevier Inc. All rights reserved.

Different roles of retinal dopamine in albino Guinea pig myopia.

PubMed

Mao, Junfeng; Liu, Shuangzhen

2017-02-03

To investigate whether the different role of ocular dopamine was involved in the myopic development between spontaneous myopia (SM) and form deprivation myopia (FDM) in albino guinea pigs. 55 myopic animals were randomly divided into SM, Levodapa (L-DOPA), L-DOPA+carbidopa and vehicle. 70 non-myopic animals were randomly divided into normal control, FDM, L-DOPA+FDM, L-DOPA+carbidopa+FDM and vehicle. Once per day, for 14days, L-DOPA (10mg/kg) was injected intraperitoneally, and carbidopa (1μg) was injected at the same time into the peribulbar space of the right eye. Refractive parameters and dopamine content in neural retina and RPE/choroid complex were measured. In SM animals, high myopia was formed at 5 week of ages. L-DOPA treatment could reduce its myopic degree, and inhibit the increase of axial length and vitreous chamber depth with the increase of retinal dopamine in both eyes. Administration of carbidopa could prevent the increase of retinal dopamine induced by L-DOPA, but no influenced on its refractive state in the injected eyes. In non-SM animals, intraperitoneal L-DOPA could inhibit FDM, accompanied by the increase of retinal dopamine. Carbidopa treatment diminished the inhibition of FDM and prevented the increase in retinal dopamine by L-Dopa. Retinal dopamine was highly correlated with ocular refraction in FDM, but not in SM. There was no significant difference in dopamine content of RPE/choroid complex among all groups. The role of retinal dopamine was different between SM and FDM in albino guinea pigs. Although systemic L-DOPA could inhibit the development of SM and FDM, retinal dopamine was only involved in the L-DOPA inhibition on FDM, but not on SM. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Modulation of PC12 cell viability by forskolin-induced cyclic AMP levels through ERK and JNK pathways: an implication for L-DOPA-induced cytotoxicity in nigrostriatal dopamine neurons.

PubMed

Park, Keun Hong; Park, Hyun Jin; Shin, Keon Sung; Choi, Hyun Sook; Kai, Masaaki; Lee, Myung Koo

2012-07-01

The intracellular levels of cyclic AMP (cAMP) increase in response to cytotoxic concentrations of L-DOPA in PC12 cells, and forskolin that induces intracellular cAMP levels either protects PC12 cells from L-DOPA-induced cytotoxicity or enhances cytotoxicity in a concentration-dependent manner. This study investigated the effects of cAMP induced by forskolin on cell viability of PC12 cells, relevant to L-DOPA-induced cytotoxicity in Parkinson's disease therapy. The low levels of forskolin (0.01 and 0.1 μM)-induced cAMP increased dopamine biosynthesis and tyrosine hydroxylase (TH) phosphorylation, and induced transient phosphorylation of ERK1/2 within 1 h. However, at the high levels of forskolin (1.0 and 10 μM)-induced cAMP, dopamine biosynthesis and TH phosphorylation did not increase, but rapid differentiation in neurite-like formation was observed with a steady state. The high levels of forskolin-induced cAMP also induced sustained increase in ERK1/2 phosphorylation within 0.25-6 h and then led to apoptosis, which was apparently mediated by JNK1/2 and caspase-3 activation. Multiple treatment of PC12 cells with nontoxic L-DOPA (20 μM) for 4-6 days induced neurite-like formation and decreased intracellular dopamine levels by reducing TH phosphorylation. These results suggest that the low levels of forskolin-induced cAMP increased dopamine biosynthesis in cell survival via transient ERK1/2 phosphorylation. In contrast, the high levels of forskolin-induced cAMP induced differentiation via sustained ERK1/2 phosphorylation and then led to apoptosis. Taken together, the intracellular levels of cAMP play a dual role in cell survival and death through the ERK1/2 and JNK1/2 pathways in PC12 cells.

Repeated administration of the monoamine reuptake inhibitor BTS 74 398 induces ipsilateral circling in the 6-hydroxydopamine lesioned rat without sensitizing motor behaviours.

PubMed

Lane, E L; Cheetham, S C; Jenner, P

2005-01-01

BTS 74 398 (1-[1-(3,4-dichlorophenyl)cyclobutyl]-2-(3-diaminethylaminopropylthio)ethanone monocitrate) is a monoamine reuptake inhibitor that reverses motor deficits in MPTP-treated (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) common marmosets without provoking established dyskinesia. However, it is not known whether BTS 74 398 primes the basal ganglia for dyskinesia induction. In this study, the ability of BTS 74 398 to sensitize 6-hydroxydopamine (6-OHDA)-lesioned rats for the production of abnormal motor behaviours and the induction of striatal DeltaFosB were determined in comparison with l-3,4-dihydroxyphenylalanine methyl ester (L-dopa). Acute administration of BTS 74 398 induced a dose-dependent ipsilateral circling response in unilaterally 6-OHDA-lesioned rats whereas L-dopa produced dose-dependent contraversive rotation. The ipsilateral circling response to BTS 74 398 did not alter during 21 days of administration. In contrast, L-dopa treatment for 21 days caused a marked increase in rotational response. Repeated administration of both L-dopa and BTS 74 398 increased general motor activity and stereotypic behaviour. In L-dopa-treated rats, orolingual, locomotive, forelimb and axial abnormal movements developed whereas BTS 74 398 produced only locomotion with a side bias but no other abnormal movements. Sensitization of circling responses and the development of abnormal movements in 6-OHDA-lesioned rats have been associated with the potential of dopaminergic drugs to induce dyskinesia. Furthermore, striatal DeltaFosB immunoreactivity, shown to correlate with dyskinesia induction, was increased by L-dopa but was unaffected by repeated BTS 74 398 administration. The lack of such changes following repeated BTS 74 398 treatment suggests that it may be an effective antiparkinsonian therapy that is unlikely to produce involuntary movements.

Parkinson's disease: carbidopa, nausea, and dyskinesia.

PubMed

Hinz, Marty; Stein, Alvin; Cole, Ted

2014-01-01

When l-dopa use began in the early 1960s for the treatment of Parkinson's disease, nausea and reversible dyskinesias were experienced as continuing side effects. Carbidopa or benserazide was added to l-dopa in 1975 solely to control nausea. Subsequent to the increasing use of carbidopa has been the recognition of irreversible dyskinesias, which have automatically been attributed to l-dopa. The research into the etiology of these phenomena has identified the causative agent of the irreversible dyskinesias as carbidopa, not l-dopa. The mechanism of action of the carbidopa and benserazide causes irreversible binding and inactivation of vitamin B6 throughout the body. The consequences of this action are enormous, interfering with over 300 enzyme and protein functions. This has the ability to induce previously undocumented profound antihistamine dyskinesias, which have been wrongly attributed to l-dopa and may be perceived as irreversible if proper corrective action is not taken.

Parkinson’s disease: carbidopa, nausea, and dyskinesia

PubMed Central

Hinz, Marty; Stein, Alvin; Cole, Ted

2014-01-01

When l-dopa use began in the early 1960s for the treatment of Parkinson’s disease, nausea and reversible dyskinesias were experienced as continuing side effects. Carbidopa or benserazide was added to l-dopa in 1975 solely to control nausea. Subsequent to the increasing use of carbidopa has been the recognition of irreversible dyskinesias, which have automatically been attributed to l-dopa. The research into the etiology of these phenomena has identified the causative agent of the irreversible dyskinesias as carbidopa, not l-dopa. The mechanism of action of the carbidopa and benserazide causes irreversible binding and inactivation of vitamin B6 throughout the body. The consequences of this action are enormous, interfering with over 300 enzyme and protein functions. This has the ability to induce previously undocumented profound antihistamine dyskinesias, which have been wrongly attributed to l-dopa and may be perceived as irreversible if proper corrective action is not taken. PMID:25484598

Evidence for a role for α6* nAChRs in L-dopa-induced dyskinesias using parkinsonian α6* nAChR gain-of-function mice

PubMed Central

Bordia, Tanuja; McGregor, Matthew; McIntosh, J.M.; Drenan, Ryan M.; Quik, Maryka

2015-01-01

L-Dopa-induced dyskinesias (LIDs) are a serious side effect of dopamine replacement therapy for Parkinson's disease. The mechanisms that underlie LIDs are currently unclear. However, preclinical studies indicate that nicotinic acetylcholine receptors (nAChRs) play a role, suggesting that drugs targeting these receptors may be of therapeutic benefit. To further understand the involvement of α6β2* nAChRs in LIDs, we used gain-of-function α6* nAChR (α6L9S) mice that exhibit a 20-fold enhanced sensitivity to nAChR agonists. Wildtype (WT) and α6L9S mice were lesioned by unilateral injection of 6-hydroxydopamine (6-OHDA, 3 μg/ml) into the medial forebrain bundle. Three to 4 wk later, they were administered L-dopa (3 mg/kg) plus benserazide (15 mg/kg) until stably dyskinetic. L-dopa-induced abnormal involuntary movements (AIMs) were similar in α6L9S and WT mice. WT mice were then given nicotine in the drinking water in gradually increasing doses to a final 300 μg/ml, which resulted in a 40% decline AIMs. By contrast, there was no decrease in AIMs in α6L9S mice at a maximally tolerated nicotine dose of 20 μg/ml. However, the nAChR antagonist mecamylamine (1 mg/kg ip 30 min before L-dopa) reduced L-dopa-induced AIMs in both α6L9S and WT mice. Thus, both a nAChR agonist and antagonist decreased AIMs in WT mice, but only the antagonist was effective in α6L9S mice. Since nicotine appears to reduce LIDs via desensitization, hypersensitive α6β2* nAChRs may desensitize less readily. The present data show that α6β2* nAChRs are key regulators of LIDs, and may be useful therapeutic targets for their management in Parkinson's disease. PMID:25813704

Synthesis of adhesive peptides similar to those found in blue mussel (Mytilus edulis) using papain and tyrosinase.

PubMed

Numata, Keiji; Baker, Peter James

2014-08-11

The blue mussel (Mytilus edulis) foot protein 5 (Mefp-5) is an adhesive protein that is mainly composed of glycine, l-lysine, and 3,4-dihydroxy-l-phenylalanine (DOPA). Thousands of adhesive pads have been analyzed in previous studies, whereby it has been found that adhesion is largely achieved by the redox-chemistry of DOPA, and that l-lysine (approximately 20 mol %) affects the formation of molecular networks. While DOPA and lysine are essential for biomimetic adhesive design, the synthesis of copolymers containing DOPA is limited, in terms of yield, by the multiple reaction steps required. Here, we synthesized adhesive peptides containing DOPA and l-lysine via two enzymatic reactions, namely, chemoenzymatic synthesis of copolypeptides of l-tyrosine and l-lysine by Papaya peptidase I (papain), as well as the enzymatic conversion from l-tyrosine to DOPA by tyrosinase. The synthesis was characterized in terms of yield, degree of polymerization, and composition of the polypeptide. In addition, the conversion of tyrosine to DOPA by tyrosinase was evaluated quantitatively by nuclear magnetic resonance and amino acid analysis. The adhesive properties of the resulting peptides, consisting of DOPA, l-lysine, and l-tyrosine, were evaluated at various pH levels with different protonation/deprotonation states. Our results show that deprotonated DOPA is required for adhesive function, and the deprotonated primary amine group of lysine induces molecular networks by varying the elastic moduli of the adhesives. In this study, we demonstrate the benefit of combining multiple enzymatic reactions, including chemoenzymatic polymerization, in obtaining new types of peptide-based materials.

Biophenols: Enzymes (β-secretase, Cholinesterases, histone deacetylase and tyrosinase) inhibitors from olive (Olea europaea L.).

PubMed

Omar, Syed Haris; Scott, Christopher J; Hamlin, Adam S; Obied, Hassan K

2018-07-01

The focus of this study was on inhibition of enzymes involved in the pathogenesis Alzheimer's disease (AD) including prime amyloid beta (Aβ) producing enzyme (β-secretase: BACE-1) and disease progression enzymes including acetylcholinesterase (AChE), butyrylcholinesterase (BChE), histone deacetylase (HDAC), and tyrosinase along with the catecholamine L-DOPA, by using olive biophenols. Here we report the strongest inhibition of BACE-1 from rutin (IC 50 : 3.8 nM) followed by verbascoside (IC 50 : 6.3 nM) and olive fruit extract (IC 50 : 18 ng), respectively. Olive biophenol, quercetin exhibited strongest enzyme inhibitory activity against tyrosinase (IC 50 : 10.73 μM), BChE (IC 50 : 19.08 μM), AChE (IC 50 : 55.44 μM), and HDAC (IC 50 : 105.1 μM) enzymes. Furthermore, olive biophenol verbascoside (IC 50 : 188.6 μM), and hydroxytyrosol extreme extract (IC 50 : 66.22 μg) were showed the highest levels of inhibition against the HDAC enzyme. Neuroprotective capacity against levodopa-induced toxicity in neuroblastoma (SH-SY5Y) cells of olive biophenols were assessed, where rutin indicated the highest neuroprotection (74%), followed by caffeic acid (73%), and extract hydroxytyrosol extreme (97%), respectively. To the best of our knowledge, this is the first in vitro report on the enzymes inhibitory activity of olive biophenols. Taken together, our in vitro results data suggest that olive biophenols could be a promising natural inhibitor, which may reduce the enzyme-induced toxicity associated with the oxidative stress involved in the progression of AD. Acetylthiocholine iodide (PubChem CID: 74629); S-Butyrylthiocholine chloride (PubChem CID: 3015121); Caffeic acid (PubChem CID: 689043); Dimethyl sulfoxide (DMSO) (PubChem: 679); L-3,4-Dihydroxyphenylalanine (L-DOPA) (PubChem CID: 6047); 5,5'-Dithiobis (2-nitrobenzoic acid) (DTNB) (PubChem CID: 6254); Epigallocatechin gallate (EGCG) (PubChem CID: 65064); Ethylenediamine tetraacetic acid (EDTA) (PubChem CID: 6049); Galantamine hydrobromide (PubChem CID: 121587); l-Glutamine (PubChem CID: 5961); Hydroxytyrosol (PubChem CID: 82755); Kojic acid (PubChem CID: 3840); Luteolin (PubChem CID: 5280445); Oleuropein (PubChem CID: 5281544); Penicillin-streptomycin (PubChem CID: 131715954); Quercetin (PubChem CID: 5280343); Rutin (PubChem CID: 5280805); Tris-HCl buffer (PubChem: 93573); Trypan blue (PubChem: 9562061). Copyright © 2018 Elsevier B.V. All rights reserved.

DOR agonist (SNC-80) exhibits anti-parkinsonian effect via downregulating UPR/oxidative stress signals and inflammatory response in vivo.

PubMed

Begum M, Erfath Thanjeem; Sen, Dwaipayan

2018-06-21

The pathophysiology of Parkinson's disease exhibit imperative roles in unfolded protein response stress-induced oxidative stress and inflammation in general. Although, delta opioid receptor (DOR), has been found to represent anti-parkinsonian effect at behavioral level, its underlying mechanism remains elusive till date. In the present study the role of DOR agonist, SNC-80 and the consorted molecular mechanisms, which translates to behavioral recuperation, has been delineated. In order to mimic PD, mice were intra-peritoneally injected with MPTP, following exposure to SNC-80 and L-DOPA to elucidate amelioration of the MPTP-induced behavioral impairments. The results obtained suggest that the severity of the compromised motor functions up-regulated the UPR stress sensors: IRE-1α/Bip/CHOP, oxidative stress along with the pro-inflammatory cytokines: IL1β/IFNγ/TNFα and IL-6. These inimical factors combined, aids the persistence of the disease in MPTP intoxicated mice. Supplementation with SNC-80 significantly improved motor functions via down-regulation of the UPR stress sensors and inflammatory cytokines. Additionally, SNC-80 could upregulate Nrf-2 and Heme oxygenase-1 (HO-1) protein expression indicating their involvement in SNC-80's potential anti-oxidant function. There was also a significant reduction in protein carbonyl content indicating the positive role of SNC-80 in dampening MPTP induced oxidative stress. Concomitantly, L-DOPA also demonstrated an enhanced effect towards improvement of motor functions but did not suppress the UPR and inflammatory responses caused due to MPTP intoxication. Hence, these results suggest that SNC-80 could hold a pivotal role in replenishing motor functions essentially via regulating UPR and inflammation. Copyright © 2018 Elsevier B.V. All rights reserved.

L-tyrosine and L-DOPA as hormone-like regulators of melanocytes functions

PubMed Central

Slominski, Andrzej; Zmijewski, Michal; Pawelek, John

2011-01-01

Summary Evidence reveals that L-tyrosine and L-DOPA, besides serving as substrates and intermediates of melanogenesis, are also bioregulatory agents acting not only as inducers and positive regulators of melanogenesis but also as regulators of other cellular functions. These can be mediated through action on specific receptors or through non-receptor mediated mechanisms. The substrate induced (L-tyrosine and/or L-DOPA) melanogenic pathway would autoregulate itself as well as it would regulate the melanocyte functions through activity of its structural or regulatory proteins and through intermediates of melanogenesis and melanin itself. Dissection of regulatory and autoregulatory elements of this process may elucidate how substrate induced autoregulatory pathways have evolved from prokaryotic or simple eukaryotic organisms to complex systems in vertebrates. This could substantiate older theory proposing that receptors for amino-acid derived hormones arose from the receptors for those amino acids, and that nuclear receptors evolved from primitive intracellular receptors binding nutritional factors or metabolic intermediates. PMID:21834848

L-DOPA Preloading Increases the Uptake of Borophenylalanine in C6 Glioma Rat Model: A New Strategy to Improve BNCT Efficacy

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

Capuani, Silvia; Enrico Fermi Center, Rome; Gili, Tommaso

Purpose: Boron neutron capture therapy (BNCT) is a radiotherapeutic modality based on {sup 10}B(n,{alpha}){sup 7}Li reaction, for the treatment of malignant gliomas. One of the main limitations for BNCT effectiveness is the insufficient intake of {sup 10}B nuclei in the tumor cells. This work was aimed at investigating the use of L-DOPA as a putative enhancer for {sup 10}B-drug 4-dihydroxy-borylphenylalanine (BPA) uptake in the C6-glioma model. The investigation was first performed in vitro and then extended to the animal model. Methods and Materials: BPA accumulation in C6-glioma cells was assessed using radiowave dielectric spectroscopy, with and without L-DOPA preloading. Twomore » L-DOPA incubation times (2 and 4 hours) were investigated, and the corresponding effects on BPA accumulation were quantified. C6-glioma cells were also implanted in the brain of 32 rats, and tumor growth was monitored by magnetic resonance imaging. Rats were assigned to two experimental branches: (1) BPA administration; (2) BPA administration after pretreatment with L-DOPA. All animals were sacrificed, and assessments of BPA concentrations in tumor tissue, normal brain, and blood samples were performed using high-performance liquid chromatography. Results: L-DOPA preloading induced a massive increase of BPA concentration in C6-glioma cells only after a 4-hour incubation. In the animal model, L-DOPA pretreatment produced a significantly higher accumulation of BPA in tumor tissue but not in normal brain and blood samples. Conclusions: This study suggests the potential use of L-DOPA as enhancer for BPA accumulation in malignant gliomas eligible for BNCT. L-DOPA preloading effect is discussed in terms of membrane transport mechanisms.« less

Levodopa inhibits the development of form-deprivation myopia in guinea pigs.

PubMed

Mao, Junfeng; Liu, Shuangzhen; Qin, Wenjuan; Li, Fengyun; Wu, Xiaoying; Tan, Qian

2010-01-01

It has been shown that visual deprivation leads to a myopic refractive error and also reduces the retinal concentration of dopamine. Exogenously 3,4-dihydroxy-L-phenylalanine (levodopa, L-DOPA) can be converted into dopamine in vivo, which safely and effectively treats Parkinson disease. Moreover, L-DOPA was also used in the treatment of amblyopia in clinical studies. However, the effect of L-DOPA on the development of myopia has not been studied. The aim of this study was to investigate whether intraperitoneal injection of L-DOPA could inhibit form-deprivation myopia in guinea pigs and to explore a new strategy for drug treatment of myopia. Sixty guinea pigs, at age of 4 weeks, were randomly divided into six groups: normal control, L-DOPA group, saline group, deprived group, deprived plus L-DOPA group, and deprived plus saline group. Form deprivation was induced with translucent eye shields on the right eye and lasted for 10 days. L-DOPA was injected intraperitoneally into the guinea pig once a day. The corneal radius of curvature, refraction, and axial length were measured in all animals. Subsequently, retinal dopamine content was evaluated by high-performance liquid chromatography with electrochemical detection. Ten days of eye occlusion caused the form-deprived eyes to elongate and become myopic, and retinal dopamine content to decrease, but the corneal radius of curvature was not affected. Repeated intraperitoneal injection of L-DOPA could inhibit the myopic shift (from -3.62 +/- 0.98 D to -1.50 +/- 0.38 D; p < 0.001) due to goggles occluding and compensate retinal dopamine (from 0.65 +/- 0.10 ng to 1.33 +/- 0.23 ng; p < 0.001). Administration of L-DOPA to the unoccluded animals had no effect on its ocular refraction. There was no effect of intraperitoneal saline on the ocular refractive state and retinal dopamine. Systemic L-DOPA was partly effective in this guinea pig model and, therefore, is worth testing for effectiveness in progressing human myopes.

The Parkinson's disease death rate: carbidopa and vitamin B6.

PubMed

Hinz, Marty; Stein, Alvin; Cole, Ted

2014-01-01

The only indication for carbidopa and benserazide is the management of L-3,4-dihydroxyphenylalanine (L-dopa)-induced nausea. Both drugs irreversibly bind to and permanently deactivate pyridoxal 5'-phosphate (PLP), the active form of vitamin B6, and PLP-dependent enzymes. PLP is required for the function of over 300 enzymes and proteins. Virtually every major system in the body is impacted directly or indirectly by PLP. The administration of carbidopa and benserazide potentially induces a nutritional catastrophe. During the first 15 years of prescribing L-dopa, a decreasing Parkinson's disease death rate was observed. Then, in 1976, 1 year after US Food and Drug Administration approved the original L-dopa/carbidopa combination drug, the Parkinson's disease death rate started increasing. This trend has continued to the present, for 38 years and counting. The previous literature documents this increasing death rate, but no hypothesis has been offered concerning this trend. Carbidopa is postulated to contribute to the increasing Parkinson's disease death rate and to the classification of Parkinson's as a progressive neurodegenerative disease. It may contribute to L-dopa tachyphylaxis.

The Parkinson’s disease death rate: carbidopa and vitamin B6

PubMed Central

Hinz, Marty; Stein, Alvin; Cole, Ted

2014-01-01

The only indication for carbidopa and benserazide is the management of L-3,4-dihydroxyphenylalanine (L-dopa)-induced nausea. Both drugs irreversibly bind to and permanently deactivate pyridoxal 5′-phosphate (PLP), the active form of vitamin B6, and PLP-dependent enzymes. PLP is required for the function of over 300 enzymes and proteins. Virtually every major system in the body is impacted directly or indirectly by PLP. The administration of carbidopa and benserazide potentially induces a nutritional catastrophe. During the first 15 years of prescribing L-dopa, a decreasing Parkinson’s disease death rate was observed. Then, in 1976, 1 year after US Food and Drug Administration approved the original L-dopa/carbidopa combination drug, the Parkinson’s disease death rate started increasing. This trend has continued to the present, for 38 years and counting. The previous literature documents this increasing death rate, but no hypothesis has been offered concerning this trend. Carbidopa is postulated to contribute to the increasing Parkinson’s disease death rate and to the classification of Parkinson’s as a progressive neurodegenerative disease. It may contribute to L-dopa tachyphylaxis. PMID:25364278

Stress-induced changes in brain serotonergic activity, plasma cortisol and aggressive behavior in Arctic charr (Salvelinus alpinus) is counteracted by L-DOPA.

PubMed

Höglund, E; Kolm, N; Winberg, S

2001-10-01

Arctic charr (Salvelinus alpinus) were tested for aggressive behavior using intruder tests, before and after 2 days of dyadic social interaction. Following social interaction, half of the dominant and half of the subordinate fish were given L-DOPA (10 mg/kg, orally), whereas the remaining dominant and subordinate fish were given vehicle. One hour following drug treatment, the fish were tested for aggressive behavior again in a third and final intruder test, after which blood plasma and brain tissue were sampled for analysis of plasma cortisol concentrations and brain levels of monoamines and monoamine metabolites. Subordinate fish showed a reduction in the number of attacks launched against the intruder, as well as an increase in attack latency, as compared to prior to dyadic social interactions. Social subordination also resulted in an elevation of brain serotonergic activity. Fish receiving L-DOPA prior to the final intruder test showed shorter attack latency than vehicle controls. Drug treatment was a stressful experience and vehicle controls showed elevated plasma cortisol levels and longer attack latency as compared to before treatment. L-DOPA-treated fish showed lower plasma levels of cortisol and lower serotonergic activity in certain brain areas than vehicle controls. These results suggest that L-DOPA counteracts the stress-induced inhibition of aggressive behavior, and at the same time inhibits stress-induced effects on brain serotonergic activity and plasma cortisol concentrations.

5-s-Cysteinyl-conjugates of catecholamines induce cell damage, extensive DNA base modification and increases in caspase-3 activity in neurons.

PubMed

Spencer, Jeremy P E; Whiteman, Matthew; Jenner, Peter; Halliwell, Barry

2002-04-01

A decrease in reduced glutathione levels in dopamine containing nigral cells in Parkinson's disease may result from the formation of cysteinyl-adducts of catecholamines, which in turn exert toxicity on nigral cells. We show that exposure of neurons (CSM 14.1) to 5-S-cysteinyl conjugates of dopamine, L-DOPA, DOPAC or DHMA causes neuronal damage, increases in oxidative DNA base modification and an elevation of caspase-3 activity in cells. Damage to neurons was apparent 12-48 h of post-exposure and there were increases in caspase-3 activity in neurons after 6 h. These changes were paralleled by large increases in pyrimidine and purine base oxidation products, such as 8-OH-guanine suggesting that 5-S-cysteinyl conjugates of catecholamines are capable of diffusing into cells and stimulating the formation of reactive oxygen species (ROS), which may then lead to a mechanism of cell damage involving caspase-3. Indeed, intracellular ROS were observed to rise sharply on exposure to the conjugates. These results suggest one mechanism by which oxidative stress may occur in the substantia nigra in Parkinson's disease.

Behavioral and Neurochemical Effects of Alpha-Lipoic Acid in the Model of Parkinson's Disease Induced by Unilateral Stereotaxic Injection of 6-Ohda in Rat

PubMed Central

de Araújo, Dayane Pessoa; De Sousa, Caren Nádia Soares; Araújo, Paulo Victor Pontes; Menezes, Carlos Eduardo de Souza; Sousa Rodrigues, Francisca Taciana; Escudeiro, Sarah Souza; Lima, Nicole Brito Cortez; Patrocínio, Manoel Claúdio Azevedo; Aguiar, Lissiana Magna Vasconcelos; Viana, Glauce Socorro de Barros; Vasconcelos, Silvânia Maria Mendes

2013-01-01

This study aimed to investigate behavioral and neurochemical effects of α-lipoic acid (100 mg/kg or 200 mg/kg) alone or associated with L-DOPA using an animal model of Parkinson's disease induced by stereotaxic injection of 6-hydroxydopamine (6-OHDA) in rat striatum. Motor behavior was assessed by monitoring body rotations induced by apomorphine, open field test and cylinder test. Oxidative stress was accessed by determination of lipid peroxidation using the TBARS method, concentration of nitrite and evaluation of catalase activity. α-Lipoic acid decreased body rotations induced by apomorphine, as well as caused an improvement in motor performance by increasing locomotor activity in the open field test and use of contralateral paw (in the opposite side of the lesion produced by 6-OHDA) at cylinder test. α-lipoic acid showed antioxidant effects, decreasing lipid peroxidation and nitrite levels and interacting with antioxidant system by decreasing of endogenous catalase activity. Therefore, α-lipoic acid prevented the damage induced by 6-OHDA or by chronic use of L-DOPA in dopaminergic neurons, suggesting that α-lipoic could be a new therapeutic target for Parkinson's disease prevention and treatment. PMID:24023579

Identification of a phenoloxidase- and melanin-dependent defence mechanism in Achatina fulica infected with Angiostrongylus vasorum.

PubMed

Coaglio, Aytube Lucas; Ferreira, Mônica Alves Neves Diniz; Dos Santos Lima, Walter; de Jesus Pereira, Cíntia Aparecida

2018-02-27

Angiostrongylus vasorum has different freshwater aquatic and terrestrial gastropod molluscs as an intermediate host, e.g. Arion spp. The mollusc Achatina fulica is a danger to public health, given the large diversity of nematodes utilizing it as an intermediate host, such as the parasites of the genus Angiostrongylus, of importance in human and veterinary medicine. Achatina fulica has been shown to have an excellent capacity for maintaining outbreaks and natural infections with A. cantonensis in Asia. Within the mollusc, the nematode parasites activate haemocytes and/or haemolymph factors and in some invertebrates, phenoloxidase (PO), that induces the release of toxic elements and eliminates the parasites. Despite the importance of A. fulica in the life-cycle of nematodes, little is known regarding the defence mechanisms involving PO in molluscs infected with nematodes. Here, the presence of PO and nitric oxide (NO) in the haemolymph and haemocytes of A. fulica infected with first-stage (L1) larvae of Angiostrongylus vasorum was evaluated, together with the presence of melanin in the cephalopod mollusc tissue. An increase in PO at one day post infection (dpi), in comparison with the control using the substrates L-tyrosine (F (4,90)  = 6.73, P = 0.00006), L-DOPA (F (4,90)  = 22.67, P = 0.02) and p-phenylenediamine (PPD) (F (4,90)  = 27.58, P = 0.0019), was observed. PO increase coincided with the presence of melanin in the cephalopodal tissue. At 8 dpi, PO activity, compared to L-DOPA (F (4,90)  = 22.67, P = 0.00002) and PPD (F (4,90)  = 27.58, P = 0.079) decreased, while melanin increased. At 13 dpi, PO decreased with PPD (F (4,90)  = 27.58, P = 0.000015) and also the amount of melanin observed in histology. At 30 dpi, PO increased along with the substrates L-DOPA and PPD, while melanin decreased. NO levels increased until 8 dpi, and decreased after 13 dpi. To our knowledge, this is the first study that illustrates PO activity in a helminth-infected A. fulica and provides the first observation of an L-tyrosine dependent PO activity in molluscs infected with A. vasorum. This work suggests that PO pathway may help to control A. vasorum infection in A. fulica.

Perry syndrome due to the DCTN1 G71R mutation – a distinctive L-DOPA responsive disorder with behavioural syndrome, vertical gaze palsy and respiratory failure

PubMed Central

Newsway, Victoria; Fish, Mark; Rohrer, Jonathan D.; Majounie, Elisa; Williams, Nigel; Hack, Melissa; Warren, Jason; Morris, Huw R

2015-01-01

Perry syndrome is a rare form of autosomal dominant parkinsonism with respiratory failiure recently defined as being due to mutations in the DCTN1 gene. We describe a new family carrying a G71R mutation in the DCTN1 gene. The proband displayed a series of distinctive features not previously described in Perry syndrome: a disorder of vertical downward saccades accompanied by progressive midbrain atrophy, predominant non-motor symptoms responsive to L-DOPA, distinctive cranio-cervical L-DOPA induced dyskinesias, and a good response to high dose L-DOPA therapy and respiratory support. The family was initially thought to have autosomal dominant behavioural variant frontotemporal dementia with parkinsonism. This report expands the clinical definition of this distinctive syndrome. PMID:20437543

Presynaptic Mechanisms of l-DOPA-Induced Dyskinesia: The Findings, the Debate, and the Therapeutic Implications.

PubMed

Cenci, M Angela

2014-01-01

The dopamine (DA) precursor l-DOPA has been the most effective treatment for Parkinson's disease (PD) for over 40 years. However, the response to this treatment changes with disease progression, and most patients develop dyskinesias (abnormal involuntary movements) and motor fluctuations within a few years of l-DOPA therapy. There is wide consensus that these motor complications depend on both pre- and post-synaptic disturbances of nigrostriatal DA transmission. Several presynaptic mechanisms converge to generate large DA swings in the brain concomitant with the peaks-and-troughs of plasma l-DOPA levels, while post-synaptic changes engender abnormal functional responses in dopaminoceptive neurons. While this general picture is well-accepted, the relative contribution of different factors remains a matter of debate. A particularly animated debate has been growing around putative players on the presynaptic side of the cascade. To what extent do presynaptic disturbances in DA transmission depend on deficiency/dysfunction of the DA transporter, aberrant release of DA from serotonin neurons, or gliovascular mechanisms? And does noradrenaline (which is synthetized from DA) play a role? This review article will summarize key findings, controversies, and pending questions regarding the presynaptic mechanisms of l-DOPA-induced dyskinesia. Intriguingly, the debate around these mechanisms has spurred research into previously unexplored facets of brain plasticity that have far-reaching implications to the treatment of neuropsychiatric disease.

Effect of melatonin on sleep disorders in a monkey model of Parkinson's disease.

PubMed

Belaid, Hayat; Adrien, Joelle; Karachi, Carine; Hirsch, Etienne C; François, Chantal

2015-10-01

To evaluate and compare the effects of melatonin and levodopa (L-dopa) on sleep disorders in a monkey model of Parkinson's disease. The daytime and nighttime sleep patterns of four macaques that were rendered parkinsonian by administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) were recorded using polysomnography in four conditions: at baseline, during the parkinsonian condition; after administration of L-dopa, and after administration of a combination of melatonin with L-dopa. It was confirmed that MPTP intoxication induces sleep disorders, with sleep episodes during daytime and sleep fragmentation at nighttime. L-dopa treatment significantly reduced the awake time during the night and tended to improve all other sleep parameters, albeit not significantly. In comparison to the parkinsonian condition, combined treatment with melatonin and L-dopa significantly increased total sleep time and sleep efficiency, and reduced the time spent awake during the night in all animals. A significant decrease in sleep latencies was also observed in three out of four animals. Compared with L-dopa alone, combined treatment with melatonin and L-dopa significantly improved all these sleep parameters in two animals. On the other hand, combined treatment had no effect on sleep architecture and daytime sleep. These data demonstrated, for the first time, objective improvement on sleep parameters of melatonin treatment in MPTP-intoxicated monkeys, showing that melatonin treatment has a real therapeutic potential to treat sleep disturbances in people with Parkinson's disease. Copyright © 2015 Elsevier B.V. All rights reserved.

Sensorimotor rhythm neurofeedback as adjunct therapy for Parkinson's disease.

PubMed

Philippens, Ingrid H C H M; Wubben, Jacqueline A; Vanwersch, Raymond A P; Estevao, Dave L; Tass, Peter A

2017-08-01

Neurofeedback may enhance compensatory brain mechanisms. EEG-based sensorimotor rhythm neurofeedback training was suggested to be beneficial in Parkinson's disease. In a placebo-controlled study in parkinsonian nonhuman primates we here show that sensorimotor rhythm neurofeedback training reduces MPTP-induced parkinsonian symptoms and both ON and OFF scores during classical L-DOPA treatment. Our findings encourage further development of sensorimotor rhythm neurofeedback training as adjunct therapy for Parkinson's disease which might help reduce L-DOPA-induced side effects.

Inducing mutations through γ-irradiation in seeds of Mucuna pruriens for developing high L-DOPA-yielding genotypes.

PubMed

Singh, Susheel Kumar; Yadav, Deepti; Lal, Raj Kishori; Gupta, Madan M; Dhawan, Sunita Singh

2017-04-01

To develop elite genotypes in Mucuna pruriens (L.) DC with high L-DOPA (L-3, 4 dihydroxyphenylalanine) yields, with non-itching characteristics and better adaptability by applying γ-irradiation. Molecular and chemical analysis was performed for screening based on specific characteristics desired for developing suitable genotypes. Developed, mutant populations were analyzed for L-DOPA % in seeds through TLC (thin layer chromatography), and the results obtained were validated with the HPLC (High performance liquid chromatography). The DNA (Deoxyribonucleic acid) was isolated from the leaf at the initial stage and used for DNA polymorphism. RNA (Ribonucleic acid) was isolated from the leaf during maturity and used for expression analysis. The selected mutant T-I-7 showed 5.7% L-DOPA content compared to 3.18% of parent CIM-Ajar. The total polymorphism obtained was 57% with the molecular marker analysis. The gene expression analysis showed higher fold change expression of the dopadecarboxylase gene (DDC) in control compared to selected mutants (T-I-7, T-II-23, T-IV-9, T-VI-1). DNA polymorphism was used for the screening of mutants for efficient screening at an early stage. TLC was found suitable for the large-scale comparative chemical analysis of L-DOPA. The expression profile of DDC clearly demonstrated the higher yields of L-DOPA in selected mutants developed by γ-irradiation in the seeds of the control.

Regulation of Pleiotrophin and Fyn in the striatum of rats undergoing L-DOPA-induced dyskinesia.

PubMed

Gomez, Gimena; Saborido, Mariano D; Bernardi, M Alejandra; Gershanik, Oscar S; Taravini, Irene R; Ferrario, Juan E

2018-02-14

L-DOPA is the gold standard pharmacological therapy for symptomatic treatment of Parkinson's disease (PD), however, its long-term use is associated with the emergence of L-DOPA-induced dyskinesia (LID). Understanding the underlying molecular mechanisms of LID is crucial for the development of newer and more effective therapeutic approaches. In previous publications, we have shown that Pleiotrophin (PTN), a developmentally regulated trophic factor, is up-regulated by L-DOPA in the striatum of dopamine denervated rats. We have also shown that both mRNA and protein levels of RPTPζ/β, a PTN receptor, were upregulated in the same experimental condition and expressed in striatal medium spiny neurons. The PTN-RPTPζ/β intracellular pathway has not been fully explored and it might be implicated in the striatal plastic changes triggered by L-DOPA treatment. RPTPζ/β is part of the postsynaptic density zone and modulates Fyn, a Src tyrosine kinase that regulates the NR2A and NR2B subunits of the NMDA receptor and has been singled out as a key molecule in the development of LID. In this study, we evaluated the changes in PTN and Fyn protein levels and Fyn phosphorylation status in the 6-OHDA rat model of PD rendered dyskinetic with L-DOPA. We found an increase in the number of PTN immunoreactive neurons, no changes in the amount of total Fyn but a significant increase in Fyn phosphorylation in the dorsolateral striatum of dyskinetic rats. Our results support the idea that both PTN and Fyn may be involved in the development of LID, further contributing to the understanding of its molecular mechanisms. Copyright © 2017 Elsevier B.V. All rights reserved.

Safinamide reduces dyskinesias and prolongs L-DOPA antiparkinsonian effect in parkinsonian monkeys.

PubMed

Grégoire, Laurent; Jourdain, Vincent A; Townsend, Matthew; Roach, Arthur; Di Paolo, Thérèse

2013-05-01

Safinamide is a compound under investigation for use in the treatment of Parkinson's disease for combination with pharmacological therapy currently available. The objective of this study was to test the effects of safinamide in an animal model of l-DOPA-induced dyskinesias (LID), the MPTP lesioned dyskinetic macaque monkey, in comparison to and in combination with amantadine. LID and parkinsonian symptoms were measured in dyskinetic monkeys treated with l-DOPA with and without several dose levels of safinamide, amantadine, and the two in combination. Safinamide plasma levels were monitored during the experiments. Safinamide pre-treatment (3, 10, 20 and 30 mg/kg) dose-dependently reduced LID scores, in two acute and one semi-chronic experiment. Intensity and duration of LID were reduced and inversely correlated with safinamide blood levels. All doses of safinamide tested prolonged the duration of the beneficial antiparkinsonian effect of l-DOPA. Amantadine (5 and 20 mg/kg) reduced LID, but reduced duration of antiparkinsonian response to l-DOPA. When added to amantadine (5 mg/kg), safinamide showed no (3 mg/kg) or modest (20 mg/kg) additional beneficial effects on LID while the combined treatment prevented the reduction of the duration of the l-DOPA antiparkinsonian effect observed with amantadine only. Safinamide and amantadine reduced LID in this primate model while only safinamide increased the duration of the antiparkinsonian response of l-DOPA, suggesting that safinamide may have effects on LID that are pharmacologically distinct from amantadine, which is in current clinical use for control of LID. Copyright © 2013 Elsevier Ltd. All rights reserved.

Effects of chronic fructose overload on renal dopaminergic system: alteration of urinary L-dopa/dopamine index correlates to hypertension and precedes kidney structural damage.

PubMed

Rukavina Mikusic, Natalia L; Kouyoumdzian, Nicolás M; Del Mauro, Julieta S; Cao, Gabriel; Trida, Verónica; Gironacci, Mariela M; Puyó, Ana M; Toblli, Jorge E; Fernández, Belisario E; Choi, Marcelo R

2018-01-01

Insulin resistance induced by a high-fructose diet has been associated to hypertension and renal damage. The aim of this work was to assess alterations in the urinary L-dopa/dopamine ratio over three time periods in rats with insulin resistance induced by fructose overload and its correlation with blood pressure levels and the presence of microalbuminuria and reduced nephrin expression as markers of renal structural damage. Male Sprague-Dawley rats were randomly divided into six groups: control (C) (C4, C8 and C12) with tap water to drink and fructose-overloaded (FO) rats (FO4, FO8 and FO12) with a fructose solution (10% w/v) to drink for 4, 8 and 12 weeks. A significant increase of the urinary L-dopa/dopamine ratio was found in FO rats since week 4, which positively correlated to the development of hypertension and preceded in time the onset of microalbuminuria and reduced nephrin expression observed on week 12 of treatment. The alteration of this ratio was associated to an impairment of the renal dopaminergic system, evidenced by a reduction in renal dopamine transporters and dopamine D1 receptor expression, leading to an overexpression and overactivation of the enzyme Na + , K + -ATPase with sodium retention. In conclusion, urinary L-dopa/dopamine ratio alteration in rats with fructose overload positively correlated to the development of hypertension and preceded in time the onset of renal structural damage. This is the first study to propose the use of the urinary L-dopa/dopamine index as marker of renal dysfunction that temporarily precedes kidney structural damage induced by fructose overload. Copyright © 2017 Elsevier Inc. All rights reserved.

Role of dopamine D3 and serotonin 5-HT 1A receptors in L: -DOPA-induced dyskinesias and effects of sarizotan in the 6-hydroxydopamine-lesioned rat model of Parkinson's disease.

PubMed

Gerlach, Manfred; Bartoszyk, Gerd D; Riederer, Peter; Dean, Olivia; van den Buuse, Maarten

2011-12-01

Sarizotan, a 5-HT(1A) agonist with additional affinity for D(3) and D(4) receptors, has been demonstrated to have anti-dyskinetic effects. The mechanism by which these effects occur is not clear. Using unilateral 6-hydroxydopamine-lesioned rats that received chronic intraperitoneal (ip) administration of L: -3,4-dihydroxyphenylalanine (L: -DOPA) we investigated the involvement of D(3) and 5-HT(1A) receptors in the effects of sarizotan on contraversive circling and abnormal involuntary movements (AIMs). Before sensitization by chronic L: -DOPA treatment (12.5 with 3.25 mg/kg benserazide ip, twice daily for 21 days), no effect of the selective D(3) agonist, PD128907 (1 or 3 mg/kg ip), or the selective D(3) antagonist, GR103691 (0.5 or 1.5 mg/kg ip), was observed. Treatment with sarizotan (1 or 5 mg/kg ip) dose-dependently inhibited the L: -DOPA-induced contraversive turning and AIMs. In co-treatment with the 5-HT(1A) antagonist, WAY100635 (1 mg/kg ip), sarizotan failed to affect this behaviour, confirming the prominent 5-HT(1A) receptor-mediated mechanism of action. In the presence of PD128907 (3 mg/kg ip), the effects of sarizotan on contraversive turning, locomotive dyskinesia and axial dystonia, but not on orolingual and forelimb dyskinesia, were blocked. On its own, PD128907 had no effect on the behavioural effects of L: -DOPA except that it tended to reduce orolingual and forelimb dyskinesia. GR103691 had no effect on its own or in combination with sarizotan. These data identify an involvement of D(3) receptors in the action of sarizotan on some, but not all L: -DOPA-induced motor side effects. This selective involvement is in contrast to the more general involvement of 5-HT(1A) receptors in the anti-dyskinetic effects of sarizotan.

Voltammetric Sensor Based on Fe-doped ZnO and TiO2 Nanostructures-modified Carbon-paste Electrode for Determination of Levodopa

NASA Astrophysics Data System (ADS)

Anaraki Firooz, Azam; Hosseini Nia, Bahram; Beheshtian, Javad; Ghalkhani, Masoumeh

2017-10-01

In this study, undoped and 1 wt.% Fe-doped with ZnO, and TiO2 nanostructures were synthesized by a simple hydrothermal method without using templates. The influence of the Fe dopant on structural, optical and electrochemical response was studied by x-ray diffraction, scanning electron microscopy, UV-Vis spectra, photoluminescence spectra and electrochemical characterization system. The electrochemical response of the carbon paste electrode modified with synthesized nanostructures (undoped ZnO and TiO2 as well as doped with Fe ions) toward levodopa (L-Dopa) was studied. Cyclic voltammetry using provided modified electrodes showed electro-catalytic properties for electro-oxidation of L-Dopa and a significant reduction was observed in the anodic overvoltage compared to the bare electrode. The results indicated the presence of the sufficient dopants. The best response was obtained in terms of the current enhancement, overvoltage reduction, and reversibility improvement of the L-Dopa oxidation reaction under experimental conditions by the modified electrode with TiO2 nanoparticles doped with Fe ions.

Unique Configurations of Compression and Truncation of Neuronal Activity Underlie l-DOPA-Induced Selection of Motor Patterns in Aplysia.

PubMed

Neveu, Curtis L; Costa, Renan M; Homma, Ryota; Nagayama, Shin; Baxter, Douglas A; Byrne, John H

2017-01-01

A key issue in neuroscience is understanding the ways in which neuromodulators such as dopamine modify neuronal activity to mediate selection of distinct motor patterns. We addressed this issue by applying either low or high concentrations of l-DOPA (40 or 250 μM) and then monitoring activity of up to 130 neurons simultaneously in the feeding circuitry of Aplysia using a voltage-sensitive dye (RH-155). l-DOPA selected one of two distinct buccal motor patterns (BMPs): intermediate (low l-DOPA) or bite (high l-DOPA) patterns. The selection of intermediate BMPs was associated with shortening of the second phase of the BMP (retraction), whereas the selection of bite BMPs was associated with shortening of both phases of the BMP (protraction and retraction). Selection of intermediate BMPs was also associated with truncation of individual neuron spike activity (decreased burst duration but no change in spike frequency or burst latency) in neurons active during retraction. In contrast, selection of bite BMPs was associated with compression of spike activity (decreased burst latency and duration and increased spike frequency) in neurons projecting through specific nerves, as well as increased spike frequency of protraction neurons. Finally, large-scale voltage-sensitive dye recordings delineated the spatial distribution of neurons active during BMPs and the modification of that distribution by the two concentrations of l-DOPA.

The Metabotropic Glutamate Receptor 4-Positive Allosteric Modulator VU0364770 Produces Efficacy Alone and in Combination with l-DOPA or an Adenosine 2A Antagonist in Preclinical Rodent Models of Parkinson's Disease

PubMed Central

Jones, Carrie K.; Bubser, Michael; Thompson, Analisa D.; Dickerson, Jonathan W.; Turle-Lorenzo, Nathalie; Amalric, Marianne; Blobaum, Anna L.; Bridges, Thomas M.; Morrison, Ryan D.; Jadhav, Satyawan; Engers, Darren W.; Italiano, Kimberly; Bode, Jacob; Daniels, J. Scott; Lindsley, Craig W.; Hopkins, Corey R.; Conn, P. Jeffrey

2012-01-01

Parkinson's disease (PD) is a debilitating neurodegenerative disorder associated with severe motor impairments caused by the loss of dopaminergic innervation of the striatum. Previous studies have demonstrated that positive allosteric modulators (PAMs) of metabotropic glutamate receptor 4 (mGlu4), including N-phenyl-7-(hydroxyimino)cyclopropa[b]chromen-1a-carboxamide, can produce antiparkinsonian-like effects in preclinical models of PD. However, these early mGlu4 PAMs exhibited unsuitable physiochemical properties for systemic dosing, requiring intracerebroventricular administration and limiting their broader utility as in vivo tools to further understand the role of mGlu4 in the modulation of basal ganglia function relevant to PD. In the present study, we describe the pharmacologic characterization of a systemically active mGlu4 PAM, N-(3-chlorophenyl)picolinamide (VU0364770), in several rodent PD models. VU0364770 showed efficacy alone or when administered in combination with l-DOPA or an adenosine 2A (A2A) receptor antagonist currently in clinical development (preladenant). When administered alone, VU0364770 exhibited efficacy in reversing haloperidol-induced catalepsy, forelimb asymmetry-induced by unilateral 6-hydroxydopamine (6-OHDA) lesions of the median forebrain bundle, and attentional deficits induced by bilateral 6-OHDA nigrostriatal lesions in rats. In addition, VU0364770 enhanced the efficacy of preladenant to reverse haloperidol-induced catalepsy when given in combination. The effects of VU0364770 to reverse forelimb asymmetry were also potentiated when the compound was coadministered with an inactive dose of l-DOPA, suggesting that mGlu4 PAMs may provide l-DOPA-sparing activity. The present findings provide exciting support for the potential role of selective mGlu4 PAMs as a novel approach for the symptomatic treatment of PD and a possible augmentation strategy with either l-DOPA or A2A antagonists. PMID:22088953

L-3,4-Dihydroxyphenylalanine (l-DOPA) induces neuroendocrinological, physiological, and immunological regulation in white shrimp, Litopenaeus vannamei.

PubMed

Mapanao, Ratchaneegorn; Kuo, Hsin-Wei; Chang, Chin-Chuan; Liu, Kuan-Fu; Cheng, Winton

2018-03-01

L-3,4-Dihydroxyphenylalanine (l-DOPA) is a precursor for dopamine (DA) synthesis. Assessments were conducted to analyze the effects of l-DOPA on mediating regulation of neuroendocrinological, immunological, and physiological parameters in the shrimp, Litopenaeus vannamei when they were individually injected with 0.01 N HCl or l-DOPA at 0.5 or 1.0 μmol shrimp -1 for 60, 120, and 240 min. For catecholamine synthesis evaluation, tyrosine hydroxylase (TH) and DA beta hydroxylase (DBH) activities, l-DOPA, DA, and norepinephrine (NE) levels in hemolymph were determined. The total hemocyte count (THC), differential hemocyte count (DHC), phenoloxidase (PO) activity, respiratory bursts (RBs), superoxide dismutase (SOD) activity, phagocytic activity, and clearance efficiency in response to the pathogen, Vibrio alginolyticus were assessed for immune responses, and plasma glucose and lactate levels were for physiological response. Results showed that the TH activity, THC, hyaline cells (HCs), and semigranular cells (SGCs) at 120 min, DA levels at 60-240 min, PO activity in hemocytes per 50 μL of hemolymph at 60-120 min, and PO activity per granulocyte (granular cells (GCs) + SGCs) at 60 min significantly increased, but TH activity, l-DOPA levels, GCs, SGCs, and respiratory bursts in hemocytes per 10 μL of hemolymph at 60 min, respiratory bursts per hemocyte and SOD activity at 120 min, phagocytic activity at 60-240 min, and the clearance efficiency at 60-120 min significantly decreased in shrimp injected with l-DOPA at 1.0 μmol shrimp -1 . In another experiment, 60 min after shrimp had received l-DOPA at 0.5 or 1.0 μmol shrimp -1 , they were challenged with an injection of V. alginolyticus at 2 × 10 5  colony-forming units (cfu) shrimp -1 . The injection of l-DOPA at 1.0 μmol shrimp -1 also significantly increased the cumulative mortality of shrimp by 16.7%, compared to the HCl-challenged control after 120 h. These results suggest that l-DOPA administration at 1.0 μmol shrimp -1 can mediate the transient regulation of neuroendocrinological, immunological, and physiologic responses resulting in immunosuppression, which in turn promoted the susceptibility of L. vannamei to V. alginolyticus. Copyright © 2018 Elsevier Ltd. All rights reserved.

Correlation of nitric oxide (NO) activity and gonadal function in Japanese quail, Coturnix coturnix japonica following temporal phase relation of serotonergic and dopaminergic oscillations.

PubMed

Kumar, Pankaj; Chaturvedi, Chandra Mohini

2008-06-01

Nitric oxide (NO), a highly reactive and short-lived radical, is considered to be an important trigger molecule for several physiological mechanisms including gonadotrophin releasing hormone (GnRH) secretion in mammals, although there is no such information in avian literature. On the other hand, specific temporal phase relation of circadian neural (serotonergic and dopaminergic) oscillations is reported to modulate reproductive activity in many avian species including Japanese quail. The present study was undertaken to investigate the correlation of NO activity and gonadal function of Japanese quail. In experiment I, the effect of serotonin and dopamine precursors, (5-hydroxytryptophan (5-HTP) and L-dihydroxyphenyalanine (L-DOPA) respectively; 5 mg per 100g body weight) administered at intervals of 8 or 12h over a period of 13 days, was studied on reproductive responses and NO activity. Measurements of body weight, cloacal gland size, testosterone concentration, spermatogenesis, nitrite-nitrate concentration in plasma, hypothalamus and testes, and NADPH-diaphorase (NADPH-d) activity in testes were made on the 2nd, 3rd, 6th and 11th days of treatment and 2nd and 30th day post-treatment. In experiment II, quail were divided into five groups including the control. One experimental group received 13 daily injections of 5-HTP and L-DOPA at intervals of 8h along with 0.1 ml of normal saline administered orally (8-hr+Veh), while another group of 8-hr quail received NO donor (sodium nitroprusside (SNP), 5 mg per 100 g body weight) orally (8-hr+SNP). The third experimental group received 5-HTP and L-DOPA at intervals of 12h along with normal saline (12-hr+Veh), while the fourth group of quail along with 5-HTP and L-DOPA at intervals of 12h also received the NOS inhibitor (N-nitro-L-arginine methyl ester, L-NAME, 25 microg per 100 g body weight) intraperitoneally (12-hr+L-NAME) for 13 days. This experiment was terminated after 21 days of the treatment. Results indicate that 5-HTP and L-DOPA administered 8h apart (8-hr) suppressed but if given 12h apart (12-hr) stimulated the reproductive system and NO activity compared to the control. These effects were apparent on the 6th day of injections and were maintained 30 days following the termination of the treatment. A significant decrease in nitrite and nitrate concentration and NADPH-d activity in reproductively inhibited 8-hr group and an increase in reproductively stimulated 12-hr quail was also evident. In contrast, these activities were stimulated in 8-hr+SNP quail and were suppressed in 12-hr+L-NAME group quail. It is concluded that activity of the reproductive system and NO activity waxes and wanes simultaneously in Japanese quail. Moreover, experimental modulation of gonadal activity (following changes in the phase relation of serotonergic and dopaminergic activity) or NO activity (following the administration of NO modulator or inhibitor) affects each other maintaining a parallel relation between the two systems. Further, it is interesting to note that the gonado-stimulatory effect of SNP overpowers the gonado-inhibitory effects of the 8-hr time interval and inhibitory effects of L-NAME mask the stimulatory effects of 12-hr temporal relation of 5-HTP and L-DOPA administration. These findings strongly suggest that reproductive effects may be induced via changes in NO activity, however the exact mechanism by which NO drives gonadal axis needs to be ascertained.

Alizarin Red S-Confined Layer-By-Layer Films as Redox-Active Coatings on Electrodes for the Voltammetric Determination of L-Dopa

PubMed Central

Takahashi, Shigehiro; Suzuki, Iwao; Sugawara, Tatsuro; Seno, Masaru; Minaki, Daichi; Anzai, Jun-Ichi

2017-01-01

The preparation of redox-active coatings is a key step in fabricating electrochemical biosensors. To this goal, a variety of coating materials have been used in combination with redox-active compounds. In this study, alizarin red S (ARS) was confined in layer-by-layer (LbL) films composed of poly(ethyleneimine) (PEI) and carboxymethylcellulose (CMC) to study the redox properties. A gold (Au) disc electrode coated with PEI/CMC LbL film was immersed in an ARS solution to uptake ARS into the film. ARS was successfully confined in the LbL film through electrostatic interactions. The cyclic voltammogram (CV) of ARS-confined PEI/CMC film-coated electrodes thus prepared exhibited redox waves in the potential range from −0.5 to −0.7 V originating from 9,10-anthraquinone moiety in ARS, demonstrating that ARS preserves its redox activity in the LbL film. An additional oxidation peak appeared around −0.4 V in the CV recorded in the solution containing phenylboronic acid (PBA), due to the formation of a boronate ester of ARS (ARS-PBA) in the film. The oxidation peak current at −0.4 V decreased upon addition of 3,4-dihydroxyphenylalanine (L-dopa) to the solution. Thus, the results suggest a potential use of the ARS-confined PEI/CMC films for constructing voltammetric sensors for L-dopa. PMID:28772942

Method of making L-dopa from L-tyrosine

DOEpatents

Xun, Luying; Lee, Jang Young

1998-01-01

The invention is a method of making a L-dopa from L-tyrosine in the presence of an enzyme catalyst and oxygen. By starting with L-tyrosine, no variant of the L-dopa is produced and the L-dopa is stable in the presence of the enzyme catalyst. In other words, the reaction favors the L-dopa and is not reversible.

Method of making L-dopa from L-tyrosine

DOEpatents

Xun, L.; Lee, J.Y.

1998-11-17

The invention is a method of making a L-dopa from L-tyrosine in the presence of an enzyme catalyst and oxygen. By starting with L-tyrosine, no variant of the L-dopa is produced and the L-dopa is stable in the presence of the enzyme catalyst. In other words, the reaction favors the L-dopa and is not reversible. 3 figs.

Noninvasive monitoring of plasma L-dopa concentrations using sweat samples in Parkinson's disease.

PubMed

Tsunoda, Makoto; Hirayama, Masaaki; Tsuda, Takao; Ohno, Kinji

2015-03-10

L-dopa (l-3,4-dihydroxyphenylalanine) is commonly used for treating Parkinson's disease (PD). However, regardless of its prominent effect, therapeutic range of L-dopa narrows down with disease progression, which leads to development of motor complications including wearing off and dyskinesias. In addition, intestinal absorption of L-dopa is inversely correlated with the amount of oral protein intake, and shows intra- and inter-day variability. Hence, frequent monitoring of plasma L-dopa concentrations is beneficial, but frequent venipuncture imposes physical and psychological burdens on patients with PD. We investigated the usefulness of sweat samples instead of plasma samples for monitoring L-dopa concentrations. With a monolithic silica disk-packed spin column and the high-performance liquid chromatography-electrochemical detection system, L-dopa in sweat samples was successfully quantified and analyzed in 23 PD patients. We found that the Pearson's correlation coefficient of the plasma and sweat l-dopa concentrations was 0.678. Although the disease durations and severities were not correlated with the deviation of the actual sweat L-dopa concentrations from the fitted line, acquisition of the sweat samples under a stable condition was technically difficult in severely affected patients. The deviations may also be partly accounted for by skin permeability of L-dopa. Measuring L-dopa concentrations in sweat is suitable to get further insights into the L-dopa metabolism. Copyright © 2015 Elsevier B.V. All rights reserved.

The medical treatment of Parkinson disease from James Parkinson to George Cotzias.

PubMed

Fahn, Stanley

2015-01-01

It took exactly 150 years since James Parkinson's description in 1817 of the illness bearing his name until the development of effective therapy for this disorder, namely, the introduction of high-dosage levodopa by George Cotzias in 1967. During the first 50 years, no effective therapy was available, but neurologists reported using different agents, including metals. Then, around 1867, Charcot found solanaceous alkaloids to be somewhat helpful, and these became the accepted and popular therapy for the next 75 years. When basic scientists discovered that these alkaloids had central antimuscarinic activity, pharmaceutical chemists developed synthetic chemical agents that were equally effective, with possibly less adverse effects, and around 1950 these synthetic drugs became the standard medical therapy for Parkinson's disease (PD). The link between dopamine and PD did not take place until 1957, 140 years after Parkinson's Essay. The clue came from research on reserpine, a drug derived from the Rauwolfia plant that caused a sedative effect, now recognized as a drug-induced parkinsonian state. Initial investigations revealed that reserpine caused the release and depletion of serotonin stores in the brain. With that knowledge, Arvid Carlsson, a young pharmacologist in Sweden, decided to explore the possibility that reserpine might also affect brain catecholamines. In his now famous, elegant, and simple experiment, he showed that injecting l-dopa, the precursor of catecholamines, alleviated the reserpine-induced parkinsonian state in animals, whereas the precursor of serotonin failed to do so. Carlsson then developed a highly sensitive assay to measure dopamine, and his lab found that dopamine is selectively present in high concentrations in the striatum and that administered l-dopa could restore the dopamine depleted by reserpine. Carlsson postulated that all these findings implicate dopamine in motor disorders. Oleh Hornykiewicz, a young pharmacologist in Vienna, on being aware of the regional localization of brain dopamine, decided to measure it in the brains of people who had PD and postencephalitic parkinsonism. In 1960, he reported finding markedly depleted dopamine in the striatum in these conditions. Immediately after, Hornykiewicz teamed up with the geriatrician, Walther Birkmayer, to inject small doses of l-dopa intravenously (IV) into PD patients. They found benefit and pursued this treatment, but the gastrointestinal side effects limited the dosage, and many neurologists were doubtful that the effects from l-dopa were any better than those with antimuscarinic agents. A number of neurologists tested such low doses of IV l-dopa and even higher oral dosages, but without showing any dramatic benefit, not better than the antimuscarinics. Some of these studies were small, controlled trials. This general lack of efficacy with l-dopa prevailed, and neurologists were discouraged about l-dopa until 1967, when George C. Cotzias, a neuropharmacologist in New York, reported his results. He thought that PD may be result from the loss of neuromelanin in the substantia nigra, and he decided to try to replenish the depleted neuromelanin. Among the agents he tried was dl-dopa. He wisely began with low oral doses and increased the dosage slowly and steadily, thereby limiting the gastrointestinal complication. He also treated his patients for a long duration, months in a government-supported hospital. In the accompanying videotape of an interview Cotzias gave in 1970, he describes much of his success to be able to observe his patients over months while building up the dosage very slowly and observe for signs of toxicity. When higher doses, usually over 12 g/day, were reached, dramatic antiparkinsonian effects were observed, and a revolutionary new treatment for PD was established. © 2014 International Parkinson and Movement Disorder Society.

Dopa-decarboxylase gene polymorphisms affect the motor response to L-dopa in Parkinson's disease.

PubMed

Devos, David; Lejeune, Stéphanie; Cormier-Dequaire, Florence; Tahiri, Khadija; Charbonnier-Beaupel, Fanny; Rouaix, Nathalie; Duhamel, Alain; Sablonnière, Bernard; Bonnet, Anne-Marie; Bonnet, Cecilia; Zahr, Noel; Costentin, Jean; Vidailhet, Marie; Corvol, Jean-Christophe

2014-02-01

In Parkinson's disease (PD), the response to L-dopa is highly variable and unpredictable. The major pathway for dopamine synthesis from L-dopa is decarboxylation by aromatic L-amino acid decarboxylase (AAAD, encoded by the DDC gene). To determine the motor response to L-dopa in PD patients as a function of the DDC gene promoter polymorphisms (rs921451 T > C polymorphism (DDC(T/C)) and rs3837091 AGAG del (DDC(AGAG/-))). Thirty-three Caucasian PD patients underwent an acute l-dopa challenge together with the peripheral AAAD inhibitor benserazide and were genotyped for rs921451 and rs3837091. The primary efficacy criterion was the motor response to L-dopa, as estimated by the area under the curve for the change in the Unified Parkinson's Disease Rating Scale part III (UPDRS) score relative to baseline (AUCΔUPDRS) in the 4 h following L-dopa administration. Secondary endpoints were pharmacokinetic parameters for plasma levels of L-dopa and dopamine. Investigators and patients were blinded to genotypes data throughout the study. When adjusted for the L-dopa dose, the AUCΔUPDRS was significantly lower in DDC(CC/CT) patients (n = 14) than in DDC(TT) patients (n = 19) and significantly lower in DDC(-/- or AGAG/-) patients (n = 8) than in DDC(AGAG/AGAG) patients (n = 25). There were no significant intergroup differences in plasma pharmacokinetic parameters for L-dopa and dopamine. The rs921451 and rs3837091 polymorphisms of the DDC gene promoter influence the motor response to L-dopa but do not significantly change peripheral pharmacokinetic parameters for L-dopa and dopamine. Our results suggest that DDC may be a genetic modifier of the l-dopa response in Parkinson's disease. Copyright © 2013 Elsevier Ltd. All rights reserved.

Gypenosides ameliorate memory deficits in MPTP-lesioned mouse model of Parkinson's disease treated with L-DOPA.

PubMed

Zhao, Ting Ting; Kim, Kyung Sook; Shin, Keon Sung; Park, Hyun Jin; Kim, Hyun Jeong; Lee, Kyung Eun; Lee, Myung Koo

2017-09-06

Previous studies have revealed that gypenosides (GPS) improve the symptoms of anxiety disorders in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned rat model of Parkinson's disease (PD). The present study aimed to investigate the effects of GPS on memory deficits in an MPTP-lesioned mouse model of PD treated with L-3,4-dihydroxyphenylalanine (L-DOPA). MPTP (30 mg/kg/day, 5 days)-lesioned mice were treated with GPS (50 mg/kg) and/or L-DOPA (10 and 25 mg/kg) for 21 days. After the final treatments, behavioral changes were assessed in all mice using passive avoidance and elevated plus-maze tests. We then evaluated the biochemical influences of GPS treatment on levels of tyrosine hydroxylase (TH), dopamine, N-methyl-D-aspartate (NMDA) receptors, extracellular signal-regulated kinase (ERK1/2), and cyclic AMP-response element binding protein (CREB) phosphorylation. MPTP-lesioned mice exhibited deficits associated with habit learning and spatial memory, which were further aggravated by treatment with L-DOPA (25 mg/kg). However, treatment with GPS (50 mg/kg) ameliorated memory deficits. Treatment with GPS (50 mg/kg) also improved L-DOPA (25 mg/kg)-treated MPTP lesion-induced decreases in retention latency on the passive avoidance test, as well as levels of TH-immunopositive cells and dopamine in the substantia nigra and striatum. GPS treatment also attenuated increases in retention transfer latency on the elevated plus-maze test and in NMDA receptor expression, as well as decreases in the phosphorylation of ERK1/2 and CREB in the hippocampus. Treatment with L-DOPA (10 mg/kg) also ameliorated deficits in habit learning and spatial memory in MPTP-lesioned mice, and this effect was further enhanced by treatment with GPS (50 mg/kg). GPS ameliorate deficits in habit learning and spatial memory by modulating the dopaminergic neuronal and N-methyl-D-aspartate receptor-mediated signaling systems in MPTP-lesioned mice treated with L-DOPA. GPS may serve as an adjuvant therapeutic agent for memory deficits in patients with PD receiving L-DOPA.

The neurochemical and behavioral effects of the novel cholinesterase–monoamine oxidase inhibitor, ladostigil, in response to L-dopa and L-tryptophan, in rats

PubMed Central

Sagi, Yotam; Driguès, Noam; Youdim, Moussa B H

2005-01-01

The novel drugs, ladostigil (TV3326) and TV3279, are R and S isomers, respectively, derived from a combination of the carbamate cholinesterase (ChE) inhibitor, rivastigmine, and the pharmacophore of the monoamine oxidase (MAO) B inhibitor, rasagiline. They were developed for the treatment of comorbidity of dementia with Parkinsonism. In the present study, we determined the effects of these drugs on both aminergic neurotransmitter levels and motor behavioral activity in naïve and in L-dopa- or L-tryptophan-induced rats. Chronic treatment of rats with ladostigil (52 mg kg−1 for 21 days) inhibited hippocampal and striatal MAO A and B activities by >90%, increased striatal levels of dopamine and serotonin, and inhibited striatal ChE activity by ∼50%. Chronic TV3279 (26 mg kg−1 for 21 days) similarly inhibited ∼50% of striatal ChE activity, but did not affect MAO activity or amine levels. In sharp contrast to the inductive effect of the MAO A/B inhibitor, tranylcypromine (TCP), on stereotyped hyperactivity in response to L-dopa (50 mg kg−1) or L-tryptophan (100 mg kg−1), ladostigil completely inhibited these behavioral hyperactivity syndromes. Accordingly, acute rivastigmine (2 mg kg−1) and chronic TV3279 abolished the ability of TCP to initiate L-dopa-induced hyperactivity, while scopolamine (0.5 mg kg−1) reversed the inhibitory effect of chronic ladostigil on L-dopa-induced hyperactivity, suggesting that ladostigil may attenuate successive locomotion by activating central cholinergic muscarinic receptors. Finally, while chronic ladostigil administration to naïve rats resulted in preserved spontaneous motor behavior, acute treatment with ladostigil decreased motor performance, compared to control animals. In contrast, chronic as well as acute treatments with TV3279 reduced spontaneous motor activity. Thus, the aminergic potentiation by ladostigil may counteract its cholinergic inhibitory effect on spontaneous motor behavior. Our results suggest that potentiation of both aminergic and cholinergic transmission systems by ladostigil contributes equally to motor behavior performance, which is substantially impaired in comorbidity of dementia with Parkinsonism including dementia with Lewy bodies (DLB). PMID:16086033

New treatments for levodopa-induced motor complications.

PubMed

Rascol, Olivier; Perez-Lloret, Santiago; Ferreira, Joaquim J

2015-09-15

Levodopa (l-dopa)-induced motor complications, including motor fluctuations and dyskinesia, affect almost all patients with Parkinson's disease (PD) at some point during the disease course, with relevant implications in global health status. Various dopaminergic and nondopaminergic pharmacological approaches as well as more invasive strategies including devices and functional surgery are available to manage such complications. In spite of undisputable improvements during the last decades, many patients remain significantly disabled, and a fully satisfying management of l-dopa-induced motor complications is still an important unmet need of PD therapy. This article reviews the recent trial results published from 2013 to April 2015 about pharmacological and nonpharmacological interventions to treat motor complications. Randomized controlled trials conducted in patients suffering from already established complications showed that new levodopa (l-dopa) formulations such as intrajejunal l-dopa-carbidopa infusion and bilayered extended-release l-dopa-carbidopa (IPX066) can improve motor fluctuations. Positive results were also obtained with a new monoamine oxidase B (MAO-B) inhibitor (safinamide) and a catechol-O-methyltransferase COMT inhibitor (opicapone). Pilot data suggest that new formulations of dopamine agonists (inhaled apomorphine) are also of potential interest. The development of novel nondopaminergic adenosine A2A antagonists (istradefylline, preladenant, and tozadenant) to treat motor fluctuations showed conflicting results in phase 2 and phase 3 trials. For dyskinesia, trials with new amantadine extended-release formulations confirmed the interest of the glutamatergic N-methyl-d-aspartate (NMDA) antagonist approach. Positive pilot antidyskinetic effects were also recently reported using serotonin agents such as eltoprazine and glutamate mGluR5 modulators such as mavoglurant. However, the translation to clinical practice of such innovative concepts remains challenging, because subsequent phase 2 trials conducted to confirm the antidyskynetic effects of mavoglurant failed, leading to the interruption of the development of this compound for this indication. © 2015 International Parkinson and Movement Disorder Society.

Serotonin System Implication in l-DOPA-Induced Dyskinesia: From Animal Models to Clinical Investigations

PubMed Central

Carta, Manolo; Tronci, Elisabetta

2014-01-01

In the recent years, the serotonin system has emerged as a key player in the induction of l-DOPA-induced dyskinesia (LID) in animal models of Parkinson’s disease. In fact, serotonin neurons possess the enzymatic machinery able to convert exogenous l-DOPA to dopamine (DA), and mediate its vesicular storage and release. However, serotonin neurons lack a feedback control mechanism able to regulate synaptic DA levels. While in a situation of partial DA depletion spared DA terminals can buffer DA released from serotonin neurons, the progression of DA neuron degeneration impairs this protective mechanism, causing swings in synaptic DA levels and pulsatile stimulation of post-synaptic DA receptors. In line with this view, removal of serotonin neurons by selective toxin, or pharmacological silencing of their activity, produced complete suppression of LID in animal models of Parkinson’s disease. In this article, we will revise the experimental evidence pointing to the important role of serotonin neurons in dyskinesia, and we will discuss the clinical implications. PMID:24904522

Unique Configurations of Compression and Truncation of Neuronal Activity Underlie l-DOPA–Induced Selection of Motor Patterns in Aplysia

PubMed Central

Homma, Ryota; Nagayama, Shin; Baxter, Douglas A.

2017-01-01

A key issue in neuroscience is understanding the ways in which neuromodulators such as dopamine modify neuronal activity to mediate selection of distinct motor patterns. We addressed this issue by applying either low or high concentrations of l-DOPA (40 or 250 μM) and then monitoring activity of up to 130 neurons simultaneously in the feeding circuitry of Aplysia using a voltage-sensitive dye (RH-155). l-DOPA selected one of two distinct buccal motor patterns (BMPs): intermediate (low l-DOPA) or bite (high l-DOPA) patterns. The selection of intermediate BMPs was associated with shortening of the second phase of the BMP (retraction), whereas the selection of bite BMPs was associated with shortening of both phases of the BMP (protraction and retraction). Selection of intermediate BMPs was also associated with truncation of individual neuron spike activity (decreased burst duration but no change in spike frequency or burst latency) in neurons active during retraction. In contrast, selection of bite BMPs was associated with compression of spike activity (decreased burst latency and duration and increased spike frequency) in neurons projecting through specific nerves, as well as increased spike frequency of protraction neurons. Finally, large-scale voltage-sensitive dye recordings delineated the spatial distribution of neurons active during BMPs and the modification of that distribution by the two concentrations of l-DOPA. PMID:29071298

Mucuna pruriens (Velvet bean) rescues motor, olfactory, mitochondrial and synaptic impairment in PINK1B9 Drosophila melanogaster genetic model of Parkinson's disease.

PubMed

Poddighe, Simone; De Rose, Francescaelena; Marotta, Roberto; Ruffilli, Roberta; Fanti, Maura; Secci, Pietro Paolo; Mostallino, Maria Cristina; Setzu, Maria Dolores; Zuncheddu, Maria Antonietta; Collu, Ignazio; Solla, Paolo; Marrosu, Francesco; Kasture, Sanjay; Acquas, Elio; Liscia, Anna

2014-01-01

The fruit fly Drosophila melanogaster (Dm) mutant for PTEN-induced putative kinase 1 (PINK1B9) gene is a powerful tool to investigate physiopathology of Parkinson's disease (PD). Using PINK1B9 mutant Dm we sought to explore the effects of Mucuna pruriens methanolic extract (Mpe), a L-Dopa-containing herbal remedy of PD. The effects of Mpe on PINK1B9 mutants, supplied with standard diet to larvae and adults, were assayed on 3-6 (I), 10-15 (II) and 20-25 (III) days old flies. Mpe 0.1% significantly extended lifespan of PINK1B9 and fully rescued olfactory response to 1-hexanol and improved climbing behavior of PINK1B9 of all ages; in contrast, L-Dopa (0.01%, percentage at which it is present in Mpe 0.1%) ameliorated climbing of only PINK1B9 flies of age step II. Transmission electron microscopy analysis of antennal lobes and thoracic ganglia of PINK1B9 revealed that Mpe restored to wild type (WT) levels both T-bars and damaged mitochondria. Western blot analysis of whole brain showed that Mpe, but not L-Dopa on its own, restored bruchpilot (BRP) and tyrosine hydroxylase (TH) expression to age-matched WT control levels. These results highlight multiple sites of action of Mpe, suggesting that its effects cannot only depend upon its L-Dopa content and support the clinical observation of Mpe as an effective medication with intrinsic ability of delaying the onset of chronic L-Dopa-induced long-term motor complications. Overall, this study strengthens the relevance of using PINK1B9 Dm as a translational model to study the properties of Mucuna pruriens for PD treatment.

Morinda citrifolia mitigates rotenone-induced striatal neuronal loss in male Sprague-Dawley rats by preventing mitochondrial pathway of intrinsic apoptosis.

PubMed

Kishore Kumar, S Narasimhan; Deepthy, Jayakumar; Saraswathi, Uthamaraman; Thangarajeswari, Mohan; Yogesh Kanna, Sathyamoorthy; Ezhil, Pannerselvam; Kalaiselvi, Periandavan

2017-11-01

Parkinson disease (PD) is a neurodegenerative disorder affecting mainly the motor system, as a result of death of dopaminergic neurons in the substantia nigra pars compacta. The present scenario of research in PD is directed to identify novel molecules that can be administered individually or co-administered with L-Dopa to prevent the L-Dopa-Induced Dyskinesia (LID) like states that arise during chronic L-Dopa administration. Hence, in this study, we investigated whether Morinda citrifolia has therapeutic effects in rotenone-induced Parkinson's disease (PD) with special reference to mitochondrial dysfunction mediated intrinsic apoptosis. Male Sprague-Dawley rats were stereotaxically infused with rotenone (3 µg in both SNPc and VTA) and co-treated with the ethyl acetate extract of Morinda citrifolia and levodopa. The results revealed that rotenone-induced cell death was reduced by MCE treatment as measured by decline in the levels of pro-apoptotic proteins. Moreover, MCE treatment significantly augmented the levels of anti-apoptotic Bcl2 and blocks the release of cytochrome c, thereby alleviating the rotenone-induced dopaminergic neuronal loss, as evidenced by tyrosine hydroxylase (TH) immunostaining in the striatum. Taken together, the results suggest that Morinda citrifolia may be beneficial for the treatment of neurodegenerative diseases like PD.

Consequence of dopamine D2 receptor blockade on the hyperphagic effect induced by cannabinoid CB1 and CB2 receptors in layers.

PubMed

Khodadadi, M; Zendehdel, M; Baghbanzadeh, A; Babapour, V

2017-10-01

1. Endocannabinoids (ECBs) and their receptors play a regulatory function on several physiological processes such as feed-intake behaviour, mainly in the brain. This study was carried out in order to investigate the effects of the dopaminergic D1 and D2 receptors on CB1/CB2 ECB receptor-induced hyperphagia in 3-h feed-deprived neonatal layer chickens. 2. A total of 8 experiments were designed to explore the interplay of these two modulatory systems on feed intake in neonatal chickens. In Experiment 1, chickens were intracerebroventricular (ICV) injected with control solution, l-DOPA (levo-dihydroxyphenylalanine as precursor of dopamine; 125 nmol), 2-AG (2-arachidonoylglycerol as CB 1 receptor agonist; 2 µg) and co-administration of l-DOPA (125 nmol) plus 2-AG (2 µg). Experiments 2-4 were similar to Experiment 1 except birds were injected with either 6-OHDA (6-hydroxydopamine as dopamine synthesis inhibitor; 150 nmol), SCH23390 (D1 receptor antagonist; 5 nmol) and AMI-193 (D2 receptor antagonist; 5 nmol) instead of l-DOPA, respectively. Additionally, Experiments 5-8 followed the previous ones using the same dose of l-DOPA, 6-OHDA and dopamine antagonists except that birds were injected with CB65 (CB2 receptor agonist; 5 µg) instead of 2-AG. Coadministrations were at the same dose for each experiment. Cumulative feed intakes were measured until 120 min after each injection. 3. ICV administration of 6-OHDA and AMI-193 significantly attenuated 2-AG-induced hyperphagia. Interestingly, the hyperphagic effect of CB65 was significantly attenuated by administration of l-DOPA, whereas the administration of 6-OHDA and AMI-193 together amplified the hyperphagic effect of CB65. 4. It was concluded that cannabinoid-induced feeding behaviour is probably modulated by dopamine receptors in neonatal layer-type chickens. It seems that their interaction may be mediated by the D2-dopamine receptor.

Catalyzed and Electrocatalyzed Oxidation of l-Tyrosine and l-Phenylalanine to Dopachrome by Nanozymes.

PubMed

Hou, Jianwen; Vázquez-González, Margarita; Fadeev, Michael; Liu, Xia; Lavi, Ronit; Willner, Itamar

2018-06-13

Catalyzed oxygen insertion into C-H bonds represents a continuous challenge in chemistry. Particularly, driving this process at ambient temperature and aqueous media represents a "holy grail" in catalysis. We report on the catalyzed cascade transformations of l-tyrosine or l-phenylalanine to dopachrome in the presence of l-ascorbic acid/H 2 O 2 as oxidizing mixture and CuFe-Prussian Blue-like nanoparticles, Fe 3 O 4 nanoparticles or Au nanoparticles as catalysts. The process involves the primary transformation of l-tyrosine to l-DOPA that is further oxidized to dopachrome. The transformation of l-phenylalanine to dopachrome in the presence of CuFe-Prussian Blue-like nanoparticles and l-ascorbic acid/H 2 O 2 involves in the first step the formation of l-tyrosine and, subsequently, the operation of the catalytic oxidation cascade of l-tyrosine to l-DOPA and dopachrome. Electron spin resonance experiments demonstrate that ascorbate radicals and hydroxyl radicals play cooperative functions in driving the different oxygen-insertion processes. In addition, the aerobic elecrocatalyzed oxidation of l-tyrosine to dopachrome in the presence of naphthoquinone-modified Fe 3 O 4 nanoparticles and l-ascorbic acid is demonstrated. In this system, magnetic-field attraction of the naphthoquinone-modified Fe 3 O 4 nanoparticles onto the electrode allows the quinone-mediated electrocatalyzed reduction of O 2 to H 2 O 2 (bias potential -0.5 V vs SCE). The electrogenerated H 2 O 2 is then utilized to promote the transformation of l-tyrosine to dopachrome in the presence of l-ascorbic acid and Fe 3 O 4 catalyst.

Motor complications in Parkinson's disease: Striatal molecular and electrophysiological mechanisms of dyskinesias.

PubMed

Picconi, Barbara; Hernández, Ledia F; Obeso, Jose A; Calabresi, Paolo

2017-12-08

Long-term levodopa (l-dopa) treatment in patients with Parkinson´s disease (PD) is associated with the development of motor complications (ie, motor fluctuations and dyskinesias). The principal etiopathogenic factors are the degree of nigro-striatal dopaminergic loss and the duration and dose of l-dopa treatment. In this review article we concentrate on analysis of the mechanisms underlying l-dopa-induced dyskinesias, a phenomenon that causes disability in a proportion of patients and that has not benefited from major therapeutic advances. Thus, we discuss the main neurotransmitters, receptors, and pathways that have been thought to play a role in l-dopa-induced dyskinesias from the perspective of basic neuroscience studies. Some important advances in deciphering the molecular pathways involved in these abnormal movements have occurred in recent years to reveal potential targets that could be used for therapeutic purposes. However, it has not been an easy road because there have been a plethora of components involved in the generation of these undesired movements, even bypassing the traditional and well-accepted dopamine receptor activation, as recently revealed by optogenetics. Here, we attempt to unify the available data with the hope of guiding and fostering future research in the field of striatal activation and abnormal movement generation. © 2017 International Parkinson and Movement Disorder Society. © 2017 International Parkinson and Movement Disorder Society.

Delayed O-methylation of l-DOPA in MB-COMT-deficient mice after oral administration of l-DOPA and carbidopa.

PubMed

Tammimäki, Anne; Aonurm-Helm, Anu; Männistö, Pekka T

2018-04-01

1. Catechol-O-methyltransferase (COMT) is involved in the O-methylation of l-DOPA, dopamine, and other catechols. The enzyme is expressed in two isoforms: soluble (S-COMT), which resides in the cytoplasm, and membrane-bound (MB-COMT), which is anchored to intracellular membranes. 2. To obtain specific information on the functions of COMT isoforms, we studied how a complete MB-COMT deficiency affects the total COMT activity in the body, peripheral l-DOPA levels, and metabolism after l-DOPA (10 mg kg -1 ) plus carbidopa (30 mg kg -1 ) administration by gastric tube in wild-type (WT) and MB-COMT-deficient mice. l-DOPA and 3-O-methyl-l-DOPA (3-OMD) levels were assayed in plasma, duodenum, and liver. 3. We showed that the selective lack of MB-COMT did not alter the total COMT activity, COMT enzyme kinetics, l-DOPA levels, or the total O-methylation of l-DOPA but delayed production of 3-OMD in plasma and peripheral tissues.

M13 bacteriophage displaying DOPA on surfaces: fabrication of various nanostructured inorganic materials without time-consuming screening processes.

PubMed

Park, Joseph P; Do, Minjae; Jin, Hyo-Eon; Lee, Seung-Wuk; Lee, Haeshin

2014-01-01

M13 bacteriophage (phage) was engineered for the use as a versatile template for preparing various nanostructured materials via genetic engineering coupled to enzymatic chemical conversions. First, we engineered the M13 phage to display TyrGluGluGlu (YEEE) on the pVIII coat protein and then enzymatically converted the Tyr residue to 3,4-dihydroxyl-l-phenylalanine (DOPA). The DOPA-displayed M13 phage could perform two functions: assembly and nucleation. The engineered phage assembles various noble metals, metal oxides, and semiconducting nanoparticles into one-dimensional arrays. Furthermore, the DOPA-displayed phage triggered the nucleation and growth of gold, silver, platinum, bimetallic cobalt-platinum, and bimetallic iron-platinum nanowires. This versatile phage template enables rapid preparation of phage-based prototype devices by eliminating the screening process, thus reducing effort and time.

DOPA Decarboxylase Modulates Tau Toxicity.

PubMed

Kow, Rebecca L; Sikkema, Carl; Wheeler, Jeanna M; Wilkinson, Charles W; Kraemer, Brian C

2018-03-01

The microtubule-associated protein tau accumulates into toxic aggregates in multiple neurodegenerative diseases. We found previously that loss of D 2 -family dopamine receptors ameliorated tauopathy in multiple models including a Caenorhabditis elegans model of tauopathy. To better understand how loss of D 2 -family dopamine receptors can ameliorate tau toxicity, we screened a collection of C. elegans mutations in dopamine-related genes (n = 45) for changes in tau transgene-induced behavioral defects. These included many genes responsible for dopamine synthesis, metabolism, and signaling downstream of the D 2 receptors. We identified one dopamine synthesis gene, DOPA decarboxylase (DDC), as a suppressor of tau toxicity in tau transgenic worms. Loss of the C. elegans DDC gene, bas-1, ameliorated the behavioral deficits of tau transgenic worms, reduced phosphorylated and detergent-insoluble tau accumulation, and reduced tau-mediated neuron loss. Loss of function in other genes in the dopamine and serotonin synthesis pathways did not alter tau-induced toxicity; however, their function is required for the suppression of tau toxicity by bas-1. Additional loss of D 2 -family dopamine receptors did not synergize with bas-1 suppression of tauopathy phenotypes. Loss of the DDC bas-1 reduced tau-induced toxicity in a C. elegans model of tauopathy, while loss of no other dopamine or serotonin synthesis genes tested had this effect. Because loss of activity upstream of DDC could reduce suppression of tau by DDC, this suggests the possibility that loss of DDC suppresses tau via the combined accumulation of dopamine precursor levodopa and serotonin precursor 5-hydroxytryptophan. Published by Elsevier Inc.

Camellia sinensis L. Extract and Its Potential Beneficial Effects in Antioxidant, Anti-Inflammatory, Anti-Hepatotoxic, and Anti-Tyrosinase Activities.

PubMed

Thitimuta, Surached; Pithayanukul, Pimolpan; Nithitanakool, Saruth; Bavovada, Rapepol; Leanpolchareanchai, Jiraporn; Saparpakorn, Patchreenart

2017-03-04

The aims of this study were to investigate the potential benefits of antioxidant, anti-inflammatory, anti-hepatotoxic, and anti-tyrosinase activities of a methanolic extract of fresh tea leaves (FTE) ( Camellia sinensis L.). The antioxidant capacity was investigated using three different methods at different temperatures. The anti-inflammatory activity was studied in vitro by the inhibition of 5-lipoxygenase assay. The anti-hepatotoxic effect was investigated in CCl₄-induced liver injury in rats. The anti-tyrosinase activities of the FTE and its principal phenolic compounds were investigated in l-3,4-dihydroxyphenylalanine (l-DOPA) oxidation by a mushroom tyrosinase. A molecular docking study was conducted to determine how the FTE's principal catechins interact with the tyrosinase. The FTE exhibited the best shelf life at low temperatures and demonstrated concentration-dependent antioxidant, anti-inflammatory, anti-hepatotoxic, and anti-tyrosinase effects compared to positive references. Treatment of rats with the FTE at 2000 mg/kg/day for 28 consecutive days reversed CCl₄-induced oxidative damage in hepatic tissues by lowering the levels of alanine aminotransferase by 69% and malondialdehyde by 90%. Our findings suggest that the FTE has the capacity to scavenge free radicals and can protect against oxidative stress induced by CCl₄ intoxication. The docking results were consistent with our in vitro data, indicating the anti-tyrosinase potency of the principal catechins.

Synthesis of dopamine in E. coli using plasmid-based expression system and its marked effect on host growth profiles.

PubMed

Das, Arunangshu; Verma, Anita; Mukherjee, Krishna J

2017-09-14

L-Dopa and dopamine are important pathway intermediates toward the synthesis of catecholamine such as epinephrine and norepinephrine from amino acid L-tyrosine. Dopamine, secreted from dopaminergic nerve cells, serves as an important neurotransmitter. We report the synthesis of dopamine by extending the aromatic amino acid pathway of Escherichia coli DH5α by the expression of 4-hydroxyphenylacetate-3-hydrolase (HpaBC) from E. coli and an engineered dopa decarboxylase (DDC) from pig kidney cell. The activity of HpaBC and DDC require 200 µM iron supplementation and 50 µM vitamin B6, respectively as additives to the growth media. The maximum concentration of L-dopa and dopamine obtained from the broth was around 26 and 27 mg/L after 24 hr of separate shake flask studies. We observed that in the presence of dopamine synthesized in vivo host growth was remarkably enhanced. These observations lead us to an interesting finding about the role of these catecholamines on bacterial growth. It is clear that synthesis of dopamine in vivo actually promotes growth much efficiently as compared to when dopamine is added to the system from outside. From HPLC and GC-MS data it was further observed that L-dopa was stable within the observable time of experiments whereas dopamine actually was subjected to degradation via oxidation and host consumption.

Simultaneous determination of levodopa and carbidopa from fava bean, green peas and green beans by high performance liquid gas chromatography.

PubMed

Mehran S M, Mohseni; B, Golshani

2013-06-01

According to many studies, sprouted fava beans are a rich source of levo-dihydroxy phenylalanine (L-dopa) the precursor of dopamine, and they are now being investigated for use in the management of Parkinson's disease. The addition of Carbidopa (C-dopa) can reduce the daily use of the L-dopa dosage requirements and it can also reduce the side effects which are associated with the L-dopa administration. The present research was conducted to find the levo-dihydroxy phenylalanine (L-dopa) and Carbidopa (C-dopa) in fava beans, green peas and green beans by High Performance Gas Chromatography (HPLC). Carbidopa (C-dopa) is a peripheral decarboxylase inhibitor. As a substitution therapy, it used in combination to treat Parkinson's disease. We obtained L-dopa and C-dopa from fava beans which were in the fresh and dry sprouted form, whose concentrations were 1.4,1.5 and 2.6,2.4 mg/ml respectively. The maximal stimulation of the L-DOPA content was seen on day 8 for the fava beans, which was 100% higher than that of the control level. The results of this study indicate that faba beans are a good source of natural L-dopa and C-dopa. The quantification of this capacity according to the stage and the plant part could be suitable for applications in the food industry and in plant medicine. The consumption of fava beans can increase the levels of L-dopa and C-dopa in the blood, with a marked improvement in the motor performance of the patients with parkinson disease, without any side effects.

Na+-independent transporters, LAT-2 and b0,+, exchange L-DOPA with neutral and basic amino acids in two clonal renal cell lines.

PubMed

Gomes, P; Soares-da-Silva, P

2002-03-15

The present study examined the functional characteristics of L-DOPA transporters in two functionally different clonal subpopulations of opossum kidney (OKLC and OKHC) cells. The uptake of L-DOPA was largely Na+-independent, though in OKHC cells a minor component (approximately 15%) required extracellular Na+. At least two Na+-independent transporters appear to be involved in L-DOPA uptake. One of these transporters has a broad specificity for small and large neutral amino acids, is stimulated by acid pH and inhibited by 2-aminobicyclo(2,2,l)-heptane-2-carboxylic acid (BCH; OKLC, Ki = 291 mM; OKHC, Ki = 380 mM). The other Na+-independent transporter binds neutral and basic amino acids and also recognizes the di-amino acid cystine. [14C]-L-DOPA efflux from OKLC and OKHC cells over 12 min corresponded to a small amount of intracellular [14C]-L-DOPA. L-Leucine, nonlabelled L-DOPA, BCH and L-arginine, stimulated the efflux of [14C]-L-DOPA in a Na+-independent manner. It is suggested that L-DOPA uses at least two major transporters, systems LAT-2 and b0,+. The transport of L-DOPA by LAT-2 corresponds to a Na+-independent transporter with a broad specificity for small and large neutral amino acids, stimulated by acid pH and inhibited by BCH. The transport of L-DOPA by system b0,+ is a Na+-independent transporter for neutral and basic amino acids that also recognizes cystine. LAT-2 was found equally important at the apical and basolateral membranes, whereas system b0,+ had a predominant distribution in apical membranes.

Targeting β-arrestin2 in the treatment of l-DOPA–induced dyskinesia in Parkinson’s disease

PubMed Central

Urs, Nikhil M.; Bido, Simone; Peterson, Sean M.; Daigle, Tanya L.; Bass, Caroline E.; Gainetdinov, Raul R.; Bezard, Erwan; Caron, Marc G.

2015-01-01

Parkinson’s disease (PD) is characterized by severe locomotor deficits and is commonly treated with the dopamine (DA) precursor l-3,4-dihydroxyphenylalanine (l-DOPA), but its prolonged use causes dyskinesias referred to as l-DOPA–induced dyskinesias (LIDs). Recent studies in animal models of PD have suggested that dyskinesias are associated with the overactivation of G protein-mediated signaling through DA receptors. β-Arrestins desensitize G protein signaling at DA receptors (D1R and D2R) in addition to activating their own G protein-independent signaling events, which have been shown to mediate locomotion. Therefore, targeting β-arrestins in PD l-DOPA therapy might prove to be a desirable approach. Here we show in a bilateral DA-depletion mouse model of Parkinson’s symptoms that genetic deletion of β-arrestin2 significantly limits the beneficial locomotor effects while markedly enhancing the dyskinesia-like effects of acute or chronic l-DOPA treatment. Viral rescue or overexpression of β-arrestin2 in knockout or control mice either reverses or protects against LIDs and its key biochemical markers. In other more conventional animal models of DA neuron loss and PD, such as 6-hydroxydopamine–treated mice or rats and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine–treated nonhuman primates, β-arrestin2 overexpression significantly reduced dyskinesias while maintaining the therapeutic effect of l-DOPA. Considerable efforts are being spent in the pharmaceutical industry to identify therapeutic approaches to block LIDs in patients with PD. Our results point to a potential therapeutic approach, whereby development of either a genetic or pharmacological intervention to enhance β-arrestin2- or limit G protein-dependent D1/D2R signaling could represent a more mechanistically informed strategy. PMID:25918399

Antidepressant-like properties of sarizotan in experimental Parkinsonism.

PubMed

Zhang, Xiaoqun; Egeland, Martin; Svenningsson, Per

2011-12-01

Depression and anxiety are common symptoms in Parkinson's disease for which there are no optimal treatments. Sarizotan, an agonist at serotonin receptors and partial agonist at dopamine D₂-like receptors, has shown antidyskinetic effects in Parkinson's disease. Based on its pharmacological profile, we hypothesized that sarizotan could also have antidepressant-like properties. Examine effects of sarizotan on behavioral and histological measures known to be regulated by established antidepressants in normal and unilaterally 6-hydroxydopamine-lesioned rats. Sarizotan was found to significantly reduce immobility in the modified forced swim test, a measure of antidepressant-like activity, but had no effects on thigmotaxis or corner time, measures of anxiety-like behavior, in the unilaterally 6-hydroxydopamine-lesioned rats. At the same dose, sarizotan counteracted L: -DOPA/benserazide-induced supersentitized rotational behavior and dyskinesias without significantly affecting L: -DOPA/benserazide-induced locomotion. At the histological level, sarizotan alone or in combination with L: -DOPA/benserazide stimulated cell proliferation, measured by bromodeoxyuridine incorporation or Ki-67 staining, both in the subgranular zone of the dentate gyrus and in the subventricular zone of the striatum in the 6-hydroxydopamine-lesioned hemisphere. Likewise, combined sarizotan and L: -DOPA/benserazide treatment stimulated doublecortin levels in the subgranular zone of the dentate gyrus. These significant effects of sarizotan in the modified forced swim test and on cell proliferation are reminiscent of those found after various antidepressant therapies. These data suggest that sarizotan may have some antidepressant-like and restorative properties in Parkinsonism.

Protective effects of Sesamum indicum extract against oxidative stress induced by vanadium on isolated rat hepatocytes.

PubMed

Hosseini, Mir-Jamal; Shahraki, Jafar; Tafreshian, Saman; Salimi, Ahmad; Kamalinejad, Mohammad; Pourahmad, Jalal

2016-08-01

Vanadium toxicity is a challenging problem to human and animal health with no entirely understanding cytotoxic mechanisms. Previous studies in vanadium toxicity showed involvement of oxidative stress in isolated liver hepatocytes and mitochondria via increasing of ROS formation, release of cytochrome c and ATP depletion after incubation with different concentrations (25-200 µM). Therefore, we aimed to investigate the protective effects of Sesamum indicum seed extract (100-300 μg/mL) against oxidative stress induced by vanadium on isolated rat hepatocytes. Our results showed that quite similar to Alpha-tocopherol (100 µM), different concentrations of extract (100-300 μg/mL) protected the isolated hepatocyte against all oxidative stress/cytotoxicity markers induced by vanadium in including cell lysis, ROS generation, mitochondrial membrane potential decrease and lysosomal membrane damage. Besides, vanadium induced mitochondrial/lysosomal toxic interaction and vanadium reductive activation mediated by glutathione in vanadium toxicity was significantly (P < 0.05) ameliorated by Sesamum indicum extracts. These findings suggested a hepato-protective role for extracts against liver injury resulted from vanadium toxicity. © 2015 Wiley Periodicals, Inc. Environ Toxicol 31: 979-985, 2016. © 2015 Wiley Periodicals, Inc.

Biochemical characterization of a novel tyrosine phenol-lyase from Fusobacterium nucleatum for highly efficient biosynthesis of l-DOPA.

PubMed

Zheng, Ren-Chao; Tang, Xiao-Ling; Suo, Hui; Feng, Li-Lin; Liu, Xiao; Yang, Jian; Zheng, Yu-Guo

2018-05-01

Tyrosine phenol-lyase (TPL) catalyzes the reversible cleavage of l-tyrosine to phenol, pyruvate and ammonia. When pyrocatechol is substituted for phenol, l-dihydroxyphenylalanine (l-DOPA) is produced. The TPL-catalyzed route was regarded as the most economic process for l-DOPA production. In this study, a novel TPL from Fusobacterium nucleatum (Fn-TPL) was successfully overexpressed in Escherichia coli and screened for l-DOPA synthesis with a specific activity of 2.69Umg -1 . Fn-TPL was found to be a tetramer, and the optimal temperature and pH for α, β-elimination of l-tyrosine was 60°C and pH 8.5, respectively. The enzyme showed broad substrate specificity toward natural and synthetic l-amino acids. Kinetic analysis suggested that the k cat /K m value for l-tyrosine decomposition was much higher than that for l-DOPA decomposition, while Fn-TPL exhibited similar catalytic efficiency for synthesis of l-tyrosine and l-DOPA. With whole cells of recombinant E. coli as biocatalyst, l-DOPA yield reached 110gL -1 with a pyrocatechol conversion of 95%, which was comparable to the reported highest level. The results demonstrated the great potential of Fn-TPL for industrial production of l-DOPA. Copyright © 2017 Elsevier Inc. All rights reserved.

High performance microbiological transformation of L-tyrosine to L-dopa by Yarrowia lipolytica NRRL-143

PubMed Central

Ali, Sikander; Shultz, Jeffry L; Ikram-ul-Haq

2007-01-01

Background The 3,4-dihydroxy phenyl L-alanine (L-dopa) is a drug of choice for Parkinson's disease, controlling changes in energy metabolism enzymes of the myocardium following neurogenic injury. Aspergillus oryzae is commonly used for L-dopa production; however, potential improvements in ease of handling, growth rate and environmental impact have led to an interest in exploiting alternative yeasts. The two important elements required for L-dopa production are intracellular tyrosinases (thus pre-grown yeast cells are required for the transformation of L-tyrosine to L-dopa) and L-ascorbate, which acts as a reducing agent. Results Pre-grown cells of Yarrowia lipolytica NRRL-143 were used for the microbiological transformation of L-tyrosine to L-dopa. Different diatomite concentrations (0.5–3.0 mg/ml) were added to the acidic (pH 3.5) reaction mixture. Maximum L-dopa biosynthesis (2.96 mg/ml L-dopa from 2.68 mg/ml L-tyrosine) was obtained when 2.0 mg/ml diatomite was added 15 min after the start of the reaction. After optimizing reaction time (30 min), and yeast cell concentration (2.5 mg/ml), an overall 12.5 fold higher L-dopa production rate was observed when compared to the control. Significant enhancements in Yp/s, Qs and qs over the control were observed. Conclusion Diatomite (2.0 mg/ml) addition 15 min after reaction commencement improved microbiological transformation of L-tyrosine to L-dopa (3.48 mg/ml; p ≤ 0.05) by Y. lipolytica NRRL-143. A 35% higher substrate conversion rate was achieved when compared to the control. PMID:17705832

Optogenetic activation of striatal cholinergic interneurons regulates L-dopa-induced dyskinesias

PubMed Central

Heiss, Jaime; Zhang, Danhui; Quik, Maryka

2016-01-01

L-dopa-induced dyskinesias (LIDs) are a serious complication of L-dopa therapy for Parkinson's disease. Emerging evidence indicates that the nicotinic cholinergic system plays a role in LIDs, although the pathways and mechanisms are poorly understood. Here we used optogenetics to investigate the role of striatal cholinergic interneurons in LIDs. Mice expressing cre-recombinase under the control of the choline acetyltransferase promoter (ChAT-Cre) were lesioned by unilateral injection of 6-hydroxydopamine. AAV5-ChR2-eYFP or AAV5-control-eYFP was injected into the dorsolateral striatum, and optical fibers implanted. After stable virus expression, mice were treated with L-dopa. They were then subjected to various stimulation protocols for 2 h and LIDs rated. Continuous stimulation with a short duration optical pulse (1-5 ms) enhanced LIDs. This effect was blocked by the general muscarinic acetylcholine receptor (mAChR) antagonist atropine indicating it was mAChR-mediated. By contrast, continuous stimulation with a longer duration optical pulse (20 ms to 1 s) reduced LIDs to a similar extent as nicotine treatment (~50%). The general nicotinic acetylcholine receptor (nAChR) antagonist mecamylamine blocked the decline in LIDs with longer optical pulses showing it was nAChR-mediated. None of the stimulation regimens altered LIDs in control-eYFP mice. Lesion-induced motor impairment was not affected by optical stimulation indicating that cholinergic transmission selectively regulates LIDs. Longer pulse stimulation increased the number of c-Fos expressing ChAT neurons, suggesting that changes in this immediate early gene may be involved. These results demonstrate that striatal cholinergic interneurons play a critical role in LIDs and support the idea that nicotine treatment reduces LIDs via nAChR desensitization. PMID:26921469

Nicotine-mediated improvement in L-dopa-induced dyskinesias in MPTP-lesioned monkeys is dependent on dopamine nerve terminal function.

PubMed

Quik, Maryka; Mallela, Archana; Chin, Matthew; McIntosh, J Michael; Perez, Xiomara A; Bordia, Tanuja

2013-02-01

L-dopa-induced dyskinesias (LIDs) are abnormal involuntary movements that develop with long term L-dopa therapy for Parkinson's disease. Studies show that nicotine administration reduced LIDs in several parkinsonian animal models. The present work was done to understand the factors that regulate the nicotine-mediated reduction in LIDs in MPTP-lesioned nonhuman primates. To approach this, we used two groups of monkeys, one with mild-moderate and the other with more severe parkinsonism rendered dyskinetic using L-dopa. In mild-moderately parkinsonian monkeys, nicotine pretreatment (300 μg/ml via drinking water) prevented the development of LIDs by ~75%. This improvement was maintained when the nicotine dose was lowered to 50 μg/ml but was lost with nicotine removal. Nicotine re-exposure again decreased LIDs. By contrast, nicotine treatment did not reduce LIDs in monkeys with more severe parkinsonism. We next determined how nicotine's ability to reduce LIDs correlated with lesion-induced changes in the striatal dopamine transporter and (3)H-dopamine release in these two groups of monkeys. The striatal dopamine transporter was reduced to 54% and 28% of control in mild-moderately and more severely parkinsonian monkeys, respectively. However, basal, K(+), α4β2* and α6β2* nAChR-evoked (3)H-dopamine release were near control levels in striatum of mild-moderately parkinsonian monkeys. By contrast, these same release measures were reduced to a significantly greater extent in striatum of more severely parkinsonian monkeys. Thus, nicotine best improves LIDs in lesioned monkeys in which striatal dopamine transmission is still relatively intact. These data suggest that nicotine treatment would most effectively reduce LIDs in patients with mild to moderate Parkinson's disease. Copyright © 2012 Elsevier Inc. All rights reserved.

Chemogenetic stimulation of striatal projection neurons modulates responses to Parkinson’s disease therapy

PubMed Central

Alcacer, Cristina; Andreoli, Laura; Sebastianutto, Irene; Jakobsson, Johan; Fieblinger, Tim; Cenci, Maria Angela

2017-01-01

Parkinson’s disease (PD) patients experience loss of normal motor function (hypokinesia), but can develop uncontrollable movements known as dyskinesia upon treatment with L-DOPA. Poverty or excess of movement in PD has been attributed to overactivity of striatal projection neurons forming either the indirect (iSPNs) or the direct (dSPNs) pathway, respectively. Here, we investigated the two pathways’ contribution to different motor features using SPN type–specific chemogenetic stimulation in rodent models of PD (PD mice) and L-DOPA–induced dyskinesia (LID mice). Using the activatory Gq-coupled human M3 muscarinic receptor (hM3Dq), we found that chemogenetic stimulation of dSPNs mimicked, while stimulation of iSPNs abolished the therapeutic action of L-DOPA in PD mice. In LID mice, hM3Dq stimulation of dSPNs exacerbated dyskinetic responses to L-DOPA, while stimulation of iSPNs inhibited these responses. In the absence of L-DOPA, only chemogenetic stimulation of dSPNs mediated through the Gs-coupled modified rat muscarinic M3 receptor (rM3Ds) induced appreciable dyskinesia in PD mice. Combining D2 receptor agonist treatment with rM3Ds-dSPN stimulation reproduced all symptoms of LID. These results demonstrate that dSPNs and iSPNs oppositely modulate both therapeutic and dyskinetic responses to dopamine replacement therapy in PD. We also show that chemogenetic stimulation of different signaling pathways in dSPNs leads to markedly different motor outcomes. Our findings have important implications for the design of effective antiparkinsonian and antidyskinetic drug therapies. PMID:28112685

Statistically optimized biotransformation protocol for continuous production of L-DOPA using Mucuna monosperma callus culture.

PubMed

Inamdar, Shrirang Appasaheb; Surwase, Shripad Nagnath; Jadhav, Shekhar Bhagwan; Bapat, Vishwas Anant; Jadhav, Jyoti Prafull

2013-01-01

L-DOPA (3,4-dihydroxyphenyl-L-alanine), a modified amino acid, is an expansively used drug for the Parkinson's disease treatment. In the present study, optimization of nutritional parameters influencing L-DOPA production was attempted using the response surface methodology (RSM) from Mucuna monosperma callus. Optimization of the four factors was carried out using the Box-Behnken design. The optimized levels of factors predicted by the model include tyrosine 0.894 g l(-1), pH 4.99, ascorbic acid 31.62 mg l(-1)and copper sulphate 23.92 mg l(-1), which resulted in highest L-DOPA yield of 0.309 g l(-1). The optimization of medium using RSM resulted in a 3.45-fold increase in the yield of L-DOPA. The ANOVA analysis showed a significant R (2) value (0.9912), model F-value (112.465) and probability (0.0001), with insignificant lack of fit. Optimized medium was used in the laboratory scale column reactor for continuous production of L-DOPA. Uninterrupted flow column exhibited maximum L-DOPA production rate of 200 mg L(-1) h(-1) which is one of the highest values ever reported using plant as a biotransformation source. L-DOPA production was confirmed by HPTLC and HPLC analysis. This study demonstrates the synthesis of L- DOPA using Mucuna monosperma callus using a laboratory scale column reactor.

Mucuna pruriens (Velvet bean) Rescues Motor, Olfactory, Mitochondrial and Synaptic Impairment in PINK1B9 Drosophila melanogaster Genetic Model of Parkinson’s Disease

PubMed Central

Ruffilli, Roberta; Fanti, Maura; Secci, Pietro Paolo; Mostallino, Maria Cristina; Setzu, Maria Dolores; Zuncheddu, Maria Antonietta; Collu, Ignazio; Solla, Paolo; Marrosu, Francesco; Kasture, Sanjay; Acquas, Elio; Liscia, Anna

2014-01-01

The fruit fly Drosophila melanogaster (Dm) mutant for PTEN-induced putative kinase 1 (PINK1B9) gene is a powerful tool to investigate physiopathology of Parkinson's disease (PD). Using PINK1B9 mutant Dm we sought to explore the effects of Mucuna pruriens methanolic extract (Mpe), a L-Dopa-containing herbal remedy of PD. The effects of Mpe on PINK1B9 mutants, supplied with standard diet to larvae and adults, were assayed on 3–6 (I), 10–15 (II) and 20–25 (III) days old flies. Mpe 0.1% significantly extended lifespan of PINK1B9 and fully rescued olfactory response to 1-hexanol and improved climbing behavior of PINK1B9 of all ages; in contrast, L-Dopa (0.01%, percentage at which it is present in Mpe 0.1%) ameliorated climbing of only PINK1B9 flies of age step II. Transmission electron microscopy analysis of antennal lobes and thoracic ganglia of PINK1B9 revealed that Mpe restored to wild type (WT) levels both T-bars and damaged mitochondria. Western blot analysis of whole brain showed that Mpe, but not L-Dopa on its own, restored bruchpilot (BRP) and tyrosine hydroxylase (TH) expression to age-matched WT control levels. These results highlight multiple sites of action of Mpe, suggesting that its effects cannot only depend upon its L-Dopa content and support the clinical observation of Mpe as an effective medication with intrinsic ability of delaying the onset of chronic L-Dopa-induced long-term motor complications. Overall, this study strengthens the relevance of using PINK1B9 Dm as a translational model to study the properties of Mucuna pruriens for PD treatment. PMID:25340511

Protective effect of vinpocetine against neurotoxicity of manganese in adult male rats.

PubMed

Nadeem, Rania I; Ahmed, Hebatalla I; El-Sayeh, Bahia M

2018-04-18

Manganese (Mn) is required for many essential biological processes as well as in the development and functioning of the brain. Extensive accumulation of Mn in the brain may cause central nervous system dysfunction known as manganism, a motor disorder associated with cognitive and neuropsychiatric deficits similar to parkinsonism. Vinpocetine, a synthetic derivative of the alkaloid vincamine, is used to improve the cognitive function in cerebrovascular diseases. It possesses antioxidant and antiinflammatory properties. The present work was designed to explore the potential neuroprotective mechanisms exerted by vinpocetine in the Mn-induced neurotoxicity in rats. Rats were allocated into four groups. First group was given saline. The other three groups were given MnCl 2 ; two of them were treated with either L-dopa, the gold standard antiparkinsonian drug, or vinpocetine. Rats receiving MnCl 2 exhibited lengthened catalepsy duration in the grid and bar tests, motor impairment in the open-field test and short-term memory deficit in the Y-maze test. Additionally, histological examination revealed structural alterations and degeneration in different brain regions. Besides, striatal monoamines and mitochondrial complex I contents were declined, apoptotic biomarker caspase-3 expression and acetylcholinesterase activity were elevated. Moreover, oxidative stress and inflammation were detected in the striata. L-dopa or vinpocetine exerted protective effects against MnCl 2 -induced neurotoxicity. It could be hypothesized that modulation of monoamines, upregulation of mitochondrial complex I, antioxidant, antiinflammatory, and antiapoptotic activities are significant mechanisms underlying the neuroprotective effect of vinpocetine in the Mn-induced neurotoxicity model in rats.

Overview on the biotechnological production of L-DOPA.

PubMed

Min, Kyoungseon; Park, Kyungmoon; Park, Don-Hee; Yoo, Young Je

2015-01-01

L-DOPA (3,4-dihydroxyphenyl-L-alanine) has been widely used as a drug for Parkinson's disease caused by deficiency of the neurotransmitter dopamine. Since Monsanto developed the commercial process for L-DOPA synthesis for the first time, most of currently supplied L-DOPA has been produced by the asymmetric method, especially asymmetric hydrogenation. However, the asymmetric synthesis shows critical limitations such as a poor conversion rate and a low enantioselectivity. Accordingly, alternative biotechnological approaches have been researched for overcoming the shortcomings: microbial fermentation using microorganisms with tyrosinase, tyrosine phenol-lyase, or p-hydroxyphenylacetate 3-hydroxylase activity and enzymatic conversion by immobilized tyrosinase. Actually, Ajinomoto Co. Ltd commercialized Erwinia herbicola fermentation to produce L-DOPA from catechol. In addition, the electroenzymatic conversion system was recently introduced as a newly emerging scheme. In this review, we aim to not only overview the biotechnological L-DOPA production methods, but also to briefly compare and analyze their advantages and drawbacks. Furthermore, we suggest the future potential of biotechnological L-DOPA production as an industrial process.

The newly synthesized pool of dopamine determines the severity of methamphetamine-induced neurotoxicity.

PubMed

Thomas, David M; Francescutti-Verbeem, Dina M; Kuhn, Donald M

2008-05-01

The neurotransmitter dopamine (DA) has long been implicated as a participant in the neurotoxicity caused by methamphetamine (METH), yet, its mechanism of action in this regard is not fully understood. Treatment of mice with the tyrosine hydroxylase (TH) inhibitor alpha-methyl-p-tyrosine (AMPT) lowers striatal cytoplasmic DA content by 55% and completely protects against METH-induced damage to DA nerve terminals. Reserpine, by disrupting vesicle amine storage, depletes striatal DA by more than 95% and accentuates METH-induced neurotoxicity. l-DOPA reverses the protective effect of AMPT against METH and enhances neurotoxicity in animals with intact TH. Inhibition of MAO-A by clorgyline increases pre-synaptic DA content and enhances METH striatal neurotoxicity. In all conditions of altered pre-synaptic DA homeostasis, increases or decreases in METH neurotoxicity paralleled changes in striatal microglial activation. Mice treated with AMPT, l-DOPA, or clorgyline + METH developed hyperthermia to the same extent as animals treated with METH alone, whereas mice treated with reserpine + METH were hypothermic, suggesting that the effects of alterations in cytoplasmic DA on METH neurotoxicity were not strictly mediated by changes in core body temperature. Taken together, the present data reinforce the notion that METH-induced release of DA from the newly synthesized pool of transmitter into the extracellular space plays an essential role in drug-induced striatal neurotoxicity and microglial activation. Subtle alterations in intracellular DA content can lead to significant enhancement of METH neurotoxicity. Our results also suggest that reactants derived from METH-induced oxidation of released DA may serve as neuronal signals that lead to microglial activation early in the neurotoxic process associated with METH.

Aspergillus niger PA2: a novel strain for extracellular biotransformation of L-tyrosine into L-DOPA.

PubMed

Agarwal, Pragati; Pareek, Nidhi; Dubey, Swati; Singh, Jyoti; Singh, R P

2016-05-01

L-DOPA (3,4-dihydroxyphenyl-L-alanine), an amino acid derivative is the most widely used drug of choice for the treatment of Parkinson's disease and other neurologic injuries. The present study deals with the elevated biochemical transformation of L-tyrosine to L-DOPA by Aspergillus niger PA2, a potent tyrosinase producer, isolated from decomposed food wastes. This appears to be the first report on A. niger as a notable extracellular tyrosinase producer. The extracellular tyrosinase activity produced remarkably higher levels of L-DOPA, i.e. 2.44 mg mL(-1) when the media was supplemented with 5 mg mL(-1) L-tyrosine. The optimum pH for tyrosinase production was 6.0, with the maximal L-DOPA production at the same pH. The product thus produced was analyzed by thin-layer chromatography, UV spectroscopy, high-performance liquid chromatography and Fourier transform infrared spectroscopy, that had denoted this to be L-DOPA. Kinetic parameters viz. Y p/s, Q s and Q p had further indicated the notable levels of production. Thus, Aspergillus niger PA2 could be a promising resource and may be further exploited for large-scale production of L-DOPA.

TBBPA induces developmental toxicity, oxidative stress, and apoptosis in embryos and zebrafish larvae (Danio rerio).

PubMed

Wu, Shengmin; Ji, Guixiang; Liu, Jining; Zhang, Shenghu; Gong, Yang; Shi, Lili

2016-10-01

Tetrabromobisphenol A (TBBPA) is currently one of the most frequently used brominated flame retardants and can be considered as a high production volume chemical. In this study, zebrafish embryos and larvae served as a biological model to evaluate TBBPA-induced developmental toxicity, oxidative stress, oxidant-associated gene expression, and cell apoptosis. Abnormalities, including hyperemia and pericardial edema, were induced in zebrafish larvae. The results showed that toxicity endpoints such as hatching rate, survival rate, malformation rate, and growth rate had a significant dose-response relationship with TBBPA. Further studies revealed that TBBPA did not alter the enzyme activities of Copper/Zinc Superoxide dismutase (Cu/Zn-SOD), catalase (CAT), and glutathioneperoxidase (GPx) at 0.10 mg/L, but decreased activities following exposure to 0.40, 0.70, and 1.00 mg/L. Despite the significantly decreased gene expression of Cu/Zn-SOD, CAT, and GPx1a in the 1.00 mg/L treatment group, other treatments (0.10, 0.40, 0.70 mg/L) did not alter gene expression. Moreover, Acridine orange staining results showed that apoptotic cells mainly accumulated in the brain, heart, and tail, indicating possible TBBPA-induced brain, cardiac, and blood circulation system impairment in zebrafish embryos and larvae. Histological analysis also showed evidence of obvious heart impairment in TBBPA-treated groups. This study provides new evidence on the developmental toxicity, oxidative stress, and apoptosis of embryos and zebrafish larvae, which is important for the evaluation of environmental toxicity and chemical risk. © 2015 Wiley Periodicals, Inc. Environ Toxicol 31: 1241-1249, 2016. © 2015 Wiley Periodicals, Inc.

Enhanced production of L-DOPA in cell cultures of Mucuna pruriens L. and Mucuna prurita H.

PubMed

Raghavendra, S; Kumar, V; Ramesh, C K; Khan, M H Moinuddin

2012-01-01

A comparative study on the production of 3,4-dihydroxyphenylalanine (L-DOPA) was carried out in cell cultures of two Mucuna species by elicitor treatment and precursor feeding. The influence of elicitors and the precursor molecule on L-DOPA production, polyphenol oxidase (PPO) and tyrosinase activities was also studied. Callus cultures were initiated in Mucuna pruriens L. and Mucuna prurita H. on MS medium supplemented with BAP and IAA at different concentrations. Suspension cultures were established in MS liquid medium supplemented with BAP, IAA, the elicitors methyl jasmonate, chitin and pectin or the precursor L-tyrosine at different concentrations for L-DOPA production. Compared to the controls, several-fold increases in L-DOPA concentration were observed in elicitor-treated and precursor-fed suspension cultures of both plant species. L-DOPA concentrations were comparatively higher in precursor-fed cultures than those receiving elicitor treatments. A parallel increase in tyrosinase and PPO levels was also observed. Loss of cell viability was observed at high concentrations of elicitor-treated cultures, whereas L-tyrosine did not cause any cell death. Compared to elicitor treatments, precursor feeding resulted in higher concentrations of L-DOPA production and tyrosinase activity. The efficacy of L-DOPA production was found to be higher for suspension cultures of M. pruriens compared to M. prurita in all treatments.

Slow-Binding Inhibition: A Theoretical and Practical Course for Students

ERIC Educational Resources Information Center

Golicnik, Marko; Stojan, Jure

2004-01-01

Tyrosinase (EC 1.14.18.1) catalyzes the oxidation of L-3,4-dihydroxyphenylalanine (L-DOPA) to 2,3,5,6-tetrahydro-5,6-dioxo-1H-indole-2-carboxylate (dopachrome), according to the classical Michaelis-Menten kinetic mechanism. The enzyme is strongly but slowly inhibited by alpha-amino-beta-[N-(3-hydroxy-4-pyridone)] propionic acid (L-mimosine), a…

Novel L-Dopa and dopamine prodrugs containing a 2-phenyl-imidazopyridine moiety.

PubMed

Denora, Nunzio; Laquintana, Valentino; Lopedota, Angela; Serra, Mariangela; Dazzi, Laura; Biggio, Giovanni; Pal, Dhananjay; Mitra, Ashim K; Latrofa, Andrea; Trapani, Giuseppe; Liso, Gaetano

2007-07-01

The aim of this study was to gain insight into the feasibility of enhancing the delivery of L-Dopa and dopamine to the brain by linking these neurotransmitters and L-Dopa ethyl ester to 2-phenyl-3-carboxymethyl-imidazopyridine compounds giving rise to the so-called Dopimid compounds. A number of Dopimid compounds were synthesized and both stability and binding studies to dopaminergic and benzodiazepine receptors were performed. To evaluate whether Dopimid compounds are P-gp substrates, [(3)H]ritonavir uptake experiments and bi-directional transport studies on confluent MDCKII-MDR1 monolayers were carried out. The brain penetration properties of Dopimid compounds were estimated by the Clark's computational model and evaluated by investigation of their transport across BBMECs monolayers. The dopamine levels following the intraperitoneal administration of the selected Dopimid compounds were measured in vivo by using brain microdialysis in rat. Tested compounds were adequately stable in solution buffered at pH 7.4 but undergo faster cleavage in dilute rat serum at 37 degrees C. Receptor binding studies showed that Dopimid compounds are essentially devoid of affinity for dopaminergic and benzodiazepine receptors. [(3)H]ritonavir uptake experiments indicated that selected Dopimid compounds, like L-Dopa and dopamine hydrochloride, are not substrates of P-gp and it was also confirmed by bi-directional transport experiments across MDCKII-MDR1 monolayers. By Clark's model a significant brain penetration was deduced for L-Dopa ethyl ester and dopamine derivatives. Transport studies involving BBMECs monolayers indicated that some of these compounds should be able to cross the BBB. Interestingly, the rank order of apparent permeability (P (app)) values observed in these assays parallels that calculated by the computational approach. Brain microdialysis experiments in rat showed that intraperitoneal acute administration of some Dopimid compounds induced a dose-dependent increase in cortical dopamine output. Based on these results, it may be concluded that some Dopimid compounds can be proposed as novel L-Dopa and dopamine prodrugs.

The Kinase Fyn As a Novel Intermediate in L-DOPA-Induced Dyskinesia in Parkinson's Disease.

PubMed

Sanz-Blasco, Sara; Bordone, Melina P; Damianich, Ana; Gomez, Gimena; Bernardi, M Alejandra; Isaja, Luciana; Taravini, Irene R; Hanger, Diane P; Avale, M Elena; Gershanik, Oscar S; Ferrario, Juan E

2018-06-01

Dopamine replacement therapy with L-DOPA is the treatment of choice for Parkinson's disease; however, its long-term use is frequently associated with L-DOPA-induced dyskinesia (LID). Many molecules have been implicated in the development of LID, and several of these have been proposed as potential therapeutic targets. However, to date, none of these molecules have demonstrated full clinical efficacy, either because they lie downstream of dopaminergic signaling, or due to adverse side effects. Therefore, discovering new strategies to reduce LID in Parkinson's disease remains a major challenge. Here, we have explored the tyrosine kinase Fyn, as a novel intermediate molecule in the development of LID. Fyn, a member of the Src kinase family, is located in the postsynaptic density, where it regulates phosphorylation of the NR2B subunit of the N-methyl-D-aspartate (NMDA) receptor in response to dopamine D1 receptor stimulation. We have used Fyn knockout and wild-type mice, lesioned with 6-hydroxydopamine and chronically treated with L-DOPA, to investigate the role of Fyn in the induction of LID. We found that mice lacking Fyn displayed reduced LID, ΔFosB accumulation and NR2B phosphorylation compared to wild-type control mice. Pre-administration of saracatinib (AZD0530), an inhibitor of Fyn activity, also significantly reduced LID in dyskinetic wild-type mice. These results support that Fyn has a critical role in the molecular pathways affected during the development of LID and identify Fyn as a novel potential therapeutic target for the management of dyskinesia in Parkinson's disease.

Ciprofloxacin induces oxidative stress in duckweed (Lemna minor L.): Implications for energy metabolism and antibiotic-uptake ability.

PubMed

Gomes, Marcelo Pedrosa; Gonçalves, Cíntia Almeida; de Brito, Júlio César Moreira; Souza, Amanda Miranda; da Silva Cruz, Fernanda Vieira; Bicalho, Elisa Monteze; Figueredo, Cleber Cunha; Garcia, Queila Souza

2017-04-15

We investigate the physiological responses and antibiotic-uptake capacity of Lemna minor exposed to ciprofloxacin. Ciprofloxacin (Cipro) induced toxic effects and hormesis in plants by significantly modifying photosynthesis and respiration pathways. A toxic effect was induced by a concentration ≥1.05mg ciprofloxacin l -1 while hormesis occurs at the lowest concentration studied (0.75mg ciprofloxacin l -1 ). By impairing normal electron flow in the respiratory electron transport chain, ciprofloxacin induces hydrogen peroxide (H 2 O 2 ) production. The ability of plants to cope with H 2 O 2 accumulation using antioxidant systems resulted in stimulation/deleterious effects to photosynthesis by Cipro. Cipro-induced oxidative stress was also associated with the ability of L. minor plants to uptake the antibiotic and, therefore, with plant-uptake capacity. Our results indicate that instead of being a photosystem II binding molecule, Cipro induces oxidative stress by targeting the mitochondrial ETC, which would explain the observed effects of the antibiotic on non-target eukaryotic organisms. The selection of plants species with a high capacity to tolerate oxidative stress may constitute a strategy to be used in Cipro-remediation programs. Copyright © 2017 Elsevier B.V. All rights reserved.

Losartan prevents the imbalance between renal dopaminergic and renin angiotensin systems induced by fructose overload. L-dopa/dopamine index as new potential biomarker of renal dysfunction.

PubMed

Mikusic, Natalia Lucía Rukavina; Kouyoumdzian, Nicolás Martín; Uceda, Ana; Del Mauro, Julieta Sofía; Pandolfo, Marcela; Gironacci, Mariela Mercedes; Puyó, Ana María; Toblli, Jorge Eduardo; Fernández, Belisario Enrique; Choi, Marcelo Roberto

2018-05-01

The renin angiotensin system (RAS) and the renal dopaminergic system (RDS) act as autocrine and paracrine systems to regulate renal sodium management and inflammation and their alterations have been associated to hypertension and renal damage. Nearly 30-50% of hypertensive patients have insulin resistance (IR), with a strong correlation between hyperinsulinemia and microalbuminuria. The aim of this study was to demonstrate the existence of an imbalance between RAS and RDS associated to IR, hypertension and kidney damage induced by fructose overload (FO), as well as to establish their prevention, by pharmacological inhibition of RAS with losartan. Ninety-six male Sprague-Dawley rats were randomly divided into four groups and studied at 4, 8 and 12 weeks: control group (C4, C8 and C12; tap water to drink); fructose-overloaded group (F4, F8 and F12; 10% w/v fructose solution to drink); losartan-treated control (L) group (L4, L8 and L12; losartan 30 mg/kg/day, in drinking water); and fructose-overloaded plus losartan group (F + L4, F + L8 and F + L12, in fructose solution). FO induced metabolic and hemodynamic alterations as well as an imbalance between RAS and RDS, characterized by increased renal angiotensin II levels and AT 1 R overexpression, reduced urinary excretion of dopamine, increased excretion of L-dopa (increased L-dopa/dopamine index) and down-regulation of D 1 R and tubular dopamine transporters OCT-2, OCT-N1 and total OCTNs. This imbalance was accompanied by an overexpression of renal tubular Na + , K + -ATPase, pro-inflammatory (NF-kB, TNF-α, IL-6) and pro-fibrotic (TGF-β1 and collagen) markers and by renal damage (microalbuminuria and reduced nephrin expression). Losartan prevented the metabolic and hemodynamic alterations induced by FO from week 4. Increased urinary L-dopa/dopamine index and decreased D 1 R renal expression associated to FO were also prevented by losartan since week 4. The same pattern was observed for renal expression of OCTs/OCTNs, Na + , K + -ATPase, pro-inflammatory and pro-fibrotic markers from week 8. The appearance of microalbuminuria and reduced nephrin expression was prevented by losartan at week 12. The results of this study provide new insight regarding the mechanisms by which a pro-hypertensive and pro-inflammatory system, such as RAS, downregulates another anti-hypertensive and anti-inflammatory system such as RDS. Additionally, we propose the use of L-dopa/dopamine index as a biochemical marker of renal dysfunction in conditions characterized by sodium retention, IR and/or hypertension, and as a predictor of response to treatment and follow-up of these processes. Copyright © 2018. Published by Elsevier Inc.

L-DOPA-Coated Manganese Oxide Nanoparticles as Dual MRI Contrast Agents and Drug-Delivery Vehicles.

PubMed

McDonagh, Birgitte Hjelmeland; Singh, Gurvinder; Hak, Sjoerd; Bandyopadhyay, Sulalit; Augestad, Ingrid Lovise; Peddis, Davide; Sandvig, Ioanna; Sandvig, Axel; Glomm, Wilhelm Robert

2016-01-20

Manganese oxide nanoparticles (MONPs) are capable of time-dependent magnetic resonance imaging contrast switching as well as releasing a surface-bound drug. MONPs give T2/T2* contrast, but dissolve and release T1-active Mn(2+) and L-3,4-dihydroxyphenylalanine. Complementary images are acquired with a single contrast agent, and applications toward Parkinson's disease are suggested. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Toxic Effects of Nickel Oxide Bulk and Nanoparticles on the Aquatic Plant Lemna gibba L.

PubMed Central

Oukarroum, Abdallah; Barhoumi, Lotfi; Samadani, Mahshid

2015-01-01

The aquatic plant Lemna gibba L. was used to investigate and compare the toxicity induced by 30 nm nickel oxide nanoparticles (NiO-NPs) and nickel(II) oxide as bulk (NiO-Bulk). Plants were exposed during 24 h to 0–1000 mg/L of NiO-NPs or NiO-Bulk. Analysis of physicochemical characteristics of nanoparticles in solution indicated agglomerations of NiO-NPs in culture medium and a wide size distribution was observed. Both NiO-NPs and NiO-Bulk caused a strong increase in reactive oxygen species (ROS) formation, especially at high concentration (1000 mg/L). These results showed a strong evidence of a cellular oxidative stress induction caused by the exposure to NiO. Under this condition, NiO-NPs and NiO-Bulk induced a strong inhibitory effect on the PSII quantum yield, indicating an alteration of the photosynthetic electron transport performance. Under the experimental conditions used, it is clear that the observed toxicity impact was mainly due to NiO particles effect. Therefore, results of this study permitted determining the use of ROS production as an early biomarker of NiO exposure on the aquatic plant model L. gibba used in toxicity testing. PMID:26075242

Ameliorative role of nano-ceria against amine coated Ag-NP induced toxicity in Labeo rohita

NASA Astrophysics Data System (ADS)

Khan, Muhammad Saleem; Qureshi, Naureen Aziz; Jabeen, Farhat

2018-03-01

Silver nanoparticles (Ag-NPs) and its byproducts can spread pollution in aquatic habitat. Liver and gills are key target for toxicity. Oxidative stress, tissue alterations, and hemotoxicity are assumed to be associated with Ag-NPs in target animals. Cerium oxide nanoparticles (nano-ceria) show antioxidant potential in scavenging the free radicals generated in Ag-NP-induced oxidative stress. We determined ameliorated role of nano-ceria against Ag-NP-induced toxicity in fresh water Labeo rohita (L. rohita). Four groups were used in study including control, nano-ceria, Ag-NPs, and Ag-NPs + nano-ceria. Ag-NPs (30 mg l-1) and nano-ceria (50 µg kg-1) were given through water and prepared feed, respectively. The samples were taken after 28 days. Results demonstrated that pre-treatment of nano-ceria recovered L. rohita from Ag-NP-induced toxicity and oxidative stress. Nano-ceria pre-treatment actively mimics the activity of GST, GSH, CAT, and SOD. Furthermore, Ag-NPs' treatment caused severe inflammation and necrosis in hepatic parenchyma which leaded to congestion of blood in hepatic tissues. Accumulation of a yellow pigment in hepatic tissue was also seen due to necrosis of affected cells. In nano-ceria pre-treatment, there was no congestion in hepatic tissue. Vacuolization of cells and necrosis in some area was recorded in nano-ceria pre-treated group, but the gill and hepatic tissue showed improvement against Ag-NP-induced damage. Nano-ceria pre-treatment also improved hematological parameters in Ag-NP-treated fish. This study concluded that Ag-NP-induced toxicity in treated fish and pre-treatment of nano-ceria show ameliorative role.

Recombinant heat shock protein 27 (HSP27/HSPB1) protects against cadmium-induced oxidative stress and toxicity in human cervical cancer cells.

PubMed

Alvarez-Olmedo, Daiana G; Biaggio, Veronica S; Koumbadinga, Geremy A; Gómez, Nidia N; Shi, Chunhua; Ciocca, Daniel R; Batulan, Zarah; Fanelli, Mariel A; O'Brien, Edward R

2017-05-01

Cadmium (Cd) is a carcinogen with several well-described toxicological effects in humans, but its molecular mechanisms are still not fully understood. Overexpression of heat shock protein 27 (HSP27/HSPB1)-a multifunctional protein chaperone-has been shown to protect cells from oxidative damage and apoptosis triggered by Cd exposure. The aims of this work were to investigate the potential use of extracellular recombinant HSP27 to prevent/counteract Cd-induced cellular toxicity and to evaluate if peroxynitrite was involved in the development of Cd-induced toxicity. Here, we report that the harmful effects of Cd correlated with changes in oxidative stress markers: upregulation of reactive oxygen species, reduction in nitric oxide (NO) bioavailability, increment in lipid peroxidation, peroxynitrite (PN), and protein nitration; intracellular HSP27 was reduced. Treatments with Cd (100 μM) for 24 h or with the peroxynitrite donor, SIN-1, decreased HSP27 levels (~50%), suggesting that PN formation is responsible for the reduction of HSP27. Pre-treatments of the cells either with Nω-nitro-L-arginine methyl ester hydrochloride (L-NAME) (a pharmacological inhibitor of NO synthase) or with recombinant HSP27 (rHSP27) attenuated the disruption of the cellular metabolism induced by Cd, increasing in a 55 and 52%, respectively, the cell viability measured by CCK-8. Cd induced necrotic cell death pathways, although apoptosis was also activated; pre-treatment with L-NAME or rHSP27 mitigated cell death. Our findings show for the first time a direct relationship between Cd-induced toxicity and PN production and a role for rHSP27 as a potential therapeutic agent that may counteract Cd toxicity.

Enantiomeric determination of DOPA in dietary supplements containing Mucuna pruriens by liquid chromatography/mass spectrometry.

PubMed

Hasegawa, Takashi; Takahashi, Kazunaga; Fukiwake, Tomohide; Saijo, Masaaki; Motoki, Yuji

2013-01-01

We developed a simple and rapid liquid chromatography/mass spectrometry (LC/MS) method for the enantiomeric determination of DOPA in dietary supplements containing Mucuna pruriens. L- and D-DOPA were ultrasonically extracted with 1% formic acid aqueous solution. The isolated extracts were analyzed by LC/MS using a Crownpak CR (-) column at 30℃. The mass spectrometer was operated in the positive mode of electrospray ionization, and the mobile phase was aqueous formic acid (pH 2.0). L-DOPA-ring-d3 was used as an internal standard. The method was validated for a dietary supplement spiked with L- and D-DOPA at 50 and 500 μg/g, respectively, and the recoveries of the DOPA enantiomers were between 97.5% and 101.3%. Relative standard deviation values of repeatability and intermediate precision were less than 7%. The method was applied to 14 dietary supplements. L-DOPA was detected in these supplements in the range of 0.88-12.8 mg/unit. D-DOPA was not detected.

Effect of l-DOPA on local field potential relationship between the pedunculopontine nucleus and primary motor cortex in a rat model of Parkinson's disease.

PubMed

Geng, Xiwen; Wang, Xuenan; Xie, Jinlu; Zhang, Xiao; Wang, Xiusong; Hou, Yabing; Lei, Chengdong; Li, Min; Han, Hongyu; Yao, Xiaomeng; Zhang, Qun; Wang, Min

2016-12-15

Levodopa (l-DOPA) has been proved to reverse the pathologic neuron activities in many brain regions related to Parkinson's disease (PD). But little is known about the effect of l-DOPA on the altered electrophysiological coherent activities between pedunculopontine nucleus (PPN) and motor cortex. To investigate this, local field potentials (LFPs) of PPN and primary motor cortex (M1) were recorded simultaneously in control, 6-hydroxydopamine lesioned and lesioned rats with l-DOPA chronic treatment. The results revealed that in resting state, chronic l-DOPA treatment could correct the suppressed power of LFPs in PPN and M1 in low-frequency band (1-7Hz) and the enhanced power in high-frequency band (7-70Hz in PPN and 12-70Hz in M1) of lesioned rats. In locomotor state, l-DOPA treatment could correct the alterations in most of frequency bands except the δ band in PPN and α band in M1. Moreover, l-DOPA could also reverse the altered coherent relationships caused by dopamine depletion in resting state between PPN and M1 in β band. And in locomotor state, l-DOPA had therapeutic effect on the alterations in δ and β bands but not in the α band. These findings provide evidence that l-DOPA can reverse the altered LFP activities in PPN and M1 and their relationships in a rat model of PD, which contributes to better understanding the electrophysiological mechanisms of the pathophysiology and therapy of PD. Copyright © 2016. Published by Elsevier B.V.

Schizotypal Traits are Linked to Dopamine-Induced Striato-Cortical Decoupling: A Randomized Double-Blind Placebo-Controlled Study.

PubMed

Rössler, Julian; Unterassner, Lui; Wyss, Thomas; Haker, Helene; Brugger, Peter; Rössler, Wulf; Wotruba, Diana

2018-06-07

The dopamine hypothesis of schizophrenia implies that alterations in the dopamine system cause functional abnormalities in the brain that may converge to aberrant salience attribution and eventually lead to psychosis. Indeed, widespread brain disconnectivity across the psychotic spectrum has been revealed by resting-state functional magnetic resonance imaging (rs-fMRI). However, the dopaminergic involvement in intrinsic functional connectivity (iFC) and its putative relationship to the development of psychotic spectrum disorders remains partly unclear-in particular at the low-end of the psychosis continuum. Therefore, we investigated dopamine-induced changes in striatal iFC and their modulation by psychometrically assessed schizotypy. Our randomized, double-blind placebo-controlled study design included 54 healthy, right-handed male participants. Each participant was assessed with the Schizotypal Personality Questionnaire (SPQ) and underwent 10 minutes of rs-fMRI scanning. Participants then received either a placebo or 200 mg of L-DOPA, a dopamine precursor. We analyzed iFC of 6 striatal seeds that are known to evoke modulation of dopamine-related networks. The main effect of L-DOPA was a significant functional decoupling from the right ventral caudate to both occipital fusiform gyri. This dopamine-induced decoupling emerged primarily in participants with low SPQ scores, while participants with high positive SPQ scores showed decoupling indifferently of the L-DOPA challenge. Taken together, these findings demonstrate that schizotypal traits may be the result of dopamine-induced striato-occipital decoupling.

Synthesis of Fe-based core@ZnO shell nanopowders by laser pyrolysis for biomedical applications

NASA Astrophysics Data System (ADS)

Gavrila-Florescu, Lavinia; Dumitrache, Florian; Balas, Mihaela; Fleaca, Claudiu Teodor; Scarisoreanu, Monica; Morjan, Iuliana P.; Dutu, Elena; Ilie, Alina; Banici, Ana-Maria; Locovei, Claudiu; Prodan, Gabriel

2017-12-01

Nano-sized Fe-based (metallic, carbidic and/or oxidic) core@ZnO shell particles have been successfully synthesized in one step by the laser-induced pyrolysis method in an oxygen-deficient environment. The specific precursors were separately introduced through a three concentric nozzles injector: Fe(CO)5 vapors carried by C2H4 sensitizer (central flow), Zn(C2H5)2 vapors carried and diluted with Ar (middle annular coflow) and Ar containing low amount of O2 (external flow). Keeping constant the ethylene-carried Fe(CO)5 and O2 flows, while diminishing the Zn(C2H5)2 flow, we observed an increase of the Fe/Zn ratio in the resulted nanopowders. Also, using the same metal precursor flows, a nonlinear correlation between O2 external flow and nanocomposite atomic oxygen content is evidenced, indicating a possible interference of supplementary oxidation after air exposure. However, the lowest oxygen content along with metallic zinc was found in the sample synthesized in the most oxygen-deficient environment. Transmission electron microscopy (TEM), high-resolution electron microscopy (HRTEM), selected area electron diffraction (SAED), X-ray diffraction (XRD), energy-dispersive X-ray analysis (EDS), X-ray photoelectron spectroscopy (XPS) and magnetic analyses were performed for a comprehensive characterization. The aqueous Fe-based@ZnO nanoparticles (NPs) suspensions were prepared using L-Dopa ( l-3,4-dihydroxy-phenylalanine) as stabilizing agent in physiologic media. Also, a biocompatibility in vitro study was performed for PBS (phosphate buffered saline)-dispersed L-Dopa-stabilized Fe-based@ZnO nanoparticles with the best core-shell structural features on both human normal lung fibroblasts and tumoral colorectal cells. Our results proved the ability of these newly synthesized nanostructures to target cancer cells in order to induce cytotoxicity and to exhibit biocompatibility on normal cells for maintaining the proper function of healthy tissue.

Levodopa in Mucuna pruriens and its degradation

NASA Astrophysics Data System (ADS)

Pulikkalpura, Haridas; Kurup, Rajani; Mathew, Paravanparampil Jacob; Baby, Sabulal

2015-06-01

Mucuna pruriens is the best known natural source of L-dopa, the gold standard for treatment of Parkinsonism. M. pruriens varieties are protein rich supplements, and are used as food and fodder worldwide. Here, we report L-dopa contents in seeds of fifty six accessions of four M. pruriens varieties, M. pruriens var. pruriens, M. pruriens var. hirsuta, M. pruriens var. utilis and M. pruriens var. thekkadiensis, quantified by HPTLC-densitometry. L-dopa contents varied between 0.58 to 6.42 (%, dr. wt.). High and low L-dopa yielding genotypes/chemotypes of M. pruriens could be multiplied for medicinal and nutritional purposes, respectively. HPTLC profiles of M. pruriens seeds on repeated extraction (24 h) in 1:1 formic acid-alcohol followed by development in butanol:acetic acid:water (4:1:1, v/v) showed consistent degradation of L-dopa (Rf 0.34 ± 0.02) into a second peak (Rf 0.41 ± 0.02). An average of 52.11% degradation of L-dopa was found in seeds of M. pruriens varieties. Since M. pruriens seeds and/or L-dopa are used for treatment of Parkinson’s disease and as an aphrodisiac both in modern and/or traditional systems of medicine, the finding of high level of L-dopa degradation (in pure form and in M. pruriens extracts) into damaging quinones and ROS is very significant.

Levodopa in Mucuna pruriens and its degradation.

PubMed

Pulikkalpura, Haridas; Kurup, Rajani; Mathew, Paravanparampil Jacob; Baby, Sabulal

2015-06-09

Mucuna pruriens is the best known natural source of L-dopa, the gold standard for treatment of Parkinsonism. M. pruriens varieties are protein rich supplements, and are used as food and fodder worldwide. Here, we report L-dopa contents in seeds of fifty six accessions of four M. pruriens varieties, M. pruriens var. pruriens, M. pruriens var. hirsuta, M. pruriens var. utilis and M. pruriens var. thekkadiensis, quantified by HPTLC-densitometry. L-dopa contents varied between 0.58 to 6.42 (%, dr. wt.). High and low L-dopa yielding genotypes/chemotypes of M. pruriens could be multiplied for medicinal and nutritional purposes, respectively. HPTLC profiles of M. pruriens seeds on repeated extraction (24 h) in 1:1 formic acid-alcohol followed by development in butanol:acetic acid:water (4:1:1, v/v) showed consistent degradation of L-dopa (Rf 0.34 ± 0.02) into a second peak (Rf 0.41 ± 0.02). An average of 52.11% degradation of L-dopa was found in seeds of M. pruriens varieties. Since M. pruriens seeds and/or L-dopa are used for treatment of Parkinson's disease and as an aphrodisiac both in modern and/or traditional systems of medicine, the finding of high level of L-dopa degradation (in pure form and in M. pruriens extracts) into damaging quinones and ROS is very significant.

Levodopa in Mucuna pruriens and its degradation

PubMed Central

Pulikkalpura, Haridas; Kurup, Rajani; Mathew, Paravanparampil Jacob; Baby, Sabulal

2015-01-01

Mucuna pruriens is the best known natural source of L-dopa, the gold standard for treatment of Parkinsonism. M. pruriens varieties are protein rich supplements, and are used as food and fodder worldwide. Here, we report L-dopa contents in seeds of fifty six accessions of four M. pruriens varieties, M. pruriens var. pruriens, M. pruriens var. hirsuta, M. pruriens var. utilis and M. pruriens var. thekkadiensis, quantified by HPTLC-densitometry. L-dopa contents varied between 0.58 to 6.42 (%, dr. wt.). High and low L-dopa yielding genotypes/chemotypes of M. pruriens could be multiplied for medicinal and nutritional purposes, respectively. HPTLC profiles of M. pruriens seeds on repeated extraction (24 h) in 1:1 formic acid-alcohol followed by development in butanol:acetic acid:water (4:1:1, v/v) showed consistent degradation of L-dopa (Rf 0.34 ± 0.02) into a second peak (Rf 0.41 ± 0.02). An average of 52.11% degradation of L-dopa was found in seeds of M. pruriens varieties. Since M. pruriens seeds and/or L-dopa are used for treatment of Parkinson’s disease and as an aphrodisiac both in modern and/or traditional systems of medicine, the finding of high level of L-dopa degradation (in pure form and in M. pruriens extracts) into damaging quinones and ROS is very significant. PMID:26058043

Physical Exercise Modulates L-DOPA-Regulated Molecular Pathways in the MPTP Mouse Model of Parkinson's Disease.

PubMed

Klemann, Cornelius J H M; Xicoy, Helena; Poelmans, Geert; Bloem, Bas R; Martens, Gerard J M; Visser, Jasper E

2018-07-01

Parkinson's disease (PD) is characterized by the degeneration of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc), resulting in motor and non-motor dysfunction. Physical exercise improves these symptoms in PD patients. To explore the molecular mechanisms underlying the beneficial effects of physical exercise, we exposed 1-methyl-4-phenyl-1,2,3,6-tetrahydropyrimidine (MPTP)-treated mice to a four-week physical exercise regimen, and subsequently explored their motor performance and the transcriptome of multiple PD-linked brain areas. MPTP reduced the number of DA neurons in the SNpc, whereas physical exercise improved beam walking, rotarod performance, and motor behavior in the open field. Further, enrichment analyses of the RNA-sequencing data revealed that in the MPTP-treated mice physical exercise predominantly modulated signaling cascades that are regulated by the top upstream regulators L-DOPA, RICTOR, CREB1, or bicuculline/dalfampridine, associated with movement disorders, mitochondrial dysfunction, and epilepsy-related processes. To elucidate the molecular pathways underlying these cascades, we integrated the proteins encoded by the exercise-induced differentially expressed mRNAs for each of the upstream regulators into a molecular landscape, for multiple key brain areas. Most notable was the opposite effect of physical exercise compared to previously reported effects of L-DOPA on the expression of mRNAs in the SN and the ventromedial striatum that are involved in-among other processes-circadian rhythm and signaling involving DA, neuropeptides, and endocannabinoids. Altogether, our findings suggest that physical exercise can improve motor function in PD and may, at the same time, counteract L-DOPA-mediated molecular mechanisms. Further, we hypothesize that physical exercise has the potential to improve non-motor symptoms of PD, some of which may be the result of (chronic) L-DOPA use.

The sigma-1 antagonist BMY-14802 inhibits L-DOPA-induced abnormal involuntary movements by a WAY-100635-sensitive mechanism

PubMed Central

Paquette, Melanie A.; Foley, Katherine; Brudney, Elizabeth G.; Meshul, Charles K.; Johnson, Steven W.; Berger, S. Paul

2010-01-01

Rationale Levodopa (L-DOPA), the gold standard treatment for Parkinson's disease (PD), eventually causes L-DOPA-induced dyskinesia (LID) in up to 80% of patients. In the 6-hydroxydopamine (6-OHDA) rat model of PD, L-DOPA induces a similar phenomenon, which has been termed abnormal involuntary movement (AIM). We previously demonstrated that BMY-14802 suppresses AIM expression in this model. Objectives Although BMY-14802 is widely used as a sigma-1 antagonist, it is also an agonist at serotonin (5-HT) 1A and adrenergic α-1 receptors. The current study was conducted to determine which of these mechanisms underlies BMY-14802's AIM-suppressing effect. This characterization included testing the 5-HT1A agonist buspirone and multiple sigma agents. When these studies implicated a 5-HT1A mechanism, we subsequently undertook a pharmacological reversal study, evaluating whether the 5-HT1A antagonist WAY-100635 counteracted BMY-14802's AIM-suppressing effects. Results Buspirone dose-dependently suppressed AIM, supporting past findings. However, no AIM-suppressing effects were produced by drugs with effects at sigma receptors, including BD-1047, finasteride, SM-21, DTG, trans-dehydroandrosterone (DHEA), carbetapentane, and opipramol. Finally, we show for the first time that the AIM-suppressing effect of BMY-14802 was dose-dependently prevented by WAY-100635 but not by the α-1 antagonist prazosin. Conclusions BMY-14802 exerts its AIM-suppressing effects via a 5-HT1A agonist mechanism, similar to buspirone. Other 5-HT1A agonists have failed clinical trials, possibly due to submicromolar affinity at other receptors, including D2, which may exacerbate PD symptoms. BMY-14802 is a promising candidate for clinical trials due to its extremely low affinity for the D2 receptor and lack of extrapyramidal effects during prior clinical trials for schizophrenia. PMID:19283364

The combined effect of subthalamic nuclei deep brain stimulation and L-dopa increases emotion recognition in Parkinson's disease.

PubMed

Mondillon, Laurie; Mermillod, Martial; Musca, Serban C; Rieu, Isabelle; Vidal, Tiphaine; Chambres, Patrick; Auxiette, Catherine; Dalens, Hélène; Marie Coulangeon, Louise; Jalenques, Isabelle; Lemaire, Jean-Jacques; Ulla, Miguel; Derost, Philippe; Marques, Ana; Durif, Franck

2012-10-01

Deep brain stimulation of the subthalamic nucleus (DBS) is a widely used surgical technique to suppress motor symptoms in Parkinson's disease (PD), and as such improves patients' quality of life. However, DBS may produce emotional disorders such as a reduced ability to recognize emotional facial expressions (EFE). Previous studies have not considered the fact that DBS and l-dopa medication can have differential, common, or complementary consequences on EFE processing. A thorough way of investigating the effect of DBS and l-dopa medication in greater detail is to compare patients' performances after surgery, with the two therapies either being administered ('on') or not administered ('off'). We therefore used a four-condition (l-dopa 'on'/DBS 'on', l-dopa 'on'/DBS 'off', l-dopa 'off'/DBS 'on', and l-dopa 'off'/DBS 'off') EFE recognition paradigm and compared implanted PD patients to healthy controls. The results confirmed those of previous studies, yielding a significant impairment in the detection of some facial expressions relative to controls. Disgust recognition was impaired when patients were 'off' l-dopa and 'on' DBS, and fear recognition impaired when 'off' of both therapies. More interestingly, the combined effect of both DBS and l-dopa administration seems much more beneficial for EFE recognition than the separate administration of each individual therapy. We discuss the implications of these findings in the light of the inverted U curve function that describes the differential effects of dopamine level on the right orbitofrontal cortex (OFC). We propose that, while l-dopa could "overdose" in dopamine the ventral stream of the OFC, DBS would compensate for this over-activation by decreasing OFC activity, thereby restoring the necessary OFC-amygdala interaction. Another finding is that, when collapsing over all treatment conditions, PD patients recognized more neutral faces than the matched controls, a result that concurs with embodiment theories. Copyright © 2012 Elsevier Ltd. All rights reserved.

Effects of gypenosides on anxiety disorders in MPTP-lesioned mouse model of Parkinson's disease.

PubMed

Shin, Keon Sung; Zhao, Ting Ting; Choi, Hyun Sook; Hwang, Bang Yeon; Lee, Chong Kil; Lee, Myung Koo

2014-06-03

Ethanol extract (GP-EX) of Gynostemma pentaphyllum (GP) ameliorates chronic stress-induced anxiety in mice. The present study investigated the effects of gypenoside-enriched components (GPS), GP-EX and water extract of GP (GP-WX) on MPTP lesion-induced affective disorders in C57BL/6 mice. GPS (50mg/kg) and GP-EX (50mg/kg) for 21 day-treatment period improved the symptom of anxiety disorders in the MPTP-lesioned mouse model of PD with or without L-DOPA treatment, which was examined by the elevated plus-maze and marble burying tests. In these states, treatments with GPS (50mg/kg) and GP-EX (50mg/kg) significantly increased the brain levels of dopamine and serotonin in the MPTP-lesioned mouse model of PD with or without l-DOPA treatment. In addition, treatments with GPS (50mg/kg) and GP-EX (50mg/kg) showed protective effects on dopaminergic neurons in MPTP-lesioned mouse model of PD with or without L-DOPA treatment. In contrast, GPS (30 mg/kg) and GP-WX (50mg/kg) showed anxiolytic effects in the same animal models, but it was not significant. These results suggest that GPS (50mg/kg) and GP-EX (50mg/kg) showed anxiolytic effects on affective disorders and protective effects on dopaminergic neurons by modulating the brain levels of dopamine and serotonin in the MPTP-lesioned mouse model of PD with or without l-DOPA treatment. Clinical trials of GPS and GP-EX need to be conducted further so as to develop adjuvant therapeutic agents for PD patients. Copyright © 2014 Elsevier B.V. All rights reserved.

Protective effect of acetyl-L-carnitine on propofol-induced toxicity in embryonic neural stem cells.

PubMed

Liu, Fang; Rainosek, Shuo W; Sadovova, Natalya; Fogle, Charles M; Patterson, Tucker A; Hanig, Joseph P; Paule, Merle G; Slikker, William; Wang, Cheng

2014-05-01

Propofol is a widely used general anesthetic. A growing body of data suggests that perinatal exposure to general anesthetics can result in long-term deleterious effects on brain function. In the developing brain there is evidence that general anesthetics can cause cell death, synaptic remodeling, and altered brain cell morphology. Acetyl-L-carnitine (L-Ca), an anti-oxidant dietary supplement, has been reported to prevent neuronal damage from a variety of causes. To evaluate the ability of L-Ca to protect against propofol-induced neuronal toxicity, neural stem cells were isolated from gestational day 14 rat fetuses and on the eighth day in culture were exposed for 24h to propofol at 10, 50, 100, 300 and 600 μM, with or without L-Ca (10 μM). Markers of cellular proliferation, mitochondrial health, cell death/damage and oxidative damage were monitored to determine: (1) the effects of propofol on neural stem cell proliferation; (2) the nature of propofol-induced neurotoxicity; (3) the degree of protection afforded by L-Ca; and (4) to provide information regarding possible mechanisms underlying protection. After propofol exposure at a clinically relevant concentration (50 μM), the number of dividing cells was significantly decreased, oxidative DNA damage was increased and a significant dose-dependent reduction in mitochondrial function/health was observed. No significant effect on lactase dehydrogenase (LDH) release was observed at propofol concentrations up to 100 μM. The oxidative damage at 50 μM propofol was blocked by L-Ca. Thus, clinically relevant concentrations of propofol induce dose-dependent adverse effects on rat embryonic neural stem cells by slowing or stopping cell division/proliferation and causing cellular damage. Elevated levels of 8-oxoguanine suggest enhanced oxidative damage [reactive oxygen species (ROS) generation] and L-Ca effectively blocks at least some of the toxicity of propofol, presumably by scavenging oxidative species and/or reducing their production. Published by Elsevier B.V.

Dopamine disposition in the presynaptic process regulates the severity of methamphetamine-induced neurotoxicity.

PubMed

Kuhn, Donald M; Francescutti-Verbeem, Dina M; Thomas, David M

2008-10-01

Methamphetamine (METH) is well known for its ability to cause damage to dopamine (DA) nerve endings of the striatum. The mechanisms by which METH causes neurotoxicity are not fully understood, but likely candidates are increased oxidative and nitrosative stress and mitochondrial dysfunction. Microglial activation is also emerging as an important element of the METH neurotoxic cascade, and it appears that extensive cross-talk between these cells and DA nerve endings is an early event in this process. It may seem paradoxical, but DA itself is also thought to be an essential factor in the neuronal damaging effects of METH, but issues relating to its precise role in this regard remain unanswered. We present in this overview a summary of studies that tested how alterations in the disposition of presynaptic DA (injections of reserpine, L-DOPA, or clorgyline) modulate METH neurotoxicity. In all cases, these drugs significantly increased the magnitude of microglial activation as well as the severity of damage to striatal DA nerve endings caused by METH. The enhancement of METH effects in striatum by reserpine, L-DOPA, and clorgyline persisted for 14 days and showed no evidence of recovery. These data establish that subtle shifts in the newly synthesized pool of DA can cause substantial changes in the severity of METH-induced neurotoxicity. DA released into the synapse by METH is very likely the source of downstream reactants that provoke microglial activation and the ensuing damage to DA nerve endings.

L-DOPA therapy interferes with urine catecholamine analysis in children with suspected neuroblastoma: a case series.

PubMed

Kelly, Alison U; Srivastava, Rajeev; Dow, Ellie; Davidson, D Fraser

2017-09-01

Neuroblastoma is the most common solid extracranial malignancy diagnosed in childhood. Clinical presentation is variable, and metastatic disease is common at diagnosis. Analyses of urinary catecholamines and their metabolites are commonly requested as a first-line investigation when clinical suspicion exists. Levodopa (L-Dopa) therapy is utilized as a treatment for a number of disorders in childhood, including Dopa-responsive dystonia. Neuroblastoma may mimic some of the clinical features of this disorder. L-Dopa can interfere with analysis of urinary catecholamines and their metabolites and complicate the interpretation of results. We present the cases of three children who were prescribed L-dopa at the time of analysis of urinary catecholamines and metabolites as a screen for neuroblastoma, but who did not have the disease. Comparison of their results with those from cases with true neuroblastoma reveal that it is impossible to reliably distinguish true neuroblastoma from L-Dopa therapy using these tests. We recommend that patients should be off L-dopa therapy, if possible when these tests are performed. These cases illustrate the importance of providing clinical details and drug history to the laboratory in order to avoid diagnostic confusion.

Deep brain stimulation of the center median-parafascicular complex of the thalamus has efficient anti-parkinsonian action associated with widespread cellular responses in the basal ganglia network in a rat model of Parkinson's disease.

PubMed

Jouve, Loréline; Salin, Pascal; Melon, Christophe; Kerkerian-Le Goff, Lydia

2010-07-21

The thalamic centromedian-parafascicular (CM/Pf) complex, mainly represented by Pf in rodents, is proposed as an interesting target for the neurosurgical treatment of movement disorders, including Parkinson's disease. In this study, we examined the functional impact of subchronic high-frequency stimulation (HFS) of Pf in the 6-hydroxydopamine-lesioned hemiparkinsonian rat model. Pf-HFS had significant anti-akinetic action, evidenced by alleviation of limb use asymmetry (cylinder test). Whereas this anti-akinetic action was moderate, Pf-HFS totally reversed lateralized neglect (corridor task), suggesting potent action on sensorimotor integration. At the cellular level, Pf-HFS partially reversed the dopamine denervation-induced increase in striatal preproenkephalin A mRNA levels, a marker of the neurons of the indirect pathway, without interfering with the markers of the direct pathway (preprotachykinin and preprodynorphin). Pf-HFS totally reversed the lesion-induced changes in the gene expression of cytochrome oxidase subunit I in the subthalamic nucleus, the globus pallidus, and the substantia nigra pars reticulata, and partially in the entopeduncular nucleus. Unlike HFS of the subthalamic nucleus, Pf-HFS did not induce per se dyskinesias and directly, although partially, alleviated L-3,4-dihydroxyphenylalanine (L-DOPA)-induced forelimb dyskinesia. Conversely, L-DOPA treatment negatively interfered with the anti-parkinsonian effect of Pf-HFS. Altogether, these data show that Pf-DBS, by recruiting a large basal ganglia circuitry, provides moderate to strong anti-parkinsonian benefits that might, however, be affected by L-DOPA. The widespread behavioral and cellular outcomes of Pf-HFS evidenced here demonstrate that CM/Pf is an important node for modulating the pathophysiological functioning of basal ganglia and related disorders.

Effective L-Tyrosine Hydroxylation by Native and Immobilized Tyrosinase

PubMed Central

Lewańczuk, Marcin; Koźlecki, Tomasz; Liesiene, Jolanta; Bryjak, Jolanta

2016-01-01

Hydroxylation of L-tyrosine to 3,4-dihydroxyphenylalanine (L-DOPA) by immobilized tyrosinase in the presence of ascorbic acid (AH2), which reduces DOPA-quinone to L-DOPA, is characterized by low reaction yields that are mainly caused by the suicide inactivation of tyrosinase by L-DOPA and AH2. The main aim of this work was to compare processes with native and immobilized tyrosinase to identify the conditions that limit suicide inactivation and produce substrate conversions to L-DOPA of above 50% using HPLC analysis. It was shown that immobilized tyrosinase does not suffer from partitioning and diffusion effects, allowing a direct comparison of the reactions performed with both forms of the enzyme. In typical processes, additional aeration was applied and boron ions to produce the L-DOPA and AH2 complex and hydroxylamine to close the cycle of enzyme active center transformations. It was shown that the commonly used pH 9 buffer increased enzyme stability, with concomitant reduced reactivity of 76%, and that under these conditions, the maximal substrate conversion was approximately 25 (native) to 30% (immobilized enzyme). To increase reaction yield, the pH of the reaction mixture was reduced to 8 and 7, producing L-DOPA yields of approximately 95% (native enzyme) and 70% (immobilized). A three-fold increase in the bound enzyme load achieved 95% conversion in two successive runs, but in the third one, tyrosinase lost its activity due to strong suicide inactivation caused by L-DOPA processing. In this case, the cost of the immobilized enzyme preparation is not overcome by its reuse over time, and native tyrosinase may be more economically feasible for a single use in L-DOPA production. The practical importance of the obtained results is that highly efficient hydroxylation of monophenols by tyrosinase can be obtained by selecting the proper reaction pH and is a compromise between complexation and enzyme reactivity. PMID:27711193

Root Growth and Enzymes Related to the Lignification of Maize Seedlings Exposed to the Allelochemical L-DOPA

PubMed Central

Siqueira-Soares, Rita de Cássia; Parizotto, Angela Valderrama; Ferrarese, Maria de Lourdes Lucio

2013-01-01

L-3,4-Dihydroxyphenylalanine (L-DOPA) is a known allelochemical exuded from the roots of velvet bean (Mucuna pruriens L. Fabaceae). In the current work, we analyzed the effects of L-DOPA on the growth, the activities of phenylalanine ammonia-lyase (PAL), tyrosine ammonia-lyase (TAL), and peroxidase (POD), and the contents of phenylalanine, tyrosine, and lignin in maize (Zea mays) roots. Three-day-old seedlings were cultivated in nutrient solution with or without 0.1 to 2.0 mM L-DOPA in a growth chamber (25°C, light/dark photoperiod of 12/12, and photon flux density of 280 μmol m−2 s−1) for 24 h. The results revealed that the growth (length and weight) of the roots, the PAL, TAL, and soluble and cell wall-bound POD activities decreased, while phenylalanine, tyrosine, and lignin contents increased after L-DOPA exposure. Together, these findings showed the susceptibility of maize to L-DOPA. In brief, these results suggest that the inhibition of PAL and TAL can accumulate phenylalanine and tyrosine, which contribute to enhanced lignin deposition in the cell wall followed by a reduction of maize root growth. PMID:24348138

Estimation of L-dopa from Mucuna pruriens LINN and formulations containing M. pruriens by HPTLC method.

PubMed

Modi, Ketan Pravinbhai; Patel, Natvarlal Manilal; Goyal, Ramesh Kishorilal

2008-03-01

A selective, precise, and accurate high-performance thin-layer chromatographic (HPTLC) method has been developed for the analysis of L-dopa in Mucuna pruriens seed extract and its formulations. The method involves densitometric evaluation of L-dopa after resolving it by HPTLC on silica gel plates with n-butanol-acetic acid-water (4.0+1.0+1.0, v/v) as the mobile phase. Densitometric analysis of L-dopa was carried out in the absorbance mode at 280 nm. The relationship between the concentration of L-dopa and corresponding peak areas was found to be linear in the range of 100 to 1200 ng/spot. The method was validated for precision (inter and intraday), repeatability, and accuracy. Mean recovery was 100.30%. The relative standard deviation (RSD) values of the precision were found to be in the range 0.64-1.52%. In conclusion, the proposed TLC method was found to be precise, specific and accurate and can be used for identification and quantitative determination of L-dopa in herbal extract and its formulations.

Stereospecificity of mushroom tyrosinase immobilized on a chiral and a nonchiral support.

PubMed

Marín-Zamora, María Elisa; Rojas-Melgarejo, Francisco; García-Canovas, Francisco; García-Ruiz, Pedro Antonio

2007-05-30

Mushroom tyrosinase was immobilized from an extract onto glass beads covered with the cross-linked totally cinnamoylated derivates of d-sorbitol (sorbitol cinnamate) and glycerine (glycerine cinnamate). The enzyme was immobilized onto the support by direct adsorption, and the quantity of immobilized tyrosinase was higher for sorbitol cinnamate, the support with the higher number of esterified hydroxyls per unit of monosacharide, than for glycerine cinnamate. The results obtained from the stereospecificity study of the monophenolase and diphenolase activity of immobilized mushroom tyrosinase are reported. The enantiomers L-tyrosine, DL-tyrosine, D-tyrosine, L-dopa, DL-dopa, D-dopa, L-alpha-methyldopa, DL-alpha-methyldopa, L-isoprenaline, DL-isoprenaline, L-adrenaline, DL-adrenaline, L-noradrenaline, and D-noradrenaline were assayed with tyrosinase immobilized on a chiral support (sorbitol cinnamate), whereas L-tyrosine, DL-tyrosine, D-tyrosine, L-dopa, DL-dopa, D-dopa, L-alpha-methyldopa, and DL-alpha-methyldopa were assayed with tyrosinase immobilized on a nonchiral support (glycerine cinnamate). The same Vmax(app) values for each series of enantiomers were obtained. However, the Km(app) values were different, the l isomers showing lower values than the dl isomers, whereas the highest Km(app) value was obtained with d isomers. No difference was observed in the stereospecificity of tyrosinase immobilized on a chiral (sorbitol cinnamate) or nonchiral (glycerine cinnamate) support.

Potentiometric and NMR complexation studies of phenylboronic acid PBA and its aminophosphonate analog with selected catecholamines

NASA Astrophysics Data System (ADS)

Ptak, Tomasz; Młynarz, Piotr; Dobosz, Agnieszka; Rydzewska, Agata; Prokopowicz, Monika

2013-05-01

Boronic acids are a class of intensively explored compounds, which according to their specific properties have been intensively explored in last decades. Among them phenylboronic acids and their derivatives are most frequently examined as receptors for diverse carbohydrates. In turn, there is a large gap in basic research concerning complexation of catecholamines by these compounds. Therefore, we decided to undertake studies on interaction of chosen catecholamines, namely: noradrenaline (norephinephrine), dopamine, L-DOPA, DOPA-P (phosphonic analog of L-DOPA) and catechol, with simple phenyl boronic acid PBA by means of potentiometry and NMR spectroscopy. For comparison, the binding properties of recently synthesized phenylboronic receptor 1 bearing aminophosphonate function in meta-position were investigated and showed promising ability to bind catecholamines. The protonation and stability constants of PBA and receptor 1 complexes were examined by potentiometry. The obtained results demonstrated that PBA binds the catecholamines with the following affinity order: noradrenaline ⩾ dopamine ≈ L-DOPA > catechol > DOPA-P, while its modified analog 1 reveals slightly different preferences: dopamine > noradrenaline > catechol > L-DOPA > DOPA-P.

Transcriptomic and physiological analysis of common duckweed Lemna minor responses to NH4(+) toxicity.

PubMed

Wang, Wenguo; Li, Rui; Zhu, Qili; Tang, Xiaoyu; Zhao, Qi

2016-04-18

Plants can suffer ammonium (NH4 (+)) toxicity, particularly when NH4 (+) is supplied as the sole nitrogen source. However, our knowledge about the underlying mechanisms of NH4 (+) toxicity is still largely unknown. Lemna minor, a model duckweed species, can grow well in high NH4 (+) environment but to some extent can also suffer toxic effects. The transcriptomic and physiological analysis of L. minor responding to high NH4 (+) may provide us some interesting and useful information not only in toxic processes, but also in tolerance mechanisms. The L. minor cultured in the Hoagland solution were used as the control (NC), and in two NH4 (+) concentrations (NH4 (+) was the sole nitrogen source), 84 mg/L (A84) and 840 mg/L (A840) were used as stress treatments. The NH4 (+) toxicity could inhibit the growth of L. minor. Reactive oxygen species (ROS) and cell death were studied using stained fronds under toxic levels of NH4 (+). The malondialdehyde content and the activities of superoxide dismutase and peroxidase increased from NC to A840, rather than catalase and ascorbate peroxidase. A total of 6.62G nucleotides were generated from the three distinct libraries. A total of 14,207 differentially expressed genes (DEGs) among 70,728 unigenes were obtained. All the DEGs could be clustered into 7 profiles. Most DEGs were down-regulated under NH4 (+) toxicity. The genes required for lignin biosynthesis in phenylpropanoid biosynthesis pathway were up-regulated. ROS oxidative-related genes and programmed cell death (PCD)-related genes were also analyzed and indicated oxidative damage and PCD occurring under NH4 (+) toxicity. The first large transcriptome study in L. minor responses to NH4 (+) toxicity was reported in this work. NH4 (+) toxicity could induce ROS accumulation that causes oxidative damage and thus induce cell death in L. minor. The antioxidant enzyme system was activated under NH4 (+) toxicity for ROS scavenging. The phenylpropanoid pathway was stimulated under NH4 (+) toxicity. The increased lignin biosynthesis might play an important role in NH4 (+) toxicity resistance.

Nitrogen-doped carbon dots: a facile and general preparation method, photoluminescence investigation, and imaging applications.

PubMed

Xu, Yang; Wu, Ming; Liu, Yang; Feng, Xi-Zeng; Yin, Xue-Bo; He, Xi-Wen; Zhang, Yu-Kui

2013-02-11

Carbon dots (Cdots) are an important probe for imaging and sensing applications because of their fluorescence property, good biocompatibility, and low toxicity. However, complex procedures and strong acid treatment are often required and Cdots suffer from low photoluminescence (PL) emission. Herein, a facile and general strategy using carbonization of precursors and then extraction with solvents is proposed for the preparation of nitrogen-doped Cdots (N-Cdots) with 3-(3,4-dihydroxyphenyl)-L-alanine (L-DOPA), L-histidine, and L-arginine as precursor models. After they are heated, the precursors become carbonized. Nitrogen-doped Cdots are subsequently extracted into N,N'-dimethylformamide (DMF) from the carbogenic solid. A core-shell structure of Cdots with a carbon core and the oxygen-containing shell was observed. Nitrogen has different forms in N-Cdots and oxidized N-Cdots. The doped nitrogen and low oxidation level in N-Cdots improve their emission significantly. The N-Cdots show an emission with a nitrogen-content-dependent intensity and Cdot-size-dependent emission-peak wavelength. Imaging of HeLa cells, a human cervical cancer cell line, and HepG2 cells, a human hepatocellular liver carcinoma line, was observed with high resolution using N-Cdots as a probe and validates their use in imaging applications and their multicolor property in the living cell system. Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Chronopharmacology of L-DOPA: implications for orthochronal therapy in the prevention of circadian dyschronism

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

Ehret, C.F.; Meinert, J.C.; Groh, K.R.

1978-01-01

Two experimental results showed a significant influence of the circadian phase time-of-administration of L-DOPA upon the circadian rhythm of the rat, as judged by measures of core temperature. It is concluded that, in order to minimize the deleterious side effects and maximize the beneficial effects of a drug such as L-DOPA, orthochronal therapy is indicated. How orthochronal is to be defined when extrapolated to organisms apparently deficient in either tyrosine hydroxylase or in L-DOPA itself (as in the case of Parkinson's disease) will require experimental trial with appropriate subjects.

Case of Levodopa Toxicity from Ingestion of Mucuna gigantea

PubMed Central

Kim, Brian B; McMurtray, Aaron M; Nakamoto, Beau K

2013-01-01

Hawai‘i is home to 1000 native species of flowering plants. Mucuna gigantea is one such Hawaiian species which has been studied as affordable sustenance and as a cover crop in developing countries. Mucuna gigantea and other Mucuna species (spp.) in general, are known to contain natural levodopa and its utility in the treatment of Parkinson's Disease has also been evaluated. Levodopa is converted in the periphery into dopamine which can then act on dopamine receptors to cause nausea, vomiting, arrhythmias, and hypotension. We describe a case in which a patient presents with abdominal pain, nausea, and vomiting after legume ingestion. The bean was ultimately identified as Mucuna gigantea and the patient was diagnosed with levodopa-induced gastrointestinal toxicity from consumption of the legume. A literature review was conducted using the database search engines, Biological Abstracts and PubMed, with a broad combination of keywords of which include “mucuna, “gigantean,” “levodopa,” “l-dopa,” “toxicity,” and the association between Mucuna gigantea ingestion and levodopa toxicity is discussed. These findings expand the differential diagnosis of abdominal pain associated with nausea and vomiting in the correct clinical context. PMID:23795319

Raman, IR, UV-vis and EPR characterization of two copper dioxolene complexes derived from L-dopa and dopamine

NASA Astrophysics Data System (ADS)

Barreto, Wagner J.; Barreto, Sônia R. G.; Ando, Rômulo A.; Santos, Paulo S.; DiMauro, Eduardo; Jorge, Thiago

2008-12-01

The anionic complexes [Cu(L 1-) 3] 1-, L - = dopasemiquinone or L-dopasemiquinone, were prepared and characterized. The complexes are stable in aqueous solution showing intense absorption bands at ca. 605 nm for Cu(II)-L-dopasemiquinone and at ca. 595 nm for Cu(II)-dopasemiquinone in the UV-vis spectra, that can be assigned to intraligand transitions. Noradrenaline and adrenaline, under the same reaction conditions, did not yield Cu-complexes, despite the bands in the UV region showing that noradrenaline and adrenaline were oxidized during the process. The complexes display a resonance Raman effect, and the most enhanced bands involve ring modes and particularly the νCC + νCO stretching mode at ca. 1384 cm -1. The free radical nature of the ligands and the oxidation state of the Cu(II) were confirmed by the EPR spectra that display absorptions assigned to organic radicals with g = 2.0005 and g = 2.0923, and for Cu(II) with g = 2.008 and g = 2.0897 for L-dopasemiquinone and dopasemiquinone, respectively. The possibility that dopamine and L-dopa can form stable and aqueous-soluble copper complexes at neutral pH, whereas noradrenaline and adrenaline cannot, may be important in understanding how Cu(II)-dopamine crosses the cellular membrane as proposed in the literature to explain the role of copper in Wilson disease.

Quantitative Determination of L-DOPA in Seeds of Mucuna Pruriens Germplasm by High Performance Thin Layer Chromatography

PubMed Central

Raina, Archana P.; Khatri, Renu

2011-01-01

Mucuna pruriens Linn. is an important medicinal plant used for treatment of Parkinson's disease and many others in ancient Indian medical system. L-DOPA extracted from seeds of Mucuna is a constituent of more than 200 indigenous drug formulations and is more effective as drug than the synthetic counterpart. A densitometric high performance thin-layer chromatographic (HPTLC) method was developed for quantification of L-DOPA content present in the seeds extract. The method involves separation of L-DOPA on precoated silica gel 60 GF254 HPTLC plates using a solvent system of n-butanol-acetic-acid-water (4:1:1, v/v) as the mobile phase. Quantification was done at 280 nm using absorbance reflectance mode. Linearity was found in the concentration range of 100 to 1000 ng/spot with the correlation coefficient value of 0.9980. The method was validated for accuracy, precision and repeatability. Mean recovery was 100.89%. The LOD and LOQ for L-DOPA determination were found to be 3.41 ng/spot and 10.35 ng/spot respectively. The proposed HPTLC method was found to be precise, specific and accurate for quantitative determination of L-DOPA. It can be used for rapid screening of large germplasm collections of Mucuna pruriens for L-DOPA content. The method was used to study variation in fifteen accessions of Mucuna germplasm collected from different geographical regions. PMID:22707835

Quantitative Determination of L-DOPA in Seeds of Mucuna Pruriens Germplasm by High Performance Thin Layer Chromatography.

PubMed

Raina, Archana P; Khatri, Renu

2011-07-01

Mucuna pruriens Linn. is an important medicinal plant used for treatment of Parkinson's disease and many others in ancient Indian medical system. L-DOPA extracted from seeds of Mucuna is a constituent of more than 200 indigenous drug formulations and is more effective as drug than the synthetic counterpart. A densitometric high performance thin-layer chromatographic (HPTLC) method was developed for quantification of L-DOPA content present in the seeds extract. The method involves separation of L-DOPA on precoated silica gel 60 GF(254) HPTLC plates using a solvent system of n-butanol-acetic-acid-water (4:1:1, v/v) as the mobile phase. Quantification was done at 280 nm using absorbance reflectance mode. Linearity was found in the concentration range of 100 to 1000 ng/spot with the correlation coefficient value of 0.9980. The method was validated for accuracy, precision and repeatability. Mean recovery was 100.89%. The LOD and LOQ for L-DOPA determination were found to be 3.41 ng/spot and 10.35 ng/spot respectively. The proposed HPTLC method was found to be precise, specific and accurate for quantitative determination of L-DOPA. It can be used for rapid screening of large germplasm collections of Mucuna pruriens for L-DOPA content. The method was used to study variation in fifteen accessions of Mucuna germplasm collected from different geographical regions.

L-DOPA concentration variation in the leaf and flower tissues of six faba bean lines with common and rare flower colors

USDA-ARS?s Scientific Manuscript database

Faba bean is one of the a few plant species that can produce the medicinally important molecule, L-3,4-dihydroxy phenylalanine (L-DOPA), the major ingredient of several prescription drugs used to treat Parkinson’s disease. L-DOPA can cross the blood-brain barrier, where it is converted to dopamine, ...

Mussel-inspired catalytic selenocystamine-dopamine coatings for long-term generation of therapeutic gas on cardiovascular stents.

PubMed

Yang, Zhilu; Yang, Ying; Zhang, Li; Xiong, Kaiqin; Li, Xiangyang; Zhang, Feng; Wang, Jin; Zhao, Xin; Huang, Nan

2018-06-07

The development of a nitric oxide (NO)-generating surface with long-term, stable and controllable NO release improves the therapeutic efficacy of cardiovascular stents. In this work, we developed a "one-pot" method inspired by mussel adhesive proteins for copolymerization of selenocystamine (SeCA) and dopamine (Dopa) to form a NO-generating coating on a 316 L stainless steel (SS) stent. This "one-pot" method is environmentally friendly and easy to popularize, with many advantages including simple manufacturing procedure, high stability and no involvement of organic solvents. Such SeCA/Dopa coatings also enabled us to develop a catalytic surface for local NO-generation by reaction of endogenously existing S-nitrothiol species from fresh blood. We found that the developed SeCA/Dopa coatings could release NO in a controllable and stable manner for more than 60 days. Additionally, the released NO significantly inhibited smooth muscle cell (SMC) proliferation and migration, as well as platelet activation and aggregation through the up-regulation of cyclic guanosine monophosphate synthesis. Moreover, such NO generation enhanced the adhesion, proliferation and migration of endothelial cells (ECs), and achieved rapid in vivo re-endothelialization, effectively reducing in-stent restenosis and neointimal hyperplasia. We envision that the SeCA/Dopa-coated 316 L SS stent could be a promising platform for treatment of cardiovascular diseases. Copyright © 2018. Published by Elsevier Ltd.

Comparative effects of L-DOPA and velvet bean seed extract on soybean lignification.

PubMed

Bido, Graciene de Souza; Silva, Hingrid Ariane da; Bortolo, Tiara da Silva Coelho; Maldonado, Marcos Rodrigues; Marchiosi, Rogério; Dos Santos, Wanderley Dantas; Ferrarese-Filho, Osvaldo

2018-04-03

Velvet bean (Mucuna pruriens) is an efficient cover forage that controls weeds, pathogens and nematodes, and the non-protein amino acid L-3,4-dihydroxyphenylalanine (L-DOPA) is its main allelochemical. The effects of 3 g L -1 of an aqueous extract of velvet bean seeds, along with 0.5 mM L-DOPA for comparison, were evaluated in roots, stems and leaves of soybean (Glycine max). The activities of phenylalanine ammonia lyase (PAL) and cinnamyl alcohol dehydrogenase (CAD) were determined, along with the lignin content and its monomeric composition. The results revealed similar effects caused by L-DOPA and the aqueous extract. Both treatments reduced PAL and CAD activities, lignin, and lignin monomer contents in roots; PAL and CAD activities in stems, and CAD activity in leaves. These findings provide further evidence that the effects of velvet bean cover forage on root lignification were due to the L-DOPA, its major allelochemical.

Mucuna pruriens in Parkinson's disease: a double blind clinical and pharmacological study

PubMed Central

Katzenschlager, R; Evans, A; Manson, A; Patsalos, P; Ratnaraj, N; Watt, H; Timmermann, L; Van der Giessen, R; Lees, A

2004-01-01

Background: The seed powder of the leguminous plant, Mucuna pruriens has long been used in traditional Ayurvedic Indian medicine for diseases including parkinsonism. We have assessed the clinical effects and levodopa (L-dopa) pharmacokinetics following two different doses of mucuna preparation and compared them with standard L-dopa/carbidopa (LD/CD). Methods: Eight Parkinson's disease patients with a short duration L-dopa response and on period dyskinesias completed a randomised, controlled, double blind crossover trial. Patients were challenged with single doses of 200/50 mg LD/CD, and 15 and 30 g of mucuna preparation in randomised order at weekly intervals. L-Dopa pharmacokinetics were determined, and Unified Parkinson's Disease Rating Scale and tapping speed were obtained at baseline and repeatedly during the 4 h following drug ingestion. Dyskinesias were assessed using modified AIMS and Goetz scales. Results: Compared with standard LD/CD, the 30 g mucuna preparation led to a considerably faster onset of effect (34.6 v 68.5 min; p = 0.021), reflected in shorter latencies to peak L-dopa plasma concentrations. Mean on time was 21.9% (37 min) longer with 30 g mucuna than with LD/CD (p = 0.021); peak L-dopa plasma concentrations were 110% higher and the area under the plasma concentration v time curve (area under curve) was 165.3% larger (p = 0.012). No significant differences in dyskinesias or tolerability occurred. Conclusions: The rapid onset of action and longer on time without concomitant increase in dyskinesias on mucuna seed powder formulation suggest that this natural source of L-dopa might possess advantages over conventional L-dopa preparations in the long term management of PD. Assessment of long term efficacy and tolerability in a randomised, controlled study is warranted. PMID:15548480

Levodopa delivery systems: advancements in delivery of the gold standard.

PubMed

Ngwuluka, Ndidi; Pillay, Viness; Du Toit, Lisa C; Ndesendo, Valence; Choonara, Yahya; Modi, Girish; Naidoo, Dinesh

2010-02-01

Despite the fact that Parkinson's disease (PD) was discovered almost 200 years ago, its treatment and management remain immense challenges because progressive loss of dopaminergic nigral neurons, motor complications experienced by the patients as the disease progresses and drawbacks of pharmacotherapeutic management still persist. Various therapeutic agents have been used in the management of PD, including levodopa (l-DOPA), selegiline, amantadine, bromocriptine, entacapone, pramipexole dihydrochloride and more recently istradefylline and rasagiline. Of all agents, l-DOPA although the oldest, remains the most effective. l-DOPA is easier to administer, better tolerated, less expensive and is required by almost all PD patients. However, l-DOPA's efficacy in advanced PD is significantly reduced due to metabolism, subsequent low bioavailability and irregular fluctuations in its plasma levels. Significant strides have been made to improve the delivery of l-DOPA in order to enhance its bioavailability and reduce plasma fluctuations as well as motor complications experienced by patients purportedly resulting from pulsatile stimulation of the striatal dopamine receptors. Drug delivery systems that have been instituted for the delivery of l-DOPA include immediate release formulations, liquid formulations, dispersible tablets, controlled release formulations, dual-release formulations, microspheres, infusion and transdermal delivery, among others. In this review, the l-DOPA-loaded drug delivery systems developed over the past three decades are elaborated. The ultimate aim was to assess critically the attempts made thus far directed at improving l-DOPA absorption, bioavailability and maintenance of constant plasma concentrations, including the drug delivery technologies implicated. This review highlights the fact that neuropharmaceutics is at a precipice, which is expected to spur investigators to take that leap to enable the generation of innovative delivery systems for the effective management of PD.

The effects of cysteamine in a mouse model of levodopa-induced dyskinesias.

PubMed

David, Linda S; Saint-Pierre, Martine; Lamontagne-Proulx, Jérôme; Cicchetti, Francesca

2018-01-01

Levo-dopa (L-DOPA) has shown significant and long-lasting efficacy in the treatment of motor features characteristic of Parkinson's disease (PD). However, the effects tend to wear off at a time typically when side-effects, such as L-DOPA induced dyskinesias (LIDs), start to emerge and for which the treatment options are very limited. In recent years, we have reported on the neuroprotective and neurorestorative properties of the compounds cystamine/cysteamine in ameliorating several aspects of PD. Building on these observations, we set out to further evaluate the benefits of cysteamine on LIDs. We thus treated mice displaying LIDs with single cysteamine challenges at various doses (20, 50 and 30mg/kg) or chronically for 2 weeks using cysteamine at a dose of 30mg/kg. None of the regimens nor doses ameliorated any LID-related behavioral impairments. Mice displaying LIDs did, however, respond to a single treatment of 60mg/kg of amantadine, a drug used to clinically manage LIDs. Taken together, our results suggest that cysteamine does not induce benefits on LIDs, at least at the doses and regimen tested in our study. However, the disease-modifying effects depicted by cystamine/cysteamine, which we have shown in several reports, would strongly encourage its continued evaluation in the clinical setting. Copyright © 2017 Elsevier B.V. All rights reserved.

Synthesis of N-formyl-3,4-di-t-butoxycarbonyloxy-6-(trimethylstannyl)-L-phenylalanine ethyl ester and its regioselective radiofluorodestannylation to 6-[.sup.18 F]fluoro-L-dopa

DOEpatents

Satyamurthy, Nagichettiar; Barrio, Jorge R.; Bishop, Allyson J.; Namavari, Mohammad

1995-01-01

A protected 6-trimethylstannyl dopa derivative has been synthesized for the as a precursor for the preparation of 6-[.sup.18 F]fluoro-L-dopa. The tin derivative readily reacts with electrophilic radiofluorinating agents such as [.sup.18 F]F.sub.2, [.sup.18 F]OF.sub.2 and [.sup.18 F]AcOF. The [.sup.18 F]fluoro intermediate was easily hydrolyzed with HBr and the product 6-[.sup.18 F]fluoro-L-dopa was isolated after HPLC purification in a maximum radiochemical yield of 23%, ready for human use.

Evaluation of growth hormone release in children using arginine and L-dopa in combination.

PubMed

Weldon, V V; Gupta, S K; Klingensmith, G; Clarke, W L; Duck, S C; Haymond, M W; Pagliara, A S

1975-10-01

L-Dopa in a dose ranging from 125-500 mg and arginine monochloride in a dose of 0.5 gm/kg were given simultaneously to 56 children with short stature (height less than third percentile). Sixteen of these children were subsequently diagnosed as having growth hormone deficiency. The diagnosis of hyposomatotropism was based on clinical findings and on responses to the combination test and to arginine and L-dopa administered as separate tests. All of the remaining 40 children had a normal GH response of greater than 6 ng/ml to the combination test. However, in this group, nine children were identified who responded to the combination test but who failed to respond to arginine and L-dopa in individual tests. The data suggest that a positive response to arginine and L-dopa in combination in children, who do not respond to the usual provocative tests when administered individually, may fail to identify children with partial GH deficiency who would benefit from treatment. The integrated stimulated GH response in the 31 children in whom a normal GH response to all three tests occurred suggests that the effects of L-dopa and arginine are additive.

[The effect of droxidopa on the monoamine metabolsim in the human brain].

PubMed

Maruyama, W; Naoi, M; Narabayashi, H

1994-10-01

Droxidopa (L-threo-3,4-dihydroxyphenylserine) is an artificial amino acid, which is used to supplement noradrenaline (NA) in neurodegenerative disorders. Droxidopa is decarboxylated into NA by aromatic L-amino acid decarboxylase in the brain, but its effects on other monoamine neurotransmitters, such as dopamine (DA) and serotonin (5-HT) have not been systematically examined. The monoamine metabolism has been suggested to interact with each other in the brain, and by analysis of the cerebrospinal fluid, L-DOPA, a precursor amino acid used for supplement of DA, was found to inhibit serotonin synthesis in the brain. To examine the effects of droxidopa on the monoamine metabolism, the intraventricular fluid of the patients administered with droxidopa and L-DOPA was analyzed. The levels of monoamines, their precursor amino acids, and their metabolites were compared between the patients administered with L-DOPA. In the patients administered by droxidopa and L-DOPA, droxidopa was shown to increase the concentrations of monoamines (NA, DA and 5-HT), but the difference was not statistically significant by comparison with those treated by L-DOPA alone. The metbolites of DA and 5-HT by monoamine oxidase, 3,4-dihydroxyphenylacetic acid (DOPAC) and 5-hydroxyindoleacetic acid (5-HIAA) were also found to increase by droxidopa administration. On the other hand, the metabolites of NA and DA by catechol-O-methyltransferase (COMT), normetanephrine (NMN) and 3-methoxytyramine (3-MT), decreased in the patients treated with droxidopa and L-DOPA compared with the patients administered with L-DOPA alone and control patients.(ABSTRACT TRUNCATED AT 250 WORDS)

An evaluation of extracts of five traditional medicinal plants from Iran on the inhibition of mushroom tyrosinase activity and scavenging of free radicals.

PubMed

Khazaeli, P; Goldoozian, R; Sharififar, F

2009-10-01

This study aimed to evaluate the free radical scavenging and inhibition properties of five medicinal plants, including Quercus infectoria Olive., Terminalia chebula Retz., Lavendula stoechas L., Mentha longifolia L., Rheum palmatum L., toward the activity of mushroom tyrosinase using L-tyrosine and L-3,4-dihydroxyphenylalanine (L-DOPA) as the substrate.The methanol extracts of Q. infectoria and T. chebula showed strong radical scavenging effect in 2,2'-dipheny L-1-picrylhydrazyl (DPPH) assay(IC50 = 15.3 and 82.2 microg mL)1 respectively).These plants also showed inhibitory effects against the activity of mushroom tyrosinase in hydroxylation of L-tyrosine (85.9% and 82.2% inhibition,respectively). These two plants also inhibited the oxidation of l-DOPA similar to kojic acid as positive control (IC50 = 102.8 and 192.6 microg mL)1 respectively). In general Q. infectoria and T. chebula significantly inhibited tyrosinase activity and DPPH radical. Both activities were concentration dependant but not in linear manner. It is needed to study the cytotoxicity of these plant extracts in pigment cell culture before further evaluation and moving to in vivo conditions.

Selenium alleviates chromium toxicity by preventing oxidative stress in cabbage (Brassica campestris L. ssp. Pekinensis) leaves.

PubMed

Qing, Xuejiao; Zhao, Xiaohu; Hu, Chengxiao; Wang, Peng; Zhang, Ying; Zhang, Xuan; Wang, Pengcheng; Shi, Hanzhi; Jia, Fen; Qu, Chanjuan

2015-04-01

The beneficial role of selenium (Se) in alleviation of chromium (Cr)-induced oxidative stress is well established. However, little is known about the underlying mechanism. The impacts of exogenous Se (0.1mg/L) on Cr(1mg/L)-induced oxidative stress and antioxidant systems in leaves of cabbage (Brassica campestris L. ssp. Pekinensis) were investigated by using cellular and biochemical approaches. The results showed that supplementation of the medium with Se was effective in reducing Cr-induced increased levels of lipid peroxides and superoxide free radicals (O(-)2(·)), as well as increasing activities of superoxide dismutase (SOD) and peroxidase (POD). Meanwhile, 1mg/L Cr induced loss of plasma membrane integrity, growth inhibition, as well as ultrastructural changes of leaves were significantly reversed due to Se supplementation in the medium. In addition, Se application significantly altered the subcellular distribution of Cr which transported from mitochondria, nucleus and the cell-wall material to the soluble fraction and chloroplasts. However, Se application did no significant alteration of Cr effects on osmotic adjustment accumulating products. The study suggested that Se is able to protect leaves of cabbage against Cr toxicity by alleviation of Cr induced oxidative stress, and re-distribution of Cr in the subcellular of the leaf. Furthermore, free radicals, lipid peroxides, activity of SOD and POD, and subcellular distribution of Cr can be considered the efficient biomarkers to indicate the efficiency of Se to detoxification Cr. Copyright © 2015 Elsevier Inc. All rights reserved.

Dopamine Signaling Leads to Loss of Polycomb Repression and Aberrant Gene Activation in Experimental Parkinsonism

PubMed Central

Lerdrup, Mads; Gomes, Ana-Luisa; Kryh, Hanna; Spigolon, Giada; Caboche, Jocelyne; Fisone, Gilberto; Hansen, Klaus

2014-01-01

Polycomb group (PcG) proteins bind to and repress genes in embryonic stem cells through lineage commitment to the terminal differentiated state. PcG repressed genes are commonly characterized by the presence of the epigenetic histone mark H3K27me3, catalyzed by the Polycomb repressive complex 2. Here, we present in vivo evidence for a previously unrecognized plasticity of PcG-repressed genes in terminally differentiated brain neurons of parkisonian mice. We show that acute administration of the dopamine precursor, L-DOPA, induces a remarkable increase in H3K27me3S28 phosphorylation. The induction of the H3K27me3S28p histone mark specifically occurs in medium spiny neurons expressing dopamine D1 receptors and is dependent on Msk1 kinase activity and DARPP-32-mediated inhibition of protein phosphatase-1. Chromatin immunoprecipitation (ChIP) experiments showed that increased H3K27me3S28p was accompanied by reduced PcG binding to regulatory regions of genes. An analysis of the genome wide distribution of L-DOPA-induced H3K27me3S28 phosphorylation by ChIP sequencing (ChIP-seq) in combination with expression analysis by RNA-sequencing (RNA-seq) showed that the induction of H3K27me3S28p correlated with increased expression of a subset of PcG repressed genes. We found that induction of H3K27me3S28p persisted during chronic L-DOPA administration to parkisonian mice and correlated with aberrant gene expression. We propose that dopaminergic transmission can activate PcG repressed genes in the adult brain and thereby contribute to long-term maladaptive responses including the motor complications, or dyskinesia, caused by prolonged administration of L-DOPA in Parkinson's disease. PMID:25254549

Light/dark phase-dependent spontaneous activity is maintained in dopamine-deficient mice.

PubMed

Fujita, Masayo; Hagino, Yoko; Takeda, Taishi; Kasai, Shinya; Tanaka, Miho; Takamatsu, Yukio; Kobayashi, Kazuto; Ikeda, Kazutaka

2017-10-16

Dopamine is important for motor control and involved in the regulation of circadian rhythm. We previously found that dopamine-deficient (DD) mice became hyperactive in a novel environment 72 h after the last injection of L-3,4-dihydroxyphenylalanine (L-DOPA) when dopamine was almost completely depleted. DD mice did not initially exhibit hyperactivity in their home cages, but the animals exhibited hyperactivity several hours after the last L-DOPA injection. The regulation of motor activity in a novel environment and in home cages may be different. A previous study reported that DD mice became active again approximately 24 h after the last L-DOPA injection. One speculation was that light/dark phase-dependent spontaneous activity might be maintained despite dopamine deficiency. The present study investigated whether spontaneous home cage activity is maintained in DD mice 24-43 h and 72-91 h after the last L-DOPA injection. Spontaneous activity was almost completely suppressed during the light phase of the light/dark cycle in DD mice 24 and 72 h after the last L-DOPA injection. After the dark phase began, DD mice became active 24 and 72 h after the last L-DOPA injection. DD mice exhibited a similar amount of locomotor activity as wildtype mice 24 h after the last L-DOPA injection. Although DD mice presented a decrease in activity 72 h after the last L-DOPA injection, they maintained dark phase-stimulated locomotor activation. Despite low levels of dopamine in DD mice, they exhibited feeding behavior that was similar to wildtype mice. Although grooming and rearing behavior significantly decreased, DD mice retained their ability to perform these activities. Haloperidol treatment significantly suppressed all of these behaviors in wildtype mice but not in DD mice. These results indicate that DD mice maintain some aspects of light/dark phase-dependent spontaneous activity despite dopamine depletion, suggesting that compensatory dopamine-independent mechanisms might play a role in the DD mouse phenotype.

Synthesis of N-formyl-3,4-di-t-butoxycarbonyloxy-6(trimethylstannyl)-L-phenylalanine ethyl ester and its regioselective radiofluorodestannylation to 6-[{sup 18}F]fluoro-L-dopa

DOEpatents

Satyamurthy, N.; Barrio, J.R.; Bishop, A.J.; Namavari, M.

1995-02-28

A protected 6-trimethylstannyl dopa derivative has been synthesized for the as a precursor for the preparation of 6-[{sup 18}F]fluoro-L-dopa. The tin derivative readily reacts with electrophilic radiofluorinating agents such as [{sup 18}F]F{sub 2}, [{sup 18}F]OF{sub 2} and [{sup 18}F]AcOF. The [{sup 18}F]fluoro intermediate was easily hydrolyzed with HBr and the product 6-[{sup 18}F]fluoro-L-dopa was isolated after HPLC purification in a maximum radiochemical yield of 23%, ready for human use. 1 fig.

Synthesis of N-formyl-3,4-di-t-butoxycarbonyloxy-6(trimethylstannyl)-L-phenylalanine ethyl ester and its regioselective radiofluorodestannylation to 6-[{sup 18}F]fluoro-L-dopa

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

Satyamurthy, N.; Barrio, J.R.; Bishop, A.J.

A protected 6-trimethylstannyl dopa derivative has been synthesized for the as a precursor for the preparation of 6-[{sup 18}F]fluoro-L-dopa. The tin derivative readily reacts with electrophilic radiofluorinating agents such as [{sup 18}F]F{sub 2}, [{sup 18}F]OF{sub 2} and [{sup 18}F]AcOF. The [{sup 18}F]fluoro intermediate was easily hydrolyzed with HBr and the product 6-[{sup 18}F]fluoro-L-dopa was isolated after HPLC purification in a maximum radiochemical yield of 23%, ready for human use. 1 fig.

Construction of Compact Polyelectrolyte Multilayers Inspired by Marine Mussel: Effects of Salt Concentration and pH As Observed by QCM-D and AFM.

PubMed

Wang, Weina; Xu, Yisheng; Backes, Sebastian; Li, Ang; Micciulla, Samantha; Kayitmazer, A Basak; Li, Li; Guo, Xuhong; von Klitzing, Regine

2016-04-12

Biomimetic multilayers based on layer-by-layer (LbL) assembly were prepared as functional films with compact structure by incorporating the mussel-inspired catechol cross-linking. Dopamine-modified poly(acrylic acid) (PAADopa) was synthesized as a polyanion to offer electrostatic interaction with the prelayer polyethylenimine (PEI) and consecutively cross-linked by zinc to generate compact multilayers with tunable physicochemical properties. In situ layer-by-layer growth and cross-linking were monitored by a quartz crystal microbalance with dissipation (QCM-D) to reveal the kinetics of the process and the influence of Dopa chemistry. Addition of Dopa enhanced the mass adsorption and led to the formation of a more compact structure. An increase of ionic strength induced an increase in mass adsorption in the Dopa-cross-linked multilayers. This is a universal approach for coating of various surfaces such as Au, SiO2, Ti, and Al2O3. Roughness observed by AFM in both wet and dry conditions was compared to confirm the compact morphology of Dopa-cross-linked multilayers. Because of the pH sensitivity of Dopa moiety, metal-chelated Dopa groups can be turned into softer structure at higher pH as revealed by reduction of Young's modulus determined by MFP-3D AFM. A deeper insight into the growth and mechanical properties of Dopa-cross-linked polyelectrolyte multilayers was addressed in the present study. This allows a better control of these systems for bioapplications.

Behavior of fluorinated analogs of L-(3,4-dihydroxyphenyl)alanine and L-threo-(3,4-dihydroxyphenyl)serine as substrates for Dopa decarboxylase.

PubMed

Borri Voltattorni, Carla; Bertoldi, Mariarita; Bianconi, Silvia; Deng, Wei-ping; Wong, Kelli; Kim, InHo; Herbert, Brian; Kirk, Kenneth L

2002-07-05

We have determined the kinetic parameters for Dopa decarboxylase (DDC) of three ring-fluorinated analogs of 3,4-dihydroxyphenylalanine (Dopa). The rank order of catalytic efficiency of decarboxylation (k(cat)/K(m)) is Dopa>6-F-Dopa>2-F-Dopa>5-F-Dopa. This rank is consistent with previous in vivo and in vitro studies which indicate that, of the fluorinated analogs, 6-F-Dopa has pharmacokinetics that are most suited for positron emission tomographic (PET) evaluation of dopamine function. The effectiveness of PET as a diagnostic tool, the convenient half-life of (18)F (110 min) and the favorable pharmacokinetics of 6-[(18)F]FDOPA have combined to make this an extremely valuable reagent to study dopaminergic activity. The reactions of the related fluorinated DOPS analogs show that, while 6-F-threo-3,4-(dihydroxyphenyl)serine (DOPS) is decarboxylated at approximately the same rate as the non-fluorinated substrate, 2-F-threo-DOPS is not converted into the corresponding amine. In both cases a Pictet-Spengler condensation with the pyridoxal 5(')-phosphate (PLP) cofactor occurs to produce tetrahydroisoquinolines. Condensation of fluorinated catecholamines and catechol amino acids with endogenous aldehydes will be investigated as an approach to study possible mechanisms of L-Dopa-linked neurotoxicity. (c) 2002 Elsevier Science (USA).

Clay and DOPA containing polyelectrolyte multilayer film for imparting anticorrosion properties to galvanized steel.

PubMed

Faure, Emilie; Halusiak, Emilie; Farina, Fabrice; Giamblanco, Nicoletta; Motte, Cécile; Poelman, Mireille; Archambeau, Catherine; Van de Weerdt, Cécile; Martial, Joseph; Jérôme, Christine; Duwez, Anne-Sophie; Detrembleur, Christophe

2012-02-07

A facile and green approach is developed to impart remarkable protection against corrosion to galvanized steel. A protecting multilayer film is formed by alternating the deposition of a polycation bearing catechol groups, used as corrosion inhibitors, with clay that induces barrier properties. This coating does not affect the esthetical aspect of the surface and does not release any toxic molecules in the environment.

In vitro evaluation of antioxidants of fruit extract of Momordica charantia L. on fibroblasts and keratinocytes.

PubMed

Kumar, Ramadhar; Balaji, S; Sripriya, R; Nithya, N; Uma, T S; Sehgal, P K

2010-02-10

The antioxidant activity of the total aqueous extract (TAE) and total phenolic extract (TPE) of Momordica charantia fruits was assayed by radical-scavenging methods and cytoprotective effects on hydrogen peroxide (H(2)O(2))- and hypoxanthin-xanthin oxidase (HX-XO)-induced damage to rat cardiac fibroblasts (RCFs), NIH 3T3, and keratinocyte (A431). Cell viability was monitored by a 3-[4,5-dimethyltriazol-2-yl]-2,5-diphenyltretrazolium (MTT) assay. For fibroblasts, TPE at 200 and 300 microg/mL showed maximum and consistent cytoprotection against oxidants. The extract at 50 microg/mL also had significant and slightly protective effects on fibroblasts against H(2)O(2)- and HX-XO-induced damage, respectively. RCF was more tolerant toward the damage. For keratinocytes, a dose-dependent relationship of oxidant toxicity was only seen with H(2)O(2) but the protective action of the extract correlated with oxidant dosage. At 200 and 300 microg/mL TPE, cytoprotection was dose-dependent against oxidants. Extracts had no effect on HX-XO toxicity at 50 microg/mL. Pretreatment with both the extracts did not show any cytoprotection.

Surface-mounted MOF templated fabrication of homochiral polymer thin film for enantioselective adsorption of drugs.

PubMed

Gu, Zhi-Gang; Fu, Wen-Qiang; Liu, Min; Zhang, Jian

2017-01-26

A self-polymerized chiral monomer 3,4-dihydroxy-l-phenylalanine (l-DOPA) has been introduced into the pores of an achiral surface-mounted metal organic framework (SURMOF), and then the homochiral poly(l-DOPA) thin film has been successfully formed after UV light irradiation and etching of the SURMOF. Remarkably, such a poly(l-DOPA) thin film exhibited enantioselective adsorption of naproxen. This study opened a SURMOF-templated approach for preparing porous polymer thin films.

Impact of phosphate on glyphosate uptake and toxicity in willow.

PubMed

Gomes, Marcelo Pedrosa; Le Manac'h, Sarah Gingras; Moingt, Matthieu; Smedbol, Elise; Paquet, Serge; Labrecque, Michel; Lucotte, Marc; Juneau, Philippe

2016-03-05

Phosphate (PO4(3-)) has been shown to increase glyphosate uptake by willow, a plant species known for its phytoremediation potential. However, it remains unclear if this stimulation of glyphosate uptake can result in an elevated glyphosate toxicity to plants (which could prevent the use of willows in glyphosate-remediation programs). Consequently, we studied the effects of PO4(3-) on glyphosate uptake and toxicity in a fast growing willow cultivar (Salix miyabeana SX64). Plants were grown in hydroponic solution with a combination of glyphosate (0, 0.001, 0.065 and 1 mg l(-1)) and PO4(3-) (0, 200 and 400 mg l(-1)). We demonstrated that PO4(3-) fertilization greatly increased glyphosate uptake by roots and its translocation to leaves, which resulted in increased shikimate concentration in leaves. In addition to its deleterious effects in photosynthesis, glyphosate induced oxidative stress through hydrogen peroxide accumulation. Although it has increased glyphosate accumulation, PO4(3-) fertilization attenuated the herbicide's deleterious effects by increasing the activity of antioxidant systems and alleviating glyphosate-induced oxidative stress. Our results indicate that in addition to the glyphosate uptake, PO4(3-) is involved in glyphosate toxicity in willow by preventing glyphosate induced oxidative stress. Copyright © 2015 Elsevier B.V. All rights reserved.

Protective effect of quercetin and/or l-arginine against nano-zinc oxide-induced cardiotoxicity in rats

NASA Astrophysics Data System (ADS)

Faddah, L. M.; Baky, Nayira A. Abdel; Mohamed, Azza M.; Al-Rasheed, Nouf M.; Al-Rasheed, Nawal M.

2013-04-01

The aim of this study was to investigate the protective role of quercetin and/or l-arginine against the cardiotoxic potency of zinc oxide nanoparticle (ZnO-NP)-induced cardiac infarction. ZnO-NPs (50 nm) were administered orally at either 600 mg or 1 g/kg body weight for 5 consecutive days. The results revealed that co-administration of quercetin and/or l-arginine (each 200 mg/kg body weight) daily for 3 weeks to rats intoxicated by either of the two doses markedly ameliorated increases in serum markers of cardiac infarction, including troponin T, creatine kinase-MB, and myoglobin, as well as increases in proinflammatory biomarkers, including tumor necrosis factor-α, interleukin-6, and C-reactive protein, compared with intoxicated, untreated rats. Each agent alone or in combination also successfully modulated the alterations in serum vascular endothelial growth factor, cardiac calcium concentration, and oxidative DNA damage as well as the increase in the apoptosis marker caspase 3 of cardiac tissue in response to ZnO-NP toxicity. In conclusion, early treatment with quercetin and l-arginine may protect cardiac tissue from infarction induced by the toxic effects of ZnO-NPs.

Effects of glyphosate and its formulation, roundup, on reproduction in zebrafish (Danio rerio).

PubMed

Uren Webster, Tamsyn M; Laing, Lauren V; Florance, Hannah; Santos, Eduarda M

2014-01-21

Roundup and its active ingredient glyphosate are among the most widely used herbicides worldwide and may contaminate surface waters. Research suggests both Roundup and glyphosate induce oxidative stress in fish and may also cause reproductive toxicity in mammalian systems. We aimed to investigate the reproductive effects of Roundup and glyphosate in fish and the potential associated mechanisms of toxicity. To do this, we conducted a 21-day exposure of breeding zebrafish (Danio rerio) to 0.01, 0.5, and 10 mg/L (glyphosate acid equivalent) Roundup and 10 mg/L glyphosate. 10 mg/L glyphosate reduced egg production but not fertilization rate in breeding colonies. Both 10 mg/L Roundup and glyphosate increased early stage embryo mortalities and premature hatching. However, exposure during embryogenesis alone did not increase embryo mortality, suggesting that this effect was caused primarily by exposure during gametogenesis. Transcript profiling of the gonads revealed 10 mg/L Roundup and glyphosate induced changes in the expression of cyp19a1 and esr1 in the ovary and hsd3b2, cat, and sod1 in the testis. Our results demonstrate that these chemicals cause reproductive toxicity in zebrafish, although only at high concentrations unlikely to occur in the environment, and likely mechanisms of toxicity include disruption of the steroidogenic biosynthesis pathway and oxidative stress.

Striatal output markers do not alter in response to circling behaviour in 6-OHDA lesioned rats produced by acute or chronic administration of the monoamine uptake inhibitor BTS 74 398.

PubMed

Lane, E L; Cheetham, S; Jenner, P

2008-01-01

The monoamine uptake inhibitor BTS 74 398 induces ipsilateral circling in 6-hydroxydopamine (6-OHDA) lesioned rats without induction of abnormal motor behaviours associated with L-dopa administration. We examined whether this was reflected in the expression of peptide mRNA in the direct and indirect striatal output pathways.6-OHDA lesioning of the nigrostriatal pathway increased striatal expression of PPE-A mRNA and decreased levels of PPT mRNA with PPE-B mRNA expression remaining unchanged. Acute L-dopa administration normalised PPE-A mRNA and elevated PPT mRNA while PPE-B mRNA expression remained unchanged. Acute administration of BTS 74 398 did not alter striatal peptide mRNA levels. Following chronic treatment with L-dopa, PPE-A mRNA expression in the lesioned striatum continued to be normalised and PPT mRNA was increased compared to the intact side. PPE-B mRNA expression was also markedly increased relative to the non-lesioned striatum. Chronic BTS 74 398 administration did not alter mRNA expression in the 6-OHDA lesioned striatum although small increases in PPT mRNA expression in the intact and sham lesioned striatum were observed. The failure of BTS 74 398 to induce changes in striatal neuropeptide mRNA correlated with its failure to induce abnormal motor behaviours or behavioural sensitisation but does not explain how it produces a reversal of motor deficits. An action in another area of the brain appears likely and may explain the subsequent failure of BTS 74 398 and related compounds to exert anti-parkinsonian actions in man.

Oxidative Stress Response Induced by Butachlor in Zebrafish Embryo/Larvae: The Protective Effect of Vitamin C.

PubMed

Xiang, Qingqing; Xu, Bofan; Ding, Yilun; Liu, Xiaoyi; Zhou, Ying; Ahmad, Farooq

2018-02-01

The widespread contamination and persistence of the herbicide butachlor in the environment resulted in the exposure of non-target organisms. The present study investigated the toxicity effect of butachlor (1-15 µmol/L) and the protective effect of vitamin C (VC) against butachlor-induced toxicity in zebrafish. It was found that butachlor significantly increased the mortality and malformation rates in a dose-dependent manner, which caused elevation in reactive oxygen species (ROS) and malondialdehyde (MDA) after 72 h exposure. Compared with butachlor treatment group, the protective effect of VC against butachlor-induced toxicity were observed after adding 40, 80 mg/L VC respectively. VC significantly decreased the mortality, malformation rates, ROS, MDA, and normalized antioxidant enzymes activities of zebrafish after 72 h exposure. The result shows VC has mitigative effect on butachlor-induced toxicity and it can be used as an effective antioxidant in aquaculture.

[Scans without Evidence of Dopamine Deficit (SWEDDs)].

PubMed

Mukai, Yohei; Murata, Miho

2016-01-01

Dopamine transporter (DaT) single-photon emission computed tomography (SPECT) and [18F]fluoro-L-DOPA ([18F]DOPA) positron emission tomography (PET) facilitate the investigation of dopaminergic hypofunction in neurodegenerative diseases. DaT SPECT and [18F]DOPA PET have been adopted as survey tools in clinical trials. In a large study on Parkinson's disease, 4-15% of subjects clinically diagnosed with early-stage Parkinson's disease had normal dopaminergic functional imaging scans. These are called Scans without Evidence of Dopamine Deficit (SWEDDs), and are considered to represent a state different from Parkinson's disease. Neurological diseases that exhibit parkinsonism and have normal dopaminergic cells in the nigrostriatal system (e.g., essential tremor, psychogenic parkinsonism, DOPA-responsive dystonia, vascular parkinsonism, drug-induced parkinsonism, manganism, brain tumor, myoclonus-dystonia (DYT11), and fragile X syndrome) might be diagnosed with SWEDDs. True bradykinesia with fatigue or decrement may be useful for distinguishing between Parkinson's disease and SWEDDs. However, because SWEDDs encompass many diseases, their properties may not be uniform. In this review, we discuss DaT SPECT, the concept of SWEDDs, and differential diagnosis.

Tyrosinase-catalyzed oxidation of fluorophenols.

PubMed

Battaini, Giuseppe; Monzani, Enrico; Casella, Luigi; Lonardi, Emanuela; Tepper, Armand W J W; Canters, Gerard W; Bubacco, Luigi

2002-11-22

The activity of the type 3 copper enzyme tyrosinase toward 2-, 3-, and 4-fluorophenol was studied by kinetic methods and (1)H and (19)F NMR spectroscopy. Whereas 3- and 4-fluorophenol react with tyrosinase to give products that undergo a rapid polymerization process, 2-fluorophenol is not reactive and actually acts as a competitive inhibitor in the enzymatic oxidation of 3,4-dihydroxyphenylalanine (L-dopa). The tyrosinase-mediated polymerization of 3- and 4-fluorophenols has been studied in detail. It proceeds through a phenolic coupling pathway in which the common reactive fluoroquinone, produced stereospecifically by tyrosinase, eliminates an inorganic fluorine ion. The enzymatic reaction studied as a function of substrate concentration shows a prominent lag that is completely depleted in the presence of L-dopa. The kinetic parameters of the reactions can be correlated to the electronic and steric effects of the fluorine substituent position. Whereas the fluorine electron withdrawing effect appears to control the binding of the substrates (K(m) for 3- and 4-fluorophenols and K(I) for 2-fluorophenol), the k(cat) parameters do not follow the expected trend, indicating that in the transition state some additional steric effect rules the reactivity.

H2S protects against methionine-induced oxidative stress in brain endothelial cells.

PubMed

Tyagi, Neetu; Moshal, Karni S; Sen, Utpal; Vacek, Thomas P; Kumar, Munish; Hughes, William M; Kundu, Soumi; Tyagi, Suresh C

2009-01-01

Homocysteine (Hcy) causes cerebrovascular dysfunction by inducing oxidative stress. However, to date, there are no strategies to prevent Hcy-induced oxidative damage. Hcy is an H2S precursor formed from methionine (Met) metabolism. We aimed to investigate whether H2S ameliorated Met-induced oxidative stress in mouse brain endothelial cells (bEnd3). The bEnd3 cells were exposed to Met treatment in the presence or absence of NaHS (donor of H2S). Met-induced cell toxicity increased the levels of free radicals in a concentration-dependent manner. Met increased NADPH-oxidase-4 (NOX-4) expression and mitigated thioredxion-1(Trx-1) expression. Pretreatment of bEnd3 with NaHS (0.05 mM) attenuated the production of free radicals in the presence of Met and protected the cells from oxidative damage. Furthermore, NaHS enhanced inhibitory effects of apocynin, N-acetyl-l-cysteine (NAC), reduced glutathione (GSH), catalase (CAT), superoxide dismutase (SOD), Nomega-nitro-l-arginine methyl ester (L-NAME) on ROS production and redox enzymes levels induced by Met. In conclusion, the administration of H2S protected the cells from oxidative stress induced by hyperhomocysteinemia (HHcy), which suggested that NaHS/H2S may have therapeutic potential against Met-induced oxidative stress.

Mucuna pruriens Protects against MPTP Intoxicated Neuroinflammation in Parkinson's Disease through NF-κB/pAKT Signaling Pathways.

PubMed

Rai, Sachchida N; Birla, Hareram; Singh, Saumitra S; Zahra, Walia; Patil, Ravishankar R; Jadhav, Jyoti P; Gedda, Mallikarjuna R; Singh, Surya P

2017-01-01

Till date, drugs that have been used to manage Parkinson's disease (PD) have only shown symptomatic relief with several adverse effects besides their inability to prevent neurodegeneration. Neuroinflammation plays an important role in the advancement of PD and can be targeted for its effective treatment. Researchers have suggested that herbal plants exhibiting the anti-inflammatory and anti-oxidant properties are therefore beneficial to human health. Conventionally, Mucuna pruriens (Mp) seeds are used for maintaining male virility in India. Reportedly, Mp is used as a rejuvenator drug having neuroprotective property. Our study aimed to investigate effects of aqueous extract of Mp (100 mg/kgbwt) on neuroinflammation, orally administered to mice intoxicated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) as well as the molecular mechanism involved in the progression of PD. In this study, we have observed significant behavioral abnormalities beside decreased antioxidant defense in MPTP intoxicated mice. We have also observed significant increase in inflammatory parameters like Glial Fibrillary Acidic Protein, Inducible Nitric Oxide Synthase, Intercellular Cell Adhesion Molecule, and Tumor Necrosis Factor alpha in substantia nigra pars compacta (SNpc) of parkinsonian mice, while Mp treatment has notably reduced these inflammatory parameters. Mp also inhibited the MPTP induced activation of NF-κB and promoted pAkt1 activity which further prevented the apoptosis of the dopaminergic neurons. Moreover, Mp exhibited significant antioxidant defense by inhibiting the lipid peroxidation and nitrite level, and by improving catalase activity and enhancing GSH level in nigrostriatal region of mouse brain. Mp also recovered the behavioral abnormalities in MPTP treated mice. Additionally, Mp treatment considerably increased the immunoreactivity of Tyrosine Hydroxylase and Dopamine Transporter in SNpc of parkinsonian mice. Our high performance liquid chromatography analysis of the Mp seed extract have shown L-DOPA, gallic acid, phytic acid, quercetin, and catechin equivalents as the major components which might cause neuroprotection in PD mice. Our result suggested that Mp extract treatment containing L-DOPA and a mixture of rich novel phytochemicals significantly alleviates the MPTP induced neurotoxicity by NF-κB and pAkt pathway. The findings observed thereby indicate that Mp extract have suggestively ameliorated MPTP induced neuroinflammation, restored the biochemical and behavioral abnormalities in PD mouse and thus provided a scientific basis for its traditional claim.

Mucuna pruriens Protects against MPTP Intoxicated Neuroinflammation in Parkinson’s Disease through NF-κB/pAKT Signaling Pathways

PubMed Central

Rai, Sachchida N.; Birla, Hareram; Singh, Saumitra S.; Zahra, Walia; Patil, Ravishankar R.; Jadhav, Jyoti P.; Gedda, Mallikarjuna R.; Singh, Surya P.

2017-01-01

Till date, drugs that have been used to manage Parkinson’s disease (PD) have only shown symptomatic relief with several adverse effects besides their inability to prevent neurodegeneration. Neuroinflammation plays an important role in the advancement of PD and can be targeted for its effective treatment. Researchers have suggested that herbal plants exhibiting the anti-inflammatory and anti-oxidant properties are therefore beneficial to human health. Conventionally, Mucuna pruriens (Mp) seeds are used for maintaining male virility in India. Reportedly, Mp is used as a rejuvenator drug having neuroprotective property. Our study aimed to investigate effects of aqueous extract of Mp (100 mg/kgbwt) on neuroinflammation, orally administered to mice intoxicated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) as well as the molecular mechanism involved in the progression of PD. In this study, we have observed significant behavioral abnormalities beside decreased antioxidant defense in MPTP intoxicated mice. We have also observed significant increase in inflammatory parameters like Glial Fibrillary Acidic Protein, Inducible Nitric Oxide Synthase, Intercellular Cell Adhesion Molecule, and Tumor Necrosis Factor alpha in substantia nigra pars compacta (SNpc) of parkinsonian mice, while Mp treatment has notably reduced these inflammatory parameters. Mp also inhibited the MPTP induced activation of NF-κB and promoted pAkt1 activity which further prevented the apoptosis of the dopaminergic neurons. Moreover, Mp exhibited significant antioxidant defense by inhibiting the lipid peroxidation and nitrite level, and by improving catalase activity and enhancing GSH level in nigrostriatal region of mouse brain. Mp also recovered the behavioral abnormalities in MPTP treated mice. Additionally, Mp treatment considerably increased the immunoreactivity of Tyrosine Hydroxylase and Dopamine Transporter in SNpc of parkinsonian mice. Our high performance liquid chromatography analysis of the Mp seed extract have shown L-DOPA, gallic acid, phytic acid, quercetin, and catechin equivalents as the major components which might cause neuroprotection in PD mice. Our result suggested that Mp extract treatment containing L-DOPA and a mixture of rich novel phytochemicals significantly alleviates the MPTP induced neurotoxicity by NF-κB and pAkt pathway. The findings observed thereby indicate that Mp extract have suggestively ameliorated MPTP induced neuroinflammation, restored the biochemical and behavioral abnormalities in PD mouse and thus provided a scientific basis for its traditional claim. PMID:29311905

Evaluation of Functional SiO₂ Nanoparticles Toxicity by a 3D Culture Model.

PubMed

Pellen-Mussi, Pascal; Tricot-Doleux, Sylvie; Neaime, Chrystelle; Nerambourg, Nicolas; Cabello-Hurtado, Francisco; Cordier, Stéphane; Grasset, Fabien; Jeanne, Sylvie

2018-05-01

as a kind of non-metal oxide SiO2 NPs have been extensively used in biomedicine, pharmaceuticals and other industrial manufacturing fields, such as DNA delivery, cancer therapy… Our group had developed a method based on microemulsion process to prepare SiO2 NPs incorporating photonic or magnetic nanocrystals and luminescent nanosized inorganic metal atom clusters. However, the toxicity of nanoparticles is known to be closely related to their physico-chemical characteristics and chemical composition. it is therefore of interest to investigate the toxicity of these novel SiO2 NPs to the cells that may come in contact. the potential toxic effect of the functional @SiO2 NPs containing Mo6 clusters with or without gold nanoparticles was investigated, at concentrations 1 μg/mL, 10 μg/mL and 100 μg/mL each, on three different cell lines. Cell viability was measured by the MTT test in monolayer's culture whereas the cytotoxicity in spheroid model was examined by the APH assay. In a second time, oxidative-stress-induced cytotoxicity was investigated through glutathione levels dosages. the results indicated that both A549 and L929 cell lines did not exhibit susceptibility to functional @SiO2 NPs-induced oxidative stress unlike KB cells. SiO2 NPs containing CMB may become toxic to cultured cells but only at a very high dosage level. Therefore, this toxicity depends on cell lines and more, on the model of cell cultures. The selection of appropriate cell line remains a critical component in nanotoxicology. these results are relevant to future applications of SiO2 gold-cluster NPs in controlled release applications.

The role of L-DOPA in plants

PubMed Central

Soares, Anderson Ricardo; Marchiosi, Rogério; Siqueira-Soares, Rita de Cássia; Barbosa de Lima, Rogério; Dantas dos Santos, Wanderley; Ferrarese-Filho, Osvaldo

2014-01-01

Since higher plants regularly release organic compounds into the environment, their decay products are often added to the soil matrix and a few have been reported as agents of plant-plant interactions. These compounds, active against higher plants, typically suppress seed germination, cause injury to root growth and other meristems, and inhibit seedling growth. Mucuna pruriens is an example of a successful cover crop with several highly active secondary chemical agents that are produced by its seeds, leaves and roots. The main phytotoxic compound encountered is the non-protein amino acid L-3,4-dihydroxyphenylalanine (L-DOPA), which is used in treating the symptoms of Parkinson disease. In plants, L-DOPA is a precursor of many alkaloids, catecholamines, and melanin and is released from Mucuna into soils, inhibiting the growth of nearby plant species. This review summarizes knowledge regarding L-DOPA in plants, providing a brief overview about its metabolic actions. PMID:24598311

[Cellular and molecular biology of ischemic retina].

PubMed

Honda, Y

1996-12-01

We introduce our studies on the retinal ischemia in light of both pre- and post-Noell viewpoints. For several years now, we have employed in vivo intraretinal microelectrodes for this field of experiments. This series of studies on the cat eye revealed that the sensory retina as well as the retinal pigment epithelium is severely damaged after only a ten-minute stoppage of blood flow. This phenomenon in usually masked in the routine electroretinogram, a mass electrical response of the retina monitored from the ocular surface. Our studies, employing cultured amacrine cells from embryonic rat eyes, revealed that ischemic changes in neural cells are induced by an increase in extracellular glutamate. Among the glutamate analogs, N-methyl-D-aspartate (NMDA) is responsive to this change. An influx of calcium through NMDA receptor channels activates nitric oxide synthase (NOS), inducing intracellular nitric oxide (NO) in selected amacrine cells. Nitric oxide reacts with free radicals in the cell and induces peroxinitrite, which is toxic. This cascade triggered by ischemia is interrupted by extracellular zinc, magnesium, hemoglobin, nitroprusside, s-nitrosocysteine, and some NMDA antagonists. In terms of clinical application, there is a possibility that dihydroxyphenylalanine (DOPA), superoxide dismutase (SOD), and catalase (CAT), as well as vitamins B6 and B12, are important candidates for administration before an ischemic attack for prevention of damage to the retinal neurons. Gene expression of NOS, interleukin (IL)-1, IL-6, tumor necrosing factor (TNF), and transforming growth factor (TGF)-beta in the ischemic retina was investigated in order to discover reaction substances common to ischemic change and inflammation.

Chinese culture permeation in the treatment of Parkinson disease: a cross-sectional study in four regions of China.

PubMed

Zhang, Zhen-Xin; Chen, Honglei; Chen, Sheng-Di; Shao, Ming; Sun, Sheng-Gang; Qu, Qiu-Min; Zhang, Bao-Rong; Liu, Yi-Ming; Xu, Qun; Wan, Xia; Li, Ling; Wen, Hong-Bo; Chen, Xia; Chen, Hai-Bo; Liu, Zhen-Guo; Wang, Jian; Wang, Gang

2014-01-30

Little is known about the clinical features and treatment of Chinese patients with Parkinson disease (PD). A large cross-sectional survey of clinical features, medication use, and motor complications was conducted in 901 consecutive PD patients, from 42 randomly selected university-affiliated hospitals in four urban economic regions of China, between December 2006 and May 2007. The 901 PD patients had age range 30 to 88, and median disease duration 50 months. Most (737, 81.8%) used L-dopa (median 375 mg/day), and often added low doses of other antiparkinsonian agents. Among L-dopa-treated patients, the prevalence of motor complications was low (dyskinesias: 8.5%; motor fluctuations: 18.6%), even among patients with disease duration ≥11 years (dyskinesias: 18.1%; motor fluctuations: 42.2%). Higher L-dopa use was associated with higher occurrence of dyskinesias (OR 2.44; 95% CI 1.20-5.13) and motor fluctuations (OR 2.48; 95% CI 1.49-4.14). Initiating PD treatment with L-dopa alone (OR 0.46; 95% CI 0.22-0.95) or in combination with other medications (OR 0.41; 95% CI 0.19-0.87) was associated with less dyskinesia than treatment initiated with non-L-dopa medication. Many Chinese PD patients are treated with low-dose L-dopa and added low-dose antiparkinsonian agents, with a low prevalence of motor complications, which might be influenced by Chinese culture.

Combined toxicity of microcystin-LR and copper on lettuce (Lactuca sativa L.).

PubMed

Cao, Qing; Steinman, Alan D; Wan, Xiang; Xie, Liqiang

2018-05-10

Microcystins and copper commonly co-exist in the natural environment, but their combined toxicity remains unclear, especially in terrestrial plants. The present study investigated the toxicity effects of microcystin-LR (0, 5, 50, 500, 1000 μg L -1 ) and copper (0, 50, 500, 1000, 2000 μg L -1 ), both individually and in mixture, on the germination, growth and oxidative response of lettuce. The bioaccumulation of microcystin-LR and copper was also evaluated. Results showed that the decrease in lettuce germination induced by copper alone was not significantly different from that induced by the mixture, and the combined toxicity assessment showed a simple additive effect. Lettuce growth was not significantly reduced by microcystin-LR alone, whereas it was significantly reduced by copper alone and the mixture when copper concentration was higher than 500 μg L -1 . High concentrations of microcystin-LR (1000 μg L -1 ) and copper (≥50 μg L -1 ),as well as their mixture (≥50 + 500 μg L -1 ), induced oxidative stress in lettuce. A synergistic effect on the growth and antioxidative system of lettuce was observed when exposed to low concentrations of the mixture (≤50 + 500 μg L -1 ), whereas an antagonistic effect was observed at high concentrations (≥1000 + 2000 μg L -1 ). Moreover, the interaction of microcystin-LR and copper can increase their accumulation in lettuce. Our results suggest that the toxicity effects of microcystin-LR and copper are exacerbated when they co-exist in the natural environment at low concentrations, which not only negatively affects plant growth but also poses a potential risk to human health via the food chain. Copyright © 2018. Published by Elsevier Ltd.

L-Dopa in Parkinsonism and the Influence of Previous Thalamotomy

PubMed Central

Hughes, R. C.; Polgar, J. G.; Weightman, D.; Walton, John N.

1971-01-01

A double-blind cross-over trial over 24 weeks (10 weeks on the active remedy, 4 weeks off treatment, and 10 weeks on placebo) of the effect of L-dopa on idiopathic Parkinsonism (paralysis agitans) has shown no difference in the response obtained in patients who had undergone previous stereotaxic ventrolateral thalamotomy and in those who had not. Of the 34 patients (18 men and 16 women) in the trial 18 had been operated on (nine unilateral, nine bilateral operations) and 16 had not. All patients entering the trial were taking anticholinergic drugs in stable dosage and these were continued throughout. The only factor which seemed to limit the response to treatment was pre-existing hypertension. Of 31 patients who completed the 10-week treatment period, 12 showed marked improvement, 15 moderate improvement, and 4 and mild or negligible change. It seems that previous ventrolateral thalamotomy affords some protection against the development of L-dopa-induced involuntary limb movements on the side contralateral to the operation. As found by others, maximum benefit was seen in bradykinesia and rigidity and related features but a significant reduction in tremor was also noted during treatment. Side effects (nausea, hypotension, and involuntary movements) were common but rarely limited the therapeutic response. PMID:4923653

Dosage-dependent non-linear effect of L-dopa on human motor cortex plasticity.

PubMed

Monte-Silva, Katia; Liebetanz, David; Grundey, Jessica; Paulus, Walter; Nitsche, Michael A

2010-09-15

The neuromodulator dopamine affects learning and memory formation and their likely physiological correlates, long-term depression and potentiation, in animals and humans. It is known from animal experiments that dopamine exerts a dosage-dependent, inverted U-shaped effect on these functions. However, this has not been explored in humans so far. In order to reveal a non-linear dose-dependent effect of dopamine on cortical plasticity in humans, we explored the impact of 25, 100 and 200 mg of L-dopa on transcranial direct current (tDCS)-induced plasticity in twelve healthy human subjects. The primary motor cortex served as a model system, and plasticity was monitored by motor evoked potential amplitudes elicited by transcranial magnetic stimulation. As compared to placebo medication, low and high dosages of L-dopa abolished facilitatory as well as inhibitory plasticity, whereas the medium dosage prolonged inhibitory plasticity, and turned facilitatory plasticity into inhibition. Thus the results show clear non-linear, dosage-dependent effects of dopamine on both facilitatory and inhibitory plasticity, and support the assumption of the importance of a specific dosage of dopamine optimally suited to improve plasticity. This might be important for the therapeutic application of dopaminergic agents, especially for rehabilitative purposes, and explain some opposing results in former studies.

Exhaustive Analysis of BH4 and Dopamine Biosynthesis Genes in Patients with Dopa-Responsive Dystonia

ERIC Educational Resources Information Center

Clot, Fabienne; Grabli, David; Cazeneuve, Cecile; Roze, Emmanuel; Castelnau, Pierre; Chabrol, Brigitte; Landrieu, Pierre; Nguyen, Karine; Ponsot, Gerard; Abada, Myriem; Doummar, Diane; Damier, Philippe; Gil, Roger; Thobois, Stephane; Ward, Alana J.; Hutchinson, Michael; Toutain, Annick; Picard, Fabienne; Camuzat, Agnes; Fedirko, Estelle; San, Chankannira; Bouteiller, Delphine; LeGuern, Eric; Durr, Alexandra; Vidailhet, Marie; Brice, Alexis

2009-01-01

Dopa-responsive dystonia is a childhood-onset dystonic disorder, characterized by a dramatic response to low dose of L-Dopa. Dopa-responsive dystonia is mostly caused by autosomal dominant mutations in the "GCH1" gene (GTP cyclohydrolase1) and more rarely by autosomal recessive mutations in the "TH" (tyrosine hydroxylase) or "SPR" (sepiapterin…

Evaluation of the potential cardioprotective activity of some Saudi plants against doxorubicin toxicity.

PubMed

Ashour, Osama M; Abdel-Naim, Ashraf B; Abdallah, Hossam M; Nagy, Ayman A; Mohamadin, Ahmed M; Abdel-Sattar, Essam A

2012-01-01

Doxorubicin (DOX) is an anthracycline antibiotic widely used as a chemotherapeutic agent in the treatment of several tumours. However, its cardiac toxicity limits its use at maximum therapeutic doses. Most studies implicated increased oxidative stress as the major determinant of DOX cardiotoxicity. The local Saudi flora is very rich in a variety of plants of quite known folkloric or traditional medicinal uses. Tribulus macropterus Boiss., Olea europaea L. subsp. africana (Mill.) P. S. Green, Tamarix aphylla (L.) H. Karst., Cynomorium coccineum L., Cordia myxa L., Calligonum comosum L' Hér, and Withania somnifera (L.) Dunal are Saudi plants known to have antioxidant activities. The aim of the current study was to explore the potential protective effects of methanolic extracts of these seven Saudi plants against DOX-induced cardiotoxicity in rats. Two plants showed promising cardioprotective potential in the order Calligonum comosum > Cordia myxa. The two plant extracts showed potent in vitro radical scavenging and antioxidant properties. They significantly protected against DOX-induced alterations in cardiac oxidative stress markers (GSH and MDA) and cardiac serum markers (CK-MB and LDH activities). Additionally, histopathological examination indicated a protection against DOX-induced cardiotoxicity. In conclusion, C. comosum and C. myxa exerted protective activity against DOX-induced cardiotoxicity, which is, at least partly, due to their antioxidant effect.

Psychopharmacological investigation of the monoamine oxidase inhibitory activity of molindone, a dihydroindolone neuroleptic.

PubMed

Balsara, J J; Gada, V P; Nandal, N V; Chandorkar, A G

1984-09-01

24 h pretreatment with molindone enhanced the behavioural effects of L-dopa and 5-HTP, precursors of biogenic amines (catecholamines and 5-HT respectively) preferentially deaminated by MAO-A, confirming that a metabolite of molindone inhibits MAO-A. 24 h pretreatment with molindone enhanced the behavioural effects of tryptamine and antagonized reserpine-induced ptosis, and in molindone-pretreated rats L-tryptophan induced behavioural effects, probably because of the MAO-A inhibitory activity exerted by a metabolite of molindone. Since 24 h pretreatment with molindone, unlike 30 min pretreatment with clomipramine, failed to antagonize fenfluramine and p-chloramphetamine-induced behavioural syndromes, it suggests that molindone and/or its metabolites most probably do not exert 5-HT neuronal uptake blocking activity and the potentiation of 5-HTP-induced behavioural syndrome is due to a metabolite's MAO-A inhibitory activity. As 2 h pretreatment with molindone induced catalepsy and antagonized apomorphine-induced climbing behaviour in mice and stereotypy in rats, while 24 h pretreatment failed to induce catalepsy and to antagonize apomorphine-induced behaviour, it appears that, at 24 h, the tissue levels of molindone are inadequate to block postsynaptic striatal and mesolimbic DA receptors and that, though a metabolite of molindone is biologically active so far as inhibition of MAO-A is concerned, the metabolites are devoid of neuroleptic activity. Further, since 2 h pretreatment with molindone failed to enhance the behavioural effects of L-dopa, it suggests that at 2 h the degree of MAO-A inhibition induced by molindone and/or the metabolite is not sufficient to counteract the neuroleptic activity of the parent compound.

Relationship between 4-hydroxyanisole toxicity and dopa oxidase activity for three melanoma cell lines.

PubMed

Rodriguez-Vicente, J; Vicente-Ortega, V; Canteras-Jordana, M; Calderon-Rubiales, F

1997-10-01

We studied the response of mouse B16F10 and SK-MEL-28 and SK-MEL-1 human melanoma cell lines to treatment with 4-hydroxyanisole (4-HA), and attempted to relate the response to the dopa oxidase levels and the morphological characteristics of each cell line. Clear dose-response curves were observed after 24 h of treatment in each cell line, the 4-HA being more toxic to the B16F10 cells, with an ID50 value of 215 microM. This was much lower than that observed for the SK-MEL-28 and SK-MEL-1 cell lines (ID50 of 5.98 mM and 7.17 mM, respectively). There was a direct relationship between toxicity levels and dopa oxidase activity, since the highest specific activity was obtained for B16F10 (15.9 mU), while lower activity was registered for SK-MEL-28 (4.59 mU) and SK-MEL-1 (1.24 mU), which also showed lower 4-HA toxicity. Morphologically, we observed the typical characteristics of cellular injury, with swelling and dilation of the internal membranes and organelles, an increased number of vacuoles, and an increased number of abnormal multilamellar melanosomes or thick clumps of irregularly distributed melanin. On the other hand, we observed that the two cell lines with the lowest dopa oxidase activity contained more mature fully melanized melanosomes than B16F10, pointing to possible alterations in the melanosome transference mechanism and lower enzymatic activity in the mature melanosomes of these two human cell lines.

Chlorpyrifos induces oxidative stress in oligodendrocyte progenitor cells.

PubMed

Saulsbury, Marilyn D; Heyliger, Simone O; Wang, Kaiyu; Johnson, Deadre J

2009-05-02

There are increasing concerns regarding the relative safety of chlorpyrifos (CPF) to various facets of the environment. Although published works suggest that CPF is relatively safe in adult animals, recent evidence indicates that juveniles, both animals and humans, may be more sensitive to CPF toxicity than adults. In young animals, CPF is neurotoxic and mechanistically interferes with cellular replication and cellular differentiation, which culminates in the alteration of synaptic neurotransmission in neurons. However, the effects of CPF on glial cells are not fully elucidated. Here we report that chlorpyrifos is toxic to oligodendrocyte progenitors. In addition, CPF produced dose-dependent increases in 2',7'-dichlorodihydrofluorescein diacetate (H(2)DCF-DA) and dihydroethidium (DHE) fluorescence intensities relative to the vehicle control. Moreover, CPF toxicity is associated with nuclear condensation and elevation of caspase 3/7 activity and Heme oxygenase-1 mRNA expression. Pan-caspase inhibitor QVDOPh and cholinergic receptor antagonists' atropine and mecamylamine failed to protect oligodendrocyte progenitors from CPF-induced injury. Finally, glutathione (GSH) depletion enhanced CPF-induced toxicity whereas nitric oxide synthetase inhibitor L-NAME partially protected progenitors and the non-specific antioxidant vitamin E (alpha-tocopherol) completely spared cells from injury. Collectively, this data suggests that CPF induced toxicity is independent of cholinergic stimulation and is most likely caused by the induction of oxidative stress.

Application of Organometallic Catalysis to the Commercial Production of L-DOPA.

ERIC Educational Resources Information Center

Knowles, W. S.

1986-01-01

Shows how asymmetric organometallic catalysts can be used to make complex organic molecules with extremely high enantioselectivity. The molecule considered is l-3, 4-dihydroxyphenylalanine (L-DOPA), an amino acid which was found to be effective in the treatment of Parkinson's disease. (JN)

Identification and optimization of tyrosine hydroxylase activity in Mucuna pruriens DC. var. utilis.

PubMed

Luthra, Pratibha Mehta; Singh, Satendra

2010-05-01

Tyrosine hydroxylase, an iron containing tetrahydrobiopterin dependent monooxygenase (tyrosine 3-monooxygenase; EC 1.14.16.2), catalyzes the rate-limiting step in which L: -dopa is formed from the substrate L-tyrosine. L-Dopa concentration and activity of L-tyrosine hydroxylase enzyme were measured in roots, stem, leaves, pods, and immature seeds of Mucuna pruriens. Immature seeds contained maximum L-dopa content and mature leaves possessed maximum catalytic activity of tyrosine hydroxylase. Tyrosine hydroxylase from leaf homogenate was characterized as a 55 kDa protein by SDS-PAGE and Western-blot analysis with monoclonal mouse IgG2a tyrosine hydroxylase antibody. The conditions for maximum tyrosine hydroxylase activity from the leaf extract were optimized with respect to temperature, pH, cofactor 6-MPH(4), and divalent metal ions. The tyrosine hydroxylase from leaf extract possessed a K (m) value of 808.63 microM for L-tyrosine at 37 degrees C and pH 6.0. The activity of the enzyme was slightly inhibited at 2,000 microM L-tyrosine. Higher concentrations of the cofactor 6-MPH(4), however, completely inhibited the synthesis of L-dopa. Tyrosine hydroxylase converted specific monophenols such as L-tyrosine (808.63 microM) and tyramine (K (m) 1.1 mM) to diphenols L-dopa and dopamine, respectively. Fe(II) activated the enzyme while higher concentration of other divalent metals reduced its activity. For the first time, tyrosine hydroxylase from M. pruriens is being reported in this study.

Increased L-DOPA-derived dopamine following selective MAO-A or-B inhibition in rat striatum depleted of dopaminergic and serotonergic innervation

PubMed Central

Sader-Mazbar, O; Loboda, Y; Rabey, M J; Finberg, J P M

2013-01-01

Background and Purpose Selective MAO type B (MAO-B) inhibitors are effective in potentiation of the clinical effect of L-DOPA in Parkinson's disease, but dopamine (DA) is deaminated mainly by MAO type A (MAO-A) in rat brain. We sought to clarify the roles of MAO-A and MAO-B in deamination of DA formed from exogenous L-DOPA in rat striatum depleted of dopaminergic, or both dopaminergic and serotonergic innervations. We also studied the effect of organic cation transporter-3 (OCT-3) inhibition by decinium-22 on extracellular DA levels following L-DOPA. Experimental Approach Striatal dopaminergic and/or serotonergic neuronal innervations were lesioned by 6-hydroxydopamine or 5,7-dihydroxytryptamine respectively. Microdialysate DA levels after systemic L-DOPA were measured after inhibition of MAO-A or MAO-B by clorgyline or rasagiline respectively. MAO subtype localization in the striatum was determined by immunofluorescence. Key Results Rasagiline increased DA extracellular levels following L-DOPA to a greater extent in double-than in single-lesioned rats (2.8-and 1.8-fold increase, respectively, relative to saline treatment); however, clorgyline elevated DA levels in both models over 10-fold. MAO-A was strongly expressed in medium spiny neurons (MSNs) in intact and lesioned striata, while MAO-B was localized in glia and to a small extent in MSNs. Inhibition of OCT-3 increased DA levels in the double-more than the single-lesion animals. Conclusions and Implications In striatum devoid of dopaminergic and serotonergic inputs, most deamination of L-DOPA-derived DA is mediated by MAO-A in MSN and a smaller amount by MAO-B in both MSN and glia. OCT-3 plays a significant role in uptake of DA from extracellular space. Inhibitors of OCT-3 are potential future targets for anti-Parkinsonian treatments. PMID:23992249

Enhanced permeability and antifouling performance of cellulose acetate ultrafiltration membrane assisted by l-DOPA functionalized halloysite nanotubes.

PubMed

Mu, Keguang; Zhang, Dalun; Shao, Ziqiang; Qin, Dujian; Wang, Yalong; Wang, Shuo

2017-10-15

l-Dopa functionalized halloysite nanotubes (HNTs) were prepared by the self-polymerization of l-dopa in the weak alkaline condition. Then different contents of l-dopa coated HNTs (LPDHNTs) were blended into cellulose acetate to prepare enhanced performance ultrafiltration membranes via the phase inversion method. The HNTs and LPDHNTs were characterized by FTIR, XPS, and TEM anysis. And the membranes morphologies, separation performance, antifouling performance, mechanical properties and hydrophilicity were also investigated. It was found that the composite membranes exhibited excellent antifouling performance. The pure water flux of 3.0wt% LPDHNTs/CA membrane increased from 11.4Lm -2 h -1 to 92.9Lm -2 h -1 , while the EA rejection ratio of the membrane was about 91.2%. In addition, the mechanical properties of the resultant membranes were strengthened compared with the CA ultrafiltration membrane. Copyright © 2017 Elsevier Ltd. All rights reserved.

Dopamine Receptors and Parkinson's Disease

PubMed Central

Hisahara, Shin; Shimohama, Shun

2011-01-01

Parkinson's disease (PD) is a progressive extrapyramidal motor disorder. Pathologically, this disease is characterized by the selective dopaminergic (DAergic) neuronal degeneration in the substantia nigra. Correcting the DA deficiency in PD with levodopa (L-dopa) significantly attenuates the motor symptoms; however, its effectiveness often declines, and L-dopa-related adverse effects emerge after long-term treatment. Nowadays, DA receptor agonists are useful medication even regarded as first choice to delay the starting of L-dopa therapy. In advanced stage of PD, they are also used as adjunct therapy together with L-dopa. DA receptor agonists act by stimulation of presynaptic and postsynaptic DA receptors. Despite the usefulness, they could be causative drugs for valvulopathy and nonmotor complication such as DA dysregulation syndrome (DDS). In this paper, physiological characteristics of DA receptor familyare discussed. We also discuss the validity, benefits, and specific adverse effects of pharmaceutical DA receptor agonist. PMID:25954517

Automated and manual patch clamp data of human induced pluripotent stem cell-derived dopaminergic neurons.

PubMed

Franz, Denise; Olsen, Hervør Lykke; Klink, Oliver; Gimsa, Jan

2017-04-25

Human induced pluripotent stem cells can be differentiated into dopaminergic neurons (Dopa.4U). Dopa.4U neurons expressed voltage-gated Na V and K V channels and showed neuron-like spontaneous electrical activity. In automated patch clamp measurements with suspended Dopa.4U neurons, delayed rectifier K + current (delayed K V ) and rapidly inactivating A-type K + current (fast K V ) were identified. Examination of the fast K V current with inhibitors yielded IC 50 values of 0.4 mM (4-aminopyridine) and 0.1 mM (tetraethylammonium). In manual patch clamp measurements with adherent Dopa.4U neurons, fast K V current could not be detected, while the delayed K V current showed an IC 50 of 2 mM for 4-aminopyridine. The Na V channels in adherent and suspended Dopa.4U neurons showed IC 50 values for tetrodotoxin of 27 and 2.9 nM, respectively. GABA-induced currents that could be observed in adherent Dopa.4U neurons could not be detected in suspended cells. Application of current pulses induced action potentials in approx. 70 % of the cells. Our results proved the feasibility of automated electrophysiological characterization of neuronal cells.

Synthesis and antiproliferative activity of two diastereomeric lignan amides serving as dimeric caffeic acid-l-DOPA hybrids.

PubMed

Magoulas, George E; Rigopoulos, Andreas; Piperigkou, Zoi; Gialeli, Chrysostomi; Karamanos, Nikos K; Takis, Panteleimon G; Troganis, Anastassios N; Chrissanthopoulos, Athanassios; Maroulis, George; Papaioannou, Dionissios

2016-06-01

Two new diastereomeric lignan amides (4 and 5) serving as dimeric caffeic acid-l-DOPA hybrids were synthesized. The synthesis involved the FeCl3-mediated phenol oxidative coupling of methyl caffeate to afford trans-diester 1a as a mixture of enantiomers, protection of the catechol units, regioselective saponification, coupling with a suitably protected l-DOPA derivative, separation of the two diastereomers thus obtained by flash column chromatography and finally global chemoselective deprotection of the catechol units. The effect of hybrids 4 and 5 and related compounds on the proliferation of two breast cancer cell lines with different metastatic potential and estrogen receptor status (MDA-MB-231 and MCF-7) and of one epithelial lung cancer cell line, namely A-549, was evaluated for concentrations ranging from 1 to 256μM and periods of treatment of 24, 48 and 72h. Both hybrids showed interesting and almost equipotent antiproliferative activities (IC50 64-70μM) for the MDA-MB-231 cell line after 24-48h of treatment, but they were more selective and much more potent (IC50 4-16μM) for the MCF-7 cells after 48h of treatment. The highest activity for both hybrids and both breast cancer lines was observed after 72h of treatment (IC50 1-2μM), probably as the result of slow hydrolysis of their methyl ester functions. Copyright © 2016 Elsevier Inc. All rights reserved.

Acute and long-term in vitro effects of zinc oxide nanoparticles.

PubMed

Annangi, Balasubramanyam; Rubio, Laura; Alaraby, Mohamed; Bach, Jordi; Marcos, Ricard; Hernández, Alba

2016-09-01

Since most of the toxic studies of zinc oxide nanoparticles (ZnO NPs) focused on acute and high-dose exposure conditions, the aim of the present study was to fill the existing knowledge gap of long-term effects of ZnO NPs at sub-toxic doses. To overcome this point, we have evaluated the toxic, genotoxic, and carcinogenic effects of ZnO NPs under long-term treatments (12 weeks), using a sub-toxic dose (1 µg/mL) according to acute 48-h exposure. Preliminarily, oxidative stress and genotoxic/oxidative DNA damage were determined under acute exposure and high-dose conditions. To determine the role of oxidative DNA damage, a wild-type mouse embryonic fibroblast (MEF Ogg1 (+/+)) and its isogenic 8-oxo-guanine DNA glycosylase 1 (Ogg1) knockout partner (MEF Ogg1 (-/-)) cell lines were used. Although short-term exposure (24-h) experiments demonstrated that ZnO NPs were able to induce ROS, genotoxicity, and oxidative DNA damage in both cell lines, no effects were obtained under long-term exposure scenario. Thus, 1 µg/mL exposure over 12 weeks was unable to induce genotoxicity as well as cellular transformation in both cell types, as indicated by the lack of observed morphological cell changes, variations in the secretion of matrix metalloproteinases, and anchorage-independent cell growth ability, regarded as cancer-like phenotypic hallmarks. Our results indicate that short-term effects of ZnO NP exposure are not replicated under long-term and sub-toxic dose conditions. All together, the lack of genotoxic/carcinogenic effects after chronic treatments seem to indicate a reduced risk associated with ZnO NP exposure.

Thermal gelation and tissue adhesion of biomimetic hydrogels

PubMed Central

Burke, Sean A; Ritter-Jones, Marsha; Lee, Bruce P; Messersmith, Phillip B

2008-01-01

Marine and freshwater mussels are notorious foulers of natural and manmade surfaces, secreting specialized protein adhesives for rapid and durable attachment to wet substrates. Given the strong and water-resistant nature of mussel adhesive proteins, significant potential exists for mimicking their adhesive characteristics in bioinspired synthetic polymer materials. An important component of these proteins is L-3,4-dihydroxylphenylalanine (DOPA), an amino acid believed to contribute to mussel glue solidification through oxidation and crosslinking reactions. Synthetic polymers containing DOPA residues have previously been shown to crosslink into hydrogels upon the introduction of oxidizing reagents. Here we introduce a strategy for stimuli responsive gel formation of mussel adhesive protein mimetic polymers. Lipid vesicles with a bilayer melting transition of 37 °C were designed from a mixture of dipalmitoyl and dimyristoyl phosphatidylcholines and exploited for the release of a sequestered oxidizing reagent upon heating from ambient to physiologic temperature. Colorimetric studies indicated that sodium-periodate-loaded liposomes released their cargo at the phase transition temperature, and when used in conjunction with a DOPA-functionalized poly(ethylene glycol) polymer gave rise to rapid solidification of a crosslinked polymer hydrogel. The tissue adhesive properties of this biomimetic system were determined by in situ thermal gelation of liposome/polymer hydrogel between two porcine dermal tissue surfaces. Bond strength measurements showed that the bond formed by the adhesive hydrogel (mean = 35.1 kPa, SD = 12.5 kPa, n = 11) was several times stronger than a fibrin glue control tested under the same conditions. The results suggest a possible use of this biomimetic strategy for repair of soft tissues. PMID:18458476

H2S Protects Against Methionine–Induced Oxidative Stress in Brain Endothelial Cells

PubMed Central

Tyagi, Neetu; Moshal, Karni S.; Sen, Utpal; Vacek, Thomas P.; Kumar, Munish; Hughes, William M.; Kundu, Soumi

2009-01-01

Abstract Homocysteine (Hcy) causes cerebrovascular dysfunction by inducing oxidative stress. However, to date, there are no strategies to prevent Hcy-induced oxidative damage. Hcy is an H2S precursor formed from methionine (Met) metabolism. We aimed to investigate whether H2S ameliorated Met-induced oxidative stress in mouse brain endothelial cells (bEnd3). The bEnd3 cells were exposed to Met treatment in the presence or absence of NaHS (donor of H2S). Met-induced cell toxicity increased the levels of free radicals in a concentration-dependent manner. Met increased NADPH-oxidase-4 (NOX-4) expression and mitigated thioredxion-1(Trx-1) expression. Pretreatment of bEnd3 with NaHS (0.05 mM) attenuated the production of free radicals in the presence of Met and protected the cells from oxidative damage. Furthermore, NaHS enhanced inhibitory effects of apocynin, N-acetyl-l-cysteine (NAC), reduced glutathione (GSH), catalase (CAT), superoxide dismutase (SOD), Nω-nitro-l-arginine methyl ester (L-NAME) on ROS production and redox enzymes levels induced by Met. In conclusion, the administration of H2S protected the cells from oxidative stress induced by hyperhomocysteinemia (HHcy), which suggested that NaHS/H2S may have therapeutic potential against Met-induced oxidative stress. Antioxid. Redox Signal. 11, 25–33. PMID:18837652

Site-specific detection of radicals on α-lactalbumin after a riboflavin-sensitized reaction, detected by immuno-spin trapping, ESR, and MS.

PubMed

Dalsgaard, Trine K; Triquigneaux, Mathilde; Deterding, Leesa; Summers, Fiona; Ranguelova, Kalina; Mortensen, Grith; Mason, Ronald P

2013-01-16

Free radicals and other oxidation products were characterized on α-lactalbumin with electron spin resonance (ESR), immuno-spin trapping, and mass spectrometry (MS) after riboflavin-mediated oxidation. Radicals were detected using the spin trap 5,5-dimethyl-1-pyrroline N-oxide (DMPO) in immuno-spin trapping with both enzyme-linked immunosorbent assay (ELISA) and Western blotting and further characterized with mass spectrometry. A DMPO-trapped radical was identified at His68 and another at one of the tyrosine residues, Tyr50 or Tyr36, respectively, generated by a type II or I mechanism. Not all tyrosyl radicals were trapped, as the secondary oxidation product, 3,4-dihydroxyphenylalanine (DOPA), was detected by mass spectrometry at Tyr18 and Tyr50. A further oxidation of DOPA resulted in the DOPA o-semiquinone radical, which was characterized by ESR. Both surface exposure and the neighboring residues in the local environment of the tertiary structure of α-lactalbumin seem to play a role in the generation of DMPO trapped radicals and secondary oxidation products.

Secretory expression of the non-secretory-type Lentinula edodes laccase by Aspergillus oryzae.

PubMed

Yano, Akira; Kikuchi, Sayaka; Nakagawa, Yuko; Sakamoto, Yuichi; Sato, Toshitsugu

2009-01-01

The shiitake mushroom, Lentinula edodes, has an extracelluar secretory-type laccase, Lcc1, and a fruiting-body-accumulation-type laccase, Lcc4. We previously reported the production of Lcc1 by plant cells, but had difficulty producing Lcc4. Here, we report the production of Lcc1 and Lcc4 by Aspergillus oryzae and the extracellular secretory production of Lcc4 using a modified secretion signal peptide (SP) from Lcc1. Sp-Lcc4 produced by A. oryzae had biochemical activities similar to Lcc4 produced by L. edodes. Lcc1 did not react with beta-(3,4-dihydroxyphenol) alanine (DOPA), but Lcc4 from L. edodes and A. oryzae could oxidize DOPA. K(M) values for the substrates 2,2'-azino-di-(3-ethylbenzthiazolinsulfonate), 2,6-dimethoxyphenol, guaiacol, pyrogallol, and catechol were similar for Lcc4 and Sp-Lcc4. In conclusion, a non-secretory-type fungal laccase is secreted into the culture media with its original enzymatic properties by exploiting modified secretory signal peptide. 2008 Elsevier GmbH.

Modulation of cadmium-induced phytotoxicity in Cabomba caroliniana by urea involves photosynthetic metabolism and antioxidant status.

PubMed

Huang, Wenmin; Shao, Hui; Zhou, Sining; Zhou, Qin; Li, Wei; Xing, Wei

2017-10-01

Urea is a widespread organic pollutant, which can be a nitrogen source, playing different roles in the growth of submerged macrophytes depending on concentrations, while high cadmium (Cd) concentrations are often toxic to macrophytes. In order to evaluate the combined effect of urea and Cd on a submerged macrophyte, Cabomba caroliniana, the morphological and physiological responses of C. caroliniana in the presence of urea and Cd were studied. The results showed that high concentrations of urea (400mgL -1 ) and Cd (500µmolL -1 ) had negative effects on C. caroliniana. There were strong visible symptoms of toxicity after 4 days of exposure under Cd-alone, 400mgL -1 urea, and Cd+400mgL -1 urea treatments. In addition, 400mgL -1 urea and Cd had adverse effects on C. caroliniana's pigment system. Significant losses in chlorophyll fluorescence and photosynthetic rates, as well as Rubisco activity were also observed under Cd-alone, 400mgL -1 urea, and Cd+400mgL -1 urea treatments. 400mgL -1 urea markedly enhanced Cd toxicity in C. caroliniana, reflected by a sharp decrease in photosynthetic activity and more visible toxicity symptoms. The results of thiobarbituric acid reactive substances (TBARS) pointed to extreme oxidative stress in C. caroliniana induced under Cd or 400mgL -1 urea exposure. Exogenous ascorbate (AsA) protected C. caroliniana from adverse damage in 400mgL -1 urea, which further corroborated the oxidative stress claim under 400mgL -1 urea. However, results also demonstrated that lower urea concentration (10mgL -1 ) alleviated Cd-induced phytotoxicity by stimulating chlorophyll synthesis and photosynthetic activity, as well as activating the activity of catalase (CAT) and glutathione-S-transferase (GST), which may explain the alleviating effect of urea on C. caroliniana under Cd stress. Copyright © 2017 Elsevier Inc. All rights reserved.

Antioxidant Activity of Phenolic Compounds from Fava Bean Sprouts.

PubMed

Okumura, Koharu; Hosoya, Takahiro; Kawarazaki, Kai; Izawa, Norihiko; Kumazawa, Shigenori

2016-06-01

Fava beans are eaten all over the world and recently, marketing for their sprouts began in Japan. Fava bean sprouts contain more polyphenols and l-3,4-dihydroxyphenylalanine (l-DOPA) than the bean itself. Our antioxidant screening program has shown that fava bean sprouts also possess a higher antioxidant activity than other commercially available sprouts and mature beans. However, the individual constituents of fava bean sprouts are not entirely known. In the present study, we investigated the phenolic compounds of fava bean sprouts and their antioxidant activity. Air-dried fava bean sprouts were treated with 80% methanol and the extract was partitioned in water with chloroform and ethyl acetate. HPLC analysis had shown that the ethyl acetate-soluble parts contained phenolic compounds, separated by preparative HPLC to yield 5 compounds (1-5). Structural analysis using NMR and MS revealed that the compounds isolated were kaempferol glycosides. All isolated compounds had an α-rhamnose at the C-7 position with different sugars attached at the C-3 position. Compounds 1-5 had β-galactose, β-glucose, α-rhamnose, 6-acetyl-β-galactose and 6-acetyl-β-glucose, respectively, at the C-3 position. The amount of l-DOPA in fava bean sprouts was determined by the quantitative (1) H NMR technique. The l-DOPA content was 550.45 mg ± 11.34 /100 g of the raw sprouts. The antioxidant activities of compounds 2-5 and l-DOPA were evaluated using the 2,2-diphenyl-1-picrylhydrazyl scavenging assay. l-DOPA showed high antioxidant activity, but the isolated kaempferol glycosides showed weak activity. Therefore, it can be suggested that l-DOPA contributed to the antioxidant activity of fava bean sprouts. © 2016 Institute of Food Technologists®

Inhibitions by hydrogen-occluding silica microcluster to melanogenesis in human pigment cells and tyrosinase reaction.

PubMed

Kato, Shinya; Saitoh, Yasukazu; Miwa, Nobuhiko

2013-01-01

We investigated the anti-melanogenetic efficacy of hydrogen-occluding silica microcluster (H2-Silica), which is a silsesquioxane-based compound with hydrogen interstitially embedded in a matrix of caged silica, against melanogenesis in HMV-II human melanoma cells and L-DOPA-tyrosinase reaction [EC1.14.18.1]. HMV-II cells were subjected to oxidative stress by ultraviolet ray-A (UVA) exposure of 3-times of 0.65 J/cm2 summed up to 1.95 J/cm2. After UVA irradiation, HMV-II cells were stimulated to produce melanin by 2.72-fold more abundantly than unirradiated control. When HMV-II cells were treated with H2-Silica of 20 ppm or kojic acid of 28.4 ppm before and after UVA-irradiation, the amount of melanin was repressed to 12.2% or 14.5% as compared to that of UVA-irradiated control, respectively. That is, H2-Silica exhibited a comparable efficacy to the whitening agent kojic acid. The H2-Silica could prevent melanogenesis in HMV-II cells by low-level doses at 1-10 ppm, and cell viability and apoptosis event did not change even by high-level doses at 100-1000 ppm. On the contrary, kojic acid was cytotoxic at the concentration of 14-28 ppm or more. By microscopic observation, H2-Silica suppressed such properties indicative of melanin-rich cells as cellular hypertrophy, cell process formation, and melanogenesis around the outside of nuclei. The enzymatic assay using L-DOPA and mushroom tyrosinase demonstrated that H2-Silica restrained UVA-mediated melanin formation owing to down-regulation of tyrosinase activity, which could be attributed to scavenging of free radicals and inhibition of L-DOPA-to-dopachrome oxidation by hydrogen released from H2-Silica. Thus H2-Silica has a potential to prevent melanin production against UVA and serves as a skin-lightening ingredient for supplements or cosmetics.

Toxicity profiling of water contextual zinc oxide, silver, and titanium dioxide nanoparticles in human oral and gastrointestinal cell systems.

PubMed

Giovanni, Marcella; Tay, Chor Yong; Setyawati, Magdiel Inggrid; Xie, Jianping; Ong, Choon Nam; Fan, Rongli; Yue, Junqi; Zhang, Lifeng; Leong, David Tai

2015-12-01

Engineered nanoparticles (ENPs) are increasingly detected in water supply due to environmental release of ENPs as the by-products contained within the effluent of domestic and industrial run-off. The partial recycling of water laden with ENPs, albeit at ultra-low concentrations, may pose an uncharacterized threat to human health. In this study, we investigated the toxicity of three prevalent ENPs: zinc oxide, silver, and titanium dioxide over a wide range of concentrations that encompasses drinking water-relevant concentrations, to cellular systems representing oral and gastrointestinal tissues. Based on published in silico-predicted water-relevant ENPs concentration range from 100 pg/L to 100 µg/L, we detected no cytotoxicity to all the cellular systems. Significant cytotoxicity due to the NPs set in around 100 mg/L with decreasing extent of toxicity from zinc oxide to silver to titanium dioxide NPs. We also found that noncytotoxic zinc oxide NPs level of 10 mg/L could elevate the intracellular oxidative stress. The threshold concentrations of NPs that induced cytotoxic effect are at least two to five orders of magnitude higher than the permissible concentrations of the respective metals and metal oxides in drinking water. Based on these findings, the current estimated levels of NPs in potable water pose little cytotoxic threat to the human oral and gastrointestinal systems within our experimental boundaries. © 2014 Wiley Periodicals, Inc.

Microbiological transformation of L-tyrosine to L-dopa from methanol pretreated biomass of a novel Coriolus versicolor under submerged culture.

PubMed

Ali, Sikander; Rizvi, Nazia

2014-02-01

The present study is concerned with the microbiological transformation of L-tyrosine to L-dopa by a newly isolated turkey tail mushroom Coriolus versicolor DOB-4. As tyrosinase (catechol oxidase, EC 1.10.3.1) is an extracellular enzyme, therefore biomass was used as an enzyme source in the reaction mixture. Biomass particles were pretreated with methanol and oven dried at 105 °C for 2 h. The optimal L-dopa production was achieved when 1.5 mg/ml L-tyrosine was used as the basal substrate. Thin layer chromatography and high-performance liquid chromatography analysis depicted that citric acid supports higher substrate conversion and product formation rates. A noticeable enhancement was observed when process parameters viz. L-tyrosine concentration (1.5 mg/ml), citric acid (1.5 mg/ml), time of incubation (50 min), and reaction temperature (60 °C) were optimized using Plackett-Burman design. The maximum production of L-dopa was found to be 0.872 mg/ml with L-tyrosine consumption of 1.002 mg/ml. The model terms were found highly significant (HS, p ≤ 0.05), suggesting the potential commercial utility of the culture (df = 3, LSD = 0.342).

Effect of Physalis peruviana L. on cadmium-induced testicular toxicity in rats.

PubMed

Othman, Mohamed S; Nada, Ahmed; Zaki, Hassan S; Abdel Moneim, Ahmed E

2014-06-01

Cadmium (Cd) stimulates the production of reactive oxygen species and causes tissue damage. We investigated here the protective effect of Physalis peruviana L. (family Solanaceae) against cadmium-induced testes toxicity in rats. Twenty-eight Wistar albino rats were used. They were divided into four groups (n=7). Group 1 was used as control. Group 2 was intraperitoneally injected with 6.5 mg/kg body weight (bwt) of cadmium chloride for 5 days. Group 3 was orally treated with 200 mg/kg bwt of methanolic extract of physalis (MEPh). Group 4 was pretreated with MEPh before cadmium for 5 days. Changes in body and testes weights were determined. Oxidative stress markers, antioxidant enzymes, and testosterone level were measured. Histopathological changes of testes were examined, and the immunohistochemical staining for the proapoptotic (caspase-3) protein was performed. The injection of cadmium caused a significant decrease in body weight, while a significant increase in testes weight and testes weight index was observed. Pretreatment with MEPh was associated with significant reduction in the toxic effects of Cd as shown by reduced testicular levels of malondialdehyde, nitric oxide, and caspase-3 expression and increased glutathione content, and the activities of superoxide dismutase, catalase, glutathione reductase, glutathione peroxidase, and testosterone were also increased. Testicular histopathology showed that Cd produced an extensive germ cell apoptosis, and the pretreatment of MEPh in Cd-treated rats significantly reduced Cd-induced testicular damage. On the basis of the above results, it can be hypothesized that P. peruviana L. has a protective effect against cadmium-induced testicular oxidative stress and apoptosis in the rat.

Increased FasL expression correlates with apoptotic changes in granulocytes cultured with oxidized clozapine

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

Husain, Zaheed; Department of Pathology, Harvard Medical School, Boston, MA; Almeciga, Ingrid

Clozapine has been associated with a 1% incidence of agranulocytosis. The formation of an oxidized intermediate clozapine metabolite has been implicated in direct polymorphonuclear (PMN) toxicity. We utilized two separate systems to analyze the role of oxidized clozapine in inducing apoptosis in treated cells. Human PMN cells incubated with clozapine (0-10 {mu}M) in the presence of 0.1 mM H{sub 2}O{sub 2} demonstrated a progressive decrease of surface CD16 expression along with increased apoptosis. RT-PCR analysis showed decreased CD16 but increased FasL gene expression in clozapine-treated PMN cells. No change in constitutive Fas expression was observed in treated cells. In HL-60more » cells induced to differentiate with retinoic acid (RA), a similar increase in FasL expression, but no associated changes in CD16 gene expression, was observed following clozapine treatments. Our results demonstrate increased FasL gene expression in oxidized clozapine-induced apoptotic neutrophils suggesting that apoptosis in granulocytes treated with clozapine involves Fas/FasL interaction that initiates a cascade of events leading to clozapine-induced agranulocytosis.« less

Anhedonia Is Associated with Poorer Outcomes in Contingency Management for Cocaine Use Disorder

PubMed Central

Wardle, Margaret C.; Vincent, Jessica N.; Suchting, Robert; Green, Charles E.; Lane, Scott D.; Schmitz, Joy M.

2016-01-01

This study explored anhedonia (lack of interest or pleasure in non-drug rewards) as a potentially modifiable individual difference associated with the effectiveness of Contingency Management (CM). It also tested the hypothesis that a dopaminergic drug, levodopa (L-DOPA), would improve the effectiveness of CM, particularly in individuals high in anhedonia. The study was a single-site, randomized, double-blind, parallel group, 12-week trial comparing L-DOPA with placebo, with both medication groups receiving voucher-based CM targeting cocaine-negative urines. Participants were N = 85 treatment-seeking adults with CUD. Anhedonia was measured at baseline using a validated self-report measure and a progressive ratio behavioral measure. Treatment Effectiveness Score (TES) was defined as the total number of cocaine-negative urines submitted. Analyses based on Frequentist general linear models were not significant, but Bayesian analyses indicated a high probability (92.6%) that self-reported anhedonia was associated with poor treatment outcomes (lower TES). L-DOPA did not significantly improve outcomes, nor was the effect of L-DOPA moderated by anhedonia. While the study failed to replicate positive findings from previous studies of L-DOPA in combination with CM, it does provide preliminary evidence that anhedonia may be a modifiable individual difference associated with poorer CM outcomes. PMID:27646197

Functional imaging in hyperinsulinemic hypoglycemia after gastric bypass surgery for morbid obesity.

PubMed

de Heide, Loek J M; Glaudemans, Andor W J M; Oomen, Peter H N; Apers, Jan A; Totté, Eric R E; van Beek, André P

2012-06-01

Hyperinsulinemic hypoglycemia after Roux-en-Y gastric bypass (RYGB) has been increasingly reported. It is induced by β-cell hyperplasia often referred to as nesidioblastosis. Positron emission tomography (PET) with [11C]-5-hydroxytryptophan ((11)C-HTP) and 6-[18F]fluoro-3,4-dihydroxy-l-phenylalanine ((18)F-DOPA) has been successfully applied to image neuroendocrine tumors. No data are available of the usefulness of these functional imaging techniques in post-RYGB in this new endocrine disorder, neither for diagnostic purposes nor for follow-up. We present a patient with post-RYGB hypoglycemia who underwent (11)C-HTP and (18)F-DOPA PET scintigraphy for diagnostic purposes and to evaluate the effect of additional laparoscopic adjustable banding of the pouch as a surgical therapy for this disorder. We describe a woman with biochemically confirmed post-RYGB hypoglycemia who showed diffuse uptake of the (11)C-HTP and (18)F-DOPA tracers in the entire pancreas. After failure of dietary and medical treatment options, she underwent a laparoscopic adjustable banding for pouch dilatation. Subjective improvement was noted, which coincided with decreased uptake of (18)F-DOPA and (11)C-HTP in the head of the pancreas. Functional imaging by (18)F-DOPA- and (11)C-HTP-PET can accurately visualize diffuse endocrine pancreatic activity in post-gastric bypass hyperinsulinemic hypoglycemia. Both (11)C-HTP- and (18)F-DOPA-PET imaging appear to have a similar diagnostic performance in the presented case, and uptake of both tracers potentially relates to disease activity after surgical intervention.

Synthesis and Characterization of High Molecular Weight Peptide Polymers and Copolymers Containing L-Dopa Residues

DTIC Science & Technology

1988-07-01

polymerize E- aminocaproic acid with DPPA for the S same period of time. Portions of each sample were then mixed together and the polymerization was...copolymers between GLUE polypeptides and poly(?c.-amino caproic acid ). Concurrent enzymatic oxidation studies with GLUE peptidesihas given some...insight into the crosslinking mechanisms which control relative reactivities of specific amino acid residues towards intramolecular or intermolecular bond

ST 1535: a preferential A2A adenosine receptor antagonist.

PubMed

Stasi, Maria Antonietta; Borsini, Franco; Varani, Katia; Vincenzi, Fabrizio; Di Cesare, Maria Assunta; Minetti, Patrizia; Ghirardi, Orlando; Carminati, Paolo

2006-10-01

Antagonism of the A2A adenosine function has proved beneficial in the treatment of Parkinson's disease, in that it increases L-dopa therapeutical effects without concomitant worsening of its side-effects. In this paper we describe a preferential A2A adenosine antagonist, ST 1535, with long-lasting pharmacodynamic effects. It competitively antagonizes the effects of the A2A adenosine agonist NECA on cAMP in cells cloned with the human A2A adenosine receptor (IC50=353+/-30 nM), and the effects of the A1 adenosine agonist CHA on cAMP in cells cloned with the human A1 adenosine receptor (IC50=510+/-38 nM). ST 1535, at oral doses of 5 and 10 mg/kg, antagonizes catalepsy induced by intracerebroventricular administration of the A2A adenosine agonist CGS 21680 (10 microg/5 microl) in mice. At oral doses ranging between 5 and 20 mg/kg, ST 1535 induces hypermotility and antagonizes haloperidol-induced catalepsy in mice up to 7 h. Oral ST 1535, at 1.25 and 2.5 mg/kg, potentiates L-dopa effects in reducing haloperidol-induced catalepsy. ST 1535 represents a potential new compound, with long-lasting activity, for the treatment of Parkinson's disease.

Development of a microchip-pulsed electrochemical method for rapid determination of L-DOPA and tyrosine in Mucuna pruriens.

PubMed

Li, Xinchun; Chen, Zuanguang; Yang, Fan; Pan, Jianbin; Li, Yinbao

2013-05-01

L-3,4-dihydroxyphenylalanine (L-DOPA) is a well-recognized therapeutic compound to Parkinson's disease. Tyrosine is a precursor for the biosynthesis of L-DOPA, both of which are widely found in traditional medicinal material, Mucuna pruriens. In this paper, we described a validated novel analytical method based on microchip capillary electrophoresis with pulsed electrochemical detection for the simultaneous measurement of L-DOPA and tyrosine in M. pruriens. This protocol adopted end-channel amperometric detection using platinum disk electrode on a homemade glass/polydimethylsiloxane electrophoresis microchip. The background buffer consisted of 10 mM borate (pH 9.5) and 0.02 mM cetyltrimethylammonium bromide, which can produce an effective resolution for the two analytes. In the optimal condition, sufficient electrophoretic separation and sensitive detection for the target analytes can be realized within 60 s. Both tyrosine and L-DOPA yielded linear response in the concentration range of 5.0-400 μM (R(2) > 0.99), and the LOD were 0.79 and 1.1 μM, respectively. The accuracy and precision of the established method were favorable. The present method shows several merits such as facile apparatus, high speed, low cost and minimal pollution, and provides a means for the pharmacologically active ingredients assay in M. pruriens. © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Toxic effects of strychnine and strychnine N-oxide on zebrafish embryos.

PubMed

Li, Yu; Qi, Xu; Yang, Yu-Wei; Pan, Yang; Bian, Hui-Min

2014-10-01

The application of strychnine (S) is limited due to its toxicity; strychnine N-oxide (SNO) is a derivative of strychnine. The aim was to employ zebrafish embryos to investigate and compare the developmental toxicity induced by S and SNO. The toxicity of S and SNO was examined through the hatching rate and survival rate. Morphological changes of the zebrafish were observed with a dissecting microscope. Apoptosis was detected through acridine orange (AO) staining and flow cytometry. Apoptotic genes were measured by RT-PCR. Embryo malformation was observed in the embryos exposed to S at 200 μmol·L(-1). When SNO concentration was increased to 1 mmol·L(-1), scoliolosis, and pericardial edema could be seen in some embryos. Results from fluorescence microscopy and flow cytometry analysis showed that S at 200 μmol·L(-1) induced apoptosis, whereas the apoptotic rate in the SNO-treated group (200 μmol·L(-1)) was much lower than that in the S group. RT-PCR analysis showed that p53 mRNA expression and the ratio of Bax/Bcl-2 in the S group were significantly altered compared with the control group (*P < 0.05). Moreover, Bax mRNA expression in both S and SNO group were significantly different from that in the control group (**P < 0.01). These results lead to the conclusion that SNO has significantly lower toxicity than S in zebrafish embryos. Copyright © 2014 China Pharmaceutical University. Published by Elsevier B.V. All rights reserved.

Variation of L-DOPA in the leaf and flower tissues of seven faba bean accessions with different flower colors

USDA-ARS?s Scientific Manuscript database

Faba bean (Vicia faba L.) has been selected to adapt to a wide range of environments worldwide and is grown for different end-uses such as food, feed, forage and green manure. Particularly noteworthy in faba bean is the medicinally important component L-3,4-dihydroxy phenylalanine (L-DOPA), the majo...

Variation of L-DOPA in the leaf and flower tissues of seven faba bean accessions with different flower colors.

USDA-ARS?s Scientific Manuscript database

Faba bean (Vicia faba L.) has been selected to adapt to a wide range of environments worldwide and is grown for different end-uses such as food, feed, forage and green manure. Particularly noteworthy in faba bean is the medicinally important component L-3,4-dihydroxy phenylalanine (L-DOPA), the majo...

Oxidative stress due to (R)-styrene oxide exposure and the role of antioxidants in non-Swiss albino (NSA) mice.

PubMed

Meszka-Jordan, Anna; Mahlapuu, Riina; Soomets, Ursel; Carlson, Gary P

2009-01-01

Styrene produces lung and liver damage that may be related to oxidative stress. The purpose of this study was to investigate the toxicity of (R)-styrene oxide (R-SO), the more active enantiomeric metabolite of styrene, and the protective properties of the antioxidants glutathione (GSH), N-acetylcysteine (NAC), and 4-methoxy-L-tyrosinyl-gamma-L-glutamyl-L-cysteinyl-glycine (UPF1) against R-SO-induced toxicity in non-Swiss Albino (NSA) mice. UPF1 is a synthetic GSH analog that was shown to have 60 times the ability to scavenge reactive oxygen species (ROS) in comparison to GSH. R-SO toxicity to the lung was measured by elevations in the activity of lactate dehydrogenase (LDH), protein concentration, and number of cells in bronchoalveolar lavage fluid (BALF). Toxicity to the liver was measured by increases in serum sorbitol dehydrogenase (SDH) activity. Antioxidants were not able to decrease the adverse effects of R-SO on lung. However, NAC (200 mg/kg) ip and GSH (600 mg/kg), administered orally prior to R-SO (300 mg/kg) ip, showed significant protection against liver toxicity as measured by SDH activity. Unexpectedly, a synthetic GSH analog, UPF1 (0.8 mg/kg), administered intravenously (iv) prior to R-SO, produced a synergistic effect with regard to liver and lung toxicity. Treatment with UPF1 (0.8 mg/kg) iv every other day for 1 wk for preconditioning prior to R-SO ip did not result in any protection against liver and lung toxicity, but rather enhanced the toxicity when administered prior R-SO. The results of the present study demonstrated protection against R-SO toxicity in liver but not lung by the administration of the antioxidants NAC and GSH.

The effect of copper on eumelanin photophysics and morphology

NASA Astrophysics Data System (ADS)

Birch, David J. S.; Sutter, Jens U.

2013-02-01

Despite being an important pigment in skin, hair, the eye and the brain, melanin remains one of the most enigmatic of pigments. Although the main constituents of melanin are known to be dihydroxyindoles, its photophysics is complex and its detailed structure remains unknown. In this work we have arrested prior to completion the usual synthesis of eumelanin formed via auto-oxidation of 3, 4-dihydroxy-L-phenylalanine (L-DOPA), by the addition of copper ions. Using fluorescence techniques we report how copper modifies the self assembly of eumelanin by reducing the time to the onset of aggregation at pH 10 and yet produces simplified photophysics in terms of a clearly-defined fluorescence spectrum and a fluorescence decay that is described well by a dominant single lifetime of ~ 6ns. This behavior is consistent with copper inducing an enhanced abundance of 5,5-dihydroxyindole-2-carboxylic acid (DHICA). Metal ion binding to melanin is of particular importance to neurology and has potential applications in optoelectronics.

Influence of chronic bromocriptine and levodopa administration on cerebral type 1 cannabinoid receptor binding.

PubMed

Casteels, Cindy; Vanbilloen, Bert; Vercammen, Dorien; Bosier, Barbara; Lambert, Didier M; Bormans, Guy; Van Laere, Koen

2010-08-01

The endocannabinoid system is an important modulatory system in the brain. Complex interactions with brain dopaminergic circuits have been demonstrated. The aim of this study was to investigate the in vivo effect of the commonly used antiparkinsonian drugs, levodopa (L-DOPA) and bromocriptine, on type 1 cannabinoid (CB1) receptors, using the PET radioligand [(18)F]MK-9470. Seventeen female Wistar rats were studied at baseline and after chronic exposure to either L-DOPA (6 mg/kg/day with 1.5 mg/kg/day carbidopa; n = 6), bromocriptine (4 mg/kg/day; n = 5), or saline (n = 6). [(18)F]MK-9470 binding was assessed in vivo using small animal PET imaging. [(18)F]MK-9470 parametric images were generated, anatomically standardized to Paxinos space and analyzed by voxel-based statistical parametric mapping (SPM2) and a predefined volume-of-interest (VOI) approach. In a 2 x 2 analysis design (condition vs. treatment), no significant changes in absolute or relative [(18)F]MK-9470 binding were present upon chronic exposure to L-DOPA or bromocriptine as compared to saline treatment. The post hoc comparison of chronic scans to baseline within each treatment modality showed regional increases in relative [(18)F]MK-9470 binding in the thalamus (peak average value +6.3%) and in the sensorimotor cortex and hippocampus (peak average value +10.2%) after bromocriptine exposure, while no changes were found for L-DOPA. Chronic administration of L-DOPA and bromocriptine at the applied doses does not produce major cerebral changes in in vivo cannabinoid CB1 receptor binding of [(18)F]MK-9470 in the rat brain. These results also suggest that similar chronic L-DOPA and bromocriptine usage is unlikely to interfere with human PET imaging in healthy conditions using this radioligand.

L-Dopa effect on frequency-dependent depression of the H-reflex in adult rats with complete spinal cord transection.

PubMed

Liu, Hao; Skinner, Robert D; Arfaj, Ahmad; Yates, Charlotte; Reese, Nancy B; Williams, Keith; Garcia-Rill, Edgar

2010-10-30

This study investigated whether l-dopa (DOPA), locomotor-like passive exercise (Ex) using a motorized bicycle exercise trainer (MBET), or their combination in adult rats with complete spinal cord transection (Tx) preserves and restores low frequency-dependent depression (FDD) of the H-reflex. Adult Sprague-Dawley rats (n=56) transected at T8-9 had one of five treatments beginning 7 days after transection: Tx (transection only), Tx+Ex, Tx+DOPA, Tx+Ex+DOPA, and control (Ctl, no treatment) groups. After 30 days of treatment, FDD of the H-reflex was tested. Stimulation of the tibial nerve at 0.2, 1, 5, and 10Hz evoked an H-reflex that was recorded from plantar muscles of the hind paw. No significant differences were found at the stimulation rate of 1Hz. However, at 5Hz, FDD of the H-reflex in the Tx+Ex, Tx+DOPA and Ctl groups was significantly different from the Tx group (p<0.01). At 10Hz, all of the treatment groups were significantly different from the Tx group (p<0.01). No significant difference was identified between the Ctl and any of the treatment groups. These results suggest that DOPA significantly preserved and restored FDD after transection as effectively as exercise alone or exercise in combination with DOPA. Thus, there was no additive benefit when DOPA was combined with exercise. Copyright © 2010 Elsevier Inc. All rights reserved.

The cathepsin B inhibitor z-FA-CMK induces cell death in leukemic T cells via oxidative stress.

PubMed

Liow, K Y; Chow, Sek C

2018-01-01

The cathepsin B inhibitor benzyloxycarbonyl-phenylalanine-alanine-chloromethyl ketone (z-FA-CMK) was recently found to induce apoptosis at low concentrations in Jurkat T cells, while at higher concentrations, the cells die of necrosis. In the present study, we showed that z-FA-CMK readily depletes intracellular glutathione (GSH) with a concomitant increase in reactive oxygen species (ROS) generation. The toxicity of z-FA-CMK in Jurkat T cells was completely abrogated by N-acetylcysteine (NAC), suggesting that the toxicity mediated by z-FA-CMK is due to oxidative stress. We found that L-buthionine sulfoximine (BSO) which depletes intracellular GSH through the inhibition of GSH biosynthesis in Jurkat T cells did not promote ROS increase or induce cell death. However, NAC was still able to block z-FA-CMK toxicity in Jurkat T cells in the presence of BSO, indicating that the protective effect of NAC does not involve GSH biosynthesis. This is further corroborated by the protective effect of the non-metabolically active D-cysteine on z-FA-CMK toxicity. Furthermore, in BSO-treated cells, z-FA-CMK-induced ROS increased which remains unchanged, suggesting that the depletion of GSH and increase in ROS generation mediated by z-FA-CMK may be two separate events. Collectively, our results demonstrated that z-FA-CMK toxicity is mediated by oxidative stress through the increase in ROS generation.

NADPH oxidase-derived H2O2 subverts pathogen signaling by oxidative phosphotyrosine conversion to PB-DOPA

PubMed Central

Alvarez, Luis A.; Kovačič, Lidija; Rodríguez, Javier; Gosemann, Jan-Hendrik; Kubica, Malgorzata; Pircalabioru, Gratiela G.; Friedmacher, Florian; Cean, Ada; Ghişe, Alina; Sărăndan, Mihai B.; Puri, Prem; Daff, Simon; Plettner, Erika; von Kriegsheim, Alex; Bourke, Billy; Knaus, Ulla G.

2016-01-01

Strengthening the host immune system to fully exploit its potential as antimicrobial defense is vital in countering antibiotic resistance. Chemical compounds released during bidirectional host–pathogen cross-talk, which follows a sensing-response paradigm, can serve as protective mediators. A potent, diffusible messenger is hydrogen peroxide (H2O2), but its consequences on extracellular pathogens are unknown. Here we show that H2O2, released by the host on pathogen contact, subverts the tyrosine signaling network of a number of bacteria accustomed to low-oxygen environments. This defense mechanism uses heme-containing bacterial enzymes with peroxidase-like activity to facilitate phosphotyrosine (p-Tyr) oxidation. An intrabacterial reaction converts p-Tyr to protein-bound dopa (PB-DOPA) via a tyrosinyl radical intermediate, thereby altering antioxidant defense and inactivating enzymes involved in polysaccharide biosynthesis and metabolism. Disruption of bacterial signaling by DOPA modification reveals an infection containment strategy that weakens bacterial fitness and could be a blueprint for antivirulence approaches. PMID:27562167

NADPH oxidase-derived H2O2 subverts pathogen signaling by oxidative phosphotyrosine conversion to PB-DOPA.

PubMed

Alvarez, Luis A; Kovačič, Lidija; Rodríguez, Javier; Gosemann, Jan-Hendrik; Kubica, Malgorzata; Pircalabioru, Gratiela G; Friedmacher, Florian; Cean, Ada; Ghişe, Alina; Sărăndan, Mihai B; Puri, Prem; Daff, Simon; Plettner, Erika; von Kriegsheim, Alex; Bourke, Billy; Knaus, Ulla G

2016-09-13

Strengthening the host immune system to fully exploit its potential as antimicrobial defense is vital in countering antibiotic resistance. Chemical compounds released during bidirectional host-pathogen cross-talk, which follows a sensing-response paradigm, can serve as protective mediators. A potent, diffusible messenger is hydrogen peroxide (H2O2), but its consequences on extracellular pathogens are unknown. Here we show that H2O2, released by the host on pathogen contact, subverts the tyrosine signaling network of a number of bacteria accustomed to low-oxygen environments. This defense mechanism uses heme-containing bacterial enzymes with peroxidase-like activity to facilitate phosphotyrosine (p-Tyr) oxidation. An intrabacterial reaction converts p-Tyr to protein-bound dopa (PB-DOPA) via a tyrosinyl radical intermediate, thereby altering antioxidant defense and inactivating enzymes involved in polysaccharide biosynthesis and metabolism. Disruption of bacterial signaling by DOPA modification reveals an infection containment strategy that weakens bacterial fitness and could be a blueprint for antivirulence approaches.

Sarizotan, a serotonin 5-HT1A receptor agonist and dopamine receptor ligand. 1. Neurochemical profile.

PubMed

Bartoszyk, G D; Van Amsterdam, C; Greiner, H E; Rautenberg, W; Russ, H; Seyfried, C A

2004-02-01

Sarizotan exhibited high affinities only to serotonin 5-HT1A receptors and dopamine DA D4>D3>D2 receptors with the profile of a 5-HT1A agonist and DA antagonist demonstrated by the inhibition of cAMP-stimulation and guinea pig ileum contraction, decreased accumulation of the 5-HT precursor 5-hydroxytryptophan and increased levels of 5-HT metabolites, increased accumulation of DA precursor dihydroxyphenylalanine (DOPA) and the reduced levels of DA metabolites in intact rats. However, sarizotan at higher doses decreased DA precursor accumulation in reserpinized rats and induced contralateral rotational behavior in unilaterally substantia nigra lesioned rats, indicating some intrinsic dopaminergic activity; at D2 receptors sarizotan may act as a partial agonist, depending on the dopaminergic impulse flow. Sarizotan represents a new approach for the treatment of extrapyramidal motor complications such as l-DOPA-induced dyskinesia in Parkinson's disease.

Simple 3,4-Dihydroxy-L-Phenylalanine Surface Modification Enhances Titanium Implant Osseointegration in Ovariectomized Rats.

PubMed

Ma, Ting; Ge, Xi-Yuan; Hao, Ke-Yi; Zhang, Bi-Ru; Jiang, Xi; Lin, Ye; Zhang, Yu

2017-12-19

Osteoporosis presents a challenge to the long-term success of osseointegration of endosseous implants. The bio-inspired 3,4-dihydroxy-L-phenylalanine (Dopa) coating is widely used as a basic layer to bind osteogenetic molecules that may improve osseointegration. To date, little attention has focused on application of Dopa alone or binding inhibitors of bone resorption in osteoporosis. Local use of a bisphosphonate such as zoledronic acid (ZA), an inhibitor of osteoclast-mediated bone resorption, has been proven to improve implant osseointegration. In this study, ovariectomized rats were divided into four groups and implanted with implants with different surface modifications: sandblasted and acid-etched (SLA), SLA modified with Dopa (SLA-Dopa), SLA modified with ZA (SLA-ZA), and SLA modified with Dopa and ZA (SLA-Dopa + ZA). Measurement of removal torque, micro-computed tomography and histology revealed a greater extent of bone formation around the three surface-modified implants than SLA-controls. No synergistic effect was observed for combined Dopa + ZA coating. Microarray analysis showed the Dopa coating inhibited expression of genes associated with osteoclast differentiation, similarly to the mechanism of action of ZA. Simple Dopa modification resulted in a similar improvement in osseointegration compared to ZA. Thus, our data suggest simple Dopa coating is promising strategy to promote osseointegration of implants in patients with osteoporosis.

Evaluation of the toxicity of graphene oxide exposure to the eye.

PubMed

Wu, Wei; Yan, Liang; Wu, Qian; Li, Yijian; Li, Qiyou; Chen, Siyu; Yang, Yuli; Gu, Zhanjun; Xu, Haiwei; Yin, Zheng Qin

2016-11-01

Graphene and its derivatives are the new carbon nanomaterials with the prospect for great applications in electronics, energy storage, biosensors and medicine. However, little is known about the toxicity of graphene or its derivatives in the case of occasional or repeated ocular exposure. We performed in vitro and in vivo studies to evaluate the toxicity of graphene oxide (GO) exposure to the eye. Primary human corneal epithelium cells (hCorECs) and human conjunctiva epithelium cells (hConECs) were exposed to GO (12.5-100 μg/mL). Acute GO exposure (2 h) did not induce cytotoxicity to hCorECs. However, short-term GO exposure (24 h) exerted significant cytotoxicity to hCorECs and hConECs with increased intracellular reactive oxygen species (ROS). Glutathione (GSH) reduced the GO-induced cytotoxicity. We further performed acute eye irritation tests in albino rabbits according to the Organization for Economic Cooperation and Development (OECD) guidelines, and the rabbits did not exhibit corneal opacity, conjunctival redness, abnormality of the iris, or chemosis at any time point after the instillation of 100 μg/mL of GO. However, 5-day repeated GO exposure (50 and 100 μg/mL) caused reversible mild corneal opacity, conjunctival redness and corneal epithelium damage to Sprague-Dawley rats, which was also alleviated by GSH. Therefore, our study suggests that GO-induced time- and dose-dependent cytotoxicity to hCorECs and hConECs via oxidative stress. Occasional GO exposure did not cause acute eye irritation; short-term repeated GO exposure generally resulted in reversible damage to the eye via oxidative stress, which may be alleviated by the antioxidant GSH.

Oxidative stress and DNA damage induced by imidacloprid in zebrafish (Danio rerio).

PubMed

Ge, Weili; Yan, Saihong; Wang, Jinhua; Zhu, Lusheng; Chen, Aimei; Wang, Jun

2015-02-18

Imidacloprid is a neonicotinoid insecticide that can have negative effects on nontarget animals. The present study was conducted to assess the toxicity of various imidacloprid doses (0.3, 1.25, and 5 mg/mL) on zebrafish sampled after 7, 14, 21, and 28 days of exposure. The levels of catalase (CAT), superoxide dismutase (SOD), reactive oxygen species (ROS), glutathione-S-transferase (GST), and malondialdehyde (MDA) and the extent of DNA damage were measured to evaluate the toxicity of imidacloprid on zebrafish. SOD and GST activities were noticeably increased during early exposure but were inhibited toward the end of the exposure period. In addition, the CAT levels decreased to the control level following their elevation during early exposure. High concentrations of imidacloprid (1.25 and 5 mg/L) induced excessive ROS production and markedly increased MDA content on the 21st day of exposure. DNA damage was dose- and time-dependent. In conclusion, the present study showed that imidacloprid can induce oxidative stress and DNA damage in zebrafish.

L-Dopa Modulates Functional Connectivity in Striatal Cognitive and Motor Networks: A Double-Blind Placebo-Controlled Study

PubMed Central

Kelly, Clare; de Zubicaray, Greig; Di Martino, Adriana; Copland, David A.; Reiss, Philip T.; Klein, Donald F.; Castellanos, F. Xavier; Milham, Michael P.; McMahon, Katie

2010-01-01

Functional connectivity (FC) analyses of resting-state fMRI data allow for the mapping of large-scale functional networks, and provide a novel means of examining the impact of dopaminergic challenge. Here, using a double-blind, placebo-controlled design, we examined the effect of L-dopa, a dopamine precursor, on striatal resting-state FC in 19 healthy young adults. We examined the FC of 6 striatal regions-of-interest previously shown to elicit networks known to be associated with motivational, cognitive and motor subdivisions of the caudate and putamen (Di Martino et al., Cerebral Cortex, 2008). In addition to replicating the previously demonstrated patterns of striatal FC, we observed robust effects of L-dopa. Specifically, L-dopa increased FC in motor pathways connecting the putamen ROIs with the cerebellum and brainstem. While L-dopa also increased FC between the inferior ventral striatum and ventrolateral prefrontal cortex, it disrupted ventral striatal and dorsal caudate FC with the default mode network. These alterations in FC are consistent with studies that have demonstrated dopaminergic modulation of cognitive and motor striatal networks in healthy participants. Recent studies have demonstrated altered resting state FC in several conditions believed to be characterized by abnormal dopaminergic neurotransmission. Our findings suggest that the application of similar experimental pharmacological manipulations in such populations may further our understanding of the role of dopaminergic neurotransmission in those conditions. PMID:19494158

[Drug treatment of early-stage (de novo and "honeymoon") Parkinson disease].

PubMed

Cesaro, P; Defebvre, L

2014-04-01

In this article, we discuss the management of motor symptoms during the early phases of Parkinson's disease, excluding that of any other clinical manifestation. We relied primarily upon recently published data and do not describe older publications relating to anticholinergic drugs or amantadine. The initial pharmacological treatment of idiopathic Parkinson's disease (IPD) is symptomatic and remains based upon dopaminergic drugs. However, the development of new drugs has broadened the range of strategic options and improved overall patient management. Announcing the diagnosis is a critical moment, as pointed out by patients' associations. Patients should be advised to maintain personal, professional, social and physical activities as long as possible. The potential benefit of early pharmacological treatment should be explained, focusing on the possible disease-modifying effect of drugs such as rasagiline. According to current guidelines, L-Dopa is preferred in patients above 65years of age, while those below 65 should be treated with dopamine agonists. Like monoamine oxidase inhibitors B (MAOI-B), synthetic dopamine agonists exhibit several advantages: easy-to-use treatment with a once-daily administration, delayed L-Dopa initiation, significant efficacy on motor symptoms (although lower than that of L-Dopa). MOAI can be prescribed in association with L-Dopa or dopamine agonists. Rasagiline also delays L-Dopa initiation, and consequently motor complications. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

Phenol Oxidase Mediated Protein Cross-Linking

DTIC Science & Technology

1989-06-26

proteins and Fasciola eggshell precursor proteins have their tyrosine residues oxidized to DOPA prior to secretion. We have been trying to determine...reproducibly with "Arnow’s Stain" although Fasciola DOPA protein kindly supplied by Herb Waite stains reproducibly in our hands. NOVEL SILVER STAINING OF

Deanol and physostigmine in the treatment of L-dopa-induced dyskinesias.

PubMed

Lindeboom, S F; Lakke, J P

1978-08-01

Deanol and placebo were administered to 10 parkinsonian patients with levodopa-induced dyskinesias in a double-blind, crossover fashion. Deanol and placebo did not differ significantly in their effects on dyskinesias. The reported properties of deanol seem to be attributable to a placebo effect. There was no correlation with the results of the physostigmine test. Despite these disappointing results deanol remains intriguing, because in individual cases remarkable improvements on dyskinesias are reported.

The Role of L-DOPA on Melanization and Mycelial Production in Malassezia Furfur

PubMed Central

Youngchim, Sirida; Nosanchuk, Joshua D.; Pornsuwan, Soraya; Kajiwara, Susumu; Vanittanakom, Nongnuch

2013-01-01

Melanins are synthesized by organisms of all biological kingdoms and comprise a heterogeneous class of natural pigments. Certain of these polymers have been implicated in the pathogenesis of several important human fungal pathogens. This study investigated whether the fungal skin pathogen Malassezia furfur produces melanin or melanin-like compounds. A melanin-binding monoclonal antibody (MAb) labelled in vitro cultivated yeast cells of M. furfur. In addition, melanization of Malassezia yeasts and hyphae was detected by anti-melanin MAb in scrapings from patients with pityriasis versicolor. Treatment of Malassezia yeasts with proteolytic enzymes, denaturant and concentrated hot acid yielded dark particles and electron spin resonance spectroscopy revealed that these particles contained a stable free radical compound, consistent with their identification as melanins. Malassezia yeasts required phenolic compounds, such as L-DOPA, in order to synthesize melanin. L-DOPA also triggered hyphal formation in vitro when combined with kojic acid, a tyrosinase inhibitor, in a dose-dependent manner. In this respect, L-DOPA is thought to be an essential substance that is linked to both melanization and yeast-mycelial transformation in M. furfur. In summary, M. furfur can produce melanin or melanin-like compounds in vitro and in vivo, and the DOPA melanin pathway is involved in cell wall melanization. PMID:23762233

The role of L-DOPA on melanization and mycelial production in Malassezia furfur.

PubMed

Youngchim, Sirida; Nosanchuk, Joshua D; Pornsuwan, Soraya; Kajiwara, Susumu; Vanittanakom, Nongnuch

2013-01-01

Melanins are synthesized by organisms of all biological kingdoms and comprise a heterogeneous class of natural pigments. Certain of these polymers have been implicated in the pathogenesis of several important human fungal pathogens. This study investigated whether the fungal skin pathogen Malassezia furfur produces melanin or melanin-like compounds. A melanin-binding monoclonal antibody (MAb) labelled in vitro cultivated yeast cells of M. furfur. In addition, melanization of Malassezia yeasts and hyphae was detected by anti-melanin MAb in scrapings from patients with pityriasis versicolor. Treatment of Malassezia yeasts with proteolytic enzymes, denaturant and concentrated hot acid yielded dark particles and electron spin resonance spectroscopy revealed that these particles contained a stable free radical compound, consistent with their identification as melanins. Malassezia yeasts required phenolic compounds, such as L-DOPA, in order to synthesize melanin. L-DOPA also triggered hyphal formation in vitro when combined with kojic acid, a tyrosinase inhibitor, in a dose-dependent manner. In this respect, L-DOPA is thought to be an essential substance that is linked to both melanization and yeast-mycelial transformation in M. furfur. In summary, M. furfur can produce melanin or melanin-like compounds in vitro and in vivo, and the DOPA melanin pathway is involved in cell wall melanization.

Aerobic photoreactivity of synthetic eumelanins and pheomelanins: generation of singlet oxygen and superoxide anion.

PubMed

Szewczyk, Grzegorz; Zadlo, Andrzej; Sarna, Michal; Ito, Shosuke; Wakamatsu, Kazumasa; Sarna, Tadeusz

2016-11-01

In this work, we examined photoreactivity of synthetic eumelanins, formed by autooxidation of DOPA, or enzymatic oxidation of 5,6-dihydroxyindole-2-carboxylic acid and synthetic pheomelanins obtained by enzymatic oxidation of 5-S-cysteinyldopa or 1:1 mixture of DOPA and cysteine. Electron paramagnetic resonance oximetry and spin trapping were used to measure oxygen consumption and formation of superoxide anion induced by irradiation of melanin with blue light, and time-resolved near-infrared luminescence was employed to determine the photoformation of singlet oxygen between 300 and 600 nm. Both superoxide anion and singlet oxygen were photogenerated by the synthetic melanins albeit with different efficiency. At 450-nm, quantum yield of singlet oxygen was very low (~10 -4 ) but it strongly increased in the UV region. The melanins quenched singlet oxygen efficiently, indicating that photogeneration and quenching of singlet oxygen may play an important role in aerobic photochemistry of melanin pigments and could contribute to their photodegradation and photoaging. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Effect of oxidative stress from nanoscale TiO2 particles on a Physarum polycephalum macroplasmodium under dark conditions.

PubMed

Zhang, Zhi; Zhang, Jianhua; Shi, Caixia; Guo, Heng; Ni, RuiYang; Qu, Junle; Tang, Jiaoning; Liu, Shide

2017-07-01

Information regarding the effect of nanoscale titanium dioxide particles (nTiO 2 ) on the environment under dark conditions is scarce, and the effect of nTiO 2 on fungi is largely unknown. Due to its huge size and high sensitivity to external stimuli, the slime mold fungi cell, Physarum polycephalum macroplasmodium, was utilized as a novel subject for the toxicity investigations in the present study, and oxidative stress from nTiO 2 on the macroplasmodium was assessed under dark conditions. Short exposure (2-3 h) caused an intracellular reactive oxygen species (ROS) imbalance, and an anti-oxidative mechanism was activated from intermediate doses of nTiO 2 (5-18 mg/mL). At long exposure times (~3 days), relatively low doses of nTiO 2 (≤9 mg/mL) stimulated the growth of macroplasmodium and oxidative stress without DNA damage, whereas higher doses of nTiO 2 (≥15 mg/mL) led to growth inhibition, significant DNA oxidative damage, and activation of the DNA single-strand repairing system. Although DNA oxidative damage was decreased to the same level as the control group by the supplementation of the anti-oxidant vitamin C, growth of the macroplasmodium failed to be completely restored. We inferred that nTiO 2 induced a complicated toxicity effect on P. polycephalum in addition to DNA oxidative damage. Taken as a whole, the present study implied the probability of using P. polycephalum macroplasmodium for toxicity studies at the single-cell level, indicating that nTiO 2 could induce oxidative stress or damage in P. polycephalum even under dark conditions and suggesting that the release of nTiO 2 could lead to a growth imbalance of slime molds in the environment.

Blunted epidermal L-tryptophan metabolism in vitiligo affects immune response and ROS scavenging by Fenton chemistry, part 1: Epidermal H2O2/ONOO(-)-mediated stress abrogates tryptophan hydroxylase and dopa decarboxylase activities, leading to low serotonin and melatonin levels.

PubMed

Schallreuter, Karin U; Salem, Mohamed A E L; Gibbons, Nick C J; Martinez, Aurora; Slominski, Radomir; Lüdemann, Jürgen; Rokos, Hartmut

2012-06-01

Vitiligo is characterized by a progressive loss of inherited skin color. The cause of the disease is still unknown. To date, there is accumulating in vivo and in vitro evidence for massive oxidative stress via hydrogen peroxide (H(2)O(2)) and peroxynitrite (ONOO(-)) in the skin of affected individuals. Autoimmune etiology is the favored theory. Since depletion of the essential amino acid L-tryptophan (Trp) affects immune response mechanisms, we here looked at epidermal Trp metabolism via tryptophan hydroxylase (TPH) with its downstream cascade, including serotonin and melatonin. Our in situ immunofluorescence and Western blot data reveal significantly lower TPH1 expression in patients with vitiligo. Expression is also low in melanocytes and keratinocytes under in vitro conditions. Although in vivo Fourier transform-Raman spectroscopy proves the presence of 5-hydroxytryptophan, epidermal TPH activity is completely absent. Regulation of TPH via microphthalmia-associated transcription factor and L-type calcium channels is severely affected. Moreover, dopa decarboxylase (DDC) expression is significantly lower, in association with decreased serotonin and melatonin levels. Computer simulation supports H(2)O(2)/ONOO(-)-mediated oxidation/nitration of TPH1 and DDC, affecting, in turn, enzyme functionality. Taken together, our data point to depletion of epidermal Trp by Fenton chemistry and exclude melatonin as a relevant contributor to epidermal redox balance and immune response in vitiligo.

Protective role of catechin and quercetin in sodium benzoate-induced lipid peroxidation and the antioxidant system in human erythrocytes in vitro.

PubMed

Yetuk, Gamze; Pandir, Dilek; Bas, Hatice

2014-01-01

The aim of this study was to evaluate the protective effect of catechin and quercetin in sodium benzoate- (SB-) induced oxidative stress in human erythrocytes in vitro. For this, the effects of SB (6.25, 12.5, 25, 50, and 100 μg/mL), catechin (10 μM), and quercetin (10 μM) on lipid peroxidation (LPO) and the activities of SOD, CAT, GPx, and GST were studied. Significantly higher LPO and lower activities of antioxidant enzymes were observed with the increasing concentrations of SB. Catechin or quercetin protected the erythrocytes against SB-induced toxicity only at low concentrations of SB. The presence of catechin or quercetin at 10 μM have no effect on SB-induced toxicity at high concentrations of SB (50 and 100 μg/mL). In conclusion, SB may cause oxidative stress as food additive in human erythrocytes in vitro. So, it appears that our findings provide evidence for the protection of erythrocytes from SB that could be considered for further studies.

Ameliorative influence of Urtica dioica L against cisplatin-induced toxicity in mice bearing Ehrlich ascites carcinoma.

PubMed

Özkol, Halil; Musa, Davut; Tuluce, Yasin; Koyuncu, Ismail

2012-07-01

Cisplatin (CP) is a widely used cytotoxic agent against cancer, and high doses of CP have been known to cause nephrotoxicity and hepatotoxicity. Some reports claim that antioxidants can reduce CP-induced toxicity. This study investigated the hepatoprotective, nephroprotective, and antioxidant activity of Urtica dioica L methanolic extract (UDME) against CP toxicity in Erhlich ascites tumor (EAT)-bearing mice. Levels of serum hepatic enzymes, renal function markers, and oxidant/antioxidant parameters of liver tissue were measured. Mice were inoculated with EAT on day 0 and treated with nothing else for 24 hours. After a single dose of CP administration on day 1, the extract was given at the doses of 50, 100, 200, and 400 mg/kg body weight daily during 6 days. Almost all doses of UDME performed a significant (P < 0.05) preventive role against CP toxicity by decreasing aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase, blood urea nitrogen, creatinine, lipid peroxidation, protein oxidation levels, and myeloperoxidase activity, as well as increasing reduced glutathione content, superoxide dismutase, catalase, glutathione S-transferase, and glutathione peroxidase activities. This suggests that UDME has a protective capacity and antioxidant activity against CP toxicity in EAT-bearing mice, probably by promoting antioxidative defense systems.

Controlled Striatal DOPA Production From a Gene Delivery System in a Rodent Model of Parkinson's Disease.

PubMed

Cederfjäll, Erik; Broom, Lauren; Kirik, Deniz

2015-05-01

Conventional symptomatic treatment for Parkinson's disease (PD) with long-term L-3,4-dihydroxyphenylalanine (DOPA) is complicated with development of drug-induced side effects. In vivo viral vector-mediated gene expression encoding tyrosine hydroxylase (TH) and GTP cyclohydrolase 1 (GCH1) provides a drug delivery strategy of DOPA with distinct advantages over pharmacotherapy. Since the brain alterations made with current gene transfer techniques are irreversible, the therapeutic approaches taken to the clinic should preferably be controllable to match the needs of each individual during the course of their disease. We used a recently described tunable gene expression system based on the use of destabilized dihydrofolate reductase (DD) and generated a N-terminally coupled GCH1 enzyme (DD-GCH1) while the TH enzyme was constitutively expressed, packaged in adeno-associated viral (AAV) vectors. Expression of DD-GCH1 was regulated by the activating ligand trimethoprim (TMP) that crosses the blood-brain barrier. We show that the resulting intervention provides a TMP-dose-dependent regulation of DOPA synthesis that is closely linked to the magnitude of functional effects. Our data constitutes the first proof of principle for controlled reconstitution of dopamine capacity in the brain and suggests that such next-generation gene therapy strategies are now mature for preclinical development toward use in patients with PD.

Aniline Induces Oxidative Stress and Apoptosis of Primary Cultured Hepatocytes.

PubMed

Wang, Yue; Gao, Hong; Na, Xiao-Lin; Dong, Shu-Ying; Dong, Hong-Wei; Yu, Jia; Jia, Li; Wu, Yong-Hui

2016-11-30

The toxicity and carcinogenicity of aniline in humans and animals have been well documented. However, the molecular mechanism involved in aniline-induced liver toxicity and carcinogenesis remains unclear. In our research, primary cultured hepatocytes were exposed to aniline (0, 1.25, 2.50, 5.0 and 10.0 μg/mL) for 24 h in the presence or absence of N -acetyl-l-cysteine (NAC). Levels of reactive oxygen species (ROS), malondialdehyde (MDA), and glutathione (GSH), activities of superoxide dismutase (SOD) and catalase (CAT), mitochondrial membrane potential, DNA damage, cell viability, and apoptosis were detected. Levels of ROS and MDA were significantly increased and levels of GSH and CAT, activity of SOD, and mitochondrial membrane potential in hepatocytes were significantly decreased by aniline compared with the negative control group. The tail moment and DNA content of the tail in exposed groups were significantly higher than those in the negative control group. Cell viability was reduced and apoptotic death was induced by aniline in a concentration-dependent manner. The phenomena of ROS generation, oxidative damage, loss of mitochondrial membrane potential, DNA damage and apoptosis could be prevented if ROS inhibitor NAC was added. ROS generation is involved in the loss of mitochondrial membrane potential and DNA injury, which may play a role in aniline-induced apoptosis in hepatocytes. Our study provides insight into the mechanism of aniline-induced toxicity and apoptosis of hepatocytes.

Aniline Induces Oxidative Stress and Apoptosis of Primary Cultured Hepatocytes

PubMed Central

Wang, Yue; Gao, Hong; Na, Xiao-Lin; Dong, Shu-Ying; Dong, Hong-Wei; Yu, Jia; Jia, Li; Wu, Yong-Hui

2016-01-01

The toxicity and carcinogenicity of aniline in humans and animals have been well documented. However, the molecular mechanism involved in aniline-induced liver toxicity and carcinogenesis remains unclear. In our research, primary cultured hepatocytes were exposed to aniline (0, 1.25, 2.50, 5.0 and 10.0 μg/mL) for 24 h in the presence or absence of N-acetyl-l-cysteine (NAC). Levels of reactive oxygen species (ROS), malondialdehyde (MDA), and glutathione (GSH), activities of superoxide dismutase (SOD) and catalase (CAT), mitochondrial membrane potential, DNA damage, cell viability, and apoptosis were detected. Levels of ROS and MDA were significantly increased and levels of GSH and CAT, activity of SOD, and mitochondrial membrane potential in hepatocytes were significantly decreased by aniline compared with the negative control group. The tail moment and DNA content of the tail in exposed groups were significantly higher than those in the negative control group. Cell viability was reduced and apoptotic death was induced by aniline in a concentration-dependent manner. The phenomena of ROS generation, oxidative damage, loss of mitochondrial membrane potential, DNA damage and apoptosis could be prevented if ROS inhibitor NAC was added. ROS generation is involved in the loss of mitochondrial membrane potential and DNA injury, which may play a role in aniline-induced apoptosis in hepatocytes. Our study provides insight into the mechanism of aniline-induced toxicity and apoptosis of hepatocytes. PMID:27916916

The cell labeling efficacy, cytotoxicity and relaxivity of copper-activated MRI/PET imaging contrast agents.

PubMed

Patel, Daksha; Kell, Arnold; Simard, Benoit; Xiang, Bo; Lin, Hung Yu; Tian, Ganghong

2011-02-01

A new class of nanoparticle-based dual-modality positron emission tomography/magnetic resonance imaging (PET/MRI) contrast agents has been developed. The probe consists of a superparamagnetic iron oxide (SPIO) or manganese oxide core coated with 3,4-dihydroxy-D,L-phenylalanine (DL-DOPA). The chelator 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) was conjugated to DOPA termini. The DOTA modified nanoparticles allow chelation of copper for PET imaging. These surface functionalized nanoparticle-based probes have been characterized by various analytical techniques. The cell-labeling efficacy, cytotoxicity and relaxivity of these nanoparticles have been evaluated and compared with the same properties of one of the most commonly utilized MRI contrast agents, Feridex(®). Evidently, this new nanoparticle has a great potential for use in cell tracking with MRI and PET in the absence of transfecting agent. It is noteworthy that there is a sharp increase in r(2) relaxivity of these nanoparticles on coordination with Cu(2+) ions. Thus these iron oxide nanoparticles can also be explored as the smart magnetic resonance (MR) sensor for the detection of micromolar changes in copper concentration for neurodegenerative diseases such as Alzheimer's disease, Menkes and Wilson's diseases, amyotrophic lateral sclerosis and prion diseases. Crown Copyright © 2010. Published by Elsevier Ltd. All rights reserved.

Preventive effects of fructose and N-acetyl-L-cysteine against cytotoxicity induced by the psychoactive compounds N-methyl-5-(2-aminopropyl)benzofuran and 3,4-methylenedioxy-N-methamphetamine in isolated rat hepatocytes.

PubMed

Nakagawa, Yoshio; Suzuki, Toshinari; Inomata, Akiko

2018-02-01

Psychoactive compounds, N-methyl-5-(2-aminopropyl)benzofuran (5-MAPB) and 3,4-methylenedioxy-N-methamphetamine (MDMA), are known to be hepatotoxic in humans and/or experimental animals. As previous studies suggested that these compounds elicited cytotoxicity via mitochondrial dysfunction and/or oxidative stress in rat hepatocytes, the protective effects of fructose and N-acetyl-l-cysteine (NAC) on 5-MAPB- and MDMA-induced toxicity were studied in rat hepatocytes. These drugs caused not only concentration-dependent (0-4 mm) and time-dependent (0-3 hours) cell death accompanied by the depletion of cellular levels of adenosine triphosphate (ATP) and glutathione (reduced form; GSH) but also an increase in the oxidized form of GSH. The toxic effects of 5-MAPB were greater than those of MDMA. Pretreatment of hepatocytes with either fructose at a concentration of 10 mm or NAC at a concentration of 2.5 mm prevented 5-MAPB-/MDMA-induced cytotoxicity. In addition, the exposure of hepatocytes to 5-MAPB/MDMA caused the loss of mitochondrial membrane potential, although the preventive effect of fructose was weaker than that of NAC. These results suggest that: (1) 5-MAPB-/MDMA-induced cytotoxicity is linked to mitochondrial failure and depletion of cellular GSH; (2) insufficient cellular ATP levels derived from mitochondrial dysfunction were ameliorated, at least in part, by the addition of fructose; and (3) GSH loss via oxidative stress was prevented by NAC. Taken collectively, these results indicate that the onset of toxic effects caused by 5-MAPB/MDMA may be partially attributable to cellular energy stress as well as oxidative stress. Copyright © 2017 John Wiley & Sons, Ltd.

Current options and future possibilities for the treatment of dyskinesia and motor fluctuations in Parkinson's disease.

PubMed

Cenci, M A; Ohlin, K E; Odin, P

2011-09-01

Dyskinesia and motor fluctuations affect up to 90% of patients with Parkinson's disease (PD) within ten years of L-DOPA pharmacotherapy, and represent a major challenge to a successful clinical management of this disorder. There are currently two main treatment options for these complications, namely, deep brain electrical stimulation or continuous infusion of dopaminergic agents. The latter is achieved using either subcutaneous apomorphine infusion or enteric L-DOPA delivery. Some patients also benefit from the antidyskinetic effect of amantadine as an adjunct to L-DOPA treatment. Ongoing research in animal models of PD aims at discovering additional, novel treatment options that can either prevent or reverse dyskinesia and motor fluctuations. Alternative methods of continuous L-DOPA delivery (including gene therapy), and pharmacological agents that target nondopaminergic receptor systems are currently under intense experimental scrutiny. Because clinical response profiles show large individual variation in PD, an increased number of treatment options for dyskinesia and motor fluctuations will eventually allow for antiparkinsonian and antidyskinetic therapies to be tailor-made to the needs of different patients and/or PD subtypes.

In vitro and in vivo investigation of natural compounds from seed extract of Mucuna pruriens lacking l-DOPA for the treatment of erectile dysfunction.

PubMed

Duangnin, Natthachai; Phitak, Thanyaluck; Pothacharoen, Peraphan; Kongtawelert, Prachya

2017-03-01

To investigate the biological effects of the Mucuna pruriens (M. pruriens) seed extracts that lacked l-DOPA, which was formerly reported as the active ingredient, on erectile dysfunction (ED) both in vitro and in vivo. Seed of M. pruriens plant that cultivated in Mae Taeng District, Chiang Mai Province, Thailand, was collected. Component of its seeds were extracted and isolated into 2 fractions using methanol, polar and nonpolar. Each fraction was investigated for phytochemicals using gas chromatography and mass spectroscopy and was screened for biological activity in vitro using three different cell lines. The most biological active fraction was used to treat both streptozotocin (STZ)-induced diabetes mellitus-erectile dysfunction (DM-ED) male Wistar rats and normal rats (n = 6 per groups) to compare the effect on sexual behavior parameters, including number of intromission, mounting and ejaculation, with that of rats given Sildenafil by individually pairing with their female counterparts. Penile tissues and serums were collected to determine histological structure, related gene expression and biomolecules. The phytochemicals of the polar fraction were possibly catechol and its derivatives plus polyphenols, whereas the nonpolar fraction consisted of lipid derivatives. l-DOPA was not detected in either of the extracts. The polar fraction was able to up-regulate the expression of ED-related genes including eNOS and nNOS in vitro which subsequently promotes nitric oxide production and maintains intracellular cyclic guanosine monophosphate levels. When administrated to DM-ED rats, the polar extract significantly improved all sexual behavior parameters in DM-ED rats compared to untreated group (18.3 ± 1.8 to 10.8 ± 2.9 for intromission, 9.8 ± 2.2 to 5.7 ± 1.3 for mounting, and 1.8 ± 0.6 to 0.2 ± 0.4 for ejaculation). That effect might due to the ability of the extract to stimulate the expression of eNOS and nNOS which results in nitric oxide production and subsequently maintains cyclic guanosine monophosphate levels in penile tissue. Moreover, this extract may also prevent penile tissue deterioration due to diabetes. The polar extract of M. pruriens seed can be used for ED therapy, especially in patients with metabolic diseases including diabetes. The action of the extract might be due to catechol and its derivatives and polyphenols. Copyright © 2017 Hainan Medical University. Production and hosting by Elsevier B.V. All rights reserved.

Ameliorative action of Vernonia cinerea L. on cyclophosphamide-induced immunosuppression and oxidative stress in mice.

PubMed

Pratheeshkumar, P; Kuttan, Girija

2010-08-01

Cyclophosphamide (CTX) is a widely used antineoplastic drug, which could cause toxicity to normal cells due to its toxic metabolites. The use of CTX in treating cancer patients is limited due to its severe toxicity induced mainly by oxidative stress. The present study reports the protective role of Vernonia cinerea L. against the CTX-induced toxicity in Balb/c mice. Intraperitoneal administration of the extract significantly increased the total WBC Count, bone marrow cellularity, alpha-esterase positive cells, and weights of lymphoid organs in CTX-treated animals, when compared with CTX control mice. Administration of V. cinerea was found to reduce the enhanced level of alkaline phosphatase, glutamate pyruvate transaminase, lipid peroxidation, and also significantly increased the reduced glutathione level in CTX-treated animals. Histopathological analysis of small intestine also suggests that extract could reduce the CTX-induced intestinal damage. The level of proinflammatory cytokine TNF-alpha, which was elevated during CTX administration, was significantly reduced by the V. cinerea extract administration. The lowered levels of other cytokines like IFN-gamma, IL-2, GM-CSF, after CTX treatment were also found to be increased by extract administration. Administration of V. cinerea did not compromise the anti-neoplastic activity of CTX. Infact, there was a synergistic action of CTX and V. cinerea in reducing the solid tumors in mice. Methanolic extract of V. cinerea given intraperitoneally (i.p.) showed a significant chemoprotective activity without compromising the chemotherapeutic efficacy of CTX, indicating its possible use as an adjuvant during chemotherapy.

Self-degradation of tissue adhesive based on oxidized dextran and poly-L-lysine.

PubMed

Matsumura, Kazuaki; Nakajima, Naoki; Sugai, Hajime; Hyon, Suong-Hyu

2014-11-26

We have developed a low-toxicity bioadhesive based on oxidized dextran and poly-L-lysine. Here, we report that the mechanical properties and degradation of this novel hydrogel bioadhesive can be controlled by changing the extent of oxidation of the dextran and the type or concentration of the anhydride species in the acylated poly-L-lysine. The dynamic moduli of the hydrogels can be controlled from 120 Pa to 20 kPa, suggesting that they would have mechanical compatibility with various tissues, and could have applications as tissue adhesives. Development of the hydrogel color from clear to brown indicates that the reaction between the dextran aldehyde groups and the poly-L-lysine amino groups may be induced by a Maillard reaction via Schiff base formation. Degradation of the aldehyde dextran may begin by reaction of the amino groups in the poly-L-lysine. The gel degradation can be ascribed to degradation of the aldehyde dextran in the hydrogel, although the aldehyde dextran itself is relatively stable in water. The oxidized dextran and poly-L-lysine, and the degraded hydrogel showed low cytotoxicities. These findings indicate that a hydrogel consisting of oxidized dextran and poly-L-lysine has low toxicity and a well-controlled degradation rate, and has potential clinical applications as a bioadhesive. Copyright © 2014 Elsevier Ltd. All rights reserved.

Biology and therapeutic potential of hydrogen sulfide and hydrogen sulfide-releasing chimeras

PubMed Central

Kashfi, Khosrow; Olson, Kenneth R.

2012-01-01

Hydrogen sulfide, H2S, is a colorless gas with a strong odor that until recently was only considered to be a toxic environmental pollutant with little or no physiological significance. However, the past few years have demonstrated its role in many biological systems and it is becoming increasingly clear that H2S is likely to join nitric oxide (NO) and carbon monoxide (CO) as a major player in mammalian biology. In this review, we have provided an overview of the chemistry and biology of H2S and have summarized the chemistry and biological activity of some natural and synthetic H2S-donating compounds. The naturally occurring compounds discussed include, garlic, sulforaphane, erucin, and iberin. The synthetic H2S donors reviewed include, GYY4137; cysteine analogs; S-propyl cysteine, S-allyl cysteine, S-propargyl cysteine, and N-acetyl cysteine. Dithiolethione and its NSAID and other chimeras such as, L-DOPA, sildenafil, aspirin, diclofenac, naproxen, ibuprofen, indomethacin, and mesalamine have also been reviewed in detail. The newly reported NOSH-aspirin that releases both NO and H2S has also been discussed. PMID:23103569

[Deep brain stimulation in parkinsonian patients with dopa intolerance].

PubMed

García-Ruiz, Pedro J; Feliz-Feliz, Cici; Ayerbe Gracia, Joaquín; Matías Arbelo, José; Salvador, Carlos; Val Fernández, Javier Del; García-Caldentey, Juan

2017-10-28

Deep brain stimulation (DBS) is at present, a useful treatment for patients with advanced Parkinson's disease and motor complications. The crucial step toward consistent DBS outcomes remains careful patient selection; several conditions must be fulfilled including excellent levo dopa response. We report two cases of early onset Parkinson's disease with severe intolerance to levo dopa but excellent and sustained response to DBS. DBS can be a useful alternative for parkinsonian patients with severe intolerance to levo dopa, provided a positive acute response to levo dopa or apomorphine is obtained. Copyright © 2017 Sociedad Española de Neurocirugía. Publicado por Elsevier España, S.L.U. All rights reserved.

Nitric oxide modulates cadmium influx during cadmium-induced programmed cell death in tobacco BY-2 cells.

PubMed

Ma, Wenwen; Xu, Wenzhong; Xu, Hua; Chen, Yanshan; He, Zhenyan; Ma, Mi

2010-07-01

Nitric oxide (NO) is a bioactive gas and functions as a signaling molecule in plants exposed to diverse biotic and abiotic stresses including cadmium (Cd(2+)). Cd(2+) is a non-essential and toxic heavy metal, which has been reported to induce programmed cell death (PCD) in plants. Here, we investigated the role of NO in Cd(2+)-induced PCD in tobacco BY-2 cells (Nicotiana tabacum L. cv. Bright Yellow 2). In this work, BY-2 cells exposed to 150 microM CdCl(2) underwent PCD with TUNEL-positive nuclei, significant chromatin condensation and the increasing expression of a PCD-related gene Hsr203J. Accompanied with the occurring of PCD, the production of NO increased significantly. The supplement of NO by sodium nitroprusside (SNP) had accelerated the PCD, whereas the NO synthase inhibitor Nomega-nitro-L-arginine methyl ester hydrochloride (L-NAME) and NO-specific scavenger 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide (cPTIO) alleviated this toxicity. To investigate the mechanism by which NO exerted its function, Cd(2+) concentration was measured subsequently. SNP led more Cd(2+) content than Cd(2+) treatment alone. By contrast, the prevention of NO by L-NAME decreased Cd(2+) accumulation. Using the scanning ion-selective electrode technique, we analyzed the pattern and rate of Cd(2+) fluxes. This analysis revealed the promotion of Cd(2+) influxes into cells by application of SNP, while L-NAME and cPTIO reduced the rate of Cd(2+) uptake or even resulted in net Cd(2+) efflux. Based on these founding, we concluded that NO played a positive role in CdCl(2)-induced PCD by modulating Cd(2+) uptake and thus promoting Cd(2+) accumulation in BY-2 cells.

Effect of antioxidants on vanadate-induced toxicity towards isolated perfused rat livers.

PubMed

Younes, M; Kayser, E; Strubelt, O

1991-01-01

The effect of trolox C, a water soluble vitamin E analogue, propyl gallate and ascorbate on vanadate hepatotoxicity was investigated in vitro. In isolated perfused livers from fasted rats, sodium orthovanadate (2 mmol/l) led to toxic responses including reduction of oxygen consumption, release of cytosolic (glutamate-pyruvate-transaminase (GPT) and lactate dehydrogenase (LDH)) and mitochondrial (glutamate-dehydrogenase (GLDH)) enzymes, intracellular accumulation of calcium, a marked depletion of glutathione (GSH) and an enhanced formation and release of thiobarbituric acid- (TBA) reactive material. Trolox C and propyl gallate inhibited the release of GPT and LDH partially and that of GLDH totally, but had no influence on vanadate-induced calcium accumulation or on the reduction of oxygen consumption. Both agents suppressed vanadate-induced lipid peroxidation (LPO) and partially prevented GSH depletion. Ascorbate failed to provide any protection probably due to the interference of its pro-oxidant potential with its antioxidant activity. The protection, mainly of mitochondria, afforded by those agents which also inhibited LPO substantiates our previous findings that the pro-oxidant activity of vanadate is mainly responsible for its direct hepatotoxic actions [2]. Besides, reduction of organ perfusion rate due to vasoconstriction also contributes to vanadate toxicity, but oxidative stress is not involved in this indirect toxic activity.

Therapeutic potential of natural products in Parkinson's disease.

PubMed

Mythri, Rajeswara B; Harish, Gangadharappa; Bharath, M M

2012-09-01

The central objective in treating patients with Parkinson's disease (PD) is two-fold (i) to increase the striatal dopamine content and (ii) to prevent further degeneration of the surviving dopaminergic neurons in the substantia nigra region of the ventral midbrain. Most of the current PD drugs contribute to the former and provide symptomatic relief. Although compounds such as Levodopa (L-DOPA) improve the striatal dopamine content, their long-term usage is associated with progressive decrease in drug response, motor fluctuations, dyskinesias and drug-induced toxicity. In addition, these drugs fail to prevent the progression of the degenerative process. This has shifted the focus onto alternative therapeutic approaches involving natural products that could provide independent therapy or offer neuroprotective support to the existing drugs. The current review describes the neuroprotective and therapeutic utility of such natural products including herbal extracts, phytochemicals and bioactive ingredients from other natural sources either in isolation or in combination, with potential application in PD, highlighting the relevant patents.

Synaptic plasticity and levodopa-induced dyskinesia: electrophysiological and structural abnormalities.

PubMed

Picconi, Barbara; De Leonibus, Elvira; Calabresi, Paolo

2018-02-28

Parkinson's disease (PD) is a neurodegenerative disorder characterized by progressive degeneration of dopaminergic neurons located in the midbrain. The gold-standard therapy for PD is the restoration of dopamine (DA) levels through the chronic administration of the DA precursor levodopa (L-DOPA). Although levodopa therapy is the main therapeutic approach for PD, its use is limited by the development of very disabling dyskinetic movements, mainly due to the fluctuation of DA cerebral content. Experimental animal models of PD identified in DA D1/ERK-signaling pathway aberrant activation, occurring in striatal projection neurons, coupled with structural spines abnormalities, the molecular and neuronal basis of L-DOPA-induced dyskinesia (LIDs) occurrence. Different electrophysiological approaches allowed the identification of  the alteration of homeostatic structural and synaptic changes, the neuronal bases of LIDs either in vivo in parkinsonian patients or in vitro in experimental animals. Here, we report the most recent studies showing electrophysiological and morphological evidence of aberrant synaptic plasticity in parkinsonian patients during LIDs in different basal ganglia nuclei and also in cortical transmission, accounting for the complexity of the synaptic changes during dyskinesias. All together, these studies suggest that LIDs are associated with a loss of homeostatic synaptic mechanisms.

Effect of Aronia melanocarpa fruit juice on amiodarone-induced pneumotoxicity in rats.

PubMed

Valcheva-Kuzmanova, Stefka; Stavreva, Galya; Dancheva, Violeta; Terziev, Ljudmil; Atanasova, Milena; Stoyanova, Angelina; Dimitrova, Anelia; Shopova, Veneta

2014-04-01

The fruits of Aronia melanocarpa (Michx.) Elliot is extremely rich in biologically active polyphenols. We studied the protective effect of A. melanocarpa fruit juice (AMFJ) in a model of amiodarone (AD)-induced pneumotoxicity in rats. AD was instilled intratracheally on days 0 and 2 (6.25 mg/kg). AMFJ (5 mL/kg and 10 mL/kg) was given orally from day 1 to days 2, 4, 9, and 10 to rats, which were sacrificed respectively on days 3, 5, 10, and 28 when biochemical, cytological, and immunological assays were performed. AMFJ antagonized AD-induced increase of the lung weight coefficient. In bronchoalveolar lavage fluid, AD increased significantly the protein content, total cell count, polymorphonuclear cells, lymphocytes and the activity of lactate dehydrogenase, acid phosphatase and alkaline phosphatase on days 3 and 5. In AMFJ-treated rats these indices of direct toxic damage did not differ significantly from the control values. In lung tissue, AD induced oxidative stress measured by malondialdehyde content and fibrosis assessed by the hydroxyproline level. AMFJ prevented these effects of AD. In rat serum, AD caused a significant elevation of interleukin IL-6 on days 3 and 5, and a decrease of IL-10 on day 3. In AMFJ-treated rats, these indices of inflammation had values that did not differ significantly from the control ones. AMFJ could have a protective effect against AD-induced pulmonary toxicity as evidenced by the reduced signs of AD-induced direct toxic damage, oxidative stress, inflammation, and fibrosis.

Cytogenetic evaluation of gold nanorods using Allium cepa test.

PubMed

Rajeshwari, A; Roy, Barsha; Chandrasekaran, Natarajan; Mukherjee, Amitava

2016-12-01

The current study reveals the impact of gold nanorods (NRs) capped with CTAB (cetyltrimethylammonium bromide) or PEG (polyethylene glycol) on Allium cepa. The morphology and surface charge of CTAB- and PEG-capped gold NRs were characterized by electron microscopic and zeta potential analyses. The chromosomal aberrations like clumped chromosome, chromosomal break, chromosomal bridge, diagonal anaphase, disturbed metaphase, laggard chromosome, and sticky chromosome were observed in the root tip cells exposed to different concentrations (0.1, 1, and 10 μg/mL) of CTAB- and PEG-capped gold NRs. We found that both CTAB- and PEG-capped gold NRs were able to induce toxicity in the plant system after 4-h interaction. At a maximum concentration of 10 μg/mL, the mitotic index reduction induced by CTAB-capped gold NRs was 40-fold higher than that induced by PEG-capped gold NRs. The toxicity of gold NRs was further confirmed by lipid peroxidation and oxidative stress analyses. The unbound CTAB also contributed to the toxicity in root tip cells, while PEG alone shows less toxicity to the cells. The vehicle control CTAB contributed to the toxic effects in root tip cells, while PEG alone did not show any toxicity to the cells. The results revealed that even though both the particles have adverse effects on A. cepa, there was a significant difference in the mitotic index and oxidative stress generation in root cells exposed to CTAB-capped gold NRs. Thus, this study concludes that the surface polymerization of gold NRs by PEG can reduce the toxicity of CTAB-capped gold NRs. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Nitric oxide protects the mitochondria of anterior pituitary cells and prevents cadmium-induced cell death by reducing oxidative stress.

PubMed

Poliandri, Ariel H B; Machiavelli, Leticia I; Quinteros, Alnilan F; Cabilla, Jimena P; Duvilanski, Beatriz H

2006-02-15

Cadmium (Cd2+) is a highly toxic metal that affects the endocrine system. We have previously shown that Cd2+ induces caspase-3 activation and apoptosis of anterior pituitary cells and that endogenous nitric oxide (NO) protects these cells from Cd2+. Here we investigate the mechanisms by which NO exerts this protective role. Cd2+ (25 microM) reduced the mitochondrial membrane potential (MMP) as measured by flow cytometry. Cd2+-induced apoptosis was mitochondrial dependent since cyclosporin A protected the cells from this metal. Inhibition of NO synthesis with 0.5 mM L-NAME increased the effect of Cd2+ on MMP, whereas the NO donor DETANONOate (0.1 mM) reduced it. Cd2+ increased the production of reactive oxygen species (ROS) as measured by flow cytometry. This effect was electron-transfer-chain-dependent since it was inhibited by rotenone. In fact, rotenone reduced the cytotoxic effect of the metal. The action of Cd2+ on mitochondrial integrity was ROS dependent. Trolox, an antioxidant, inhibited the effect of the metal on the MMP. Cd2+-induced increase in ROS generation was reduced by DETANONOate. There are discrepancies concerning the role of NO in Cd2+ toxicity. Here we show that NO reduces Cd2+ toxicity by protecting the mitochondria from oxidative stress in a system where NO plays a regulatory role.

Nitric oxide protects carbon assimilation process of watermelon from boron-induced oxidative injury.

PubMed

Farag, Mohamed; Najeeb, Ullah; Yang, Jinghua; Hu, Zhongyuan; Fang, Zhang Ming

2017-02-01

Nitric oxide (NO) mediates plant response to a variety of abiotic stresses; however, limited information is available on its effect on boron (B)-stressed watermelon plants. The present study investigates the mechanism through which NO protects watermelon seedlings from B deficiency and toxicity stresses. Five days old watermelon seedlings were exposed to B (0, 0.5 and 10 mg L -1 ) alone or with 75 μmole of NO donor sodium nitroprusside (SNP) for 30 days. Both low and high B concentrations in the media altered nutrient accumulation and impaired various physiological processes of watermelon seedlings, leading to a significant reduction in biomass production. The plants exposed to B deficient or toxic concentrations had 66 and 69% lower shoot dry weight, respectively compared with optimum B levels. B toxicity-induced growth inhibition of watermelon seedlings was associated with high B translocation to shoot tissues, which caused lipid membrane peroxidation (12% increase) and chlorophyll destruction (25% reduction). In contrast, B deficiency accelerated generation of reactive oxygen species (ROS), specifically OH -1 and induced cellular oxidative injury. Exogenously applied SNP promoted leaf chlorophyll, photosynthesis and consequently biomass production in B-stressed watermelon seedlings by reducing B accumulation, lipid membrane peroxidation and ROS generation. It also activated antioxidant enzymes such as SOD, POD and APX, and protected the seedlings from ROS-induced cellular burst. Copyright © 2016. Published by Elsevier Masson SAS.

Potential of Lactobacillus plantarum CCFM639 in Protecting against Aluminum Toxicity Mediated by Intestinal Barrier Function and Oxidative Stress.

PubMed

Yu, Leilei; Zhai, Qixiao; Tian, Fengwei; Liu, Xiaoming; Wang, Gang; Zhao, Jianxin; Zhang, Hao; Narbad, Arjan; Chen, Wei

2016-12-02

Aluminum (Al) is a ubiquitous metal that can seriously harm the health of animals and humans. In our previous study, we demonstrated that Lactobacillus plantarum CCFM639 can decrease Al burden in the tissues of mice by inhibiting intestinal Al absorption. The main aim of the present research was to investigate whether the protection by the strain is also associated with enhancement of the intestinal barrier, alleviation of oxidative stress and modulation of the inflammatory response. In an in vitro cell model, two protection modes (intervention and therapy) were examined and the results indicated that L. plantarum CCFM639 alleviated Al-induced cytotoxicity. In a mouse model, L. plantarum CCFM639 treatment was found to significantly alleviate oxidative stress in the intestinal tract, regulate the function of the intestinal mucosal immune system, restore the integrity of tight junction proteins and maintain intestinal permeability. These results suggest that in addition to Al sequestration, L. plantarum CCFM639 can also inhibit Al absorption by protecting the intestinal barrier, alleviating Al-induced oxidative stress and inflammatory response. Therefore, L. plantarum CCFM639 has the potential to be a dietary supplement ingredient that provides protection against Al-induced gut injury.

Functional Connectivity in an fMRI Study of Semantic and Phonological Processes and the Effect of L-Dopa

ERIC Educational Resources Information Center

Tivarus, Madalina E.; Hillier, Ashleigh; Schmalbrock, Petra; Beversdorf, David Q.

2008-01-01

We describe an fMRI experiment examining the functional connectivity (FC) between regions of the brain associated with semantic and phonological processing. We wished to explore whether L-Dopa administration affects the interaction between language network components in semantic and phonological categorization tasks, as revealed by FC. We…

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.

Silicon (Si) alleviates cotton (Gossypium hirsutum L.) from zinc (Zn) toxicity stress by limiting Zn uptake and oxidative damage.

PubMed

Anwaar, Shad Ali; Ali, Shafaqat; Ali, Skhawat; Ishaque, Wajid; Farid, Mujahid; Farooq, Muhammad Ahsan; Najeeb, Ullah; Abbas, Farhat; Sharif, Muhammad

2015-03-01

Silicon (Si) is as an important fertilizer element, which has been found effective in enhancing plant tolerance to variety of biotic and a-biotic stresses. This study investigates the Si potential to alleviate zinc (Zn) toxicity stress in cotton (Gossypium hirsutum L.). Cotton plants were grown in hydroponics and exposed to different Zn concentration, 0, 25, and 50 μM, alone and/or in combination with 1 mM Si. Incremental Zn concentration in growth media instigated the cellular oxidative damage that was evident from elevated levels of hydrogen peroxide (H2O2), electrolyte leakage, and malondialdehyde (MDA) and consequently inhibited cotton growth, biomass, chlorophyll pigments, and photosynthetic process. Application of Si significantly suppressed Zn accumulation in various plant parts, i.e., roots, stems, and leaves and thus promoted biomass, photosynthetic, growth parameters, and antioxidant enzymes activity of Zn-stressed as well unstressed plants. In addition, Si reduced the MDA and H2O2 production and electrolyte leakage suggesting its role in protecting cotton plants from Zn toxicity-induced oxidative damage. Thus, the study indicated that exogenous Si application could improve growth and development of cotton crop experiencing Zn toxicity stress by limiting Zn bioavailability and oxidative damage.

New synthesis of fluorine-18-labeled 6-fluoro-L-dopa by cleaving the carbon-silicon bond with fluorine

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

Diksic, M.; Farrokhzad, S.

A new synthesis of 3,4-dihydroxy-6-( YF)fluoro-L-phenylalanine using 6-trimethylsilyl-3,4-dimethoxy-L-dopa-ethylester as a fluorination substrate is described. The silane is prepared from the corresponding bromo compound by reacting the latter with magnesium and trimethylsilyl chloride. Reaction of the silane with ( YF)F2 in a mixture of freon-11/CCl4 (1:1) kept in a dry ice bath, subsequent hydrolysis with concentrated HBr in a bath at 140 degrees C, and simple chromatographic purification yielded YF-labeled 6-fluoro-L-dopa. A radiochemical yield of about 8% was achieved at the end of the 1-hr synthesis. The specific activity at the end of the synthesis was about 680 mCi/mmol after amore » 30-min irradiation.« less

Modulation of doxorubicin-induced oxidative stress by a grape (Vitis vinifera L.) seed extract in normal and tumor cells.

PubMed

Postescu, Ion Dan; Chereches, Gabriela; Tatomir, Corina; Daicoviciu, Doina; Filip, Gabriela Adriana

2012-07-01

The major limitation of Doxorubicin (Dox) clinical use is the development of chronic and acute toxic side effects induced through the generation of reactive oxygen species. The present work was designated to investigate in vitro effects of a red grape-seed hydroethanolic extract Burgund Mare (BM), in associated administration with Dox (30 min before drug administration) in normal (Hfl-1) and tumor cell lines (HepG2 and Mls). The BM concentrations administered were below the level of the extract cytotoxiciy threshold (40 μg gallic acid [GA] Eq/mL; 37.5, 25.0, and 12.5 μg GA Eq/mL). The antioxidant capacity of the BM extract was assessed by measuring the acute toxicity at 24 h, lipid peroxides (LP), and protein oxidation. In normal cells, the product statistically decreased cytotoxicity and markedly inhibited LP and protein carbonyl (PC) formation, in a dose-dependent relationship. On contrary, in tumor cells, such treatment resulted in a reversed effect, cell death, malondialdehyde, and PC contents increasing with BM dose enhancement. BM extract treatment prior to subsequent administration of Dox afforded a differential protection against Dox-negative toxic side effects in normal cells without weakening (even enhancing) Dox's antitumor activity.

Oxidative stress and genotoxicity induced by ketorolac on the common carp Cyprinus carpio.

PubMed

Galar-Martínez, M; García-Medina, S; Gómez-Olivan, L M; Pérez-Coyotl, I; Mendoza-Monroy, D J; Arrazola-Morgain, R E

2016-09-01

The nonsteroidal anti-inflammatory drug ketorolac is extensively used in the treatment of acute postoperative pain. This pharmaceutical has been found at concentrations of 0.2-60 µg/L in diverse water bodies around the world; however, its effects on aquatic organisms remain unknown. The present study, evaluated the oxidative stress and genotoxicity induced by sublethal concentrations of ketorolac (1 and 60 µg/L) on liver, brain, and blood of the common carp Cyprinus carpio. This toxicant induced oxidative damage (increased lipid peroxidation, hydroperoxide content, and protein carbonyl content) as well as changes in antioxidant status (superoxide dismutase, catalase, and glutathione peroxidase activity) in liver and brain of carp. In blood, ketorolac increased the frequency of micronuclei and is therefore genotoxic for the test species. The effects observed were time and concentration dependent. © 2015 Wiley Periodicals, Inc. Environ Toxicol 31: 1035-1043, 2016. © 2015 Wiley Periodicals, Inc.

Influence of mitochondrion-toxic agents on the cardiovascular system.

PubMed

Finsterer, Josef; Ohnsorge, Peter

2013-12-01

Cardiovascular disease may be induced or worsened by mitochondrion-toxic agents. Mitochondrion-toxic agents may be classified as those with or without a clinical effect, those which induce cardiac disease only in humans or animals or both, as prescribed drugs, illicit drugs, exotoxins, or nutritiants, as those which affect the heart exclusively or also other organs, as those which are effective only in patients with a mitochondrial disorder or cardiac disease or also in healthy subjects, or as solid, liquid, or volatile agents. In humans, cardiotoxic agents due to mitochondrial dysfunction include anthracyclines (particularly doxorubicin), mitoxantrone, cyclophosphamide, cisplatin, fluorouracil, imatinib, bortezomib, trastuzumab, arsenic trioxide, cyclosporine-A, zidovudine, lamotrigine, glycosides, lidocain, isoproterenol, nitroprusside, pivalic acid, alcohol, cocaine, pesticides, cadmium, mycotoxins, cyanotoxins, meat meal, or carbon monoxide. Even more agents exhibit cardiac abnormalities due to mitochondrion-toxicity only in animals or tissue cultures. The mitochondrion-toxic effect results from impairment of the respiratory chain, the oxidative phosphorylation, the Krebs cycle, or the β-oxidation, from decrease of the mitochondrion-membrane potential, from increased oxidative stress, reduced anti-oxidative capacity, or from induction of apoptosis. Cardiac abnormalities induced via these mechanisms include cardiomyopathy, myocarditis, coronary heart disease, arrhythmias, heart failure, or Takotsubo syndrome. Discontinuation of the cardiotoxic agent results in complete recovery in the majority of the cases. Antioxidants and nutritiants may be of additional help. Particularly coenzyme-Q, riboflavin, vitamin-E, vitamin-C, L-carnitine, vitamin-D, thiamin, folic acid, omega-3 fatty acids, and D-ribose may alleviate mitochondrial cardiotoxic effects. Copyright © 2013 Elsevier Inc. All rights reserved.

Imaging and cell targeting characteristics of magnetic nanoparticles modified by a functionalizable zwitterionic polymer with adhesive 3,4-dihydroxyphenyl-l-alanine linkages.

PubMed

Zhang, Lei; Xue, Hong; Gao, Changlu; Carr, Louisa; Wang, Jinnan; Chu, Baocheng; Jiang, Shaoyi

2010-09-01

Multifunctional magnetic nanoparticles (MNPs) modified by a zwitterionic polymer (pCBMA-DOPA(2)) containing one poly(carboxybetaine methacrylate) (pCBMA) chain and two 3,4-dihydroxyphenyl-L-alanine (DOPA) residue groups were developed. Results showed that MNPs modified by pCBMA were not only stable in complex media, but also provided abundant functional groups for ligand immobilization. The pCBMA-DOPA(2) MNPs had a hydrodynamic particle size of about 130 nm, a strong saturation magnetization of 110.2 emu/g Fe and a high transverse relaxivity of 428 mM(-1)s(-1). Long-term stability in phosphate-buffered saline (PBS) and 10% NaCl solution was achieved for over six months. Compared to MNPs coated with dextran, pCBMA-DOPA(2) MNPs presented better stability in 100% human blood serum at 37 degrees C. Macrophage cell uptake studies revealed that the uptake ratio of pCBMA-DOPA(2) MNPs was much lower than that of dextran MNPs. Furthermore, quantitative analysis results showed that after pCBMA-DOPA(2) MNPs were conjugated with a targeting RGD peptide, uptake by human umbilical vein endothelial cell (HUVEC) was notably increased, which was further visualized by magnetic resonance imaging (MRI). Copyright (c) 2010 Elsevier Ltd. All rights reserved.

Suitability of the adenosine antagonist istradefylline for the treatment of Parkinson's disease: pharmacokinetic and clinical considerations.

PubMed

Müller, Thomas

2013-08-01

Recent experimental and clinical research has shown that A2A adenosine receptor antagonism can bring about an improvement in the motor behavior of patients with Parkinson's disease. Istradefylline , a xanthine derivative, has the longest half-life of all the currently available A2A adenosine receptor antagonists; it can successfully permeate through the blood-brain barrier and has a high human A2A adenosine receptor affinity. In this article, the author discusses the potential role of A2A adenosine receptor antagonists in the treatment of Parkinson's disease through the evaluation of istradefylline. Specifically, the article reviews the clinical and pharmacokinetic information available to elucidate its therapeutic potential. A2A adenosine receptor antagonists are efficacious in combination with l-dopa. l-dopa has a complex pharmacokinetic behavior and causes long-term behavioral and metabolic side effects. Future research on A2A adenosine receptor antagonism should consider compounds like istradefylline as l-dopa and/or dopamine agonist-sparing treatment alternatives, since their clinical handling, safety and side-effect profile are superior to l-dopa and/or dopamine agonists. The current focus to demonstrate a specific dyskinesia-ameliorating efficacy of A2A adenosine receptor antagonism in clinical trials is risky, since the presentation of dyskinesia varies on a day-to-day basis and is considerably influenced by peripheral l-dopa metabolism. The demonstration of an antidyskinetic effect may convince authorities, but this is far less relevant in clinical practice as patients generally better tolerate dyskinesia than other phenomena and dopaminergic side effects.

Gastrin stimulates renal dopamine production by increasing the renal tubular uptake of l-DOPA.

PubMed

Jiang, Xiaoliang; Zhang, Yanrong; Yang, Yu; Yang, Jian; Asico, Laureano D; Chen, Wei; Felder, Robin A; Armando, Ines; Jose, Pedro A; Yang, Zhiwei

2017-01-01

Gastrin is a peptide hormone that is involved in the regulation of sodium balance and blood pressure. Dopamine, which is also involved in the regulation of sodium balance and blood pressure, directly or indirectly interacts with other blood pressure-regulating hormones, including gastrin. This study aimed to determine the mechanisms of the interaction between gastrin and dopamine and tested the hypothesis that gastrin produced in the kidney increases renal dopamine production to keep blood pressure within the normal range. We show that in human and mouse renal proximal tubule cells (hRPTCs and mRPTCs, respectively), gastrin stimulates renal dopamine production by increasing the cellular uptake of l-DOPA via the l-type amino acid transporter (LAT) at the plasma membrane. The uptake of l-DOPA in RPTCs from C57Bl/6J mice is lower than in RPTCs from normotensive humans. l-DOPA uptake in renal cortical slices is also lower in salt-sensitive C57Bl/6J than in salt-resistant BALB/c mice. The deficient renal cortical uptake of l-DOPA in C57Bl/6J mice may be due to decreased LAT-1 activity that is related to its decreased expression at the plasma membrane, relative to BALB/c mice. We also show that renal-selective silencing of Gast by the renal subcapsular injection of Gast siRNA in BALB/c mice decreases renal dopamine production and increases blood pressure. These results highlight the importance of renal gastrin in stimulating renal dopamine production, which may give a new perspective in the prevention and treatment of hypertension. Copyright © 2017 the American Physiological Society.

Influence of O-methylated metabolite penetrating the blood-brain barrier to estimation of dopamine synthesis capacity in human L-[β-(11)C]DOPA PET.

PubMed

Matsubara, Keisuke; Ikoma, Yoko; Okada, Maki; Ibaraki, Masanobu; Suhara, Tetsuya; Kinoshita, Toshibumi; Ito, Hiroshi

2014-02-01

O-methyl metabolite (L-[β-(11)C]OMD) of (11)C-labeled L-3,4-dihydroxyphenylalanine (L-[β-(11)C]DOPA) can penetrate into brain tissue through the blood-brain barrier, and can complicate the estimation of dopamine synthesis capacity by positron emission tomography (PET) study with L-[β-(11)C]DOPA. We evaluated the impact of L-[β-(11)C]OMD on the estimation of the dopamine synthesis capacity in a human L-[β-(11)C]DOPA PET study. The metabolite correction with mathematical modeling of L-[β-(11)C]OMD kinetics in a reference region without decarboxylation and further metabolism, proposed by a previous [(18)F]FDOPA PET study, were implemented to estimate radioactivity of tissue L-[β-(11)C]OMD in 10 normal volunteers. The component of L-[β-(11)C]OMD in tissue time-activity curves (TACs) in 10 regions were subtracted by the estimated radioactivity of L-[β-(11)C]OMD. To evaluate the influence of omitting blood sampling and metabolite correction, relative dopamine synthesis rate (kref) was estimated by Gjedde-Patlak analysis with reference tissue input function, as well as the net dopamine synthesis rate (Ki) by Gjedde-Patlak analysis with the arterial input function and TAC without and with metabolite correction. Overestimation of Ki was observed without metabolite correction. However, the kref and Ki with metabolite correction were significantly correlated. These data suggest that the influence of L-[β-(11)C]OMD is minimal for the estimation of kref as dopamine synthesis capacity.

Supplementation of Nigella sativa fixed and essential oil mediates potassium bromate induced oxidative stress and multiple organ toxicity.

PubMed

Sultan, Muhammad Tauseef; Butt, Masood Sadiq; Ahmad, Rabia Shabeer; Pasha, Imran; Ahmad, Atif Nisar; Qayyum, Mir Muhammad Nasir

2012-01-01

The plants and their functional ingredients hold potential to cure various maladies and number of plants hold therapeutic potential. The present research was designed study the health promoting potential of black cumin (Nigella sativa) fixed oil (BCFO) and essential oil (BCEO) against oxidative stress with special reference to multiple organ toxicity. For the purpose, thirty rats (Strain: Sprague Dawley) were procured and divided into three groups (10 rats/group). The groups were fed on their respective diets i.e. D1 (control), D2 (BCFO @ 4.0%) and D3 (BCEO @ 0.30%) for a period of 56 days. Mild oxidative stress was induced with the help of potassium bromate injection @ 45 mg/Kg body weight. Furthermore, the levels of cardiac and liver enzymes were assayed. The results indicated that oxidative stress increased the activities of cardiac and liver enzymes. However, supplementation of BCFO and BCEO was effective in reducing the abnormal values of enzymes. Elevated levels of lactate dehydrogenase (LDH), CPK and CPK-MB were reduced from 456 to 231, 176 to 122 and 45 to 36mg/dL, respectively. Similarly, liver enzymes were also reduced. However, the results revealed that BCEO supplementation @ 0.30% is more effectual in ameliorating the multiple organ toxicity in oxidative stressed animal modelling. In the nutshell, it can be assumed that black cumin essential oil is more effective in reducing the extent of potassium bromate induced multiple organ toxicity (cardiac and liver enzymes imbalance) that will ultimately helpful in reducing the extent of myocardial and liver necrosis.

Growth Hormone Response after Administration of L-dopa, Clonidine, and Growth Hormone Releasing Hormone in Children with Down Syndrome.

ERIC Educational Resources Information Center

Pueschel, Seigfried M.

1993-01-01

This study of eight growth-retarded children with Down's syndrome (aged 1 to 6.5 years) found that administration of growth hormone was more effective than either L-dopa or clonidine. Results suggest that children with Down's syndrome have both anatomical and biochemical hypothalamic derangements resulting in decreased growth hormone secretion and…

Antioxidant Activity of Syringic Acid Prevents Oxidative Stress in l-arginine–Induced Acute Pancreatitis: An Experimental Study on Rats

PubMed Central

Cikman, Oztekin; Soylemez, Omer; Ozkan, Omer Faruk; Kiraz, Hasan Ali; Sayar, Ilyas; Ademoglu, Serkan; Taysi, Seyithan; Karaayvaz, Muammer

2015-01-01

The aim of this study was to investigate the possible protective role of antioxidant treatment with syringic acid (SA) on l-arginine–induced acute pancreatitis (AP) using biochemical and histopathologic approaches. A total of 30 rats were divided into 3 groups. The control group received normal saline intraperitoneally. The AP group was induced by 3.2 g/kg body weight l-arginine intraperitoneally, administered twice with an interval of 1 hour between administrations. The AP plus SA group, after having AP induced by 3.2 g/kg body weight l-arginine, was given SA (50 mg kg−1) in 2 parts within 24 hours. The rats were killed, and pancreatic tissue was removed and used in biochemical and histopathologic examinations. Compared with the control group, the mean pancreatic tissue total oxidant status level, oxidative stress index, and lipid hydroperoxide levels were significantly increased in the AP group, being 30.97 ± 7.13 (P < 0.05), 1.76 ± 0.34 (P < 0.0001), and 19.18 ± 4.91 (P < 0.01), respectively. However, mean total antioxidant status and sulfhydryl group levels were significantly decreased in the AP group compared with the control group, being 1.765 ± 0.21 (P < 0.0001) and 0.21 ± 0.04 (P < 0.0001), respectively. SA reduces oxidative stress markers and has antioxidant effects. It also augments antioxidant capacity in l-arginine–induced acute toxicity of pancreas in rats. PMID:26011211

Antioxidant Activity of Syringic Acid Prevents Oxidative Stress in l-arginine-Induced Acute Pancreatitis: An Experimental Study on Rats.

PubMed

Cikman, Oztekin; Soylemez, Omer; Ozkan, Omer Faruk; Kiraz, Hasan Ali; Sayar, Ilyas; Ademoglu, Serkan; Taysi, Seyithan; Karaayvaz, Muammer

2015-05-01

The aim of this study was to investigate the possible protective role of antioxidant treatment with syringic acid (SA) on l-arginine-induced acute pancreatitis (AP) using biochemical and histopathologic approaches. A total of 30 rats were divided into 3 groups. The control group received normal saline intraperitoneally. The AP group was induced by 3.2 g/kg body weight l-arginine intraperitoneally, administered twice with an interval of 1 hour between administrations. The AP plus SA group, after having AP induced by 3.2 g/kg body weight l-arginine, was given SA (50 mg kg(-1)) in 2 parts within 24 hours. The rats were killed, and pancreatic tissue was removed and used in biochemical and histopathologic examinations. Compared with the control group, the mean pancreatic tissue total oxidant status level, oxidative stress index, and lipid hydroperoxide levels were significantly increased in the AP group, being 30.97 ± 7.13 (P < 0.05), 1.76 ± 0.34 (P < 0.0001), and 19.18 ± 4.91 (P < 0.01), respectively. However, mean total antioxidant status and sulfhydryl group levels were significantly decreased in the AP group compared with the control group, being 1.765 ± 0.21 (P < 0.0001) and 0.21 ± 0.04 (P < 0.0001), respectively. SA reduces oxidative stress markers and has antioxidant effects. It also augments antioxidant capacity in l-arginine-induced acute toxicity of pancreas in rats.

Effect of Acetyl-L-Carnitine on Antioxidant Status, Lipid Peroxidation, and Oxidative Damage of Arsenic in Rat.

PubMed

Sepand, Mohammad Reza; Razavi-Azarkhiavi, Kamal; Omidi, Ameneh; Zirak, Mohammad Reza; Sabzevari, Samin; Kazemi, Ali Reza; Sabzevari, Omid

2016-05-01

Arsenic (As) is a widespread environmental contaminant present around the world in both organic and inorganic forms. Oxidative stress is postulated as the main mechanism for As-induced toxicity. This study was planned to examine the protective effect of acetyl-L-carnitine (ALC) on As-induced oxidative damage in male rats. Animals were randomly divided into four groups of control (saline), sodium arsenite (NaAsO2, 20 mg/kg), ALC (300 mg/kg), and NaAsO2 plus ALC. Animals were dosed orally for 28 successive days. Blood and tissue samples including kidney, brain, liver, heart, and lung were collected on the 28th day and evaluated for oxidative damage and histological changes. NaAsO2 exposure caused a significant lipid peroxidation as evidenced by elevation in thiobarbituric acid-reactive substances (TBARS). The activity of antioxidant enzymes such as glutathione-S-transferase (GST), catalase (CAT), superoxide dismutase (SOD), as well as sulfhydryl group content (SH group) was significantly suppressed in various organs following NaAsO2 treatment (P < 0.05). Furthermore, NaAsO2 administration increased serum values of alanine aminotransferase (ALT), aspartate aminotransferase (AST), lactate dehydrogenase (LDH), and bilirubin. Our findings revealed that co-administration of ALC and NaAsO2 significantly suppressed the oxidative damage induced by NaAsO2. Tissue histological studies have confirmed the biochemical findings and provided evidence for the beneficial role of ALC. The results concluded that ALC attenuated NaAsO2-induced toxicity, and this protective effect may result from the ability of ALC in maintaining oxidant-antioxidant balance.

Effects from fine muscle and cutaneous afferents on spinal locomotion in cats

PubMed Central

Kniffki, K.-D.; Schomburg, E. D.; Steffens, H.

1981-01-01

1. The effects of chemically activated fine muscle afferents (groups III and IV) and electrically activated cutaneous afferents on motoneuronal discharges were studied before and during fictive locomotion induced pharmacologically by i.v. administration of nialamide and l-DOPA in high spinal cats. Efferent activity was recorded simultaneously from nerve filaments to ipsi- and contralateral extensor and flexor muscles. In addition, intracellular recordings were made from lumbar α-motoneurones. 2. After nialamide but before treatment with l-DOPA, in some cases, transient locomotor-like discharges were induced by an increased activity in fine muscle afferents. The response pattern in nerves to both hind limbs could be different showing e.g. only transient alternating activity between knee flexor and extensor of one limb but not of the other one. 3. Treatment with l-DOPA did not always cause fictive locomotion. Often not all motoneurone pools showed rhythmic activity. In these cases stimulation of group III and IV muscle afferents usually caused transient periodic activity. In cases with apparent rhythmic activity, algesic stimulation of the gastrocnemius—soleus muscle caused an accentuation of the rhythm by a more abrupt transition from the active phase to the non-active interval. Again, the response patterns on both sides were not uniform in all cases. 4. A second type of response to activation of fine muscle afferents had a quite different character: the rhythmic activity was more or less completely overridden by a strong transient tonic hyperactivity or the rhythm was transiently blocked. These phenomena did not occur in the same way in all nerves. 5. Electrical stimulation of cutaneous nerves of the hind limb generally induced the same response pattern as chemical stimulation of the group III and IV muscle afferents. The effects varied depending on the stimulus strength and the nerve. 6. The results revealed that cutaneous and fine muscle afferents not only have similar functions in the reflex control of a limb but also in evocation and modulation of locomotion. Therefore, it is assumed that both types of afferents may serve together as a peripheral feed-back to the spinal locomotor centre. PMID:7320927

Preparation and characterization of a photocrosslinkable bioadhesive inspired by marine mussel.

PubMed

Xue, Jie; Wang, Tao; Nie, Jun; Yang, Dongzhi

2013-02-05

Synthetic adhesives inspired by marine mussel have attracted great attention due to its excellent water-resistance and good biocompatibility. In this study, a photocrosslinkable bioadhesive containing 3,4-Dihydroxy-l-phenylalanine (DOPA) functional group, which is central to curing mussel adhesive proteins, was prepared by ultraviolet (UV) irradiation of a new photocurable monomer ethylene glycol acrylate methacrylate-dopamine (EGAMA-DOPA) and a UV photocrosslinkable crosslinking agent poly(vinyl alcohol) (UV-PVA) derivative. The chemical structures of EGAMA-DOPA and UV-PVA were confirmed by Fourier Transform Infrared Reflection (FTIR) and (1)H NMR spectroscopy, respectively. The effects of UV light intensity, content of photoinitiator, EGAMA-DOPA and UV-PVA on the photopolymerization kinetics were studied, and the effects of the content of UV-PVA and temperature on the adhesive strength were also investigated. It was found that the higher UV light intensity, the faster polymerization rate and the higher final conversion that was the same as the trend of photoinitiator, EGAMA-DOPA and UV-PVA. And the adhesion strength measurement showed that, for gels with 30wt.% EGAMA-DOPA, the adhesion strength was obviously improved by about 150% with 3.0wt.% UV-PVA instead of pure PVA, and for gels containing 40wt.% EGAMA-DOPA, the adhesion strength sharply enhanced by 123% with increasing the content of UV-PVA from 1.0wt.% to 3.0wt.%. Cell attachment results showed good cell viability of L929 cell on the EGAMA-DOPA/UV-PVA adhesive gels. Thanks to its strong adhesion strength and good biocompatibility, such photocrosslinkable gels could be applied to the areas of biomedical field. Copyright © 2012 Elsevier B.V. All rights reserved.

Convection-enhanced delivery of AAV vector in parkinsonian monkeys; in vivo detection of gene expression and restoration of dopaminergic function using pro-drug approach.

PubMed

Bankiewicz, K S; Eberling, J L; Kohutnicka, M; Jagust, W; Pivirotto, P; Bringas, J; Cunningham, J; Budinger, T F; Harvey-White, J

2000-07-01

Using an approach that combines gene therapy with aromatic l-amino acid decarboxylase (AADC) gene and a pro-drug (l-dopa), dopamine, the neurotransmitter involved in Parkinson's disease, can be synthesized and regulated. Striatal neurons infected with the AADC gene by an adeno-associated viral vector can convert peripheral l-dopa to dopamine and may therefore provide a buffer for unmetabolized l-dopa. This approach to treating Parkinson's disease may reduce the need for l-dopa/carbidopa, thus providing a better clinical response with fewer side effects. In addition, the imbalance in dopamine production between the nigrostriatal and mesolimbic dopaminergic systems can be corrected by using AADC gene delivery to the striatum. We have also demonstrated that a fundamental obstacle in the gene therapy approach to the central nervous system, i.e., the ability to deliver viral vectors in sufficient quantities to the whole brain, can be overcome by using convection-enhanced delivery. Finally, this study demonstrates that positron emission tomography and the AADC tracer, 6-[(18)F]fluoro-l-m-tyrosine, can be used to monitor gene therapy in vivo. Our therapeutic approach has the potential to restore dopamine production, even late in the disease process, at levels that can be maintained during continued nigrostriatal degeneration. Copyright 2000 Academic Press.

Polyamines Confer Salt Tolerance in Mung Bean (Vigna radiata L.) by Reducing Sodium Uptake, Improving Nutrient Homeostasis, Antioxidant Defense, and Methylglyoxal Detoxification Systems

PubMed Central

Nahar, Kamrun; Hasanuzzaman, Mirza; Rahman, Anisur; Alam, Md. Mahabub; Mahmud, Jubayer-Al; Suzuki, Toshisada; Fujita, Masayuki

2016-01-01

The physiological roles of PAs (putrescine, spermidine, and spermine) were investigated for their ability to confer salt tolerance (200 mM NaCl, 48 h) in mung bean seedlings (Vigna radiata L. cv. BARI Mung-2). Salt stress resulted in Na toxicity, decreased K, Ca, Mg, and Zn contents in roots and shoots, and disrupted antioxidant defense system which caused oxidative damage as indicated by increased lipid peroxidation, H2O2 content, O2•- generation rate, and lipoxygenase activity. Salinity-induced methylglyoxal (MG) toxicity was also clearly evident. Salinity decreased leaf chlorophyll (chl) and relative water content (RWC). Supplementation of salt affected seedlings with exogenous PAs enhanced the contents of glutathione and ascorbate, increased activities of antioxidant enzymes (dehydroascorbate reductase, glutathione reductase, catalase, and glutathione peroxidase) and glyoxalase enzyme (glyoxalase II), which reduced salt-induced oxidative stress and MG toxicity, respectively. Exogenous PAs reduced cellular Na content and maintained nutrient homeostasis and modulated endogenous PAs levels in salt affected mung bean seedlings. The overall salt tolerance was reflected through improved tissue water and chl content, and better seedling growth. PMID:27516763

Caffeine - rich infusion from Cola nitida (kola nut) inhibits major carbohydrate catabolic enzymes; abates redox imbalance; and modulates oxidative dysregulated metabolic pathways and metabolites in Fe2+-induced hepatic toxicity.

PubMed

Erukainure, Ochuko L; Oyebode, Olajumoke A; Sokhela, Mxolisi K; Koorbanally, Neil A; Islam, Md Shahidul

2017-12-01

The antioxidative and antidiabetic effects and toxicity of caffeine-rich infusion of Cola nitida were investigated using in vitro, ex vivo and in silico models. C. nitida was infused in boiling water and allowed to cool before concentrating at <50°C. HPLC analysis of the infusion revealed a caffeine content of 80.08%. The infusion showed potent in vitro antioxidant activity by significantly (p<0.05) scavenging 2,2'-diphenyl-1-picrylhydrazyl (DPPH). It significantly (p<0.05) inhibited α-glucosidase and α-amylase activities. Treatment of Fe 2+ induced oxidative hepatic tissues with the infusion led to increase Superoxide Dismutase (SOD) and catalase activities, and glutathione (GSH) level as well as decreased malondialdehyde (MDA) level. FTIR spectroscopy of hepatic metabolite revealed restoration of oxidative-induced depleted functional groups by the infusion. LC-MS analysis of the metabolite also revealed restoration of most depleted metabolites with concomitant generation of 4-O-Methylgallic, (-)-Epicatechin sulfate, L-Arginine, L-tyrosine, Citric acid and Decanoic acid in infusion-treated tissues. Pathway analysis of the identified metabolites revealed the presence of 21 metabolic pathways involved in normal hepatic tissues, 12 in oxidative injured tissues and 17 in the treated tissues. Treatment with the infusion restored 4 metabolic pathways common to the normal tissue and further activated 4 additional pathways. Prediction of oral toxicity of caffeine showed it to belong to class 3, with a LD 50 of 127mg/kg. Its toxicity target was predicted as Adenosine Receptor A2a. It was also predicted to be an inhibitor of CYP1A2. These results suggest the antioxidative and antidiabetic properties of C. nitida infusion, with caffeine as the major constituent. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Pre-treatment with melatonin decreases abamectin induced toxicity in a nocturnal insect Spodoptera litura (Lepidoptera: Noctuidae).

PubMed

Subala, Subramanian P; Zubero, Eduardo E; Alatorre-Jimenez, Moises A; Shivakumar, Muthugounder S

2017-12-01

Oxidative stress is an important component of the mechanism of pesticide toxicity. The aim of the present study was to investigate the time-dependent melatonin effects against abamectin-induced oxidative stress in a S.litura model. Larvae were divided into 5 different groups; (1) control group,(2) Melatonin group (4.3×10 -5 M/100ml diet), (3) Abamectin group 1.5ml/L, (4) Pre-melatonin treated group (PM) (4.3×10 -5 M/100ml diet) before abamectin exposure 1.5ml/L, (5) Post-melatonin treated group (TM) after abamectin exposure. Melatonin was supplemented via artificial diet in PM and TM animals during 24h. Midgut, fatbody, and hemolymph, were collected for the analysis of oxidative stress markers (Total ROS, GSH, nitrite, TBARS, LPO), antioxidant enzyme levels (SOD, GST, CAT, POX, APOX) in fifth instar larvae. Midgut damage was examined by using morphological analysis. Our results observed that ABA group showed significant changes (p<0.001) in the ROS and carbonyl content in midgut. The increase of antioxidant enzyme levels (SOD, CAT, POX, and APOX) in midgut was led by the continuous free radical scavenger cascade of melatonin. Significant (p<0.01) increases in CAT and APOX levels were seen in the fatbody of PM and TM treated insects. In conclusion, the results of the study revealed that abamectin toxicity generates oxidative stress in the insect, while pre-melatonin treatment reduces this damage due to its antioxidant properties, especially POX levels in midgut, fatbody, and hemolymph. Therefore, indoleamine can play a vital role curtailing the abamectin toxicity in time dependent manner in S.litura. Copyright © 2017 Elsevier B.V. All rights reserved.

Estimation of in vitro activity of tuberoinfundibular dopaminergic neurons by measurement of DOPA synthesis in the median eminence of hypothalamic slices.

PubMed

Arita, J; Kimura, F

1984-12-01

A new method for estimation of in vitro neurosecretory activity of tuberoinfundibular dopaminergic (TIDA) neurons was developed by measuring the rate of synthesis of dihydroxyphenylalanine (DOPA) in the median eminence of hypothalamic slices. Sagittal hypothalamic slices of ovariectomized rats were incubated in a medium containing 3-hydroxybenzylhydrazine (NSD 1015), an inhibitor of DOPA decarboxylase. DOPA accumulated in the median eminence following incubation with NSD 1015 was determined by high-performance liquid chromatography with electro-chemical detection. The amount of DOPA accumulated in vitro in the median eminence was maximal in a medium containing 10 mM NSD 1015 and linear up to 120 min at 37 degrees C. Increasing the concentration of tyrosine in medium stimulated the synthesis of DOPA in the median eminence. The synthesis of DOPA was blocked by 1 mM alpha-methyltyrosine, an inhibitor of tyrosine hydroxylase. The rate of in vitro synthesis of DOPA in the median eminence was 33% of that of in vivo synthesis. Incubation in a medium containing 50 mM K+ to depolarize neurons caused a 2.4-fold increase in DOPA synthesis in the median eminence. The high K+-induced increase in DOPA synthesis was blocked by omission of Ca2+ and addition of 1 mM EGTA into the medium, suggesting Ca2+ dependency of depolarization-activated DOPA synthesis. These results indicate that this in vitro assay is a useful means to study the regulatory mechanisms of TIDA neurons.

Effect of Aronia melanocarpa fruit juice on amiodarone-induced pneumotoxicity in rats

PubMed Central

Valcheva-Kuzmanova, Stefka; Stavreva, Galya; Dancheva, Violeta; Terziev, Ljudmil; Atanasova, Milena; Stoyanova, Angelina; Dimitrova, Anelia; Shopova, Veneta

2014-01-01

Background: The fruits of Aronia melanocarpa (Michx.) Elliot is extremely rich in biologically active polyphenols. Objective: We studied the protective effect of A. melanocarpa fruit juice (AMFJ) in a model of amiodarone (AD)-induced pneumotoxicity in rats. Materials and Methods: AD was instilled intratracheally on days 0 and 2 (6.25 mg/kg). AMFJ (5 mL/kg and 10 mL/kg) was given orally from day 1 to days 2, 4, 9, and 10 to rats, which were sacrificed respectively on days 3, 5, 10, and 28 when biochemical, cytological, and immunological assays were performed. Results: AMFJ antagonized AD-induced increase of the lung weight coefficient. In bronchoalveolar lavage fluid, AD increased significantly the protein content, total cell count, polymorphonuclear cells, lymphocytes and the activity of lactate dehydrogenase, acid phosphatase and alkaline phosphatase on days 3 and 5. In AMFJ-treated rats these indices of direct toxic damage did not differ significantly from the control values. In lung tissue, AD induced oxidative stress measured by malondialdehyde content and fibrosis assessed by the hydroxyproline level. AMFJ prevented these effects of AD. In rat serum, AD caused a significant elevation of interleukin IL-6 on days 3 and 5, and a decrease of IL-10 on day 3. In AMFJ-treated rats, these indices of inflammation had values that did not differ significantly from the control ones. Conclusion: AMFJ could have a protective effect against AD-induced pulmonary toxicity as evidenced by the reduced signs of AD-induced direct toxic damage, oxidative stress, inflammation, and fibrosis. PMID:24914278

Influence of basal ganglia on upper limb locomotor synergies. Evidence from deep brain stimulation and L-DOPA treatment in Parkinson's disease.

PubMed

Crenna, P; Carpinella, I; Lopiano, L; Marzegan, A; Rabuffetti, M; Rizzone, M; Lanotte, M; Ferrarin, M

2008-12-01

Clinical evidence of impaired arm swing while walking in patients with Parkinson's disease suggests that basal ganglia and related systems play an important part in the control of upper limb locomotor automatism. To gain more information on this supraspinal influence, we measured arm and thigh kinematics during walking in 10 Parkinson's disease patients, under four conditions: (i) baseline (no treatment), (ii) therapeutic stimulation of the subthalamic nucleus (STN), (iii)L-DOPA medication and (iv) combined STN stimulation and L-DOPA. Ten age-matched controls provided reference data. Under baseline conditions the range of patients' arm motion was severely restricted, with no correlation with the excursion of the thigh. In addition, the arm swing was abnormally coupled in time with oscillation of the ipsilateral thigh. STN stimulation significantly increased the gait speed and improved the spatio-temporal parameters of arm and thigh motion. The kinematic changes as a function of gait speed changes, however, were significantly smaller for the upper than the lower limb, in contrast to healthy controls. Arm motion was also less responsive after L-DOPA. Simultaneous deep brain stimulation and L-DOPA had additive effects on thigh motion, but not on arm motion and arm-thigh coupling. The evidence that locomotor automatisms of the upper and lower limbs display uncorrelated impairment upon dysfunction of the basal ganglia, as well as different susceptibility to electrophysiological and pharmacological interventions, points to the presence of heterogeneously distributed, possibly partially independent, supraspinal control channels, whereby STN and dopaminergic systems have relatively weaker influence on the executive structures involved in the arm swing and preferential action on those for lower limb movements. These findings might be considered in the light of phylogenetic changes in supraspinal control of limb motion related to primate bipedalism.

Efficacy and safety of extended- versus immediate-release pramipexole in Japanese patients with advanced and L-dopa-undertreated Parkinson disease: a double-blind, randomized trial.

PubMed

Mizuno, Yoshikuni; Yamamoto, Mitsutoshi; Kuno, Sadako; Hasegawa, Kazuko; Hattori, Nobutaka; Kagimura, Tatsuro; Sarashina, Akiko; Rascol, Olivier; Schapira, Anthony H V; Barone, Paolo; Hauser, Robert A; Poewe, Werner

2012-01-01

To compare the efficacy, safety, tolerability, and trough plasma levels of pramipexole extended-release (ER) and pramipexole immediate-release (IR), and to assess the effects of overnight switching from an IR to an ER formulation, in L-dopa-treated patients with Parkinson disease (PD). After a 1- to 4-week screening/enrollment, 112 patients who had exhibited L-dopa-related problems or were receiving suboptimal L-dopa dosage were randomized in double-blind, double-dummy, 1:1 fashion to pramipexole ER once daily or pramipexole IR 2 to 3 times daily for 12 weeks, both titrated to a maximum daily dose of 4.5 mg. Successful completers of double-blind treatment were switched to open-label pramipexole ER, beginning with a 4-week dose-adjustment phase. Among the double-blind treatment patients (n = 56 in each group), Unified Parkinson's Disease Rating Scale Parts II+III total scores decreased significantly from baseline and to a similar degree with pramipexole ER and IR formulations. In each group, 47 double-blind patients (83.9%) reported adverse events (AEs), requiring withdrawal of 3 ER patients (5.4%) and 2 IR patients (3.6%). Trough plasma levels at steady state (at the same doses and dose-normalized concentrations) were also similar with both formulations. Among open-label treatment patients (n = 53 from IR to ER), 83% were successfully switched (no worsening of PD symptoms) to pramipexole ER. In L-dopa-treated patients, pramipexole ER and pramipexole IR demonstrated similar efficacy, safety, tolerability, and trough plasma levels. Patients can be safely switched overnight from pramipexole IR to pramipexole ER with no impact on efficacy.

Speech and Voice Response to a Levodopa Challenge in Late-Stage Parkinson's Disease.

PubMed

Fabbri, Margherita; Guimarães, Isabel; Cardoso, Rita; Coelho, Miguel; Guedes, Leonor Correia; Rosa, Mario M; Godinho, Catarina; Abreu, Daisy; Gonçalves, Nilza; Antonini, Angelo; Ferreira, Joaquim J

2017-01-01

Parkinson's disease (PD) patients are affected by hypokinetic dysarthria, characterized by hypophonia and dysprosody, which worsens with disease progression. Levodopa's (l-dopa) effect on quality of speech is inconclusive; no data are currently available for late-stage PD (LSPD). To assess the modifications of speech and voice in LSPD following an acute l-dopa challenge. LSPD patients [Schwab and England score <50/Hoehn and Yahr stage >3 (MED ON)] performed several vocal tasks before and after an acute l-dopa challenge. The following was assessed: respiratory support for speech, voice quality, stability and variability, speech rate, and motor performance (MDS-UPDRS-III). All voice samples were recorded and analyzed by a speech and language therapist blinded to patients' therapeutic condition using Praat 5.1 software. 24/27 (14 men) LSPD patients succeeded in performing voice tasks. Median age and disease duration of patients were 79 [IQR: 71.5-81.7] and 14.5 [IQR: 11-15.7] years, respectively. In MED OFF, respiratory breath support and pitch break time of LSPD patients were worse than the normative values of non-parkinsonian. A correlation was found between disease duration and voice quality ( R  = 0.51; p  = 0.013) and speech rate ( R  = -0.55; p  = 0.008). l-Dopa significantly improved MDS-UPDRS-III score (20%), with no effect on speech as assessed by clinical rating scales and automated analysis. Speech is severely affected in LSPD. Although l-dopa had some effect on motor performance, including axial signs, speech and voice did not improve. The applicability and efficacy of non-pharmacological treatment for speech impairment should be considered for speech disorder management in PD.

Dopamine and temporal attention: An attentional blink study in Parkinson's disease patients on and off medication.

PubMed

Slagter, H A; van Wouwe, N C; Kanoff, K; Grasman, R P P P; Claassen, D O; van den Wildenberg, W P M; Wylie, S A

2016-10-01

The current study aimed to shed more light on the role of dopamine in temporal attention. To this end, we pharmacologically manipulated dopamine levels in a large sample of Parkinson's disease patients (n=63) while they performed an attentional blink (AB) task in which they had to identify two targets (T1 and T2) presented in close temporal proximity among distractors. We specifically examined 1) differences in the magnitude of the AB between unmedicated Parkinson patients, who have depleted levels of striatal dopamine, and healthy controls, and 2) effects of two dopaminergic medications (l-DOPA and dopamine agonists) on the AB in the Parkinson patients at the group level and as a function of individual baseline performance. In line with the notion that relatively low levels of striatal dopamine may impair target detection in general, Parkinson patients OFF medications displayed overall poor target perception compared to healthy controls. Moreover, as predicted, effects of dopaminergic medication on AB performance critically depended on individual baseline AB size, although this effect was only observed for l-DOPA. l-DOPA generally decreased the size of the AB in patients with a large baseline AB (i.e., OFF medications), while l-DOPA generally increased the AB in patients with a small baseline AB. These findings may support a role for dopamine in the AB and temporal attention, more generally and corroborate the notion that there is an optimum dopamine level for cognitive function. They also emphasize the need for more studies that examine the separate effects of DA agonists and l-DOPA on cognitive functioning. Copyright © 2016 Elsevier Ltd. All rights reserved.

Coal and tire burning mixtures containing ultrafine and nanoparticulate materials induce oxidative stress and inflammatory activation in macrophages.

PubMed

Gasparotto, Juciano; Somensi, Nauana; Caregnato, Fernanda F; Rabelo, Thallita K; DaBoit, Kátia; Oliveira, Marcos L S; Moreira, José C F; Gelain, Daniel P

2013-10-01

Ultra-fine and nano-particulate materials resulting from mixtures of coal and non-coal fuels combustion for power generation release to the air components with toxic potential. We evaluated toxicological and inflammatory effects at cellular level that could be induced by ultrafine/nanoparticles-containing ashes from burning mixtures of coal and tires from an American power plant. Coal fly ashes (CFA) samples from the combustion of high-S coal and tire-derived fuel, the latter about 2-3% of the total fuel feed, in a 100-MW cyclone utility boiler, were suspended in the cell culture medium of RAW 264.7 macrophages. Cell viability, assessed by MTT reduction, SRB incorporation and contrast-phase microscopy analysis demonstrated that CFA did not induce acute toxicity. However, CFA at 1mg/mL induced an increase of approximately 338% in intracellular TNF-α, while release of this proinflammatory cytokine was increased by 1.6-fold. The expression of the inflammatory mediator CD40 receptor was enhanced by 2-fold, the receptor for advanced glycation endproducts (RAGE) had a 5.7-fold increase and the stress response protein HSP70 was increased nearly 12-fold by CFA at 1mg/mL. Although CFA did not induce cell death, parameters of oxidative stress and reactive species production were found to be altered at several degrees, such as nitrite accumulation (22% increase), DCFH oxidation (3.5-fold increase), catalase (5-fold increase) and superoxide dismutase (35% inhibition) activities, lipoperoxidation (4.2 fold-increase) and sulfhydryl oxidation (40% decrease in free SH groups). The present results suggest that CFA containing ultra-fine and nano-particulate materials from coal and tire combustion may induce sub-chronic cell damage, as they alter inflammatory and oxidative stress parameters at the molecular and cellular levels, but do not induce acute cell death. © 2013.

The zerovalent iron nanoparticle causes higher developmental toxicity than its oxidation products in early life stages of medaka fish.

PubMed

Chen, Pei-Jen; Wu, Wan-Lin; Wu, Kevin Chia-Wen

2013-08-01

Nanoscale zerovalent iron (nZVI)-mediated oxidation reaction is increasingly being used for enhanced treatment of water or wastewater processes; however, the fate and eco-toxicological effects of nZVI in the surface aquifer remain unclear. We investigated bioaccumulation and lethal-to-sublethal toxic effects on early life development of Japanese medaka (Oryzias latipes) with 7-day exposure to 25-200 mg/L of well-characterized solutions containing carboxymethyl cellulose (CMC)-stabilized nZVI (CMC-nZVI), nanoscale iron oxide (nFe3O4) or ferrous ion [Fe(II)aq]. The CMC-nZVI solution had the greatest acute mortality and developmental toxic effects in embryos, with lesser and the least effects with Fe(II)aq and nFe3O4. The toxicity of CMC-nZVI was ascribed to its high reactivity in the oxygenic solution, which led to a combination of hypoxia and production of reactive oxygen species (ROS) and Fe(II)aq. nFe3O4 (50-100 mg/L) was more bioavailable to embryos and bioaccmulative in hatchlings than suspended CMC-nZVI. The antioxidant balance was differentially altered by induced intracellular ROS in hatchlings with all 3 iron species. We revealed causal toxic effects of nZVI and its oxidized products in early life stages of medaka fish using different organizational levels of biomarker assays. The toxicity results implicate a potential eco-toxicological impact of nZVI on the aquatic environment. Copyright © 2013 Elsevier Ltd. All rights reserved.

Potential of Lactobacillus plantarum CCFM639 in Protecting against Aluminum Toxicity Mediated by Intestinal Barrier Function and Oxidative Stress

PubMed Central

Yu, Leilei; Zhai, Qixiao; Tian, Fengwei; Liu, Xiaoming; Wang, Gang; Zhao, Jianxin; Zhang, Hao; Narbad, Arjan; Chen, Wei

2016-01-01

Aluminum (Al) is a ubiquitous metal that can seriously harm the health of animals and humans. In our previous study, we demonstrated that Lactobacillus plantarum CCFM639 can decrease Al burden in the tissues of mice by inhibiting intestinal Al absorption. The main aim of the present research was to investigate whether the protection by the strain is also associated with enhancement of the intestinal barrier, alleviation of oxidative stress and modulation of the inflammatory response. In an in vitro cell model, two protection modes (intervention and therapy) were examined and the results indicated that L. plantarum CCFM639 alleviated Al-induced cytotoxicity. In a mouse model, L. plantarum CCFM639 treatment was found to significantly alleviate oxidative stress in the intestinal tract, regulate the function of the intestinal mucosal immune system, restore the integrity of tight junction proteins and maintain intestinal permeability. These results suggest that in addition to Al sequestration, L. plantarum CCFM639 can also inhibit Al absorption by protecting the intestinal barrier, alleviating Al-induced oxidative stress and inflammatory response. Therefore, L. plantarum CCFM639 has the potential to be a dietary supplement ingredient that provides protection against Al-induced gut injury. PMID:27918411

Chlorogenic and Caftaric Acids in Liver Toxicity and Oxidative Stress Induced by Methamphetamine

PubMed Central

Koriem, Khaled M. M.; Soliman, Rowan E.

2014-01-01

Methamphetamine intoxication can cause acute hepatic failure. Chlorogenic and caftaric acids are the major dietary polyphenols present in various foods. The aim of this study was to evaluate the protective role of chlorogenic and caftaric acids in liver toxicity and oxidative stress induced by methamphetamine in rats. Thirty-two male albino rats were divided into 4 equal groups. Group 1, which was control group, was injected (i.p) with saline (1 mL/kg) twice a day over seven-day period. Groups 2, 3, and 4 were injected (i.p) with methamphetamine (10 mg/kg) twice a day over seven-day period, where groups 3 and 4 were injected (i.p) with 60 mg/kg chlorogenic acid and 40 mg/kg caftaric acid, respectively, one day before methamphetamine injections. Methamphetamine increased serum aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, bilirubin, cholesterol, low-density lipoprotein, and triglycerides. Also, malondialdehyde in serum, liver, and brain and plasma and liver nitric oxide levels were increased while methamphetamine induced a significant decrease in serum total protein, albumin, globulin, albumin/globulin ratio, brain serotonin, norepinephrine and dopamine, blood and liver superoxide dismutase, and glutathione peroxidase levels. Chlorogenic and caftaric acids prior to methamphetamine injections restored all the above parameters to normal values. In conclusion, chlorogenic and caftaric acids before methamphetamine injections prevented liver toxicity and oxidative stress where chlorogenic acid was more effective. PMID:25136360

Biochemical responses of duckweed (Spirodela polyrhiza) to zinc oxide nanoparticles.

PubMed

Hu, Changwei; Liu, Yimeng; Li, Xiuling; Li, Mei

2013-05-01

The present study focuses on the biochemical responses of the aquatic plant duckweed (Spirodela polyrhiza L.) to zinc oxide nanoparticles (ZnO NPs). Laboratory experiments were performed using a 96-h exposure to 25-nm NPs at different concentrations (0, 1, 10, and 50 mg/L). Growth, chlorophyll-to-pheophytin ratio (D665/D665a) and activities of superoxide dismutase, catalase, peroxidase (POD), and Na(+), K(+)-ATPase were determined as indices to evaluate the toxicity of NPs in the culture medium. To understand better whether the Zn(2+) released from the ZnO NP suspensions plays a key role in toxicity of the NPs, we investigated particle aggregation and dissolution in the medium. Furthermore, two exposure treatments for the group with the highest concentration (50 mg/L) were performed: (1) exposure for the full 96 h (50a treatment) and (2) the medium being replaced with culture medium without NPs after 12 h (50b treatment). Our results indicate that ZnO NPs induced adverse effects in S. polyrhiza at the concentration of 50 mg/L in the culture medium. Zn(2+) released from the NPs might be the main source of its toxicity to this species.

Nitric oxide is a mediator of methamphetamine (METH)-induced neurotoxicity. In vitro evidence from primary cultures of mesencephalic cells.

PubMed

Sheng, P; Cerruti, C; Ali, S; Cadet, J L

1996-10-31

METH is a monoaminergic toxic that destroys dopamine terminals in vivo. Oxidative mechanisms associated with DA metabolism are thought to play an important role in its toxic effects. These ideas were supported by the demonstration that CuZn-superoxide dismutase (CuZnSOD) transgenic mice were protected against the toxic effects of the drug. In the present study, we sought to determine if nitric oxide (NO) production was also involved in METH-induced neurotoxicity using primary cultures obtained from fetal rat mesencephalon. METH caused dose- and time-dependent cell death in vitro. Blockade of nitric oxide (NO) formation with several nitric oxide (NO) synthase blockers attenuated METH-mediated toxicity. Moreover, inhibition of ADP-ribosylation with nicotinamide and benzamide also provided protection against the toxicity of the drug. These results, together with our previous results in transgenic mice, support a role for free radicals in METH-induced toxic effects.

The thyroid endocrine disruptor perchlorate affects reproduction, growth, and survival of mosquitofish.

PubMed

Park, June-Woo; Rinchard, Jacques; Liu, Fujun; Anderson, Todd A; Kendall, Ronald J; Theodorakis, Christopher W

2006-03-01

The perchlorate anion--an oxidizer found in rockets, missiles, some ammunition, flares, airbags, and fireworks--occurs as a contaminant in ground and surface water in many parts of the United States. Its toxic effects include inhibition of thyroid hormone synthesis. To investigate its chronic toxicity, mosquitofish (Gambusia holbrooki) adults and fry were exposed to aqueous sodium perchlorate at 1, 10, and 100mg/L, and growth and reproductive performance (fecundity, eggs/embryos mass, and gonadosomatic index [GSI]) were determined. Five-day acute toxicity tests were also performed. Perchlorate had a stimulatory effect on fecundity, GSI, and egg/embryo mass, at least for some treatments. The LC50 of sodium perchlorate was 404 mg/L. Growth was enhanced at 1mg/L but inhibited at 10mg/L. These results suggest that, at environmentally relevant concentrations, perchlorate does not induce acutely toxic effects but may have mild stimulatory or hormetic effects on fitness parameters in this species.

An in vitro metabolomics approach to identify hepatotoxicity biomarkers in human L02 liver cells treated with pekinenal, a natural compound.

PubMed

Shi, Jiexia; Zhou, Jing; Ma, Hongyue; Guo, Hongbo; Ni, Zuyao; Duan, Jin'ao; Tao, Weiwei; Qian, Dawei

2016-02-01

An in vitro cell metabolomics study was performed on human L02 liver cells to investigate the toxic biomarkers of pekinenal from the herb Euphorbia pekinensis Rupr. Pekinenal significantly induced L02 cell damage, which was characterised by necrosis and apoptosis. Metabolomics combined with data pattern recognition showed that pekinenal significantly altered the profiles of more than 1299 endogenous metabolites with variable importance in the projection (VIP) > 1. Further, screening correlation coefficients between the intensities of all metabolites and the extent of L02 cell damage (MTT) identified 12 biomarker hits: ten were downregulated and two were upregulated. Among these hits, LysoPC(18:1(9Z)/(11Z)), PC(22:0/15:0) and PC(20:1(11Z)/14:1(9Z)) were disordered, implying the initiation of inflammation and cell damage. Several fatty acids (FAs) (3-hydroxytetradecanedioic acid, pivaloylcarnitine and eicosapentaenoyl ethanolamide) decreased due to fatty acid oxidation. Dihydroceramide and Cer(d18:0/14:0) were also altered and are associated with apoptosis. Additional examination of the levels of intracellular reactive oxygen species (ROS) and two eicosanoids (PGE2, PGF2α) in the cell supernatant confirmed the fatty acid oxidation and arachidonic acid metabolism pathways, respectively. In summary, cell metabolomics is a highly efficient approach for identifying toxic biomarkers and helping understand toxicity mechanisms and predict herb-induced liver injury.

New tyrosinase inhibitory decapeptide: Molecular insights into the role of tyrosine residues.

PubMed

Ochiai, Akihito; Tanaka, Seiya; Imai, Yuta; Yoshida, Hisashi; Kanaoka, Takumi; Tanaka, Takaaki; Taniguchi, Masayuki

2016-06-01

Tyrosinase, a rate-limiting enzyme in melanin biosynthesis, catalyzes the hydroxylation of l-tyrosine to 3,4-dihydroxy-l-phenylalanine (l-dopa) (monophenolase reaction) and the subsequent oxidation of l-dopa to l-dopaquinone (diphenolase reaction). Thus, tyrosinase inhibitors have been proposed as skin-lightening agents; however, many of the existing inhibitors cannot be widely used in the cosmetic industry due to their high cytotoxicity and instability. On the other hand, some tyrosinase inhibitory peptides have been reported as safe. In this study, we found that the peptide TH10, which has a similar sequence to the characterized inhibitory peptide P4, strongly inhibits the monophenolase reaction with a half-maximal inhibitory concentration of 102 μM. Seven of the ten amino acid residues in TH10 were identical to P4; however, TH10 possesses one N-terminal tyrosine, whereas P4 contains three tyrosine residues located at its N-terminus, center, and C-terminus. Subsequent analysis using sequence-shuffled variants indicated that the tyrosine residues located at the N-terminus and center of P4 have little to no contribution to its inhibitory activity. Furthermore, docking simulation analysis of these peptides with mushroom tyrosinase demonstrated that the active tyrosine residue was positioned close to copper ions, suggesting that TH10 and P4 bind to tyrosinase as a substrate analogue. Copyright © 2015 The Society for Biotechnology, Japan. Published by Elsevier B.V. All rights reserved.

Microplate based optical biosensor for L-Dopa using tyrosinase from Amorphophallus campanulatus.

PubMed

Saini, Amardeep Singh; Kumar, Jitendra; Melo, Jose Savio

2014-11-07

Developing a biosensor which is capable of simultaneously monitoring l-Dopa levels in multiple samples besides requiring small reaction volume is of great value. The present study describes the detection of l-Dopa using tyrosinase enzyme extracted from Amorphophallus campanulatus and immobilized on the surface of the microplate wells. Among the different approaches used for immobilizing tyrosinase onto the microplate wells, glutaraldehyde treatment was found to be most effective. Besides enzyme activity, ESEM-EDS (environmental scanning electron microscope-energy dispersive system) and Atomic Force Microscopy (AFM) were also carried out to confirm the immobilization of tyrosinase enzyme onto the microplate well surface. This immobilized biocomponent was then integrated with an optical transducer for l-Dopa detection and it showed good reproducibility. The sensing property of the system was studied by measuring the initial rate of dopachrome formation at 475 nm. The calibration plot gave a linear range of detection from 10-1000 μM and the detection limit was calculated to be 3 μM. The immobilized biocomponent was stable for 41 days and was reused up to nine times. Spiked samples (blood plasma) were also analyzed using this biocomponent. This microplate based biosensor thus provides a convenient system for detection of multiple samples in a single run. Copyright © 2014 Elsevier B.V. All rights reserved.

Oxidative stress-induced autophagy: Role in pulmonary toxicity

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

Malaviya, Rama; Laskin, Jeffrey D.; Laskin, Debra L., E-mail: laskin@eohsi.rutgers.edu

2014-03-01

Autophagy is an evolutionarily conserved catabolic process important in regulating the turnover of essential proteins and in elimination of damaged organelles and protein aggregates. Autophagy is observed in the lung in response to oxidative stress generated as a consequence of exposure to environmental toxicants. Whether autophagy plays role in promoting cell survival or cytotoxicity is unclear. In this article recent findings on oxidative stress-induced autophagy in the lung are reviewed; potential mechanisms initiating autophagy are also discussed. A better understanding of autophagy and its role in pulmonary toxicity may lead to the development of new strategies to treat lung injurymore » associated with oxidative stress. - Highlights: • Exposure to pulmonary toxicants is associated with oxidative stress. • Oxidative stress is known to induce autophagy. • Autophagy is upregulated in the lung following exposure to pulmonary toxicants. • Autophagy may be protective or pathogenic.« less

Surface interactions affect the toxicity of engineered metal oxide nanoparticles toward Paramecium.

PubMed

Li, Kungang; Chen, Ying; Zhang, Wen; Pu, Zhichao; Jiang, Lin; Chen, Yongsheng

2012-08-20

To better understand the potential impacts of engineered metal oxide nanoparticles (NPs) in the ecosystem, we investigated the acute toxicity of seven different types of engineered metal oxide NPs against Paramecium multimicronucleatum, a ciliated protozoan, using the 48 h LC(50) (lethal concentration, 50%) test. Our results showed that the 48 h LC(50) values of these NPs to Paramecium ranged from 0.81 (Fe(2)O(3) NPs) to 9269 mg/L (Al(2)O(3) NPs); their toxicity to Paramecium increased as follows: Al(2)O(3) < TiO(2) < CeO(2) < ZnO < SiO(2) < CuO < Fe(2)O(3) NPs. On the basis of the Derjaguin-Landau-Verwey-Overbeek (DLVO) theory, interfacial interactions between NPs and cell membrane were evaluated, and the magnitude of interaction energy barrier correlated well with the 48 h LC(50) data of NPs to Paramecium; this implies that metal oxide NPs with strong association with the cell surface might induce more severe cytotoxicity in unicellular organisms.

Species-specific sensitivity to selenium-induced impairment of cortisol secretion in adrenocortical cells of rainbow trout (Oncorhynchus mykiss) and brook trout (Salvelinus fontinalis)

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

Miller, L.L., E-mail: lana.miller@uleth.ca; Hontela, A.

Species differences in physiological and biochemical attributes exist even among closely related species and may underlie species-specific sensitivity to toxicants. Rainbow trout (RT) are more sensitive than brook trout (BT) to the teratogenic effects of selenium (Se), but it is not known whether all tissues exhibit this pattern of vulnerability. In this study, primary cultures of RT and BT adrenocortical cells were exposed to selenite (Na{sub 2}SO{sub 3}) and selenomethionine (Se-Met) to compare cell viability and ACTH-stimulated cortisol secretion in the two fish species. Cortisol, the primary stress hormone in fish, facilitates maintenance of homeostasis when fish are exposed tomore » stressors, including toxicants. Cell viability was not affected by Se, but selenite impaired cortisol secretion, while Se-Met did not (RT and BT EC{sub 50} > 2000 mg/L). RT cells were more sensitive (EC{sub 50} = 8.7 mg/L) to selenite than BT cells (EC{sub 50} = 90.4 mg/L). To identify the targets where Se disrupts cortisol synthesis, selenite-impaired RT and BT cells were stimulated with ACTH, dbcAMP, OH-cholesterol, and pregnenolone. Selenite acted at different steps in the cortisol biosynthesis pathway in RT and BT cells, confirming a species-specific toxicity mechanism. To test the hypothesis that oxidative stress mediates Se-induced toxicity, selenite-impaired RT cells were exposed to NAC, BSO and antioxidants (DETCA, ATA, Vit A, and Vit E). Inhibition of SOD by DETCA enhanced selenite-induced cortisol impairment, indicating that oxidative stress plays a role in Se toxicity; however, modifying GSH content of the cells did not have an effect. The results of this study, with two closely related salmonids, provided additional evidence for species-specific differences in sensitivity to Se which should be considered when setting thresholds and water quality guidelines. - Research Highlights: > We investigated species-specific sensitivity to Se in trout adrenocortical cells. > Selenite, not Se-Met, disrupts cortisol secretion in trout adrenocortical cells. > Rainbow trout cells are more sensitive than brook trout cells to selenite toxicity. > Superoxide dismutase may protect adrenocortical cells from selenite toxicity.« less

Postinjection L-phenylalanine increases basal ganglia contrast in PET scans of 6-18F-DOPA

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

Doudet, D.J.; McLellan, C.A.; Aigner, T.G.

The sensitivity of 18F-DOPA positron emission tomography for imaging presynaptic dopamine systems is limited by the amount of specific-to-nonspecific accumulation of radioactivity in brain. In rhesus monkeys, we have been able to increase this ratio by taking advantage of the lag time between 18F-DOPA injection and the formation of its main metabolite, the amino acid 18F-fluoromethoxydopa, the entrance of which into brain is responsible for most of the brain's nonspecific radioactivity. By infusing an unlabeled amino acid, L-phenylalanine, starting 15 min after 18F-DOPA administration, we preferentially blocked the accumulation of 18F-fluoromethoxydopa by preventing its entrance into brain through competition atmore » the large neutral amino acid transport system of the blood-brain barrier. This method appears as reliable as the original and more sensitive, as demonstrated by the comparison of normal and MPTP-treated animals under both conditions.« less

Mussel-Inspired Protein Nanoparticles Containing Iron(III)-DOPA Complexes for pH-Responsive Drug Delivery.

PubMed

Kim, Bum Jin; Cheong, Hogyun; Hwang, Byeong Hee; Cha, Hyung Joon

2015-06-15

A novel bioinspired strategy for protein nanoparticle (NP) synthesis to achieve pH-responsive drug release exploits the pH-dependent changes in the coordination stoichiometry of iron(III)-3,4-dihydroxyphenylalanine (DOPA) complexes, which play a major cross-linking role in mussel byssal threads. Doxorubicin-loaded polymeric NPs that are based on Fe(III)-DOPA complexation were thus synthesized with a DOPA-modified recombinant mussel adhesive protein through a co-electrospraying process. The release of doxorubicin was found to be predominantly governed by a change in the structure of the Fe(III)-DOPA complexes induced by an acidic pH value. It was also demonstrated that the fabricated NPs exhibited effective cytotoxicity towards cancer cells through efficient cellular uptake and cytosolic release. Therefore, it is anticipated that Fe(III)-DOPA complexation can be successfully utilized as a new design principle for pH-responsive NPs for diverse controlled drug-delivery applications. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Reduction of Aflatoxin B1 Toxicity by Lactobacillus plantarum C88: A Potential Probiotic Strain Isolated from Chinese Traditional Fermented Food "Tofu".

PubMed

Huang, Li; Duan, Cuicui; Zhao, Yujuan; Gao, Lei; Niu, Chunhua; Xu, Jingbo; Li, Shengyu

2017-01-01

In this study, we investigated the potential of Lactobacillus plantarum isolated from Chinese traditional fermented foods to reduce the toxicity of aflatoxin B1 (AFB1), and its subsequent detoxification mechanism. Among all the investigated L. plantarum strains, L. plantarum C88 showed the strongest AFB1 binding capacity in vitro, and was orally administered to mice with liver oxidative damage induced by AFB1. In the therapy groups, the mice that received L. plantarum C88, especially heat-killed L. plantarum C88, after a single dose of AFB1 exposure, showed an increase in unabsorbed AFB1 in the feces. Moreover, the effects of L. plantarum C88 on the enzymes and non-enzymes antioxidant abilities in serum and liver, histological alterations of liver were assayed. The results indicated that compared to the control group, L. plantarum C88 alone administration induced significant increase of antioxidant capacity, but did not induce any significant changes in the histological picture. Compared to the mice that received AFB1 only, L. plantarum C88 treatment could weaken oxidative stress by enhancing the activity of antioxidant enzymes and elevating the expression of Glutathione S-transferase (GST) A3 through Nuclear factor erythroid (derived factor 2) related factor 2 (Nrf2) pathway. Furthermore, cytochrome P450 (CYP 450) 1A2 and CYP 3A4 expression was inhibited by L. plantarum C88, and urinary aflatoxin B1-N7-guanine (AFB-N7-guanine), a AFB1 metabolite formed by CYP 1A2 and CYP 3A4, was significantly reduced by the presence of viable L. plantarum C88. Meanwhile, the significant improvements were showed in histological pictures of the liver tissues in mice orally administered with viable L. plantarum C88. Collectively, L. plantarum C88 may alleviate AFB1 toxicity by increasing fecal AFB1 excretion, reversing deficits in antioxidant defense systems and regulating the metabolism of AFB1.

Sodium nitrite potentiates renal oxidative stress and injury in hemoglobin exposed guinea pigs.

PubMed

Baek, Jin Hyen; Zhang, Xiaoyuan; Williams, Matthew C; Hicks, Wayne; Buehler, Paul W; D'Agnillo, Felice

2015-07-03

Methemoglobin-forming drugs, such as sodium nitrite (NaNO2), may exacerbate oxidative toxicity under certain chronic or acute hemolytic settings. In this study, we evaluated markers of renal oxidative stress and injury in guinea pigs exposed to extracellular hemoglobin (Hb) followed by NaNO2 at doses sufficient to simulate clinically relevant acute methemoglobinemia. NaNO2 induced rapid and extensive oxidation of plasma Hb in this model. This was accompanied by increased renal expression of the oxidative response effectors nuclear factor erythroid 2-derived-factor 2 (Nrf-2) and heme oxygenase-1 (HO-1), elevated non-heme iron deposition, lipid peroxidation, interstitial inflammatory cell activation, increased expression of tubular injury markers kidney injury-1 marker (KIM-1) and liver-fatty acid binding protein (L-FABP), podocyte injury, and cell death. Importantly, these indicators of renal oxidative stress and injury were minimal or absent following infusion of Hb or NaNO2 alone. Together, these results suggest that the exposure to NaNO2 in settings associated with increased extracellular Hb may potentiate acute renal toxicity via processes that are independent of NaNO2 induced erythrocyte methemoglobinemia. Published by Elsevier Ireland Ltd.

Zinc oxide nanoparticles (ZnONPs) alleviate heavy metal-induced toxicity in Leucaena leucocephala seedlings: A physiochemical analysis.

PubMed

Venkatachalam, P; Jayaraj, M; Manikandan, R; Geetha, N; Rene, Eldon R; Sharma, N C; Sahi, S V

2017-01-01

The present study describes the role of zinc oxide nanoparticles (ZnONPs) in reversing oxidative stress symptoms induced by heavy metal (Cd and Pb) exposure in Leucaena leucocephala (Lam.) de Wit. Seedling growth was significantly enhanced with the augmentation of ZnONPs following Cd and Pb exposure. Heavy metal accumulations were recorded as 1253.1 mg Cd per kg DW and 1026.8 mg Pb per kg DW for the respective treatments. Results demonstrated that ZnONPs augmentation caused an increase in photosynthetic pigment and total soluble protein contents while a significant decrease in malondialdehyde (MDA-lipid peroxidation) content in leaves. Antioxidative enzymes such as superoxide dismutase (SOD), catalase (CAT) and peroxidase (POX) were, in turn, elevated in heavy metal-exposed leaves amended with ZnONPs. The ameliorating effect of ZnO nanoparticles on oxidative stress induced toxicity was also confirmed by the reduced MDA content and the elevated level of antioxidative enzyme activities in leaf tissues of L. leucocephala seedlings. Further, addition of ZnONPs in combination with Cd and Pb metals induced distinct genomic alterations such as presence of new DNA bands and/or absence of normal bands in the RAPD pattern of the exposed plants. This study uniquely suggests a potential role of zinc oxide nanoparticles in the remediation of heavy metal contaminated media. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Mechanisms of lead-induced poisoning.

PubMed

Nemsadze, K; Sanikidze, T; Ratiani, L; Gabunia, L; Sharashenidze, T

2009-01-01

Lead is a ubiquitous environmental toxin that is capable of causing numerous acute and chronic circulatory, neurological, hematological, gastrointestinal, reproductive and immunological pathologies. The mechanism of lead induced toxicity is not fully understood. The prime targets to lead toxicity are the heme synthesis enzymes, thiol-containing antioxidants and enzymes (superoxide dismutase, catalase, glutathione peroxidase, glucose 6-phosphate dehydrogenase and antioxidant molecules like GSH). The low blood lead levels are sufficient to inhibit the activity of these enzymes and induce generation of reactive oxygen species and intensification oxidative stress. Oxidative stress plays important role in pathogenesis of lead-induced toxicity and pathogenesis of coupled disease. The primary target of lead toxicity is the central nervous system. There are different cellular, intracellular and molecular mechanisms of lead neurotoxicity: such as induction of oxidative stress, intensification of apoptosis of neurocites, interfering with Ca(2+) dependent enzyme like nitric oxide synthase. Population studies have demonstrated a link between lead exposure and subsequent development of hypertension and cardiovascular disease. The vascular endothelium is now regarded as the main target organ for the toxic effect of lead. Lead affects the vasoactive function of endothelium through the increased production of reactive oxygen species, inactivation of endogenous nitric oxide and downregulation of soluble guanylate cyclase by reactive oxygen species, leading to a limiting nitric oxide availability, impairing nitric oxide signaling. This review summarizes recent findings of the mechanism of the lead-induced toxicity and possibilities of its prevention.

Safinamide: a new hope for Parkinson's disease?

PubMed

Teixeira, Fábio G; Gago, Miguel F; Marques, Paulo; Moreira, Pedro Silva; Magalhães, Ricardo; Sousa, Nuno; Salgado, António J

2018-03-01

The loss of dopaminergic neurons (DAn) and reduced dopamine (DA) production underlies the reasoning behind the gold standard treatment for Parkinson's disease (PD) using levodopa (L-DOPA). Recently licensed by the European Medicine Agency (EMA) and US Food and Drug Administration (FDA), safinamide [a monoamine oxidase B (MOA-B) inhibitor] is an alternative to L-DOPA; as we discuss here, it enhances dopaminergic transmission with decreased secondary effects compared with L-DOPA. In addition, nondopaminergic actions (neuroprotective effects) have been reported, with safinamide inhibiting glutamate release and sodium/calcium channels, reducing the excitotoxic input to dopaminergic neuronal death. Effects of safinamide have been correlated with the amelioration of non-motor symptoms (NMS), although these remain under discussion. Overall, safinamide can be considered to have potential antidyskinetic and neuroprotective effects and future trials and/or studies should be performed to provide further evidence for its potential as an anti-PD drug. Copyright © 2018 Elsevier Ltd. All rights reserved.

Improved health-relevant functionality in dark germinated Mucuna pruriens sprouts by elicitation with peptide and phytochemical elicitors.

PubMed

Randhir, Reena; Kwon, Young-In; Shetty, Kalidas

2009-10-01

The health-relevant functionality of Mucuna pruriens was improved by priming the seeds with elicitors of the pentose phosphate pathway (PPP) such as fish protein hydrolysates (FPHs), lactoferrin (LF) and oregano extract (OE) followed by dark germination. FPH elicited the highest phenolic content of 19 mg/g FW on day 1, which was 38% higher than control sprouts. OE enhanced Parkinson's disease-relevant L-DOPA content by 33% on day 1 compared to control sprouts. Anti-diabetes-relevant alpha-amylase inhibition percent (AIP) and alpha-glucosidase inhibition percent (GIP) were high in the cotyledons and decreased following elicitation and sprouting. For potential anti-diabetic applications, low AIP and high GIP with moderate L-DOPA content on day 4 of dark germination could be optimal. Improved L-DOPA concentrations in a soluble phenolic and antioxidant-rich M. pruriens background on day 1 sprouts have potential for Parkinson's disease management.

Piezoelectric detection of ion pairs between sulphonate and catecholamines for flow injection analysis of pharmaceutical preparations.

PubMed

Mo, Z; Long, X; Zhang, M

1999-03-01

Fundamentals of ion-pair flow injection with piezoelectric detection were investigated experimentally and theoretically for the adsorption of dodecyl phenylsulfonate and interfacial ion-pair formation with epinephrine and l-dopa on silver electrode of quartz crystal microbalance. The influences of sulfonate concentration and operating parameters on the frequency response were demonstrated and provided the possibility for the discriminating determination of mixtures. The selected system of ion-pair flow injection with piezoelectric detection was applied to the determination of epinephrine and l-dopa. Calibration curves were linear in ranges 4.00-850 and 3.50-730 mug ml(-1), with detection limits of 1.22 and 1.05 mug ml(-1) and sampling frequencies of 120 samples h(-1), for epinephrine and l-dopa, respectively. The method has been satisfactorily applied to the determination of catecholamines in pharmaceutical preparations.

Highly sensitive assay for tyrosine hydroxylase activity by high-performance liquid chromatography.

PubMed

Nagatsu, T; Oka, K; Kato, T

1979-07-21

A highly sensitive assay for tyrosine hydroxylase (TH) activity by high-performance liquid chromatography (HPLC) with amperometric detection was devised based on the rapid isolation of enzymatically formed DOPA by a double-column procedure, the columns fitted together sequentially (the top column of Amberlite CG-50 and the bottom column of aluminium oxide). DOPA was adsorbed on the second aluminium oxide column, then eluted with 0.5 M hydrochloric acid, and assayed by HPLC with amperometric detection. D-Tyrosine was used for the control. alpha-Methyldopa was added to the incubation mixture as an internal standard after incubation. This assay was more sensitive than radioassays and 5 pmol of DOPA formed enzymatically could be measured in the presence of saturating concentrations of tyrosine and 6-methyltetrahydropterin. The TH activity in 2 mg of human putamen could be easily measured, and this method was found to be particularly suitable for the assay of TH activity in a small number of nuclei from animal and human brain.

Metabotropic Glutamate Receptors for Parkinson's Disease Therapy

PubMed Central

Gasparini, Fabrizio; Di Paolo, Thérèse; Gomez-Mancilla, Baltazar

2013-01-01

Excessive glutamatergic signalling within the basal ganglia is implicated in the progression of Parkinson's disease (PD) and inthe emergence of dyskinesia associated with long-term treatment with L-DOPA. There is considerable research focus on the discovery and development of compounds that modulate glutamatergic signalling via glutamate receptors, as treatments for PD and L-DOPA-induced dyskinesia (LID). Although initial preclinical studies with ionotropic glutamate receptor antagonists showed antiparkinsonian and antidyskinetic activity, their clinical use was limited due to psychiatric adverse effects, with the exception of amantadine, a weak N-methyl-d-aspartate (NMDA) antagonist, currently used to reduce dyskinesia in PD patients. Metabotropic receptor (mGlu receptor) modulators were considered to have a more favourable side-effect profile, and several agents have been studied in preclinical models of PD. The most promising results have been seen clinically with selective antagonists of mGlu5 receptor and preclinically with selective positive allosteric modulators of mGlu4 receptor. The growing understanding of glutamate receptor crosstalk also raises the possibility of more precise modulation of glutamatergic transmission, which may lead to the development of more effective agents for PD. PMID:23853735

Comparison of (68)Ga-DOTA-Tyr(3)-octreotide and (18)F-fluoro-L-dihydroxyphenylalanine positron emission tomography in neuroendocrine tumor patients.

PubMed

Putzer, D; Gabriel, M; Kendler, D; Henninger, B; Knoflach, M; Kroiss, A; Vonguggenberg, E; Warwitz, B; Virgolini, I J

2010-02-01

(68)Ga-DOTA-Tyr3-octreotide positron emission tomography ((68)Ga-DOTA-TOC PET) and (18)F-fluoro-L-dihydroxyphenylalanine PET ((18)F-DOPA PET) are emerging modalities for imaging of neuroendocrine tumors. This study reports our initial experiences with these two PET modalities on initial diagnosis, staging and restaging in NET patients. Fifteen patients with NET underwent both (68)Ga-DOTA-TOC and (18)F-DOPA PET as well as computed tomography (CT). Image findings were compared on a patient-basis (pathological uptake: yes/no) as well as on a lesion-basis. Contrast-enhanced CT and histological follow-up served as gold standard. Furthermore, imaging results were matched with tumor marker levels and quantitative tracer uptake by the tumor lesions. When comparing (68)Ga-DOTA-TOC and (18)F-DOPA PET, each modality showed a sensitivity of 64% and a specificity of 100% on a patient-based analysis. (68)Ga-DOTA-TOC PET and (18)F-DOPA PET showed equal findings in 7 out of 15 patients and disagreement in 8 patients. (68)Ga-DOTA-TOC revealed more metastases than (18)F-DOPA PET in 6 patients, while (18)F-DOPA PET detected more metastases than (68)Ga-DOTA-TOC in 4 patients. By (68)Ga-DOTA-TOC PET, 208 malignant lesions were detected, while by (18)F-DOPA only 86 lesions were found, and in CT 124, respectively. (68)Ga-DOTA-TOC and (18)F-DOPA PET are useful tools in the detection and staging of NET lesions. Our initial results allow the conclusion that (68)Ga-DOTA-TOC PET may have a stronger clinical impact in NET patients, as it does not only offer diagnostic information, but is decisive for the further treatment management, i. e. PRRT, as well.

Osthole ameliorates neurogenic and inflammatory hyperalgesia by modulation of iNOS, COX-2, and inflammatory cytokines in mice.

PubMed

Singh, Gurjit; Bhatti, Rajbir; Mannan, Rahul; Singh, Drishtant; Kesavan, Anup; Singh, Palwinder

2018-05-07

Osthole is a bioactive component reported in medicinal plants such as Angelica pubescens and Cnidium monnieri, known for analgesic activity. However, the toxicity, median effective dose (ED 50 ), and dual modulation of nitric oxide and cyclooxygenase pathways along with inflammatory cytokines of osthole are yet to be determined. The animals (mice) were assessed for general behaviour and mortality in varying doses (50, 300, and 2000 mg kg -1 ) of osthole for acute toxicity over 14 days. The analgesic activity was investigated using acetic acid and formalin-induced hyperalgesia, and anti-inflammatory activity was explored in carrageenan-induced paw oedema. ED 50 of osthole was calculated using Design Expert software. Involvement of nitric oxide and cyclooxygenase pathways was investigated by agonist challenges with L-arginine and substance P, respectively. The expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) was determined in spinal sections by immunohistochemical analysis. Lipopolysaccharide (LPS) challenge was used to assess in vivo effect on inflammatory cytokines (TNFα and IL-6). Acute toxicity studies revealed no behavioural abnormality or mortality on osthole treatment and unremarkable histological findings. Osthole was found to significantly decrease acetic acid and formalin-induced hyperalgesia (ED 50  = 5.43 mg kg -1 ) and carrageenan-induced paw oedema with no toxicity symptoms. Osthole produced a marked decrease in iNOS and COX-2 expression as well as TNFα and IL-6. The findings corroborate to modulation of iNOS and COX-2 and inflammatory cytokines by osthole. This study provides promising insights and prospects for application of osthole in pain management.

Oxidative Stress and Antioxidants in Tomato (Solanum lycopersicum) Plants Subjected to Boron Toxicity

PubMed Central

Cervilla, Luis M.; Blasco, Begoña; Ríos, Juan J.; Romero, Luis; Ruiz, Juan M.

2007-01-01

Background and Aims Boron (B) toxicity triggers the formation of reactive oxygen species in plant tissues. However, there is still a lack of knowledge as to how B toxicity affects the plant antioxidant defence system. It has been suggested that ascorbate could be important against B stress, although existing information is limited in this respect. The objective of this study was to analyse how ascorbate and some other components of the antioxidant network respond to B toxicity. Methods Two tomato (Solanum lycopersicum) cultivars (‘Kosaco’ and ‘Josefina’) were subjected to 0·05 (control), 0·5 and 2 mm B. The following were studied in leaves: dry weight; relative leaf growth rate; total and free B; H2O2; malondialdehyde; ascorbate; glutathione; sugars; total non-enzymatic antioxidant activity, and the activity of superoxide dismutase, catalase, ascorbate peroxidase, monodehydroascorbate reductase, dehydroascorbate reductase, glutathione reductase, ascorbate oxidase and l-galactose dehydrogenase. Key Results The B-toxicity treatments diminished growth and boosted the amount of B, malondialdehyde and H2O2 in the leaves of the two cultivars, these trends being more pronounced in ‘Josefina’ than in ‘Kosaco’. B toxicity increased ascorbate concentration in both cultivars and increased glutathione only in ‘Kosaco’. Activities of antioxidant- and ascorbate-metabolizing enzymes were also induced. Conclusions High B concentration in the culture medium provokes oxidative damage in tomato leaves and induces a general increase in antioxidant enzyme activity. In particular, B toxicity increased ascorbate pool size. It also increased the activity of l-galactose dehydrogenase, an enzyme involved in ascorbate biosynthesis, and the activity of enzymes of the Halliwell–Asada cycle. This work therefore provides a starting point towards a better understanding of the role of ascorbate in the plant response against B stress. PMID:17660516

Zinc-Dependent Protection of Tobacco and Rice Cells From Aluminum-Induced Superoxide-Mediated Cytotoxicity

PubMed Central

Lin, Cun; Hara, Ayaka; Comparini, Diego; Bouteau, François; Kawano, Tomonori

2015-01-01

Al3+ toxicity in growing plants is considered as one of the major factors limiting the production of crops on acidic soils worldwide. In the last 15 years, it has been proposed that Al3+ toxicity are mediated with distortion of the cellular signaling mechanisms such as calcium signaling pathways, and production of cytotoxic reactive oxygen species (ROS) causing oxidative damages. On the other hand, zinc is normally present in plants at high concentrations and its deficiency is one of the most widespread micronutrient deficiencies in plants. Earlier studies suggested that lack of zinc often results in ROS-mediated oxidative damage to plant cells. Previously, inhibitory action of Zn2+ against lanthanide-induced superoxide generation in tobacco cells have been reported, suggesting that Zn2+ interferes with the cation-induced ROS production via stimulation of NADPH oxidase. In the present study, the effect of Zn2+ on Al3+-induced superoxide generation in the cell suspension cultures of tobacco (Nicotiana tabacum L., cell-line, BY-2) and rice (Oryza sativa L., cv. Nipponbare), was examined. The Zn2+-dependent inhibition of the Al3+-induced oxidative burst was observed in both model cells selected from the monocots and dicots (rice and tobacco), suggesting that this phenomenon (Al3+/Zn2+ interaction) can be preserved in higher plants. Subsequently induced cell death in tobacco cells was analyzed by lethal cell staining with Evans blue. Obtained results indicated that presence of Zn2+ at physiological concentrations can protect the cells by preventing the Al3+-induced superoxide generation and cell death. Furthermore, the regulation of the Ca2+ signaling, i.e., change in the cytosolic Ca2+ ion concentration, and the cross-talks among the elements which participate in the pathway were further explored. PMID:26648960

Oxidative Stress and Nano-Toxicity Induced by TiO2 and ZnO on WAG Cell Line

PubMed Central

Dubey, Akhilesh; Goswami, Mukunda; Yadav, Kamalendra; Chaudhary, Dharmendra

2015-01-01

Metallic nanoparticles are widely used in cosmetics, food products and textile industry. These particles are known to cause respiratory toxicity and epithelial inflammation. They are eventually released to aquatic environment necessitating toxicity studies in cells from respiratory organs of aquatic organisms. Hence, we have developed and characterized a new cell line, WAG, from gill tissue of Wallago attu for toxicity assessment of TiO2 and ZnO nanoparticles. The efficacy of the cell line as an in vitro system for nanoparticles toxicity studies was established using electron microscopy, cytotoxicity assays, genotoxicity assays and oxidative stress biomarkers. Results obtained with MTT assay, neutral red uptake assay and lactate dehydrogenase assay showed acute toxicity to WAG cells with IC50 values of 25.29±0.12, 34.99±0.09 and 35.06±0.09 mg/l for TiO2 and 5.716±0.1, 3.160±0.1 and 5.57±0.12 mg/l for ZnO treatment respectively. The physicochemical properties and size distribution of nanoparticles were characterized using electron microscopy with integrated energy dispersive X-ray spectroscopy and Zetasizer. Dose dependent increase in DNA damage, lipid peroxidation and protein carbonylation along with a significant decrease in activity of Superoxide Dismutase, Catalase, total Glutathione levels and total antioxidant capacity with increasing concentration of exposed nanoparticles indicated that the cells were under oxidative stress. The study established WAG cell line as an in vitro system to study toxicity mechanisms of nanoparticles on aquatic organisms. PMID:26011447

Distinct role of nitric oxide and peroxynitrite in mediating oligodendrocyte toxicity in culture and in experimental autoimmune encephalomyelitis.

PubMed

Li, S; Vana, A C; Ribeiro, R; Zhang, Y

2011-06-16

Nitric oxide has been implicated in the pathogenesis of multiple sclerosis. However, it is still unclear whether nitric oxide plays a protective role or is deleterious. We have previously shown that peroxynitrite, a reaction product of nitric oxide and superoxide, is toxic to mature oligodendrocytes (OLs). The toxicity is mediated by intracellular zinc release, phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2), activation of 12-lipoxygenase (12-LOX) and the formation of reactive oxygen species (ROS). In this study, we found that the donors of nitric oxide, dipropylenetriamine NONOate (DPT NONOate) and diethylenetriamine NONOate (DETA NONOate), protected OLs from peroxynitrite or zinc-induced toxicity. The protective mechanisms appear to be attributable to their inhibition of peroxynitrite- or zinc-induced ERK1/2 phosphorylation and 12-LOX activation. In cultures of mature OLs exposed to lipopolysaccharide (LPS), induction of inducible nitric oxide synthase (iNOS) generated nitric oxide and rendered OLs resistant to peroxynitrite-induced toxicity. The protection was eliminated when 1400W, a specific inhibitor of iNOS, was co-applied with LPS. Using MOG35-55-induced experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis, we found that nitrotyrosine immunoreactivity, an indicator of peroxynitrite formation, was increased in the spinal cord white matter, which correlated with the loss of mature OLs. Targeted gene deletion of the NADPH oxidase component gp91phox reduced clinical scores, the formation of nitrotyrosine and the loss of mature OLs. These results suggest that blocking the formation specifically of peroxynitrite, rather than nitric oxide, may be a protective strategy against oxidative stress induced toxicity to OLs. Published by Elsevier Ltd.

In Vivo Determination of Mitochondrial Function Using Luciferase-Expressing Caenorhabditis elegans: Contribution of Oxidative Phosphorylation, Glycolysis, and Fatty Acid Oxidation to Toxicant-Induced Dysfunction.

PubMed

Luz, Anthony L; Lagido, Cristina; Hirschey, Matthew D; Meyer, Joel N

2016-08-01

Mitochondria are a target of many drugs and environmental toxicants; however, how toxicant-induced mitochondrial dysfunction contributes to the progression of human disease remains poorly understood. To address this issue, in vivo assays capable of rapidly assessing mitochondrial function need to be developed. Here, using the model organism Caenorhabditis elegans, we describe how to rapidly assess the in vivo role of the electron transport chain, glycolysis, or fatty acid oxidation in energy metabolism following toxicant exposure, using a luciferase-expressing ATP reporter strain. Alterations in mitochondrial function subsequent to toxicant exposure are detected by depleting steady-state ATP levels with inhibitors of the mitochondrial electron transport chain, glycolysis, or fatty acid oxidation. Differential changes in ATP following short-term inhibitor exposure indicate toxicant-induced alterations at the site of inhibition. Because a microplate reader is the only major piece of equipment required, this is a highly accessible method for studying toxicant-induced mitochondrial dysfunction in vivo. © 2016 by John Wiley & Sons, Inc. Copyright © 2016 John Wiley & Sons, Inc.

The role of oxidative stress in the ochratoxin A-mediated toxicity in proximal tubular cells.

PubMed

Schaaf, G J; Nijmeijer, S M; Maas, R F M; Roestenberg, P; de Groene, E M; Fink-Gremmels, J

2002-11-20

Balkan endemic nephropathy (BEN), a disease characterized by progressive renal fibrosis in human patients, has been associated with exposure to ochratoxin A (OTA). This mycotoxin is a frequent contaminant of human and animal food products, and is toxic to all animal species tested. OTA predominantly affects the kidney and is known to accumulate in the proximal tubule (PT). The induction of oxidative stress is implicated in the toxicity of this mycotoxin. In the present study, primary rat PT cells and LLC-PK(1) cells, which express characteristics of the PT, were used to investigate the OTA-mediated oxidative stress response. OTA exposure of these cells resulted in a concentration-dependent elevation of reactive oxygen species (ROS) levels, depletion of cellular glutathione (GSH) levels and an increase in the formation of 8-oxoguanine. The OTA-induced ROS response was significantly reduced following treatment with alpha-tocopherol (TOCO). However, this chain-braking anti-oxidant did not reduce the cytotoxicity of OTA and was unable to prevent the depletion of total GSH levels in OTA-exposed cells. In contrast, pre-incubation of the cell with N-acetyl-L-cysteine (NAC) completely prevented the OTA-induced increase in ROS levels as well as the formation of 8-oxoguanine and completely protected against the cytotoxicity of OTA. In addition, NAC treatment also limited the GSH depletion in OTA-exposed PT- and LLC-PK(1) cells. From these data, we conclude that oxidative stress contributes to the tubular toxicity of OTA. Subsequently, cellular GSH levels play a pivotal role in limiting the short-term toxicity of this mycotoxin in renal tubular cells.

Nutrient digestibility of Mucuna (Mucuna pruriens var. utilis) bean in guinea fowl (Numida meleagris, L): Effects of heat treatment and levels of incorporation in diets.

PubMed

Dahouda, M; Toléba, S S; Youssao, A K I; Hambuckers, A; Dangou-Sapoho, R; Martin, G B; Fillet, M; Hornick, J-L

2009-09-01

1. Mucuna pruriens var. utilis is a legume, the seeds of which are scarcely used in animal diets owing to their high content of 3,4-dihydroxy-L-phenylalanine (L-Dopa). 2. Experiments were conducted on guinea fowl to assess the effects of two types of heat processing (cooking and toasting) on chemical composition and nutrient digestibility of Mucuna seeds offered alone or incorporated at three concentrations (40, 120 or 200 g/kg) in complete diets. 3. Diets containing 200 g/kg seeds had more crude fibre and less ether extract. L-Dopa content increased with the amount of Mucuna inclusion. Cooking reduced markedly L-Dopa content while toasting had no effect. When fed alone, Mucuna seeds dramatically decreased feed intake. 4. Feed intake (FI) and body weight gain (BWG) were not influenced by the complete diets. Cooking significantly increased crude fibre digestibility. 5. It is suggested that cracked and cooked Mucuna bean can be incorporated at a safe level of 120 g/kg in complete diets for guinea fowl production.

Involuntary expiratory phonation as a dose-related consequence of L-dopa therapy in a patient with Parkinson's disease.

PubMed

Ishii, Kosuke; Kumada, Masanobu; Ueki, Akira; Yamamoto, Masanori; Hirose, Hajime

2003-12-01

We report a case of involuntary phonation caused by abnormal vocal cord movements during expiration in a patient with Parkinson's disease. A 60-year-old woman had been treated for parkinsonism at the outpatient clinic of the Department of Neurology since August 1999. She began to groan involuntarily in the daytime in September 2001. She could not eat well while groaning. Stridor was not noted during sleep at night. Endoscopic examination of the larynx revealed insufficient abduction of the bilateral vocal cords, although the glottis was not so small as to cause stridor during inspiration. During expiration, however, the vocal cords adducted, resulting in the involuntary production of voice. Electromyography showed an increase in the activity of the thyroarytenoid and lateral cricoarytenoid muscles. This muscle activity was further enhanced during inspiration. The involuntary phonation disappeared when the patient's dose of L-dopa was decreased, although she had a decrease in her systemic mobility as well. When the dose of L-dopa was increased to the therapeutic level, involuntary phonation recurred, and her voluntary systemic activity improved. In the present case, it was considered that excessive dopaminergic denervation occurred in the nerve innervating the laryngeal adductors. Involuntary voice appeared to be produced by hypertonus of the laryngeal adductors because of a lowering in the threshold level for L-dopa, even though the drug was administered at the usual dose.

Dysphagia Causes Symptom Fluctuations after Oral L-DOPA Treatment in a Patient with Parkinson Disease.

PubMed

Sato, Hiromasa; Yamamoto, Toshiyuki; Sato, Masako; Furusawa, Yoshihiko; Murata, Miho

2018-01-01

The causes of "delayed-on" and "no-on" phenomena in Parkinson disease (PD) are thought to have some impact on the progress of L-DOPA from the time of ingestion until it reaches the brain and is converted to dopamine. Dysphagia can cause fluctuating symptom expression in L-DOPA therapy for PD. A 69-year-old man with PD presented with "delayed-on" and "no-on" phenomena. The patient developed a gait disorder at age 60 years, and he began coughing on his food during breakfast at age 64 years. Even though he was independent in daily life, he could not eat because of dysphagia in an "off" state. Videofluoroscopic examination of swallowing in an "off" state revealed bradykinesia of the tongue and the retention of tablets in the epiglottic vallecula. We trained him to keep his tongue in strong contact with the upper incisors before swallowing. After rehabilitation of dysphagia, the frequency of "delayed-on" and "no-on" phenomena decreased, and his peak L-DOPA plasma concentration was elevated. Additionally, transdermal rotigotine (RTG) was initiated at a maintenance dose of 9.0 mg. The patient reported improvement in swallowing, and the frequency of "no-on" phenomena decreased. In PD patients, the "no-on" phenomenon can be caused by posterior contractile dysfunction of the tongue, and it can be improved with training of the tongue and transdermal RTG administration.

Redox Active Transition Metal ions Make Melanin Susceptible to Chemical Degradation Induced by Organic Peroxide.

PubMed

Zadlo, Andrzej; Pilat, Anna; Sarna, Michal; Pawlak, Anna; Sarna, Tadeusz

2017-12-01

With aging, retinal pigment epithelium melanosomes, by fusion with the age pigment lipofuscin, form complex granules called melanolipofuscin. Lipofuscin granules may contain oxidized proteins and lipid hydroperoxides, which in melanolipofuscin could chemically modify melanin polymer, while transition metal ions present in melanin can accelerate such oxidative modifications. The aim of this research was to examine the effect of selected transition metal ions on melanin susceptibility to chemical modification induced by the water-soluble tert-butyl hydroperoxide used as an oxidizing agent. Synthetic melanin obtained by DOPA autooxidation and melanosomes isolated from bovine retinal pigment epithelium were analyzed. To monitor tert-butyl hydroperoxide-induced oxidative changes of DMa and BMs, electron paramagnetic resonance spectroscopy, UV-vis absorption spectroscopy, dynamic light scattering, atomic force microscopy and electron paramagnetic resonance oximetry were employed. These measurements revealed that both copper and iron ions accelerated chemical degradation induced by tert-butyl hydroperoxide, while zinc ions had no effect. Strong prooxidant action was detected only in the case of melanosomes and melanin degraded in the presence of iron. It can be postulated that similar chemical processes, if they occur in situ in melanolipofuscin granules of the human retinal pigment epithelium, would modify antioxidant properties of melanin and its reactivity.

Hygromycin B-induced cell death is partly mediated by reactive oxygen species in rice (Oryza sativa L.).

PubMed

Oung, Hui-Min; Lin, Ke-Chun; Wu, Tsung-Meng; Chandrika, Nulu Naga Prafulla; Hong, Chwan-Yang

2015-12-01

The aminoglycoside antibiotic hygromycin B (Hyg) inhibits prokaryotic, chloroplast and mitochondrial protein synthesis. Because of the toxic effect of Hyg on plant cells, the HPT gene, encoding hygromycin phosphotransferase, has become one of the most widely used selectable markers in plant transformation. Yet the mechanism behind Hyg-induced cell lethality in plants is not clearly understood. In this study, we aimed to decipher this mechanism. With Hyg treatment, rice calli exhibited cell death, and rice seedlings showed severe growth defects, leaf chlorosis and leaf shrinkage. Rice seedlings also exhibited severe lipid peroxidation and protein carbonylation, for oxidative stress damage at the cellular level. The production of reactive oxygen species such as O2(·-), H2O2 and OH(·) was greatly induced in rice seedlings under Hyg stress, and pre-treatment with ascorbate increased resistance to Hyg-induced toxicity indicating the existence of oxidative stress. Overexpression of mitochondrial Alternative oxidase1a gene without HPT selection marker in rice enhanced tolerance to Hyg and attenuated the degradation of protein content, whereas the rice plastidial glutathione reductase 3 mutant showed increased sensitivity to Hyg. These results demonstrate that Hyg-induced cell lethality in rice is not only due to the inhibition of protein synthesis but also mediated by oxidative stress.

Hierarchical bioceramic scaffolds with 3D-plotted macropores and mussel-inspired surface nanolayers for stimulating osteogenesis

NASA Astrophysics Data System (ADS)

Xu, Mengchi; Zhai, Dong; Xia, Lunguo; Li, Hong; Chen, Shiyi; Fang, Bing; Chang, Jiang; Wu, Chengtie

2016-07-01

The hierarchical structure of biomaterials plays an important role in the process of tissue reconstruction and regeneration. 3D-plotted scaffolds have been widely used for bone tissue engineering due to their controlled macropore structure and mechanical properties. However, the lack of micro- or nano-structures on the strut surface of 3D-plotted scaffolds, especially for bioceramic scaffolds, limits their biological activity. Inspired by the adhesive versatility of mussels and the active ion-chelating capacity of polydopamine, we set out to prepare a hierarchical bioceramic scaffold with controlled macropores and mussel-inspired surface nanolayers by combining the 3D-plotting technique with the polydopamine/apatite hybrid strategy in order to synergistically accelerate the osteogenesis and angiogenesis. β-Tricalcium phosphate (TCP) scaffolds were firstly 3D-plotted and then treated in dopamine-Tris/HCl and dopamine-SBF solutions to obtain TCP-DOPA-Tris and TCP-DOPA-SBF scaffolds, respectively. It was found that polydopamine/apatite hybrid nanolayers were formed on the surface of both TCP-DOPA-Tris and TCP-DOPA-SBF scaffolds and TCP-DOPA-SBF scaffolds induced apatite mineralization for the second time during the cell culture. As compared to TCP scaffolds, both TCP-DOPA-Tris and TCP-DOPA-SBF scaffolds significantly promoted the osteogenesis of bone marrow stromal cells (BMSCs) as well as the angiogenesis of human umbilical vein endothelial cells (HUVECs), and the TCP-DOPA-SBF group presented the highest in vitro osteogenic/angiogenic activity among the three groups. Furthermore, both TCP-DOPA-Tris and TCP-DOPA-SBF scaffolds significantly improved the formation of new bone in vivo as compared to TCP scaffolds without a nanostructured surface. Our results suggest that the utilization of a mussel-inspired Ca, P-chelated polydopamine nanolayer on 3D-plotted bioceramic scaffolds is a viable and effective strategy to construct a hierarchical structure for synergistically accelerating osteogenesis.The hierarchical structure of biomaterials plays an important role in the process of tissue reconstruction and regeneration. 3D-plotted scaffolds have been widely used for bone tissue engineering due to their controlled macropore structure and mechanical properties. However, the lack of micro- or nano-structures on the strut surface of 3D-plotted scaffolds, especially for bioceramic scaffolds, limits their biological activity. Inspired by the adhesive versatility of mussels and the active ion-chelating capacity of polydopamine, we set out to prepare a hierarchical bioceramic scaffold with controlled macropores and mussel-inspired surface nanolayers by combining the 3D-plotting technique with the polydopamine/apatite hybrid strategy in order to synergistically accelerate the osteogenesis and angiogenesis. β-Tricalcium phosphate (TCP) scaffolds were firstly 3D-plotted and then treated in dopamine-Tris/HCl and dopamine-SBF solutions to obtain TCP-DOPA-Tris and TCP-DOPA-SBF scaffolds, respectively. It was found that polydopamine/apatite hybrid nanolayers were formed on the surface of both TCP-DOPA-Tris and TCP-DOPA-SBF scaffolds and TCP-DOPA-SBF scaffolds induced apatite mineralization for the second time during the cell culture. As compared to TCP scaffolds, both TCP-DOPA-Tris and TCP-DOPA-SBF scaffolds significantly promoted the osteogenesis of bone marrow stromal cells (BMSCs) as well as the angiogenesis of human umbilical vein endothelial cells (HUVECs), and the TCP-DOPA-SBF group presented the highest in vitro osteogenic/angiogenic activity among the three groups. Furthermore, both TCP-DOPA-Tris and TCP-DOPA-SBF scaffolds significantly improved the formation of new bone in vivo as compared to TCP scaffolds without a nanostructured surface. Our results suggest that the utilization of a mussel-inspired Ca, P-chelated polydopamine nanolayer on 3D-plotted bioceramic scaffolds is a viable and effective strategy to construct a hierarchical structure for synergistically accelerating osteogenesis. Electronic supplementary information (ESI) available. See DOI: 10.1039/c6nr01952h

Whole-Genome Sequencing for Optimized Patient Management

PubMed Central

Bainbridge, Matthew N.; Wiszniewski, Wojciech; Murdock, David R.; Friedman, Jennifer; Gonzaga-Jauregui, Claudia; Newsham, Irene; Reid, Jeffrey G.; Fink, John K.; Morgan, Margaret B.; Gingras, Marie-Claude; Muzny, Donna M.; Hoang, Linh D.; Yousaf, Shahed; Lupski, James R.; Gibbs, Richard A.

2012-01-01

Whole-genome sequencing of patient DNA can facilitate diagnosis of a disease, but its potential for guiding treatment has been under-realized. We interrogated the complete genome sequences of a 14-year-old fraternal twin pair diagnosed with dopa (3,4-dihydroxyphenylalanine)–responsive dystonia (DRD; Mendelian Inheritance in Man #128230). DRD is a genetically heterogeneous and clinically complex movement disorder that is usually treated with l-dopa, a precursor of the neurotransmitter dopamine. Whole-genome sequencing identified compound heterozygous mutations in the SPR gene encoding sepiapterin reductase. Disruption of SPR causes a decrease in tetrahydrobiopterin, a cofactor required for the hydroxylase enzymes that synthesize the neurotransmitters dopamine and serotonin. Supplementation of l-dopa therapy with 5-hydroxytryptophan, a serotonin precursor, resulted in clinical improvements in both twins. PMID:21677200

Voltammetric Response of Alizarin Red S-Confined Film-Coated Electrodes to Diol and Polyol Compounds: Use of Phenylboronic Acid-Modified Poly(ethyleneimine) as Film Component.

PubMed

Takahashi, Shigehiro; Suzuki, Iwao; Ojima, Takuto; Minaki, Daichi; Anzai, Jun-Ichi

2018-01-22

Alizarin red S (ARS) was confined in layer-by-layer (LbL) films composed of phenylboronic acid-modified poly(ethyleneimine) (PBA-PEI) and carboxymethylcellulose (CMC) to study the voltammetric response to diol and polyol compounds. The LbL film-coated gold (Au) electrode and quartz slide were immersed in an ARS solution to uptake ARS into the film. UV-visible absorption spectra of ARS-confined LbL film suggested that ARS formed boronate ester (ARS-PBS) in the film. The cyclic voltammetry of the ARS-confined LbL film-coated electrodes exhibited oxidation peaks at -0.50 and -0.62 V, which were ascribed to the oxidation reactions of ARS-PBS and free ARS, respectively, in the LbL film. The peak current at -0.62 V increased upon the addition of diol or polyol compounds such as L-dopa, glucose, and sorbitol into the solution, depending on the concentration, whereas the peak current at -0.50 V decreased. The results suggest a possible use of ARS-confined PBA-PEI/CMC LbL film-coated Au electrodes for the construction of voltammetric sensors for diol and polyol compounds.

Repositioning of Thiourea-Containing Drugs as Tyrosinase Inhibitors.

PubMed

Choi, Joonhyeok; Jee, Jun-Goo

2015-12-02

Tyrosinase catalyzes two distinct sequential reactions in melanin biosynthesis: The hydroxylation of tyrosine to dihydroxyphenylalanine (DOPA) and the oxidation of DOPA to dopaquinone. Developing functional modulators of tyrosinase is important for therapeutic and cosmetic purposes. Given the abundance of thiourea moiety in known tyrosinase inhibitors, we studied other thiourea-containing drugs as potential tyrosinase inhibitors. The thiourea-containing drugs in clinical use were retrieved and tested for their ability to inhibit tyrosinase. We observed that methimazole, thiouracil, methylthiouracil, propylthiouracil, ambazone, and thioacetazone inhibited mushroom tyrosinase. Except for methimazole, there was limited information regarding the activity of other drugs against tyrosinase. Both thioacetazone and ambazone significantly inhibited tyrosinase, with IC50 of 14 and 15 μM, respectively. Ambazone decreased melanin content without causing cellular toxicity at 20 μM in B16F10 cells. The activity of ambazone was stronger than that of kojic acid both in enzyme and melanin content assays. Kinetics of enzyme inhibition assigned the thiourea-containg drugs as non-competitive inhibitors. The complex models by docking simulation suggested that the intermolecular hydrogen bond via the nitrogen of thiourea and the contacts via thione were equally important for interacting with tyrosinase. These data were consistent with the results of enzyme assays with the analogues of thiourea.

Nitric oxide mitigates arsenic-induced oxidative stress and genotoxicity in Vicia faba L.

PubMed

Shukla, Pratiksha; Singh, A K

2015-09-01

The protective effects of nitric oxide (NO) against arsenic (As)-induced structural disturbances in Vicia faba have been investigated. As treatment (0.25, 0.50, and 1 mM) resulted in a declined growth of V. faba seedlings. Arsenic treatment stimulates the activity of SOD and CAT while the activities of APX and GST content were decreased. The oxidative stress markers such as superoxide radical, hydrogen peroxide and malondialdehyde (lipid peroxidation) contents were enhanced by As. Overall results revealed that significant accumulation of As suppressed growth, photosynthesis, antioxidant enzymes (SOD, CAT, APX, and GST activity), mitotic index, and induction of different chromosomal abnormalities, hence led to oxidative stress. The concentration of SNP (0.02 mM) was very effective in counteracting the adverse effect of As toxicity. These abnormalities use partially or fully reversed by a simultaneous application of As and NO donor and sodium nitroprusside and has an ameliorating effect against As-induced oxidative stress and genotoxicity in V. faba roots.

Protective Effects of Combined Selenium and Punica granatum Treatment on Some Inflammatory and Oxidative Stress Markers in Arsenic-Induced Hepatotoxicity in Rats.

PubMed

Shafik, Noha M; El Batsh, Maha M

2016-01-01

Oxidative stress is one of the major mechanisms implicated in inorganic arsenic poisoning. Punica granatum is known by its free radical scavenging properties. The aim of this study was to evaluate the protective role of combined selenium and P. granatum against arsenic-induced liver injury. Seventy-five female albino rats were divided into five groups (of 15 rats each). Toxicity was induced by oral sodium arsenite (5.5 mg/kg body weight (bw) daily) (group ІІ). Treatment of arsenic-intoxicated rats was induced by daily oral administration of sodium selenite (3 mg/kg bw) (group ІІІ), 100 mg of P. granatum ethanol extract per kilogram body weight dissolved in 300 mL distilled water in three divided doses (100 mL of this suspension every 8 h) (group IV), and combined daily oral treatment with both selenite and P. granatum ethanol extract (group V). After 3 weeks, serum and liver tissues were obtained from the decapitated rats for different estimations. Hepatotoxicity was demonstrated by significant elevation in liver weights and activities of liver enzymes, alanine aminotransferase (ALT) and aspartate aminotransferase (AST), and decrease in serum total proteins and albumin (p < 0.05) which were confirmed by histopathological examination. Additionally, arsenic hepatotoxicity led to an increased values of malondialdehyde, advanced oxidation protein products, nitric oxide, and interleukin-6 (IL-6) (p < 0.05) and decreased activity of thioredoxin reductase, values of total anti-oxidant capacity, and nuclear factor erythroid 2-related factor 2 (Nrf2) gene expression. Significant improvement in all assessed parameters was observed in rat group treated with both P. granatum and selenium. It was concluded that combined P. granatum and selenium treatment had a synergistic hepatoprotective effect against arsenic toxicity through activation of Nrf2 anti-oxidant pathway.

Toxic effects of magnesium oxide nanoparticles on early developmental and larval stages of zebrafish (Danio rerio).

PubMed

Ghobadian, Mehdi; Nabiuni, Mohammad; Parivar, Kazem; Fathi, Mojtaba; Pazooki, Jamileh

2015-12-01

Magnesium oxide nanoparticles (MgONPs) are used in medicine, manufacturing and food industries. Because of their extensive application in our daily lives, environmental exposure to these nanoparticles is inevitable. The present study examined the effects of MgONPs on zebrafish (Danio rerio) early developmental stages. The results showed that, at different concentrations, MgONPs induced cellular apoptosis and intracellular reactive oxygen species. The hatching rate and survival of embryos decreased in a dose dependent manner. The 96-h LC50 value of MgONPs on zebrafish survival was 428 mg/l and the 48-h EC50 value of MgONPs on zebrafish embryo hatching rate was 175 mg/l. Moreover different types of malformation were observed in exposed embryos. The results demonstrate the toxic effects of MgONPs on zebrafish embryos and emphasize the need for further studies. Copyright © 2015 Elsevier Inc. All rights reserved.

L-Ascorbate Protects Against Methamphetamine-Induced Neurotoxicity of Cortical Cells via Inhibiting Oxidative Stress, Autophagy, and Apoptosis.

PubMed

Huang, Ya-Ni; Yang, Ling-Yu; Wang, Jing-Ya; Lai, Chien-Cheng; Chiu, Chien-Tsai; Wang, Jia-Yi

2017-01-01

Methamphetamine (METH)-induced cell death contributes to the pathogenesis of neurotoxicity; however, the relative roles of oxidative stress, apoptosis, and autophagy remain unclear. L-Ascorbate, also called vitamin (Vit.) C, confers partial protection against METH neurotoxicity via induction of heme oxygenase-1. We further investigated the role of Vit. C in METH-induced oxidative stress, apoptosis, and autophagy in cortical cells. Exposure to lower concentrations (0.1, 0.5, 1 mM) of METH had insignificant effects on ROS production, whereas cells exposed to 5 mM METH exhibited ROS production in a time-dependent manner. We confirmed METH-induced apoptosis (by nuclear morphology revealed by Hoechst 33258 staining and Western blot showing the protein levels of pro-caspase 3 and cleaved caspase 3) and autophagy (by Western blot showing the protein levels of Belin-1 and conversion of microtubule-associated light chain (LC)3-I to LC3-II and autophagosome staining by monodansylcadaverine). The apoptosis as revealed by cleaved caspase-3 expression marked an increase at 18 h after METH exposure while both autophagic markers, Beclin 1 and LC3-II, marked an increase in cells exposed to METH for 6 and 24 h, respectively. Treating cells with Vit. C 30 min before METH exposure time-dependently attenuated the production of ROS. Vitamin C also attenuated METH-induced Beclin 1 and LC3-II expression and METH toxicity. Treatment of cells with Vit. C before METH exposure attenuated the expression of cleaved caspase-3 and reduced the number of METH-induced apoptotic cells. We suggest that the protective effect of Vit. C against METH toxicity might be through attenuation of ROS production, autophagy, and apoptosis.

Trivalent chromium induces oxidative stress in goldfish brain.

PubMed

Lushchak, Oleh V; Kubrak, Olha I; Torous, Ihor M; Nazarchuk, Tetyana Yu; Storey, Kenneth B; Lushchak, Volodymyr I

2009-03-01

Although information on the effects of Cr(6+) in biological systems is abundant, Cr(3+) has received less attention. Toxic effects of chromium compounds are partially associated with activation of redox processes. Recently we found that Cr(6+) induced oxidative stress in goldfish tissues and the glutathione system was shown to play a protective role. The present study aimed to investigate free radical processes in brain of goldfish exposed to CrCl(3). Trivalent chromium at a concentration of 50 mg L(-1) was lethal and therefore we chose to examine sublethal dosages of 1.0-10.0 mg L(-1) in aquarium water. The levels of lipid peroxides and protein carbonyls (measures of oxidative damage to lipids and proteins) in brain increased after 96 h exposure of goldfish to Cr(3+). However, exposure to 1.0-10.0 mg L(-1) Cr(3+) decreased total glutathione concentration in brain by approximately 50-60%. Oxidized glutathione levels also fell by approximately 40-60% except at the 10.0 mg L(-1) dosage where they decreased by 85%. Therefore, 10.0 mg L(-1) Cr(3+) significantly reduced the ratio [GSSG]/[totalGSH] to 35% of the control value. Chromium treatment did not affect the activity of superoxide dismutase, but reduced the activities of catalase by 55-62% and glutathione-S-transferase by 14-21%. The activities of glucose-6-phosphate dehydrogenase and glutathione reductase were unchanged under any experimental conditions used. Therefore, it can be concluded that although Cr(3+) exposure induced oxidative stress in goldfish brain, it failed to enhance the efficiency of the antioxidant system in the organ.

The influence of BPC 157 on nitric oxide agonist and antagonist induced lesions in broiler chicks.

PubMed

Grabarevic, Z; Tisljar, M; Artukovic, B; Bratulic, M; Dzaja, P; Seiwerth, S; Sikiric, P; Peric, J; Geres, D; Kos, J

1997-01-01

We describe the effects of nitric oxide (NO) agonists and antagonists and the influence of a novel organoprotective pentadecapeptide BPC 157, on the development of pulmonary hypertension syndrome and tissue lesions in chicks. Acute toxicity, which includes single dose application of saline (1 mL intraperitoneally (i.p.)), BPC 157 (10 micrograms/kg bw), L-NAME (NO antagonist, doses 50, 100, 150 mg/kg bw) and L-arginine (NO agonist/100 mg/kg bw with their combination L-NAME + BPC 157; L-NAME + L-arginine) was investigated. In this experiment pathohistological examination of the spleen, heart, liver and lungs and hematological analysis was conducted. In the chronic toxicity experiment, the animals were treated daily for 5 weeks with L-NAME (10 mg/kg bw), L-arginine (100 mg/kg bw), BPC 157 (10 micrograms/kg bw) and their combinations (L-NAME + BPC 157; L-NAME + BPC 157; L-NAME + L-arginine) i.p. Seven animals from each group, including controls (saline 1 mL i.p.) were killed every week. Application of L-NAME caused pulmonary hypertension syndrome (PHS) in the treated chicks, which was prevented by the simultaneous application of L-arginine and BPC 157. Pathohistological examination of both acute and chronic toxicity revealed that L-NAME caused severe tissue damage (myocardial and hepatic cell necrosis, necrosis of the lymphoid cells in the spleen) while L-arginine provoked predominantly congestion, edema and hemorrhages in all organs. The effect of L-NAME was successfully inhibited by the application of L-arginine and BPC 157 but the latter substance did not cause any tissue or organ damage. Hematological analysis shows significant hemoglobin and leukocyte number decrease in the L-NAME-treated groups of chicks.

Effect of certain psychopharmacological preparations on adaptation under stress conditions

NASA Technical Reports Server (NTRS)

Stanishevskaya, A. V.; Mezentseva, L. N.

1980-01-01

Experiments staged on rats demonstrated that the formation of pathological states caused by stress and accompanied by the development of ulcerative lesion of the gastric mucosa are associated with the degree of the catecholamines level drop in the mesencephalon and hypothalamus. The application of seduxen and also of combinations consisting of L-DOPA with seduxen, or with an L-adrenoblocking agent pyroxan tends to reduce the frequency of developing alcerative lesions of the stomach. The protective effect produced by the combination of L-DOPA with an L-adrenoblocking agent pyroxan is barred by an additional administration of an B-adrenoblocking agent, inderal.

Mediated effect of ultrasound treated Diclofenac on mussel hemocytes: First evidence for the involvement of respiratory burst enzymes in the induction of DCF-mediated unspecific mode of action.

PubMed

Toufexi, Eirini; Dailianis, Stefanos; Vlastos, Dimitris; Manariotis, Ioannis D

2016-06-01

The present study investigates the toxic behavior of diclofenac (DCF) before and after its ultrasound (US) treatment, as well as the involvement of intracellular target molecules, such as NADPH oxidase and NO synthase, in the DCF-induced adverse effects on hemocytes of mussel Mytilus galloprovincialis. In this context, appropriate volumes (350 and 500mL) of DCF solutions (at concentrations of 2, 2.5, 5 and 10mgL(-1)) were treated under different ultrasound operating conditions (frequency at 582 and 862kHz, electric power density at 133 and 167W) for assessing US method efficiency. In parallel, DCF and US DCF-mediated cytotoxic (in terms of cell viability measured with the use of neutral red uptake/NRU method), oxidative (in terms of superoxide anions/(.)O2(-), nitric oxides such as NO2(-) and lipid peroxidation products, such as malondialdehyde/MDA content) and genotoxic (DNA damage measured by the use of Comet assay method) effects were investigated in hemocytes exposed for 1h to 5, 10 and 100ngL(-1) and 1, 10 and 20μgL(-1) of DCF. The involvement of NADPH oxidase and NO synthase to the DCF-induced toxicity was further investigated by the use of 10μΜ L-NAME, a NO synthase inhibitor and 10μΜ DPI, a NADPH oxidase inhibitor. According to the results, 350mL of 2mgL(-1) DCF showed higher degradation (>50%) under 167W electric power density and frequency at 862kHz for 120min, compared to degradation in all other cases, followed by a significant elimination of its toxicity. Specifically, US DCF-treated hemocytes showed a significant attenuation of DCF-mediated cytotoxic, oxidative and genotoxic effects, which appeared to be caused by NADPH oxidase and NO synthase activation, since their inhibition was followed by a significant elimination of (.)O2(-) and NO2(-) generation and the concomitant oxidative damage within cells. The results of the present study showed for the first time that unspecific mode of action of DCF, associated with the induction of NADPH oxidase and NO synthase in mussel hemocytes, could be significantly diminished after partial US degradation of DCF, at least under optimized operating conditions currently tested. Copyright © 2016 Elsevier B.V. All rights reserved.

Exogenous sodium nitroprusside and glutathione alleviate copper toxicity by reducing copper uptake and oxidative damage in rice (Oryza sativa L.) seedlings.

PubMed

Mostofa, Mohammad Golam; Seraj, Zeba Islam; Fujita, Masayuki

2014-11-01

Nitric oxide (NO) and glutathione (GSH) regulate a variety of physiological processes and stress responses; however, their involvement in mitigating Cu toxicity in plants has not been extensively studied. This study investigated the interactive effect of exogenous sodium nitroprusside (SNP) and GSH on Cu homeostasis and Cu-induced oxidative damage in rice seedlings. Hydroponically grown 12-day-old seedlings were subjected to 100 μM CuSO4 alone and in combination with 200 μM SNP (an NO donor) and 200 μM GSH. Cu exposure for 48 h resulted in toxicity symptoms such as stunted growth, chlorosis, and rolling in leaves. Cu toxicity was also manifested by a sharp increase in lipoxygenase (LOX) activity, lipid peroxidation (MDA), hydrogen peroxide (H2O2), proline (Pro) content, and rapid reductions in biomass, chlorophyll (Chl), and relative water content (RWC). Cu-caused oxidative stress was evident by overaccumulation of reactive oxygen species (ROS; superoxide (O2 (•-)) and H2O2). Ascorbate (AsA) content decreased while GSH and phytochelatin (PC) content increased significantly in Cu-stressed seedlings. Exogenous SNP, GSH, or SNP + GSH decreased toxicity symptoms and diminished a Cu-induced increase in LOX activity, O2 (•-), H2O2, MDA, and Pro content. They also counteracted a Cu-induced increase in superoxide dismutase (SOD), ascorbate peroxidase (APX), glutathione reductase (GR), monodehydroascorbate reductase (MDHAR), and glyoxalase I and glyoxalase II activities, which paralleled changes in ROS and MDA levels. These seedlings also showed a significant increase in catalase (CAT), glutathione peroxidase (GPX), dehydroascorbate reductase (DHAR), glutathione S-transferase (GST) activities, and AsA and PC content compared with the seedlings stressed with Cu alone. Cu analysis revealed that SNP and GSH restricted the accumulation of Cu in the roots and leaves of Cu-stressed seedlings. Our results suggest that Cu exposure provoked an oxidative burden while reduced Cu uptake and modulating the antioxidant defense and glyoxalase systems by adding SNP and GSH play an important role in alleviating Cu toxicity. Furthermore, the protective action of GSH and SNP + GSH was more efficient than SNP alone.

Silver nanoparticle modulates gene expressions, glyoxalase system and oxidative stress markers in fluoride stressed Cajanus cajan L.

PubMed

Yadu, Bhumika; Chandrakar, Vibhuti; Korram, Jyoti; Satnami, Manmohan L; Kumar, Meetul; S, Keshavkant

2018-07-05

Application of engineered nanomaterials has increased these days due to their beneficial impacts on several sectors of the economy, including agriculture. Silver nanoparticles (AgNP) are commonly used to improve rate of seed germination, and growth and development of plants. The present study was aimed to monitor the role of engineered AgNP (non-dialysed) in the amelioration of fluoride (F)-induced oxidative injuries in Cajanus cajan L. Experimental results revealed that F-exposure inhibited growth and membrane stability index, while were enhanced with the augmentation of AgNP. The results also demonstrated that F treatment enhanced the accumulations of reactive oxygen species, malondialdehyde and oxidized glutathione, gene expression of NADPH oxidase, and activity of lipoxygenase, but were decreased by the addition of AgNP. The results indicated that exogenous application of AgNP provided tolerance against F-toxicity via enhancing the levels of proline, total and reduced glutathione, glyoxalase I and II activities, and expression of pyrroline-5-carboxylate synthetase gene. Conducted study uniquely suggested potential role of AgNP in the remediation of F-toxicity, at least in the Cajanus cajan L. radicles. Further research would be intended to unravel the molecular mechanism(s) involved precisely in the AgNP mediated alleviation of F-toxicity. Copyright © 2018 Elsevier B.V. All rights reserved.

Metoprolol induces oxidative damage in common carp (Cyprinus carpio).

PubMed

Martínez-Rodríguez, Héctor; Donkor, Kingsley; Brewer, Sharon; Galar-Martínez, Marcela; SanJuan-Reyes, Nely; Islas-Flores, Hariz; Sánchez-Aceves, Livier; Elizalde-Velázquez, Armando; Gómez-Oliván, Leobardo Manuel

2018-04-01

During the last decade, β-blockers such as metoprolol (MTP) have been frequently detected in surface water, aquatic systems and municipal water at concentrations of ng/L to μg/L. Only a small number of studies exist on the toxic effects induced by this group of pharmaceuticals on aquatic organisms. Therefore, the present study aimed to evaluate the oxidative damage induced by MTP in the common carp Cyprinus carpio, using oxidative stress biomarkers. To this end, indicators of cellular oxidation such as hydroperoxide content (HPC), lipid peroxidation (LPX) and protein carbonyl content (PCC) were determined, as well as the activity of the antioxidant enzymes superoxide dismutase (SOD) and catalase (CAT). Also, concentrations of MTP and its metabolite O-desmethyl metoprolol were determined in water as well as carp gill, liver, kidney, brain and blood, along with the partial uptake pattern of these compounds. Results show that carp takes up MTP and its metabolite in the different organs evaluated, particularly liver and gill. The oxidative stress biomarkers, HPC, LPX, and PCC, as well as SOD and CAT activity all increased significantly at most exposure times in all organs evaluated. Results indicate that MTP and its metabolite induce oxidative stress on the teleost C. carpio and that the presence of these compounds may constitute a risk in water bodies for aquatic species. Copyright © 2018 Elsevier B.V. All rights reserved.

Proteome Profiling of BEAS-2B Cells Treated with Titanium Dioxide Reveals Potential Toxicity of and Detoxification Pathways for Nanomaterial

EPA Science Inventory

Oxidative stress is known to play important roles in nanomaterial-induced toxicities. However, the proteins and signaling pathways associated with nanomaterial-mediated oxidative stress and toxicity are largely unknown. To identify oxidative stress-responding toxicity pathways an...

Involvement of phenoloxidase in browning during grinding of Tenebrio molitor larvae

PubMed Central

Lakemond, Catriona M. M.; Fogliano, Vincenzo; Renzone, Giovanni; Scaloni, Andrea; Vincken, Jean-Paul

2017-01-01

Insects are investigated as alternative protein source to meet the increasing demand for proteins in the future. Enzymatic browning occurring during grinding of insect and subsequent extraction of proteins can influence the proteins’ properties, but it is unclear which enzymes are responsible for this phenomenon. This study was performed on larvae of three commonly used insect species, namely Tenebrio molitor, Alphitobius diaperinus and Hermetia illucens. Oxygen consumption measurements on protein extracts showed activity on L-tyrosine, L-3,4-di-hydroxy-phenylalanine (L-DOPA) and L-dopamine, indicating phenoloxidase as a key player in browning. Furthermore, no reaction on 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulphonic acid) was observed, ruling out an important contribution of laccase to browning. The browning reaction was most prominent at pH 6 for T. molitor and A. diaperinus, and 7 for H. illucens. As the enzyme activity of H. illucens was the lowest with the darkest color formation, this was likely caused by another factor. The activity of phenoloxidase was confirmed for T. molitor and A. diaperinus by activity measurements after fractionation by anion-exchange chromatography. Color measurements showed the presence of activity on both L-DOPA and L-tyrosine in the same fractions. Both substrates were converted into dopachrome after incubation with enzyme-enriched fractions. No DOPA-decarboxylase, tyrosine hydroxylase and peroxidase activities were observed. By using native PAGE with L-DOPA as staining-solution, active T. molitor protein bands were resolved and characterized, identifying a tyrosinase/phenoloxidase as the active enzyme species. All together, these data confirmed that tyrosinase is an important enzyme in causing enzymatic browning in T. molitor and likely in A. diaperinus. PMID:29244828

Involvement of phenoloxidase in browning during grinding of Tenebrio molitor larvae.

PubMed

Janssen, Renske H; Lakemond, Catriona M M; Fogliano, Vincenzo; Renzone, Giovanni; Scaloni, Andrea; Vincken, Jean-Paul

2017-01-01

Insects are investigated as alternative protein source to meet the increasing demand for proteins in the future. Enzymatic browning occurring during grinding of insect and subsequent extraction of proteins can influence the proteins' properties, but it is unclear which enzymes are responsible for this phenomenon. This study was performed on larvae of three commonly used insect species, namely Tenebrio molitor, Alphitobius diaperinus and Hermetia illucens. Oxygen consumption measurements on protein extracts showed activity on L-tyrosine, L-3,4-di-hydroxy-phenylalanine (L-DOPA) and L-dopamine, indicating phenoloxidase as a key player in browning. Furthermore, no reaction on 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulphonic acid) was observed, ruling out an important contribution of laccase to browning. The browning reaction was most prominent at pH 6 for T. molitor and A. diaperinus, and 7 for H. illucens. As the enzyme activity of H. illucens was the lowest with the darkest color formation, this was likely caused by another factor. The activity of phenoloxidase was confirmed for T. molitor and A. diaperinus by activity measurements after fractionation by anion-exchange chromatography. Color measurements showed the presence of activity on both L-DOPA and L-tyrosine in the same fractions. Both substrates were converted into dopachrome after incubation with enzyme-enriched fractions. No DOPA-decarboxylase, tyrosine hydroxylase and peroxidase activities were observed. By using native PAGE with L-DOPA as staining-solution, active T. molitor protein bands were resolved and characterized, identifying a tyrosinase/phenoloxidase as the active enzyme species. All together, these data confirmed that tyrosinase is an important enzyme in causing enzymatic browning in T. molitor and likely in A. diaperinus.

Original footage of the Chilean miners with manganism published in Neurology in 1967.

PubMed

Miranda, Marcelo; Bustamante, M Leonor; Mena, Francisco; Lees, Andrew

2015-12-15

Manganism has captured the imagination of neurologists for more than a century because of its similarities to Parkinson disease and its indirect but seminal role in the "l-dopa miracle." We present unpublished footage of the original case series reported in Neurology® in 1967 by Mena and Cotzias depicting the typical neurologic signs of manganism in 4 Chilean miners and their response to high doses of l-dopa. © 2015 American Academy of Neurology.

The use of a battery of tracking tests in the quantitative evaluation of neurological function

NASA Technical Reports Server (NTRS)

Repa, B. S.; Albers, J. W.; Potvin, A. R.; Tourtellotte, W. W.

1972-01-01

A tracking test battery has been applied in a drug trail designed to compare the efficacy of L-DOPA and amantadine to that of L-DOPA and placebo in the treatment of 28 patients with Parkinson's disease. The drug trial provided an ideal opportunity for objectively evaluating the usefulness of tracking tests in assessing changes in neurologic function. Evaluating changes in patient performance resulting from disease progression and controlled clinical trials is of great importance in establishing effective treatment programs.

Removal of the precursors of N-nitrosodiethylamine (NDEA), an emerging disinfection byproduct, in drinking water treatment process and its toxicity to adult zebrafish (Danio rerio).

PubMed

Zheng, Jian; Lin, Tao; Chen, Wei

2018-01-01

N-nitrosodiethylamine (NDEA) is one of the emerging nitrogenous disinfection byproducts with probable cytotoxicity, genotoxicity, and carcinogenesis. Its potential toxicological effects have received extensive attention but remain to be poorly understood. In this study, changes in NDEA precursors in drinking water treatment process were studied using the trial of its formation potential (FP), and the toxicity induced by NDEA to adult zebrafish was investigated. NDEA FP in the raw water of Taihu Lake ranged from 46.9 to 68.3 ng/L. The NDEA precursors were removed effectively by O 3 /BAC process. Hydrophilic fraction and low-molecular-weight fraction (<1 kDa) had the highest NDEA FP. The toxicity results demonstrated that the acute lethal concentration of NDEA causing 50% mortality in 96 h (96-h LC50) was 210.4 mg/L, and NDEA was more likely to be accumulated in kidney, followed by liver and gill. NDEA induced oxidative stress and antioxidant defense to zebrafish metabolism system at concentrations over 5 μg/L. After a 42-day exposure, a significant DNA damage was observed in zebrafish liver cells at NDEA concentrations beyond 500 μg/L. This study investigated NDEA properties in both engineering prospective and toxicity evaluation, thus providing comprehensive information on its control in drinking water treatment process and its toxicity effect on zebrafish as a model animal. Copyright © 2017 Elsevier Ltd. All rights reserved.

Crystal structure and Hirshfeld surface analysis of 1-carb­oxy-2-(3,4-di­hydroxy­phen­yl)ethan-1-aminium chloride 2-ammonio-3-(3,4-di­hydroxy­phen­yl)propano­ate: a new polymorph of l-dopa HCl and isotypic with its bromide counterpart

PubMed Central

Kathiravan, Perumal; Balakrishnan, Thangavelu; Venkatesan, Perumal; Ramamurthi, Kandasamy; Percino, María Judith; Thamotharan, Subbiah

2016-01-01

The title mol­ecular salt, C9H12NO4 +·Cl−·C9H11NO4, is isotypic with that of the bromide counterpart [Kathiravan et al. (2016 ▸). Acta Cryst. E72, 1544–1548]. The title salt is a second monoclinic polymorph of the l-dopa HCl structure reported earlier in the monoclinic space group P21 [Jandacek & Earle (1971 ▸). Acta Cryst. B27, 841–845; Mostad & Rømming (1974 ▸). Acta Chemica Scand. B28, 1161–1168]. In the title compound, monoclinic space group I2, one of the dopa mol­ecules has a positive charge with a protonated α-amino group and the α-carb­oxy­lic acid group uncharged, while the second dopa mol­ecule has a neutral charge, the α-amino group is protonated and the α-carb­oxy­lic acid is deprotonated. In the previously reported form, a single dopa mol­ecule is observed in which the α-amino group is protonated and the α-carb­oxy­lic acid group is uncharged. The invariant and variations of various types of inter­molecular inter­actions present in these two forms of dopa HCl structures are discussed with the aid of two-dimensional fingerprint plots. PMID:27840723

Functional and physiological effects of treadmill training induced by buspirone, carbidopa, and L-DOPA in clenbuterol-treated paraplegic mice.

PubMed

Ung, Roth-Visal; Rouleau, Pascal; Guertin, Pierre A

2012-05-01

Chronic spinal cord injury may be complicated by weight loss, muscle atrophy, and bone loss. The authors identified a combination pharmacotherapy using buspirone, carbidopa, and L-DOPA (BCD) that elicits bouts of locomotor-like movements in spinal cord-transected (Tx) mice. They then evaluated the effects of 8 weeks of treadmill training in Tx mice that received BCD or BCD + clenbuterol, a monoaminergic agent with anabolic properties, on locomotor function, muscle atrophy, adipose tissue loss, and bone density measures. Induced locomotor movement, adipose tissue, skeletal muscle, and femoral bone properties were compared in unoperated control mice, operated controls (untreated, untrained Tx mice), and 2 groups of treated, trained Tx mice (Tx + BCD, Tx + BCD + clenbuterol) that also received training. BCD- and BCD + clenbuterol-treated mice showed comparable levels of locomotor movements that significantly improved over time. Soleus muscle mass and soleus and extensor digitorum longus cross-sectional area significantly increased in both groups of BCD-treated mice, with greater effects in BCD + clenbuterol-treated animals. Fiber type conversion, adipose tissues, bone mineral density, and content were reduced in all Tx groups compared with unoperated control mice. These findings suggest that locomotor movement and muscle properties can be restored to near-normal levels after several weeks of BCD treatment, regular training, and clenbuterol in completely paraplegic animals.

Glutathione and antioxidant enzymes serve complementary roles in protecting activated hepatic stellate cells against hydrogen peroxide-induced cell death.

PubMed

Dunning, Sandra; Ur Rehman, Atta; Tiebosch, Marjolein H; Hannivoort, Rebekka A; Haijer, Floris W; Woudenberg, Jannes; van den Heuvel, Fiona A J; Buist-Homan, Manon; Faber, Klaas Nico; Moshage, Han

2013-12-01

In chronic liver disease, hepatic stellate cells (HSCs) are activated, highly proliferative and produce excessive amounts of extracellular matrix, leading to liver fibrosis. Elevated levels of toxic reactive oxygen species (ROS) produced during chronic liver injury have been implicated in this activation process. Therefore, activated hepatic stellate cells need to harbor highly effective anti-oxidants to protect against the toxic effects of ROS. To investigate the protective mechanisms of activated HSCs against ROS-induced toxicity. Culture-activated rat HSCs were exposed to hydrogen peroxide. Necrosis and apoptosis were determined by Sytox Green or acridine orange staining, respectively. The hydrogen peroxide detoxifying enzymes catalase and glutathione-peroxidase (GPx) were inhibited using 3-amino-1,2,4-triazole and mercaptosuccinic acid, respectively. The anti-oxidant glutathione was depleted by L-buthionine-sulfoximine and repleted with the GSH-analogue GSH-monoethylester (GSH-MEE). Upon activation, HSCs increase their cellular glutathione content and GPx expression, while MnSOD (both at mRNA and protein level) and catalase (at the protein level, but not at the mRNA level) decreased. Hydrogen peroxide did not induce cell death in activated HSCs. Glutathione depletion increased the sensitivity of HSCs to hydrogen peroxide, resulting in 35% and 75% necrotic cells at 0.2 and 1mmol/L hydrogen peroxide, respectively. The sensitizing effect was abolished by GSH-MEE. Inhibition of catalase or GPx significantly increased hydrogen peroxide-induced apoptosis, which was not reversed by GSH-MEE. Activated HSCs have increased ROS-detoxifying capacity compared to quiescent HSCs. Glutathione levels increase during HSC activation and protect against ROS-induced necrosis, whereas hydrogen peroxide-detoxifying enzymes protect against apoptotic cell death. © 2013.

Triple-mixture of Zn, Mn, and Fe increases bioaccumulation and causes oxidative stress in freshwater neotropical fish.

PubMed

de Oliveira, Luciana Fernandes; Santos, Caroline; Risso, Wagner Ezequiel; Dos Reis Martinez, Claudia Bueno

2018-06-01

Metal bioaccumulation and oxidative stress biomarkers were determined in Prochilodus lineatus to understand the effects of short-term exposure to a triple-mixture of Zn, Mn, and Fe. Three independent tests were carried out, in which fish were exposed to 3 concentrations of Zn (0.18, 1.0, and 5.0 mg L -1 ), Mn (0.1, 0.5, and 5.0 mg L -1 ), and in the mix test to Fe (5.0 mg L -1 ) and a mixture of Zn (1.0 mg L -1 ) + Mn (0.5 mg L -1 ), with and without Fe. After exposure for 96 h, tissues were removed for metal bioaccumulation analysis and oxidative stress biomarkers were determined in liver, along with DNA damage in blood cells. Our results revealed that Zn and Mn were bioaccumulated in fish tissues after exposure to 5.0 mg L -1 , whereas Fe only bioaccumulated in muscle and gills after mixture exposure. Results indicated that 1 metal interfered with the other's bioaccumulation. In P. lineatus, 5 mg L -1 of both Mn and Fe were toxic, because damage was observed (lipid peroxidation [LPO] in liver and DNA damage in blood cells), whereas Zn induced liver responses (metallothionein [MT] and reduced glutathione [GSH] increases) to prevent damage. In terms of bioaccumulation and alterations of oxidative stress biomarkers, we showed that Zn, Mn, and Fe triple-mixture enhances individual metal toxicity in Neotropical fish P. lineatus. Environ Toxicol Chem 2018;37:1749-1756. © 2018 SETAC. © 2018 SETAC.

Lycopene ameliorates atrazine-induced oxidative damage in adrenal cortex of male rats by activation of the Nrf2/HO-1 pathway.

PubMed

Abass, Marwa Ahmed; Elkhateeb, Shereen Ahmed; Abd El-Baset, Samia Adel; Kattaia, Asmaa Alhosiny; Mohamed, Eman Mosallam; Atteia, Hebatallah Husseini

2016-08-01

Atrazine (ATZ) is one of the most commonly used herbicides contaminating plants, soil and water resources. Several strategies have been used to counteract ATZ toxicity. Here, we tested the hypothesis that lycopene could ameliorate ATZ-induced toxicity in the adrenal cortex. For this purpose, 35 adult male albino rats were randomized into five equal groups: untreated control, vehicle control (received 0.5 mL corn oil/day), lycopene (treated with lycopene dissolved in 0.5 mL corn oil, 10 mg/kg b.w./day), ATZ (received ATZ dissolved in 0.5 mL corn oil 300 mg/kg b.w./day), and ATZ + lycopene (treated with ATZ and lycopene at the same previously mentioned doses). All treatments were given by oral gavage for 4 weeks. We found that ATZ exposure significantly increased relative adrenal weight, plasma ACTH levels, and adrenal oxidative stress as manifested by elevated malondialdehyde levels, decreased reduced glutathione content and depressed antioxidant enzyme activities in adrenal cortex tissues with respect to control groups. Furthermore, the transcription of adrenal cortex nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), nuclear factor kappa B, and caspase-3 genes was increased significantly compared with the control groups. This was accompanied with DNA fragmentation and structural and ultrastructural changes in zona glomerulosa and zona fasiculata of the adrenal cortex. Notably, all these changes were partially ameliorated in rats treated concomitantly with ATZ and lycopene. Our results showed that lycopene exerts protective effects against ATZ-induced toxicity in rat adrenal cortex. These effects may be attributed to the antioxidative property of lycopene and its ability to activate the Nrf2/HO-1 pathway.

Iron-induced nitric oxide leads to an increase in the expression of ferritin during the senescence of Lotus japonicus nodules.

PubMed

Chungopast, Sirinapa; Duangkhet, Mallika; Tajima, Shigeyuki; Ma, Jian Feng; Nomura, Mika

2017-01-01

Iron is an essential nutrient for legume-rhizobium symbiosis and accumulates abundantly in the nodules. However, the concentration of free iron in the cells is strictly controlled to avoid toxicity. It is known that ferritin accumulates in the cells as an iron storage protein. During nodule senescence, the expression of the ferritin gene, Ljfer1, was induced in Lotus japonicus. We investigated a signal transduction pathway leading to the increase of Ljfer1 in the nodule. The Ljfer1 promoter of L. japonicus contains a conserved Iron-Dependent Regulatory Sequence (IDRS). The expression of Ljfer1 was induced by the application of iron or sodium nitroprusside, which is a nitric oxide (NO) donor. The application of iron to the nodule increased the level of NO. These data strongly suggest that iron-induced NO leads to increased expression of Ljfer1 during the senescence of L. japonicus nodules. Copyright © 2016 Elsevier GmbH. All rights reserved.

Sugary interfaces mitigate contact damage where stiff meets soft

PubMed Central

Yoo, Hee Young; Iordachescu, Mihaela; Huang, Jun; Hennebert, Elise; Kim, Sangsik; Rho, Sangchul; Foo, Mathias; Flammang, Patrick; Zeng, Hongbo; Hwang, Daehee; Waite, J. Herbert; Hwang, Dong Soo

2016-01-01

The byssal threads of the fan shell Atrina pectinata are non-living functional materials intimately associated with living tissue, which provide an intriguing paradigm of bionic interface for robust load-bearing device. An interfacial load-bearing protein (A. pectinata foot protein-1, apfp-1) with L-3,4-dihydroxyphenylalanine (DOPA)-containing and mannose-binding domains has been characterized from Atrina's foot. apfp-1 was localized at the interface between stiff byssus and the soft tissue by immunochemical staining and confocal Raman imaging, implying that apfp-1 is an interfacial linker between the byssus and soft tissue, that is, the DOPA-containing domain interacts with itself and other byssal proteins via Fe3+–DOPA complexes, and the mannose-binding domain interacts with the soft tissue and cell membranes. Both DOPA- and sugar-mediated bindings are reversible and robust under wet conditions. This work shows the combination of DOPA and sugar chemistry at asymmetric interfaces is unprecedented and highly relevant to bionic interface design for tissue engineering and bionic devices. PMID:27305949

Sugary interfaces mitigate contact damage where stiff meets soft

NASA Astrophysics Data System (ADS)

Yoo, Hee Young; Iordachescu, Mihaela; Huang, Jun; Hennebert, Elise; Kim, Sangsik; Rho, Sangchul; Foo, Mathias; Flammang, Patrick; Zeng, Hongbo; Hwang, Daehee; Waite, J. Herbert; Hwang, Dong Soo

2016-06-01

The byssal threads of the fan shell Atrina pectinata are non-living functional materials intimately associated with living tissue, which provide an intriguing paradigm of bionic interface for robust load-bearing device. An interfacial load-bearing protein (A. pectinata foot protein-1, apfp-1) with L-3,4-dihydroxyphenylalanine (DOPA)-containing and mannose-binding domains has been characterized from Atrina's foot. apfp-1 was localized at the interface between stiff byssus and the soft tissue by immunochemical staining and confocal Raman imaging, implying that apfp-1 is an interfacial linker between the byssus and soft tissue, that is, the DOPA-containing domain interacts with itself and other byssal proteins via Fe3+-DOPA complexes, and the mannose-binding domain interacts with the soft tissue and cell membranes. Both DOPA- and sugar-mediated bindings are reversible and robust under wet conditions. This work shows the combination of DOPA and sugar chemistry at asymmetric interfaces is unprecedented and highly relevant to bionic interface design for tissue engineering and bionic devices.

Discriminative sensing of DOPA enantiomers by cyclodextrin anchored graphene nanohybrids.

PubMed

Ates, Salih; Zor, Erhan; Akin, Ilker; Bingol, Haluk; Alpaydin, Sabri; Akgemci, Emine G

2017-06-01

Discriminative sensing of chiral species with a convenient and robust system is a challenge in chemistry, pharmaceutics and particularly in biomedical science. Advanced nanohybrid materials for discrimination of these biologically active molecules can be developed by combination of individual obvious advantages of different molecular scaffolds. Herein, we report on the comparison of the performance of cyclodextrin functionalized graphene derivatives (x-CD/rGO, x: α-, β-, γ-) for discrimination of DOPA enantiomers. Within this respect, electrochemical measurements were conducted and the experimental results were compared to molecular docking method. Thanks to cavity size of γ-CD and the unique properties of graphene, rGO/γ-CD nanohybrid is capable of selective recognition of DOPA enantiomers. Limit of detection (LOD) value and sensitivity were determined as 15.9 μM and 0.2525 μA μM -1 for D-DOPA, and 14.9 μM and 0.6894 μA μM -1 for L-DOPA. Copyright © 2017 Elsevier B.V. All rights reserved.

Effects of amphetamine and/or L-dopa and physiotherapy after stroke - a blinded randomized study.

PubMed

Sonde, L; Lökk, J

2007-01-01

Major therapeutic advances in the rehabilitation of subacute stroke are lacking. A promising approach is treatment with facilitating drugs like amphetamine or levodopa in combination with physiotherapy. In a randomized, double-blind, placebo-controlled clinical trail, the effect of 10 sessions with either 20 mg of D-amphetamine, 100 mg of L-dopa or 10 mg of D-amphetamine + 50 mg of L-dopa combined with physiotherapy during a 2-week period was investigated in 25 patients admitted to a stroke rehabilitation unit. Motor function (Fugl-Meyer score) and activities of daily living (Barthel's index) were assessed. All patients improved significantly over the intervention period. Drug-treated patients did not show any additional increase in motor function or ADL. It is feasible and safe to perform larger clinical trials with this type of four-arm design. However, the lack of significant effects could be because of type, dosage, and time of drugs as well as the physical intervention strategy.

The protective effects of zinc in lead-induced testicular and epididymal toxicity in Wistar rats.

PubMed

Anjum, M Reshma; Madhu, P; Reddy, K Pratap; Reddy, P Sreenivasula

2017-03-01

The aim of this study was to investigate the beneficial effects of zinc (Zn) in preventing lead (Pb)-induced reproductive toxicity in Wistar rats. The rats were divided into four groups, namely, control group, Pb group, Zn group, and Pb + Zn group. Animals were exposed to Pb (819 mg of Pb/L) or Zn (71 mg of Zn/L) or both through drinking water for 65 days. Rats exposed to Pb showed decreased weights of testes and accessory sex organs. Significant decrease in the testicular daily sperm production, epididymal sperm count, motility, viability, and number of hypoosmotic tail coiled sperm was observed in Pb-exposed rats. Testicular 3β- and 17β-hydroxysteroid dehydrogenase activity levels and circulatory testosterone levels were also decreased significantly in Pb-exposed rats. A significant increase in the lipid peroxidation products with a significant decrease in the activities of catalase and superoxide dismutase were observed in the testes and epididymis of Pb-exposed rats. Moreover, the testicular architecture showed lumens devoid of sperm in Pb-exposed rats. Supplementation of Zn mitigated Pb-induced oxidative stress and restored the spermatogenesis and steroidogenesis in Pb-exposed rats. In conclusion, cotreatment of Zn is effective for recovering suppressed spermatogenesis, steroidogenesis, elevated oxidative status, and histological damage in the testis of rats treated with Pb.

A tale of two toxicities: malformed selenoproteins and oxidative stress both contribute to selenium stress in plants

PubMed Central

Van Hoewyk, Doug

2013-01-01

Background Despite selenium's toxicity in plants at higher levels, crops supply most of the essential dietary selenium in humans. In plants, inorganic selenium can be assimilated into selenocysteine, which can replace cysteine in proteins. Selenium toxicity in plants has been attributed to the formation of non-specific selenoproteins. However, this paradigm can be challenged now that there is increasingly abundant evidence suggesting that selenium-induced oxidative stress also contributes to toxicity in plants. Scope This Botanical Briefing summarizes the evidence indicating that selenium toxicity in plants is attributable to both the accumulation of non-specific selenoproteins and selenium-induced oxidative stress. Evidence is also presented to substantiate the claim that inadvertent selenocysteine replacement probably impairs or misfolds proteins, which supports the malformed selenoprotein hypothesis. The possible physiological ramifications of selenoproteins and selenium-induced oxidative stress are discussed. Conclusions Malformed selenoproteins and oxidative stress are two distinct types of stress that drive selenium toxicity in plants and could impact cellular processes in plants that have yet to be thoroughly explored. Although challenging, deciphering whether the extent of selenium toxicity in plants is imparted by selenoproteins or oxidative stress could be helpful in the development of crops with fortified levels of selenium. PMID:23904445

Hepatoprotective efficacy of Spirulina platensis against lead-induced oxidative stress and genotoxicity in catfish; Clarias gariepinus.

PubMed

Sayed, Alaa El-Din H; El-Sayed, Yasser S; El-Far, Ali H

2017-09-01

Lead (Pb) is a toxic environmental pollutant that induces a broad range of biochemical and physiological hazards in living organisms. We investigated the possible hepatoprotective effects of Spirulina platensis (SP) in counteracting the Pb-induced oxidative damage. Ninety-six adult African catfish were allocated into four equal groups. The 1st group (control) fed basal diet while the 2nd group (Pb-treated) fed on basal diet and exposed to 1mg Pb(NO 3 ) 2 /L. The 3rd and 4th groups fed SP-supplemented basal diets at levels of 0.25% and 0.5%, respectively and exposed to Pb. Serum samples were used to analyze hepatic function biomarkers, electrolytes, and oxidant and antioxidant status. Lipid peroxidation and DNA fragmentation were determined in the liver tissues. Pb exposure induced hepatic dysfunction, electrolytes (Na + , K + , Ca +2 , and Cl - ) imbalance, as well a significant decrease in GSH content, and LDH, AChE, SOD, CAT and GST enzymes activity. SP supplementation reverted these biochemical and genetic alterations close to control levels. This amelioration was higher with 0.5% SP and at the 4th week of exposure, showing concentration- and time-dependency. Thus, the current study suggests that SP could protect the catfish liver against lead-induced injury by scavenging ROS, sustaining the antioxidant status and diminishing DNA oxidative damage. The dietary inclusion of SP can be used as a promising protective agent to counteract oxidative stress-mediated diseases and toxicities. Copyright © 2017 Elsevier Inc. All rights reserved.

Green Synthesis of Silver Nanoparticles Stabilized with Mussel-Inspired Protein and Colorimetric Sensing of Lead(II) and Copper(II) Ions

PubMed Central

Cheon, Ja Young; Park, Won Ho

2016-01-01

This articles reports a simple and green method for preparing uniform silver nanoparticles (AgNPs), for which self-polymerized 3,4-dihydroxy-l-phenylalanine (polyDOPA) is used as the reducing and stabilizing agent in aqueous media. The AgNPs functionalized by polyDOPA were analyzed by UV–Vis spectroscopy, high-resolution transmission electron microscopy (HR-TEM), Fourier transform infrared spectroscopy (FT-IR), thermogravimetric analysis (TGA), Raman spectrophotometry, and X-ray diffraction (XRD) techniques. The results revealed that the polyDOPA-AgNPs with diameters of 25 nm were well dispersed due to the polyDOPA. It was noted that the polyDOPA-AgNPs showed selectivity for Pb2+ and Cu2+ detection with the detection limits for the two ions as low as 9.4 × 10−5 and 8.1 × 10−5 μM, respectively. Therefore, the polyDOPA-AgNPs can be applied to both Pb2+ and Cu2+ detection in real water samples. The proposed method will be useful for colorimetric detection of heavy metal ions in aqueous media. PMID:27916894

Anti-apoptotic mechanism of Bacoside rich extract against reactive nitrogen species induced activation of iNOS/Bax/caspase 3 mediated apoptosis in L132 cell line.

PubMed

Anand, T; Pandareesh, M D; Bhat, Pratiksha V; Venkataramana, M

2014-10-01

Nitric oxide is a highly reactive free radical gas that reacts with a wide range of bio-molecules to produce reactive nitrogen species and exerts nitrative stress. Bacopa monniera is a traditional folk and ayurvedic medicine known to alleviate a variety of disorders. Aim of the present study is to evaluate the protective propensity of Bacopa monniera extract (BME) through its oxido-nitrosative and anti-apoptotic mechanism to attenuate sodium nitroprusside (SNP)-induced apoptosis in a human embryonic lung epithelial cell line (L132). Our results elucidate that pre-treatment of L132 cells with BME ameliorates the mitochondrial and plasma membrane damage induced by SNP as evidenced by MTT and LDH leakage assays. BME pre-treatment inhibited NO generation by down-regulating inducible nitric oxide synthase expression. BME exhibited potent antioxidant activity by up-regulating the antioxidant enzymes. SNP-induced damage to cellular, nuclear and mitochondrial integrity was also restored by BME, which was confirmed by ROS estimation, comet assay and mitochondrial membrane potential assays respectively. BME pre-treatment efficiently attenuated the SNP-induced apoptotic biomarkers such as Bax, cytochrome-c and caspase-3, which orchestrate the proteolytic damage of the cell. By considering all these findings, we report that BME protects L132 cells against SNP-induced toxicity via its free radical scavenging and anti-apoptotic mechanism.

POSSIBLE NATURE OF THE RADIATION-INDUCED SIGNAL IN NAILS: HIGH-FIELD EPR, CONFIRMING CHEMICAL SYNTHESIS, AND QUANTUM CHEMICAL CALCULATIONS

PubMed Central

Tipikin, Dmitriy S.; Swarts, Steven G.; Sidabras, Jason W.; Trompier, François; Swartz, Harold M.

2016-01-01

Exposure of finger- and toe-nails to ionizing radiation generates an Electron Paramagnetic Resonance (EPR) signal whose intensity is dose dependent and stable at room temperature for several days. The dependency of the radiation-induced signal (RIS) on the received dose may be used as the basis for retrospective dosimetry of an individual's fortuitous exposure to ionizing radiation. Two radiation-induced signals, a quasi-stable (RIS2) and stable signal (RIS5), have been identified in nails irradiated up to a dose of 50 Gy. Using X-band EPR, both RIS signals exhibit a singlet line shape with a line width around 1.0 mT and an apparent g-value of 2.0044. In this work, we seek information on the exact chemical nature of the radiation-induced free radicals underlying the signal. This knowledge may provide insights into the reason for the discrepancy in the stabilities of the two RIS signals and help develop strategies for stabilizing the radicals in nails or devising methods for restoring the radicals after decay. In this work an analysis of high field (94 GHz and 240 GHz) EPR spectra of the RIS using quantum chemical calculations, the oxidation–reduction properties and the pH dependence of the signal intensities are used to show that spectroscopic and chemical properties of the RIS are consistent with a semiquinone-type radical underlying the RIS. It has been suggested that semiquinone radicals formed on trace amounts of melanin in nails are the basis for the RIS signals. However, based on the quantum chemical calculations and chemical properties of the RIS, it is likely that the radicals underlying this signal are generated from the radiolysis of L-3,4-dihydroxyphenylalanine (DOPA) amino acids in the keratin proteins. These DOPA amino acids are likely formed from the exogenous oxidation of tyrosine in keratin by the oxygen from the air prior to irradiation. We show that these DOPA amino acids can work as radical traps, capturing the highly reactive and unstable sulfur-based radicals and/or alkyl radicals generated during the radiation event and are converted to the more stable o-semiquinone anion-radicals. From this understanding of the oxidation–reduction properties of the RIS, it may be possible to regenerate the unstable RIS2 following its decay through treatment of nail clippings. However, the treatment used to recover the RIS2 also has the ability to recover an interfering, mechanically-induced signal (MIS) formed when the nail is clipped. Therefore, to use the recovered (regenerated) RIS2 to increase the detection limits and precision of the RIS measurements and, therefore, the dose estimates calculated from the RIS signal amplitudes, will require the application of methods to differentiate the RIS2 from the recovered MIS signal. PMID:27522053

Methamidophos induces cytotoxicity and oxidative stress in human peripheral blood mononuclear cells.

PubMed

Ramirez-Vargas, Marco Antonio; Huerta-Beristain, Gerardo; Guzman-Guzman, Iris Paola; Alarcon-Romero, Luz Del Carmen; Flores-Alfaro, Eugenia; Rojas-Garcia, Aurora Elizabeth; Moreno-Godinez, Ma Elena

2017-01-01

Previous studies have shown that organophosphate pesticide (OP) exposure is associated with oxidative stress. Methamidophos (MET) is an OP widely used in agriculture, which is regarded as a highly toxic pesticide and it is a potent inhibitor of acetylcholinesterase. The aim of this study was to evaluate whether MET can induce oxidative stress at low concentrations in primary cultures of human peripheral blood mononuclear cells (PBMCs). PBMCs from healthy individuals were exposed to MET (0-80 mg/L) for 0-72 h. We performed the MTT and neutral-red assays to assess the cytotoxicity. As indicators of oxidative stress, the levels of reactive oxygen species (ROS) were assessed using flow cytometry, and the malondialdehyde (MDA) and reduced glutathione (GSH) levels were determined. MET decreased the viability of PBMCs in a dose-dependent manner. At concentrations of 3, 10, or 20 mg/L for 24 h, MET increased the ROS production significantly compared with the vehicle control. Similarly, MET increased the levels of MDA at the same concentrations that increased ROS (10 and 20 mg/L); however, no changes in GSH levels were observed. These results suggest that MET increased the generation of oxidative stress in PBMCs. © 2015 Wiley Periodicals, Inc. Environ Toxicol 32: 147-155, 2017. © 2015 Wiley Periodicals, Inc.

Effects of salinity on the toxicity and biotransformation of L-selenomethionine in Japanese medaka (Oryzias latipes) embryos: mechanisms of oxidative stress.

PubMed

Lavado, Ramon; Shi, Dalin; Schlenk, Daniel

2012-02-01

Previous studies in mammals have shown that organoselenium depletes the cellular antioxidant, glutathione (GSH) due to activation of organoselenides to organoselenoxides by flavin-containing monooxygenases (FMO). Since FMO tends to be induced in euryhaline fish exposed to hypersaline conditions, the developmental toxicity of salinity and organoselenium was examined in the euryhaline fish Japanese medaka (Oryzias latipes). FMO activity, GSH, and selenium concentrations in Japanese medaka embryos were measured following a 24-h exposure to 0.05 mM L-selenomethionine (SeMet) under different saline conditions: freshwater (<0.5 dS/m), 4.2, 6.7, and 16.8 dS/m. Concentrations of GSH and the hatch-out ratio of the SeMet-treated embryos decreased in a salinity dependent manner. While SeMet treatment led to accumulation within embryos, selenium concentrations were unaltered by salinity treatment. Compared to freshwater-exposed embryos, microsomes from embryos at 6.7 and 16.8 dS/m had enhanced oxidation of SeMet to the selenoxide (10- and 14.3-fold, respectively), which correlated with GSH depletion. The results show that increased SeMet oxidation by hypersaline conditions with subsequent GSH depletion may play an important role in the developmental toxicity of selenomethionine. Copyright © 2011 Elsevier B.V. All rights reserved.

Application of fish cell lines for evaluating the chromium induced cytotoxicity, genotoxicity and oxidative stress.

PubMed

Taju, G; Abdul Majeed, S; Nambi, K S N; Sahul Hameed, A S

2017-10-01

In the present study, we hypothesize that cytotoxicity, genotoxicity and oxidative stress play a key role in chromium induced toxicity in SISS, SISK, IEE, IEK, IEG, SICH and ICG cell lines after 24 h exposure. Three fish species namely Lates calcarifer, Etroplus suratensis and Catla catla were exposed to the concentrations of 0, 10, 20, 30, 40 and 50 mg/L of chromium for 96 h under static conditions for conducting acute toxicity tests. LC 50 was then calculated. The percentage cell survival was assessed by multiple endpoints such as MTT, NR, AB and CB assays in the seven fish cell lines exposed to different concentrations of chromium and EC 50 values of all the four endpoints were calculated. High significances were noted in the correlations between each in vitro cytotoxicity assays and in vivo mortality data. Cell shrinkage, cell detachment, vacuolations and cell swelling at the highest concentration of chromium (50 mg/L) were seen on microscopic examination of cell morphology. Comet assay and Hoechst staining were carried out to assess DNA damage and nuclear fragmentation in the seven fish lines exposed to chromium. The results of antioxidant parameters obtained indicate a significant reduction in the level of catalase, superoxide dismutase, glutathione S-transferase and Glutathione peroxidase, and increased level of lipid peroxidation in all the cell lines exposed to chromium. These results confirm that fish cell lines could be used as an alternative to whole fish for cytotoxicity, genotoxicity and oxidative stress assessment in chromium toxicity studies. Copyright © 2017 Elsevier Ltd. All rights reserved.

Expression of Aluminum-Induced Genes in Transgenic Arabidopsis Plants Can Ameliorate Aluminum Stress and/or Oxidative Stress1

PubMed Central

Ezaki, Bunichi; Gardner, Richard C.; Ezaki, Yuka; Matsumoto, Hideaki

2000-01-01

To examine the biological role of Al-stress-induced genes, nine genes derived from Arabidopsis, tobacco (Nicotiana tabacum L.), wheat (Triticum aestivum L.), and yeast (Saccharomyces cerevisiae) were expressed in Arabidopsis ecotype Landsberg. Lines containing eight of these genes were phenotypically normal and were tested in root elongation assays for their sensitivity to Al, Cd, Cu, Na, Zn, and to oxidative stresses. An Arabidopsis blue-copper-binding protein gene (AtBCB), a tobacco glutathione S-transferase gene (parB), a tobacco peroxidase gene (NtPox), and a tobacco GDP-dissociation inhibitor gene (NtGDI1) conferred a degree of resistance to Al. Two of these genes, AtBCB and parB, and a peroxidase gene from Arabidopsis (AtPox) also showed increased resistance to oxidative stress induced by diamide, while parB conferred resistance to Cu and Na. Al content of Al-treated root tips was reduced in the four Al-resistant plant lines compared with wild-type Ler-0, as judged by morin staining. All four Al-resistant lines also showed reduced staining of roots with 2′,7′-dichloro fluorescein diacetate (H2DCFDA), an indicator of oxidative stress. We conclude that Al-induced genes can serve to protect against Al toxicity, and also provide genetic evidence for a link between Al stress and oxidative stress in plants. PMID:10712528

Pharmacological strategies for the management of levodopa-induced dyskinesia in patients with Parkinson's disease.

PubMed

Schaeffer, Eva; Pilotto, Andrea; Berg, Daniela

2014-12-01

L-Dopa-induced dyskinesias (LID) are the most common adverse effects of long-term dopaminergic therapy in Parkinson's disease (PD). However, the exact mechanisms underlying dyskinesia are still unclear. For a long time, nigrostriatal degeneration and pulsatile stimulation of striatal postsynaptic receptors have been highlighted as the key factors for the development of LID. In recent years, PD models have revealed a wide range of non-dopaminergic neurotransmitter systems involved in pre- and postsynaptic changes and thereby contributing to the pathophysiology of LID. In the current review, we focus on therapeutic LID targets, mainly based on agents acting on dopaminergic, glutamatergic, serotoninergic, adrenergic, and cholinergic systems. Despite a large number of clinical trials, currently only amantadine and, to a lesser extent, clozapine are being used as effective strategies in the treatment of LID in clinical settings. Thus, in the second part of the article, we review the placebo-controlled trials on LID treatment in order to disentangle the changing scenario of drug development. Promising results include the extension of L-dopa action without inducing LID of the novel monoamine oxidase B- and glutamate-release inhibitor safinamide; however, this had no obvious effect on existing LID. Others, like the metabotropic glutamate-receptor antagonist AFQ056, showed promising results in some of the studies; however, confirmation is still lacking. Thus, to date, strategies of continuous dopaminergic stimulation seem the most promising to prevent or ameliorate LID. The success of future therapeutic strategies once moderate to severe LID occur will depend on the translation from preclinical experimental models into clinical practice in a bidirectional process.

Rebamipide, a novel antiulcer agent, attenuates Helicobacter pylori induced gastric mucosal cell injury associated with neutrophil derived oxidants.

PubMed Central

Suzuki, M; Miura, S; Mori, M; Kai, A; Suzuki, H; Fukumura, D; Suematsu, M; Tsuchiya, M

1994-01-01

The effect of rebamipide, a novel antiulcer compound, on Helicobacter pylori activated neutrophil dependent in vitro gastric epithelial cell injury was investigated. Luminol dependent chemiluminescence (ChL), which detects toxic oxidants from neutrophils exhibited a 12-fold increase when the bacterial suspension of H pylori was added to the isolated human neutrophils. This change was significantly attenuated by rebamipide at a concentration less than 1 mM, showing that rebamipide may inhibit oxidant production from H pylori elicited neutrophils. To assess whether rebamipide attenuates gastric mucosal injury, we tested its inhibitory action on H pylori induced gastric mucosal damage associated with neutrophils in vitro. Rabbit gastric mucosal cells were monolayered in culture wells and coincubated with human neutrophils and H pylori, and the cytotoxicity index was then calculated. Cultured gastric cells were significantly damaged when they were incubated with human neutrophils activated by H pylori. This cellular damage was attenuated by rebamipide in a dose-dependent manner. Furthermore, spectrophotometrical measurement showed that rebamipide (1 mM) inhibits urease activity by 21.7%. As monochloramine (an oxidant yielded by reaction of neutrophil derived chlorinated oxidant and ammonia) is proposed as an important toxic molecule in this model, the current findings suggest that the preventive effect of rebamipide on H pylori elicited neutrophil induced gastric mucosal injury may result from its inhibitory actions on the neutrophilic oxidative burst as well as H pylori derived urease activity. PMID:7959190

Apomorphine and piribedil in rats: biochemical and pharmacologic studies.

PubMed

Butterworth, R F; Poignant, J C; Barbeau, A

1975-01-01

We studied the biochemical and pharmacologic modes of action of piribedil and apomorphine in the rat. Although both drugs have many points in common, they are also different in many of their manifestations. Apomorphine causes high-intensity, short-duration stereotyped behavior; it is distributed within the brain in uneven fashion, the striatum being the area of lowest concentration as measured by fluorometry. Direct stereotactic injection within the dopaminergic mesolimbic system, and particularly the tuberculum olfactorium, produced constant intense responses. All effects of apomorphine can be blocked by pimozide, but propanolol, a beta blocker, only reduces aggression and ferocity, leaving stereotyped behaviors intact. Finally, L-5-HTP tends to reduce aggression, ferocity, and to a lesser extent stereotypy; MIF or piribedil, as well as reserpine, potentiates the stereotyped behaviors induced by apomorphine, whereas L-DOPA usually decreases them. Piribedil, on the other hand, causes low-intensity, long-duration stereotyped behavior. It is distributed within the brain almost uniformly. Most effects of piribedil can be blocked by pimozide, but propanolol blocks only aggression and ferocity, leaving stereotyped behaviors intact. On the other hand, clonidine, an alpha-receptor agonist, blocks stereotyped behaviors induced by piribedil but markedly increases aggression, ferocity, and motor activity. L-5-HTP and L-DOPA have little effect on piribedil-induced manifestations. Reserpine decreases piribedil stereotypy. The main metabolite of piribedil, S 584, had no clear-cut pharmacologic action in our hands at the dosage used. It is concluded that both apomorphine and piribedil produce stereotyped behavior by modifying the physiologic balance between mesolimbic and nigrostriatal dopaminergic systems. The other actions of apomorphine and piribedil upon aggression, ferocity, and motor activity are not always in parallel and depend probably on the fact that piribedil is less specific, affecting also noradrenergic, serotonergic, histaminergic, and/or cholinergic circuits. The usefulness of piribedil against some forms of human tremor and its low-intensity antiakinetic action probably result from this pattern of pharmacologic activity.

Comparative Proteomic Analysis of the Molecular Responses of Mouse Macrophages to Titanium Dioxide and Copper Oxide Nanoparticles Unravels Some Toxic Mechanisms for Copper Oxide Nanoparticles in Macrophages

PubMed Central

Triboulet, Sarah; Aude-Garcia, Catherine; Armand, Lucie; Collin-Faure, Véronique; Chevallet, Mireille; Diemer, Hélène; Gerdil, Adèle; Proamer, Fabienne; Strub, Jean-Marc; Habert, Aurélie; Herlin, Nathalie; Van Dorsselaer, Alain; Carrière, Marie; Rabilloud, Thierry

2015-01-01

Titanium dioxide and copper oxide nanoparticles are more and more widely used because of their catalytic properties, of their light absorbing properties (titanium dioxide) or of their biocidal properties (copper oxide), increasing the risk of adverse health effects. In this frame, the responses of mouse macrophages were studied. Both proteomic and targeted analyses were performed to investigate several parameters, such as phagocytic capacity, cytokine release, copper release, and response at sub toxic doses. Besides titanium dioxide and copper oxide nanoparticles, copper ions were used as controls. We also showed that the overall copper release in the cell does not explain per se the toxicity observed with copper oxide nanoparticles. In addition, both copper ion and copper oxide nanoparticles, but not titanium oxide, induced DNA strands breaks in macrophages. As to functional responses, the phagocytic capacity was not hampered by any of the treatments at non-toxic doses, while copper ion decreased the lipopolysaccharide-induced cytokine and nitric oxide productions. The proteomic analyses highlighted very few changes induced by titanium dioxide nanoparticles, but an induction of heme oxygenase, an increase of glutathione synthesis and a decrease of tetrahydrobiopterin in response to copper oxide nanoparticles. Subsequent targeted analyses demonstrated that the increase in glutathione biosynthesis and the induction of heme oxygenase (e.g. by lovastatin/monacolin K) are critical for macrophages to survive a copper challenge, and that the intermediates of the catecholamine pathway induce a strong cross toxicity with copper oxide nanoparticles and copper ions. PMID:25902355

Insights into the toxicity of iron oxides nanoparticles in land snails.

PubMed

Sidiropoulou, Eirini; Feidantsis, Konstantinos; Kalogiannis, Stavros; Gallios, George P; Kastrinaki, Georgia; Papaioannou, Eleni; Václavíková, Miroslava; Kaloyianni, Martha

2018-04-01

The use of manufactured nanoparticles (NPs) is spreading rapidly across technology and medicine fields, posing concerns about their consequence on ecosystems and human health. The present study aims to assess the biological responses triggered by iron oxide NPs (IONPs) and iron oxide NPs incorporated into zeolite (IONPZ) in relation to oxidative stress on the land snail Helix aspersa in order to investigate its use as a biomarker for terrestrial environments. Morphology and structure of both NPs were characterized. Snail food was supplemented with a range of concentrations of IONPs and IONPZ and values of the hemocyte lysosomal membranes' destabilization by 50% were estimated by the neutral red retention (NRRT50) assay. Subsequently, snails were fed with NPs concentrations equal to half of the NRRT50 values, 0.05 mg L -1 for IONPs and 1 mg L -1 for IONPZ, for 1, 5, 10 and 20 days. Both effectors induced oxidative stress in snails' hemocytes compared to untreated animals. The latter was detected by NRRT changes, reactive oxygen species (ROS) production, lipid peroxidation estimation, DNA integrity loss, measurement of protein carbonyl content by an enzyme-linked immunoabsorbent assay (ELISA), determination of ubiquitin conjugates and cleaved caspases conjugates levels. The results showed that the simultaneous use of the parameters tested could constitute possible reliable biomarkers for the evaluation of NPs toxicity. However, more research is required in order to enlighten the disposal and toxic impact of iron oxide NPs on the environment to ensure their safe use in the future. Copyright © 2018 Elsevier Inc. All rights reserved.

Current Experimental Studies of Gene Therapy in Parkinson's Disease

PubMed Central

Lin, Jing-ya; Xie, Cheng-long; Zhang, Su-fang; Yuan, Weien; Liu, Zhen-Guo

2017-01-01

Parkinson's disease (PD) was characterized by late-onset, progressive dopamine neuron loss and movement disorders. The progresses of PD affected the neural function and integrity. To date, most researches had largely addressed the dopamine replacement therapies, but the appearance of L-dopa-induced dyskinesia hampered the use of the drug. And the mechanism of PD is so complicated that it's hard to solve the problem by just add drugs. Researchers began to focus on the genetic underpinnings of Parkinson's disease, searching for new method that may affect the neurodegeneration processes in it. In this paper, we reviewed current delivery methods used in gene therapies for PD, we also summarized the primary target of the gene therapy in the treatment of PD, such like neurotrophic factor (for regeneration), the synthesis of neurotransmitter (for prolong the duration of L-dopa), and the potential proteins that might be a target to modulate via gene therapy. Finally, we discussed RNA interference therapies used in Parkinson's disease, it might act as a new class of drug. We mainly focus on the efficiency and tooling features of different gene therapies in the treatment of PD. PMID:28515689

The therapeutic protection of a living and dead Lactobacillus strain against aluminum-induced brain and liver injuries in C57BL/6 mice

PubMed Central

Zhai, Qixiao; Xiao, Yue; Shi, Ying; Jiang, Jinchi; Liu, Xiaoming; Zhao, Jianxin; Zhang, Hao

2017-01-01

Our previous study found that Lactobacillus plantarum CCFM639 had the ability to alleviate acute aluminum (Al) toxicity when the strain was introduced simultaneously with Al exposure. This research was designed to elucidate the therapeutic effects of living and dead L. plantarum CCFM639 against chronic Al toxicity and to gain insight into the protection modes of this strain. Animals were assigned into control, Al only, Al + living CCFM639, and Al + dead CCFM639 groups. The Al exposure model was established by drinking water for the first 4 weeks. The strain was given after Al exposure by oral gavage at 109 colony-forming units once per day for 12 weeks. The results show that the Al binding ability of dead CCFM639 was similar to that of living CCFM639 in vitro. The ingestion of living or dead CCFM639 has similar effects on levels of Al and trace element in tissues, but living strains led to more significant amelioration of oxidative stress and improvement of memory deficits in Al-exposed mice. In conclusion, in addition to intestinal Al sequestration, CCFM639 treatment offers direct protection against chronic Al toxicity by alleviation of oxidative stress. Therefore, L. plantarum CCFM639 has a potential as dietary supplement ingredient that provides protection against Al-induced injury. PMID:28388664

Studies on the protective effect of the artichoke (Cynara scolymus) leaf extract against cadmium toxicity-induced oxidative stress, hepatorenal damage, and immunosuppressive and hematological disorders in rats.

PubMed

El-Boshy, Mohamed; Ashshi, Ahmad; Gaith, Mazen; Qusty, Naeem; Bokhary, Thalat; AlTaweel, Nagwa; Abdelhady, Mohamed

2017-05-01

Our objective was to explore the protective effect of artichoke leaf extract (ALE) against cadmium (Cd) toxicity-induced oxidative organ damage in rats. Male albino Wistar rats were divided into four equal groups of eight animals each. The first group was assigned as a control. Groups 2-4 were orally administered with ALE (300 mg/kg bw), Cd (CdCl 2 , 100 mg/L drinking water), and ALE plus Cd, respectively, daily for 4 weeks. After treatment with Cd, the liver and kidney malondialdehyde (MDA) increased significantly compared with the control rats. The sera interleukin (IL)-1β, tumor necrosis factor (TNF-α), and IL-10, liver transaminase, urea, creatinine, and peripheral neutrophil count were significantly increased in Cd-exposed rats compared to the control group. The reduced glutathione (GSH), glutathione peroxidase (GPX), superoxide dismutase (SOD), and catalase (CAT) decreased in the liver and kidney in Cd-exposed group. In combination treatment, Cd and ALE significantly improved immune response, an antioxidant system, and hepatorenal function with a significant decline in MDA. In conclusion, ALE ameliorates the immunosuppressive and hepatorenal oxidative injury stimulated by Cd in rats. These results suggest that artichoke has shown promising effects against adverse effects of Cd toxicity.

Realistic mixture of illicit drugs impaired the oxidative status of the zebra mussel (Dreissena polymorpha).

PubMed

Parolini, Marco; Magni, Stefano; Castiglioni, Sara; Zuccato, Ettore; Binelli, Andrea

2015-06-01

Illicit drugs are considered to be emerging aquatic pollutants since they are commonly found in freshwater ecosystems in the high ng L(-1) to low μg L(-1) range concentrations. Although the environmental occurrence of the most common psychoactive compounds is well known, recently some investigations showed their potential toxicity toward non-target aquatic organisms. However, to date, these studies completely neglected that organisms in the real environment are exposed to a complex mixture, which could lead to dissimilar adverse effects. The present study investigated the oxidative alterations of the freshwater bivalve Dreissena polymorpha induced by a 14-d exposure to an environmentally relevant mixture of the most common illicit drugs found in the aquatic environment, namely cocaine (50 ng L(-1)), benzoylecgonine (300 ng L(-1)), amphetamine (300 ng L(-1)), morphine (100 ng L(-1)) and 3,4-methylenedioxymethamphetamine (50 ng L(-1)). The total oxidant status (TOS) was measured to investigate the increase in the reactive oxygen species' levels, while the activity of antioxidant enzymes and glutathione S-transferase were measured to note the eventual imbalances between pro-oxidant and antioxidant molecules. In addition, oxidative damage was assessed by measuring the levels of lipid peroxidation and protein carbonylation. Significant time-dependent increases of all the antioxidant activities were induced by the mixture. Moreover, the illicit drug mixture significantly increased the levels of carbonylated proteins and caused a slight variation in lipid peroxidation. Our results showed that a mixture of illicit drugs at realistic environmental concentrations can impair the oxidative status of the zebra mussel, posing a serious hazard to the health status of this bivalve species. Copyright © 2015 Elsevier Ltd. All rights reserved.

Systemic blockage of nitric oxide synthase by L-NAME increases left ventricular systolic pressure, which is not augmented further by Intralipid®.

PubMed

Shin, Il-Woo; Hah, Young-Sool; Kim, Cheol; Park, Jungchul; Shin, Heewon; Park, Kyeong-Eon; Ok, Seong-Ho; Lee, Heon-Keun; Chung, Young-Kyun; Shim, Haeng Seon; Lim, Dong Hoon; Sohn, Ju-Tae

2014-01-01

Intravenous lipid emulsions (LEs) are effective in the treatment of toxicity associated with various drugs such as local anesthetics and other lipid soluble agents. The goals of this study were to examine the effect of LE on left ventricular hemodynamic variables and systemic blood pressure in an in vivo rat model, and to determine the associated cellular mechanism with a particular focus on nitric oxide. Two LEs (Intralipid(®) 20% and Lipofundin(®) MCT/LCT 20%) or normal saline were administered intravenously in an in vivo rat model following induction of anesthesia by intramuscular injection of tiletamine/zolazepam and xylazine. Left ventricular systolic pressure (LVSP), blood pressure, heart rate, maximum rate of intraventricular pressure increase, and maximum rate of intraventricular pressure decrease were measured before and after intravenous administration of various doses of LEs or normal saline to an in vivo rat with or without pretreatment with the non-specific nitric oxide synthase inhibitor N(ω)-nitro-L-arginine-methyl ester (L-NAME). Administration of Intralipid(®) (3 and 10 ml/kg) increased LVSP and decreased heart rate. Pretreatment with L-NAME (10 mg/kg) increased LSVP and decreased heart rate, whereas subsequent treatment with Intralipid(®) did not significantly alter LVSP. Intralipid(®) (10 ml/kg) increased mean blood pressure and decreased heart rate. The increase in LVSP induced by Lipofundin(®) MCT/LCT was greater than that induced by Intralipid(®). Intralipid(®) (1%) did not significantly alter nitric oxide donor sodium nitroprusside-induced relaxation in endothelium-denuded rat aorta. Taken together, systemic blockage of nitric oxide synthase by L-NAME increases LVSP, which is not augmented further by intralipid(®).

In vitro gastrointestinal digestion promotes the protective effect of blackberry extract against acrylamide-induced oxidative stress

NASA Astrophysics Data System (ADS)

Chen, Wei; Su, Hongming; Xu, Yang; Jin, Chao

2017-01-01

Acrylamide (AA)-induced toxicity has been associated with accumulation of excessive reactive oxygen species. The present study was therefore undertaken to investigate the protective effect of blackberry digests produced after (BBD) in vitro gastrointestinal (GI) digestion against AA-induced oxidative damage. The results indicated that the BBD (0.5 mg/mL) pretreatment significantly suppressed AA-induced intracellular ROS generation (56.6 ± 2.9% of AA treatment), mitochondrial membrane potential (MMP) decrease (297 ± 18% of AA treatment) and glutathione (GSH) depletion (307 ± 23% of AA treatment), thereby ameliorating cytotoxicity. Furthermore, LC/MS/MS analysis identified eight phenolic compounds with high contents in BBD, including ellagic acid, ellagic acid pentoside, ellagic acid glucuronoside, methyl-ellagic acid pentoside, methyl-ellagic acid glucuronoside, cyanidin glucoside, gallic acid and galloyl esters, as primary active compounds responsible for antioxidant action. Collectively, our study uncovered that the protective effect of blackberry was reserved after gastrointestinal digestion in combating exogenous pollutant-induced oxidative stress.

Synthesis of N-formyl-3,4-di-t-butoxycarbonyloxy-6(trimethylstannyl)-L-phenylalanine ethyl ester and its regioselective radiofluorodestannylation to 6-[{sup 18}F]fluoro-1-dopa

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

Satyamurthy, N.; Barrio, J.R.; Bishop, A.J.

A process is revealed for forming a 6-fluoro derivative of compounds in the L-Dopa family comprising the steps of protecting the groups attached to the benzene ring in the compound followed by serially reacting the protected compound with (a) iodine and silver trifluoroacetic acid; (b) Bb{sub 3}; (c) dit-butyldicarbonate; (d) hexamethyltin; (e) a fluoro compound; (f) hydrobromic acid; and (g) raising the pH to {<=}7. 1 fig.

Synthesis of N-formyl-3,4-di-t-butoxycarbonyloxy-6(trimethylstannyl)-L-phenylalanine ethyl ester and its regioselective radiofluorodestannylation to 6-[{sup 18}F]fluoro-1-dopa

DOEpatents

Satyamurthy, N.; Barrio, J.R.; Bishop, A.J.; Namavari, M.; Bida, G.T.

1996-04-23

A process is revealed for forming a 6-fluoro derivative of compounds in the L-Dopa family comprising the steps of protecting the groups attached to the benzene ring in the compound followed by serially reacting the protected compound with (a) iodine and silver trifluoroacetic acid; (b) Bb{sub 3}; (c) dit-butyldicarbonate; (d) hexamethyltin; (e) a fluoro compound; (f) hydrobromic acid; and (g) raising the pH to {<=}7. 1 fig.

Synthesis of N-formyl-3,4-di-t-butoxycarbonyloxy-6-(trimethylstannyl)-L-phenylalanine ethyl ester and its regioselective radiofluorodestannylation to 6- .sup.18 F!fluoro-1-dopa

DOEpatents

Satyamurthy, Nagichettiar; Barrio, Jorge R.; Bishop, Allyson J.; Namavari, Mohammad; Bida, Gerald T.

1996-01-01

A process for forming a 6-fluoro derivative of compounds in the L-Dopa family comprising the steps of protecting the groups attached to the benzene ring in the compound followed by serially reacting the protected compound with (a) iodine and silver trifluoroacetic acid; (b) Bb.sub.3 ; (c) dit-butyldicarbonate; (d) hexamethyltin; (e) a fluoro compound; (f) hydrobromic acid; and (g) raising the pH to .ltoreq.7.

Biomedical Implications of Heavy Metals Induced Imbalances in Redox Systems

PubMed Central

Singh, Shweta; Siddiqi, Nikhat J.

2014-01-01

Several workers have extensively worked out the metal induced toxicity and have reported the toxic and carcinogenic effects of metals in human and animals. It is well known that these metals play a crucial role in facilitating normal biological functions of cells as well. One of the major mechanisms associated with heavy metal toxicity has been attributed to generation of reactive oxygen and nitrogen species, which develops imbalance between the prooxidant elements and the antioxidants (reducing elements) in the body. In this process, a shift to the former is termed as oxidative stress. The oxidative stress mediated toxicity of heavy metals involves damage primarily to liver (hepatotoxicity), central nervous system (neurotoxicity), DNA (genotoxicity), and kidney (nephrotoxicity) in animals and humans. Heavy metals are reported to impact signaling cascade and associated factors leading to apoptosis. The present review illustrates an account of the current knowledge about the effects of heavy metals (mainly arsenic, lead, mercury, and cadmium) induced oxidative stress as well as the possible remedies of metal(s) toxicity through natural/synthetic antioxidants, which may render their effects by reducing the concentration of toxic metal(s). This paper primarily concerns the clinicopathological and biomedical implications of heavy metals induced oxidative stress and their toxicity management in mammals. PMID:25184144

A Role of Fluoride on Free Radical Generation and Oxidative Stress in BV-2 Microglia Cells

PubMed Central

Shuhua, Xi; Ziyou, Liu; Ling, Yan; Fei, Wang; Sun, Guifan

2012-01-01

The generation of ROS and lipid peroxidation has been considered to play an important role in the pathogenesis of chronic fluoride toxicity. In the present study, we observed that fluoride activated BV-2 microglia cell line by observing OX-42 expression in immunocytochemistry. Intracellular superoxide dismutase (SOD), glutathione (GSH), malondialdehyde (MDA), reactive oxygen species (ROS), superoxide anions (O2 ∙−), nitric oxide synthase (NOS), nitrotyrosine (NT) and nitric oxide (NO), NOS in cell medium were determined for oxidative stress assessment. Our study found that NaF of concentration from 5 to 20 mg/L can stimuli BV-2 cells to change into activated microglia displaying upregulated OX-42 expression. SOD activities significantly decreased in fluoride-treated BV-2 cells as compared with control, and MDA concentrations and contents of ROS and O2 ∙− increased in NaF-treated cells. Activities of NOS in cells and medium significantly increased with fluoride concentrations in a dose-dependent manner. NT concentrations also increased significantly in 10 and 50 mg/L NaF-treated cells compared with the control cells. Our present study demonstrated that toxic effects of fluoride on the central nervous system possibly partly ascribed to activiting of microglia, which enhanced oxidative stress induced by ROS and reactive nitrogen species. PMID:22933830

Cytotoxicity and the induction of the stress protein Hsp 70 in Chang liver cells in response to zearalenone-induced oxidative stress.

PubMed

Lee, Hyungkyoung; Kang, Changgeun; Yoo, Yong-San; Hah, Do-Yun; Kim, Chung Hui; Kim, Euikyung; Kim, Jong Shu

2013-09-01

Zearalenone (ZEN) has been implicated in several cases of mycotoxicosis in farm animals and humans. The toxic effects of ZEN have been well characterized, but little is known regarding the mechanisms of ZEN toxicity, including the involvement of the oxidative stress pathway. Using Chang liver cells as a model, the aim of this study was to determine if ZEN could elevate the expression of the heat shock protein Hsp 70, induce cytotoxicity and modulate the levels of glutathione (GSH) and thiobarbituric acid reactive substance (TBARS). In addition, the cytoprotective effects of N-acetylcysteine amide (NACA) pre-treatment were assessed. Finally, the involvement of oxidative stress in ZEN-induced toxicity was confirmed. The results of this study demonstrated that ZEN-induced Hsp 70 expression in a dose- and time-dependent manners. This effect occurred at low-ZEN concentrations, and could therefore be considered a biomarker of ZEN-induced toxicity. The cytotoxicity was reduced when Chang liver cells were exposed to sub-lethal heat shock prior to ZEN treatment, demonstrating a cytoprotective effect of Hsp 70. This cytoprotective effect suggested that Hsp 70 might play a key role in the cellular defense mechanism. When cells were pre-treated with NACA prior to ZEN treatment, the cells were also protected from toxicity. This NACA cytoprotective effect suggested the involvement of oxidative stress in ZEN-induced toxicity, and this mechanism was supported by reduced Hsp 70 expression, inhibited cytolethality, increased GSH levels and decreased TBARS formation when cells were pre-treated with NACA prior to ZEN exposure. Our data clearly demonstrated that ZEN induced cytotoxicity in Chang liver cells by inhibiting cell proliferation, decreasing GSH levels and increasing TBARS formation in a dose-dependent manner. ZEN also, induced Hsp 70 expression, and the side effects of ZEN were significantly alleviated by pre-treatment with NACA. Oxidative stress is likely to be one of the primary pathways of ZEN toxicity. This oxidative stress may contribute, at least in part, to the mechanism of ZEN-induced cytotoxicity. Copyright © 2013 Elsevier B.V. All rights reserved.

Manganese enhances peroxynitrite and leukotriene E4 formation in bovine aortic endothelial cells exposed to arsenic.

PubMed

Bunderson, Melisa; Pereira, Flavia; Schneider, Mark C; Shaw, Pamela K; Coffin, J Douglas; Beall, Howard D

2006-01-01

Long-term exposure to arsenic in drinking water has been linked to cancer and other health effects, including cardiovascular disease. Arsenic in the environment is found in combination with a range of metals that could influence its toxicity. Manganese, in particular, is a metal that is typically found in conjunction with arsenic in contaminated groundwater. Peroxynitrite is a powerful oxidant formed from the reaction between nitric oxide and superoxide anion. Arsenic has been shown to increase the formation of peroxynitrite in bovine aortic endothelial cells (BAECs) and promote the formation of 3-nitrotyrosine (3-NY) in the atherosclerotic plaque of ApoE-/-/LDLr-/- mice. Arsenic exposure also increases leukotriene E4 (LTE4) formation in both the mice and BAECs, an effect that is partially reversed by the addition of Nomega-nitro-L-arginine methyl ester (L-NAME), a nitric oxide synthase (NOS) inhibitor. In the present study, we investigated the effect of adding nontoxic concentrations of manganese along with arsenic to BAEC cultures. Manganese increased arsenic toxicity and enhanced peroxynitrite, 3-NY, and LTE4 formation in BAECs. Addition of LNAME reduced 3-NY formation induced by arsenic/manganese mixtures, but in contrast to its effect on arsenic alone, L-NAME actually increased LTE4 synthesis in BAECs treated with the arsenic/manganese combination. Overall, these data suggest that manganese may exacerbate the toxic effects of arsenic on the vascular system.

Cytotoxic effects of oosporein isolated from endophytic fungus Cochliobolus kusanoi

PubMed Central

Ramesha, Alurappa; Venkataramana, M.; Nirmaladevi, Dhamodaran; Gupta, Vijai K.; Chandranayaka, S.; Srinivas, Chowdappa

2015-01-01

In the present study, oosporein, a fungal toxic secondary metabolite known to be a toxic agent causing chronic disorders in animals, was isolated from fungus Cochliobolus kusanoi of Nerium oleander L. Toxic effects of oosporein and the possible mechanisms of cytotoxicity as well as the role of oxidative stress in cytotoxicity to Madin-Darby canine kidney kidney cells and RAW 264.7 splene cells were evaluated in vitro. Also to know the possible in vivo toxic effects of oosporein on kidney and spleen, Balb/C mouse were treated with different concentrations of oosporein ranging from 20 to 200 μM). After 24 h of exposure histopathological observations were made to know the effects of oosporein on target organs. Oosporein induced elevated levels of reactive oxygen species (ROS) generation and high levels of malondialdehyde, loss of mitochondrial membrane potential, induced glutathione hydroxylase (GSH) production was observed in a dose depended manner. Effects oosporein on chromosomal DNA damage was assessed by Comet assay, and increase in DNA damage were observed in both the studied cell lines by increasing the oosporein concentration. Further, oosporein treatment to studied cell lines indicated significant suppression of oxidative stress related gene (Superoxide dismutase1 and Catalase ) expression, and increased levels of mRNA expression in apoptosis or oxidative stress inducing genes HSP70, Caspase3, Caspase6, and Caspase9 as measured by quantitative real time-PCR assay. Histopathological examination of oosporein treated mouse kidney and splenocytes further revealed that, oosporein treated target mouse tissues were significantly damaged with that of untreated sam control mice and these effects were in directly proportional to the the toxin dose. Results of the present study reveals that, ROS is the principle event prompting increased oosporein toxicity in studied in vivio and in vitro animal models. The high previlance of these fungi in temperate climates further warrants the need of safe food grain storage and processing practices to control the toxic effects of oosporein to humans and live stock. PMID:26388840

Developmental Toxicity of Zinc Oxide Nanoparticles to Zebrafish (Danio rerio): A Transcriptomic Analysis

PubMed Central

Choi, Jin Soo; Kim, Ryeo-Ok; Yoon, Seokjoo

2016-01-01

Zinc oxide nanoparticles (ZnO NPs) are being utilized in an increasing number of fields and commercial applications. While their general toxicity and associated oxidative stress have been extensively studied, the toxicological pathways that they induce in developmental stages are still largely unknown. In this study, the developmental toxicity of ZnO NPs to embryonic/larval zebrafish was investigated. The transcriptional expression profiles induced by ZnO NPs were also investigated to ascertain novel genomic responses related to their specific toxicity pathway. Zebrafish embryos were exposed to 0.01, 0.1, 1, and 10 mg/L ZnO NPs for 96 h post-fertilization. The toxicity of ZnO NPs, based on their Zn concentration, was quite similar to that in embryonic/larval zebrafish exposed to corresponding ZnSO4 concentrations. Pericardial edema and yolk-sac edema were the principal malformations induced by ZnO NPs. Gene-expression profiling using microarrays demonstrated 689 genes that were differentially regulated (fold change >1.5) following exposure to ZnO NPs (498 upregulated, 191 downregulated). Several genes that were differentially regulated following ZnO NP exposure shared similar biological pathways with those observed with ZnSO4 exposure, but six genes (aicda, cyb5d1, edar, intl2, ogfrl2 and tnfsf13b) associated with inflammation and the immune system responded specifically to ZnO NPs (either in the opposite direction or were unchanged in ZnSO4 exposure). Real-time reverse-transcription quantitative polymerase chain reaction confirmed that the responses of these genes to ZnO NPs were significantly different from their response to ZnSO4 exposure. ZnO NPs may affect genes related to inflammation and the immune system, resulting in yolk-sac edema and pericardia edema in embryonic/larval developmental stages. These results will assist in elucidating the mechanisms of toxicity of ZnO NPs during development of zebrafish. PMID:27504894

Ethanol exposure induces oxidative stress and impairs nitric oxide availability in the human placental villi: a possible mechanism of toxicity.

PubMed

Kay, H H; Grindle, K M; Magness, R R

2000-03-01

We undertook this investigation to explore the effects of ethanol exposure on nitric oxide synthase levels and nitric oxide release. Our hypothesis was that ethanol exposure modifies nitric oxide activity within the placenta as a result of oxidative stress. Four 10-g samples of term normal human placental villous tissue were perifused with nonrecirculating Dulbecco's modified Eagle's medium and 25-mmol/L N-[2-hydroxyethyl]piperazine-N'-[2-ethanesulfonic acid] with 0-, 50-, 100-, or 200-mmol/L ethanol. After 2 hours of exposure, tissue was removed, fixed, and frozen for analysis. Immunohistochemical analysis was performed for subtype I or neuronal nitric oxide synthase (nNOS), subtype II or inducible nitric oxide synthase (iNOS), and subtype III or endothelial nitric oxide synthase (eNOS) localization. Western blot analysis was performed for eNOS quantitation. Cyclic guanosine monophosphate and copper-zinc superoxide dismutase levels were measured by electroimmunoassay and kinetic assay, respectively. Nitric oxide release was analyzed by a Sievers nitric oxide analyzer. Immunohistochemical examination confirmed that only eNOS was localized to the syncytiotrophoblasts. After ethanol exposure, eNOS protein expression increased 2.5- to 3.0-fold over that of the control. Tissue cyclic guanosine monophosphate content and nitric oxide release into the effluent were decreased, whereas superoxide dismutase levels were increased at higher ethanol levels (P <.05). Ethanol exposure appears to induce oxidative stress, which may account for the decreased nitric oxide release, because nitric oxide may be shunted toward scavenging free radicals. Increased eNOS protein expression may be a response to the increased demand for nitric oxide. Decreased nitric oxide availability could adversely affect placental blood flow regulation, which could, in turn, account for the growth restriction seen in ethanol-exposed fetuses.

Toxicity of Bacillus thuringiensis var. israelensis in aqueous suspension on the South American common frog Leptodactylus latrans (Anura: Leptodactylidae) tadpoles.

PubMed

Lajmanovich, Rafael C; Junges, Celina M; Cabagna-Zenklusen, Mariana C; Attademo, Andrés M; Peltzer, Paola M; Maglianese, Mariana; Márquez, Vanina E; Beccaria, Alejandro J

2015-01-01

The effects of commercial formulations of Bacillus thuringiensisvar.israelensis (Bti) on non-target organisms are still a matter of debate; in amphibians, the risks of Bti are little known. To evaluate the toxicity of a commercial liquid (aqueous suspension, AS) formulation of Bti (Introban(®)) on Leptodactylus latrans tadpoles, including median lethal concentration (LC50) and no-and lowest-observed-effect concentrations (NOEC and LOEC, respectively), as well as the possible effects of Bti on oxidative responses, erythrocytes genotoxicity, and histology of the intestines. In the laboratory, tadpoles were exposed to nominal concentrations of 0 (control), 2.5, 5, 10, 20 and 40 mg/L of formulated Bti-AS. Glutathione S-transferase (GST) and catalase (CAT) activities, as well as formation of erythrocyte nuclear abnormalities (ENAs), and histological effect were measured in tadpoles displaying survival rates >85%. L. latrans tadpoles were sensitive to exposure to Bti-AS, reaching 100% mortality after 48 h of exposure at the highest concentration. Bti-AS induced GST and CAT enzymes and genotoxicity (erythrocyte's nuclear abnormalities), and caused intestine's histopathology. Our results demonstrate that toxicity of Bti-AS is dose-dependent for L. latrans tadpoles and that sublethal exposure alters enzymes of oxidative stress, induces genotoxicity, and causes intestine damage. Further research is needed to evaluate the ecotoxicological risk of the massive use of Bti formulations on amphibian populations that commonly used suburban wastewater or urban waterbodies to reproduce and where this biopesticide is frequently applied. Copyright © 2014 Elsevier Inc. All rights reserved.

Comparative effects of cadmium, zinc, arsenic and chromium on olfactory-mediated neurobehavior and gene expression in larval zebrafish (Danio rerio).

PubMed

Heffern, Kevin; Tierney, Keith; Gallagher, Evan P

2018-05-28

Studies have shown that olfactory-mediated behaviors that are critical to survival can be disrupted by exposure to certain metals. Polluted waterways often contain elevated levels of metals, yet only a subset have been characterized for their potential to cause olfactory toxicity. A larval zebrafish behavioral assay was developed to characterize concentration-response curves for zinc (Zn), hexavalent chromium (Cr), and arsenate (As) olfaction inhibition. Cadmium (Cd), an established olfactory toxicant, was used as a positive control. As expected, following a 24-hour exposure to Cd, we observed a reduced response to taurocholic acid (TCA), a substrate for ciliated olfactory sensory neurons (OSNs), thus validating the behavioral assay. Zn exposure similarly decreased the olfactory response toward TCA, (IC 50 : 36 μg/L and 76 μg/L, for Cd and Zn, respectively). The response towards a secondary odorant L-cysteine (Cys), a substrate for ciliated and microvillous OSNs, was significantly altered by both Cd and Zn exposure, although the response to Cys was not completely removed in Zn treated larvae, suggesting preferential toxicity towards ciliated OSNs. No significant changes in olfactory responses were observed following Cr and As exposures. Exposures to binary mixtures of Cd and Zn indicated that Zn had a protective effect against Cd toxicity at low Zn concentrations. QuantiGene (QDP) RNA analysis revealed Cd to be a potent inducer of metallothionein 2 (mt2) mRNA in zebrafish larvae, and Zn to be a weak mt2 inducer, suggesting a protective role of mt2 in Cd and Zn olfactory injury. By contrast, QDP analysis of eight other genes important in mitigating the effects of oxidative stress suggested an antioxidant response to Cd, but not Zn, As, and Cr suggesting that oxidative stress was not a primary mechanism of Zn-induced olfactory dysfunction. In summary, our study indicates that Zn inhibits zebrafish olfaction at environmental concentrations and may potentially mitigate Cd induced olfactory dysfunction when present in mixtures. The zebrafish behavioral trough assay incorporating the odorants L-cysteine and TCA is an effective assay to assess the effects of metals on olfactory function. Copyright © 2018 Elsevier B.V. All rights reserved.

Voltammetric Response of Alizarin Red S-Confined Film-Coated Electrodes to Diol and Polyol Compounds: Use of Phenylboronic Acid-Modified Poly(ethyleneimine) as Film Component

PubMed Central

Takahashi, Shigehiro; Suzuki, Iwao; Ojima, Takuto; Minaki, Daichi

2018-01-01

Alizarin red S (ARS) was confined in layer-by-layer (LbL) films composed of phenylboronic acid-modified poly(ethyleneimine) (PBA-PEI) and carboxymethylcellulose (CMC) to study the voltammetric response to diol and polyol compounds. The LbL film-coated gold (Au) electrode and quartz slide were immersed in an ARS solution to uptake ARS into the film. UV-visible absorption spectra of ARS-confined LbL film suggested that ARS formed boronate ester (ARS-PBS) in the film. The cyclic voltammetry of the ARS-confined LbL film-coated electrodes exhibited oxidation peaks at −0.50 and −0.62 V, which were ascribed to the oxidation reactions of ARS-PBS and free ARS, respectively, in the LbL film. The peak current at −0.62 V increased upon the addition of diol or polyol compounds such as L-dopa, glucose, and sorbitol into the solution, depending on the concentration, whereas the peak current at −0.50 V decreased. The results suggest a possible use of ARS-confined PBA-PEI/CMC LbL film-coated Au electrodes for the construction of voltammetric sensors for diol and polyol compounds. PMID:29361775

Induction of the nuclear factor HIF-1{alpha} in acetaminophen toxicity: Evidence for oxidative stress

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

James, Laura P.; Donahower, Brian; Burke, Angela S.

2006-04-28

Hypoxia inducible factor (HIF) controls the transcription of genes involved in angiogenesis, erythropoiesis, glycolysis, and cell survival. HIF-1{alpha} levels are a critical determinant of HIF activity. The induction of HIF-1{alpha} was examined in the livers of mice treated with a toxic dose of APAP (300 mg/kg IP) and sacrificed at 1, 2, 4, 8, and 12 h. HIF-1{alpha} was induced at 1-12 h and induction occurred prior to the onset of toxicity. Pre-treatment of mice with N-acetylcysteine (1200 mg/kg IP) prevented toxicity and HIF-1{alpha} induction. In further studies, hepatocyte suspensions were incubated with APAP (1 mM) in the presence ofmore » an oxygen atmosphere. HIF-1{alpha} was induced at 1 h, prior to the onset of toxicity. Inclusion of cyclosporine A (10 {mu}M), an inhibitor of mitochondrial permeability transition, oxidative stress, and toxicity, prevented the induction of HIF-1{alpha}. Thus, HIF-1{alpha} is induced before APAP toxicity and can occur under non-hypoxic conditions. The data suggest a role for oxidative stress in the induction of HIF-1{alpha} in APAP toxicity.« less

l-DOPA and Freezing of Gait in Parkinson’s Disease: Objective Assessment through a Wearable Wireless System

PubMed Central

Suppa, Antonio; Kita, Ardian; Leodori, Giorgio; Zampogna, Alessandro; Nicolini, Ettore; Lorenzi, Paolo; Rao, Rosario; Irrera, Fernanda

2017-01-01

Freezing of gait (FOG) is a leading cause of falls and fractures in Parkinson’s disease (PD). The episodic and rather unpredictable occurrence of FOG, coupled with the variable response to l-DOPA of this gait disorder, makes the objective evaluation of FOG severity a major clinical challenge in the therapeutic management of patients with PD. The aim of this study was to examine and compare gait, clinically and objectively, in patients with PD, with and without FOG, by means of a new wearable system. We also assessed the effect of l-DOPA on FOG severity and specific spatiotemporal gait parameters in patients with and without FOG. To this purpose, we recruited 28 patients with FOG, 16 patients without FOG, and 16 healthy subjects. In all participants, gait was evaluated clinically by video recordings and objectively by means of the wearable wireless system, during a modified 3-m Timed Up and Go (TUG) test. All patients performed the modified TUG test under and not under dopaminergic therapy (ON and OFF therapy). By comparing instrumental data with the clinical identification of FOG based on offline video-recordings, we also assessed the performance of the wearable system to detect FOG automatically in terms of sensitivity, specificity, positive and negative predictive values, and finally accuracy. TUG duration was longer in patients than in controls, and the amount of gait abnormalities was prominent in patients with FOG compared with those without FOG. l-DOPA improved gait significantly in patients with PD and particularly in patients with FOG mainly by reducing FOG duration and increasing specific spatiotemporal gait parameters. Finally, the overall wireless system performance in automatic FOG detection was characterized by excellent sensitivity (93.41%), specificity (98.51%), positive predictive value (89.55%), negative predictive value (97.31%), and finally accuracy (98.51%). Our study overall provides new information on the beneficial effect of l-DOPA on FOG severity and specific spatiotemporal gait parameters as objectively measured by a wearable sensory system. The algorithm here reported potentially opens to objective long-time sensing of FOG episodes in patients with PD. PMID:28855889

The potential protective role of Physalis peruviana L. fruit in cadmium-induced hepatotoxicity and nephrotoxicity.

PubMed

Dkhil, Mohamed A; Al-Quraishy, Saleh; Diab, Marwa M S; Othman, Mohamed S; Aref, Ahmed M; Abdel Moneim, Ahmed E

2014-12-01

This study aimed to investigate the potential protective role of Physalis peruviana L. (family Solanaceae) against cadmium-induced hepatorenal toxicity in Wistar rats. Herein, cadmium chloride (CdCl2) (6.5 mg/kg bwt/day) was intraperitoneally injected for 5 days, and methanolic extract of physalis (MEPh) was pre-administered to a group of Cd-treated rats by an oral administration at a daily dose of 200 mg/kg bwt for 5 days. The findings revealed that CdCl2 injection induced significant decreases in kidney weight and kidney index. Cadmium intoxication increased the activities of liver enzymes and the bilirubin level, in addition to the levels of uric acid, urea and creatinine were increased in the serum. The pre-administration of MEPh alleviated hepatorenal toxicity in Cd-treated rats. Physalis was noted to play a good hepatorenal protective role, reducing lipid peroxidation, nitric oxide, and enhancing enzymatic activities and non-enzymatic antioxidant molecule, glutathione, in hepatic and renal tissues of Cd-treated rats. Moreover, physalis treatment was able to reverse the histopathological changes in liver and kidney tissues and also increased the expression of Bcl-2 protein in liver and kidney of rats. Overall, the results showed that MEPh can induce antioxidant and anti-apoptotic effects and also exerts beneficial effects for the treatment of Cd-induced hepatorenal toxicity. Copyright © 2014 Elsevier Ltd. All rights reserved.

Articulation disorders and duration, severity and L-dopa dosage in idiopathic Parkinson's disease.

PubMed

Pawlukowska, Wioletta; Gołąb-Janowska, Monika; Safranow, Krzysztof; Rotter, Iwona; Amernik, Katarzyna; Honczarenko, Krystyna; Nowacki, Przemysław

2015-01-01

Parkinson's disease (PD) is one of the most common diseases of the central nervous system (CNS). It is frequently heralded by speech disturbances, which are one of its first symptoms. The aim of this paper is to share our own experience concerning the correlation between the severity of speech disorders and the PD duration, its severity and the intake of L-dopa. The research included 93 patients with idiopathic PD, aged 26-86 years (mean age 65.1 years). Participants were examined neurologically according to the Unified Parkinson's Disease Rating Scale (UPDRS) and the Hoehn and Yahr Scale. They were also assessed by Frenchay Dysarthria Assessment. Considerable and severe disorders were concurrent with impairments in the mobility of the tongue, lips, the jaw as well as the pitch and loudness of the voice. The strongest correlation but at a moderate level was found to exist between the severity of labial impairment, voice loudness and the length of the disease. There was also a positive correlation between lip movement while the motions were being diversified, lip arrangement while speaking and the intake of L-dopa. As PD progresses a significant decline in vocal articulation can be observed, which is due to reduced mobility within the lips and the jaw. Exacerbation of articulation disorders resulting from progression of the disease does not materially influence the UPDRSS scores. L-dopa has been found to positively affect the mobility of the lips while the patient is speaking and their arrangement at rest. Copyright © 2015 Polish Neurological Society. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.

Impaired intracortical transmission in G2019S leucine rich-repeat kinase Parkinson patients.

PubMed

Ponzo, Viviana; Di Lorenzo, Francesco; Brusa, Livia; Schirinzi, Tommaso; Battistini, Stefania; Ricci, Claudia; Sambucci, Manolo; Caltagirone, Carlo; Koch, Giacomo

2017-05-01

A mutation in leucine-rich repeat kinase 2 is the most common cause of hereditary Parkinson's disease (PD), yet the neural mechanisms and the circuitry potentially involved are poorly understood. We used different transcranial magnetic stimulation protocols to explore in the primary motor cortex the activity of intracortical circuits and cortical plasticity (long-term potentiation) in patients with the G2019S leucine-rich repeat kinase 2 gene mutation when compared with idiopathic PD patients and age-matched healthy subjects. Paired pulse transcranial magnetic stimulation was used to investigate short intracortical inhibition and facilitation and short afferent inhibition. Intermittent theta burst stimulation, a form of repetitive transcranial magnetic stimulation, was used to test long-term potentiation-like cortical plasticity. Leucine-rich repeat kinase 2 and idiopathic PD were tested both in ON and in OFF l-dopa therapy. When compared with idiopathic PD and healthy subjects, leucine-rich repeat kinase 2 PD patients showed a remarkable reduction of short intracortical inhibition in both ON and in OFF l-dopa therapy. This reduction was paralleled by an increase of intracortical facilitation in OFF l-dopa therapy. Leucine-rich repeat kinase 2 PD showed abnormal long-term potentiation-like cortical plasticity in ON l-dopa therapy. The motor cortex in leucine-rich repeat kinase 2 mutated PD patients is strongly disinhibited and hyperexcitable. These abnormalities could be a result of an impairment of inhibitory (gamma-Aminobutyric acid) transmission eventually related to altered neurotransmitter release. © 2017 International Parkinson and Movement Disorder Society. © 2017 International Parkinson and Movement Disorder Society.

Stronger Dopamine D1 Receptor-Mediated Neurotransmission in Dyskinesia.

PubMed

Farré, Daniel; Muñoz, Ana; Moreno, Estefanía; Reyes-Resina, Irene; Canet-Pons, Júlia; Dopeso-Reyes, Iria G; Rico, Alberto J; Lluís, Carme; Mallol, Josefa; Navarro, Gemma; Canela, Enric I; Cortés, Antonio; Labandeira-García, José L; Casadó, Vicent; Lanciego, José L; Franco, Rafael

2015-12-01

Radioligand binding assays to rat striatal dopamine D1 receptors showed that brain lateralization of the dopaminergic system were not due to changes in expression but in agonist affinity. D1 receptor-mediated striatal imbalance resulted from a significantly higher agonist affinity in the left striatum. D1 receptors heteromerize with dopamine D3 receptors, which are considered therapeutic targets for dyskinesia in parkinsonian patients. Expression of both D3 and D1-D3 receptor heteromers were increased in samples from 6-hydroxy-dopamine-hemilesioned rats rendered dyskinetic by treatment with 3, 4-dihydroxyphenyl-L-alanine (L-DOPA). Similar findings were obtained using striatal samples from primates. Radioligand binding studies in the presence of a D3 agonist led in dyskinetic, but not in lesioned or L-DOPA-treated rats, to a higher dopamine sensitivity. Upon D3-receptor activation, the affinity of agonists for binding to the right striatal D1 receptor increased. Excess dopamine coming from L-DOPA medication likely activates D3 receptors thus making right and left striatal D1 receptors equally responsive to dopamine. These results show that dyskinesia occurs concurrently with a right/left striatal balance in D1 receptor-mediated neurotransmission.

Protective effect of Uncaria tomentosa extract against oxidative stress and genotoxicity induced by glyphosate-Roundup® using zebrafish (Danio rerio) as a model.

PubMed

Santo, Glaucia Dal; Grotto, Alan; Boligon, Aline A; Da Costa, Bárbara; Rambo, Cassiano L; Fantini, Emily A; Sauer, Elisa; Lazzarotto, Luan M V; Bertoncello, Kanandra T; Júnior, Osmar Tomazelli; Garcia, Solange C; Siebel, Anna M; Rosemberg, Denis B; Magro, Jacir Dal; Conterato, Greicy M M; Zanatta, Leila

2018-04-01

Oxidative stress and DNA damage are involved in the glyphosate-based herbicide toxicity. Uncaria tomentosa (UT; Rubiaceae) is a plant species from South America containing bioactive compounds with known beneficial properties. The objective of this work was to evaluate the antioxidant and antigenotoxic potential of UT extract in a model of acute exposure to glyphosate-Roundup® (GR) in zebrafish (Danio rerio). We showed that UT (1.0 mg/mL) prevented the decrease of brain total thiols, the increase of lipid peroxidation in both brain and liver, and the decrease of liver GPx activity caused after 96 h of GR (5.0 mg/L) exposure. In addition, UT partially protected against the increase of micronucleus frequency induced by GR exposure in fish brain. Overall, our results indicate that UT protects against damage induced by a glyphosate-based herbicide by providing antioxidant and antigenotoxic effects, which may be related to the phenolic compounds identified in the extract.

Genotoxicity and oxidative stress induced by the fungicide azoxystrobin in zebrafish (Danio rerio) livers.

PubMed

Han, Yingnan; Liu, Tong; Wang, Jinhua; Wang, Jun; Zhang, Cheng; Zhu, Lusheng

2016-10-01

Azoxystrobin is a frequently used fungicide in agriculture. Its toxicological effects on non-target organisms have aroused attention. In the present work, the toxic effects of azoxystrobin on zebrafish (Danio rerio) were investigated. Male and female zebrafish were separately exposed to a control solution and three azoxystrobin treatments (1, 10, and 100μg/L) and were sampled on days 7, 14, 21, and 28. Reactive oxygen species (ROS) were accumulated in excess in the zebrafish livers. Superoxide dismutase (SOD) activity was significantly inhibited in the male zebrafish. Moreover, a notable decrease was also observed after day 21 in the female zebrafish. Catalase (CAT) activity was induced by the azoxystrobin treatments with the exception of the 1μg/L treatment. A significant increase in glutathione-S-transferase (GST) activity was observed after day 21. Lipid peroxidation (LPO) was generated, and DNA damage was enhanced in a concentration-dependent manner. In conclusion, azoxystrobin induced oxidative stress and genotoxicity in zebrafish livers. Copyright © 2016 Elsevier Inc. All rights reserved.

Modulatory effect of pineapple peel extract on lipid peroxidation, catalase activity and hepatic biomarker levels in blood plasma of alcohol-induced oxidative stressed rats

PubMed Central

Okafor, OY; Erukainure, OL; Ajiboye, JA; Adejobi, RO; Owolabi, FO; Kosoko, SB

2011-01-01

Objective To investigate the ability of the methanolic extract of pineapple peel to modulate alcohol-induced lipid peroxidation, changes in catalase activities and hepatic biochemical marker levels in blood plasma. Methods Oxidative stress was induced by oral administration of ethanol (20% w/v) at a dosage of 5 mL/kg bw in rats. After 28 days of treatment, the rats were fasted overnight and sacrificed by cervical dislocation. Blood was collected with a 2 mL syringe by cardiac puncture and was centrifuged at 3 000 rpm for 10 min. The plasma was analyzed to evaluate malondialdehyde (MDA), catalase activity, aspartate aminotransferase (AST), alkaline phosphatase (ALP) and alanine aminotransferase (ALT) concentrations. Results Administration of alcohol caused a drastic increase (87.74%) in MDA level compared with the control. Pineapple peel extract significantly reduced the MDA level by 60.16% at 2.5 mL/kg bw. Rats fed alcohol only had the highest catalase activity, treatment with pineapple peel extract at 2.5 mL/kg bw however, reduced the activity. Increased AST, ALP and ALT activities were observed in rats fed alcohol only respectively, treatment with pineapple peel extract drastically reduced their activities. Conclusions The positive modulation of lipid peroxidation, catalase activities as well as hepatic biomarker levels of blood plasma by the methanolic extract of pineapple peels under alcohol-induced oxidative stress is an indication of its protective ability in the management of alcohol-induced toxicity. PMID:23569717

Morus alba leaf extract mediates neuroprotection against glyphosate-induced toxicity and biochemical alterations in the brain.

PubMed

Rebai, Olfa; Belkhir, Manel; Boujelben, Adnen; Fattouch, Sami; Amri, Mohamed

2017-04-01

Recent studies demonstrate that glyphosate exposure is associated with oxidative stress and some neurological disorders such as Parkinson's pathology. Therefore, phytochemicals, in particular phenolic compounds, have attracted increasing attention as potential agents for neuroprotection. In the present study, we investigate the impact of glyphosate on the rat brain following i.p. injection and the possible molecular target of neuroprotective activity of the phenolic fraction from Morus alba leaf extract (MALE) and its ability to reduce oxidative damage in the brain. Wistar rats from 180 to 240 g were i.p. treated with a single dose of glyphosate (100 mg kg -1 b.w.) or MALE (100 μg mL -1  kg -1 b.w.) for 2 weeks. Brain homogenates were used to evaluate neurotoxicity induced by the pesticide. For this, biochemical parameters were measured. Data shows that MALE regulated oxidative stress and counteracted glyphosate-induced deleterious effects and oxidative damage in the brain, as it abrogated LDH, protein carbonyls, and malonyldialdehyde. MALE also appears to be able to scavenge H 2 O 2 levels, maintain iron and Ca 2+ homeostasis, and increase SOD activity. Thus, in vivo results showed that mulberry leaf extract is a potent protector against glyphosate-induced toxicity, and its protective effect could result from synergism or antagonism between the various bioactive phenolic compounds in the acetonic fraction from M. alba leaf extract.

Cerebral metabonomics study on Parkinson's disease mice treated with extract of Acanthopanax senticosus harms.

PubMed

Li, Xu-zhao; Zhang, Shuai-nan; Lu, Fang; Liu, Chang-feng; Wang, Yu; Bai, Yu; Wang, Na; Liu, Shu-min

2013-10-15

Extract of Acanthopanax senticosus harms (EAS) has neuroprotective effect on Parkinson's disease (PD) mice against dopaminergic neuronal damage. However, studies of its anti-PD mechanism are challenging, owing to the complex pathophysiology of PD, and complexity of EAS with multiple constituents acting on different metabolic pathways. Here, we have investigated the metabolic profiles and potential biomarkers in a mice model of MPTP-induced PD after treatment of EAS. Metabonomics based on ultra-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UPLC-QTOF-MS) was used to profile the metabolic fingerprints of mesencephalon obtained from 1-Methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine Hydrochloride (MPTP-HCl)-induced PD mice model with and without EAS treatment. Through partial least squares-discriminate analysis (PLS-DA), it was observed that metabolic perturbations induced by MPTP were restored after treatment with EAS. Metabolites with significant changes induced by MPTP, including L-dopa, 5'-methylthioadenosine, tetradecanoylcarnitine, phytosphingosine-1-P, Cer(d18:0/18:0), LysoPC(20:4(5Z,8Z,11Z,14Z)), L-palmitoyl -carnitine, tetracosanoylglycine, morphiceptin and stearoylcarnitine, were characterized as potential biomarkers involved in the pathogenesis of PD. The derivations of all those biomarkers can be regulated by EAS treatment except Cer(d18:0/18:0), LysoPC(20:4(5Z,8Z,11Z,14Z)), morphiceptin. The therapeutic effect of EAS on PD may involve in regulating the tyrosine metabolism, mitochondrial beta-oxidation of long chain saturated fatty acids, fatty acid metabolism, methionine metabolism, and sphingolipid metabolism. This study indicated that changed metabolites can be certainly recovered by EAS, and the treatment of EAS can be connected with the regulation of related metabolic pathways. Copyright © 2013 Elsevier GmbH. All rights reserved.

Short-term secretory regulation of ghrelin during growth hormone provocative tests in prepubertal children with various growth hormone secretory capacities.

PubMed

Matsuoka, Hisafumi; Hosoda, Hiroshi; Sugawara, Hisae; Iwama, Saika; Kim, Hye Sook; Kangawa, Kenji; Sugihara, Shigetaka

2005-01-01

Ghrelin is a novel gastric peptide which stimulates GH secretion and has been demonstrated to have orexigenic and adipogenic properties. Insulin is a physiological and dynamic modulator of plasma ghrelin, and insulinemia possibly mediates the effect of the nutritional state on the plasma concentrations of ghrelin in adults. No data on the regulation of GH secretion by ghrelin have so far been reported, nor has the possible influence of hypoglycemia on the plasma ghrelin levels in children been reported. Provocative studies were performed using a variety of stimuli, including insulin-induced hypoglycemia, and glucagon, arginine and L-dopa loading. We studied a group of 27 children with short stature being investigated for GH deficiency (10 F, 17 M; age 4-14 years; height SDS -0.92 to -3.27); the subjects were instructed to fast overnight, and the following morning, the relationships among the plasma ghrelin, GH and glucose levels were investigated by determining the plasma ghrelin profiles during those provocative tests. Using a new method for determining the two types of ghrelin, samples were obtained for determination of the plasma ghrelin, serum glucose and serum GH levels after the administration of the aforementioned stimulating agents. All the four stimuli caused a significant decrease in the circulating C- and N-ghrelin levels with a nadir at +30 min, with the exception of the N-ghrelin level following the L-dopa loading. During the same period, the plasma GH level increased following insulin, arginine and L-dopa loading, and the plasma glucose level increased significantly following glucagon loading. In the arginine and L-dopa load connected, a significant correlation was observed between the 30-min change in the serum GH level and the 30-min change in the plasma C-ghrelin level. In the multiple regression analysis to explain the 30-min change in the plasma level of C-ghrelin, the baseline plasma level of C-ghrelin (basal), height and % overweight were the only three significant parameters, accounting for 85.2% of the variance. This study demonstrated that the inverse relation between the circulating GH and ghrelin levels may indicate the existence of a feedback loop, and also lends support to the assumption of a GH-independent relationship between plasma ghrelin and glucose levels. These observations constitute further evidence to suggest that peripheral ghrelin is a direct growth-promoting hormone. Copyright 2005 S. Karger AG, Basel

Long-term effect of sub-anesthetic ketamine in reducing L-DOPA-induced dyskinesias in a preclinical model.

PubMed

Bartlett, Mitchell J; Joseph, Ria M; LePoidevin, Lindsey M; Parent, Kate L; Laude, Nicholas D; Lazarus, Levi B; Heien, Michael L; Estevez, Miguel; Sherman, Scott J; Falk, Torsten

2016-01-26

Low-dose sub-anesthetic ketamine infusion treatment has led to a long-term reduction of treatment-resistant depression and posttraumatic stress disorder (PTSD) symptom severity, as well as reduction of chronic pain states, including migraine headaches. Ketamine also is known to change oscillatory electric brain activity. One commonality between migraine headaches, depression, PTSD, Parkinson's disease (PD) and l-DOPA-induced dyskinesias (LID) is hypersynchrony of electric activity in the brain, including the basal ganglia. Therefore, we investigated the use of low-dose sub-anesthetic ketamine in the treatment of LID. In a preclinical rodent model of LID, ketamine (5-20mg/kg) led to long-term dose-dependent reduction of abnormal involuntary movements, only when low-dose ketamine was given for 10h continuously (5× i.p. injections two hours apart) and not after a single acute low-dose ketamine i.p. injection. Pharmacokinetic analysis of plasma levels showed ketamine and its major metabolites were not detectable any more at time points when a lasting anti-dyskinetic effect was seen, indicating a plastic change in the brain. This novel use of low-dose sub-anesthetic ketamine infusion could lead to fast clinical translation, and since depression and comorbid pain states are critical problems for many PD patients could open up the road to a new dual therapy for patients with LID. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Acute Pre-/Post-Treatment with 8th Day SOD-Like Supreme (a Free Radical Scavenging Health Product) Protects against Oxidant-Induced Injury in Cultured Cardiomyocytes and Hepatocytes In Vitro as Well as in Mouse Myocardium and Liver In Vivo.

PubMed

Leong, Pou Kuan; Chen, Jihang; Chan, Wing Man; Leung, Hoi Yan; Chan, Lincoln; Ko, Kam Ming

2017-04-10

8th Day superoxide dismutase (SOD)-Like Supreme (SOD-Like Supreme, a free radical scavenging health product) is an antioxidant-enriched fermentation preparation with free radical scavenging properties. In the present study, the cellular/tissue protective actions of SOD-Like Supreme against menadione toxicity in cultured H9c2 cardiomyocytes and in AML12 hepatocytes as well as oxidant-induced injury in the mouse myocardium and liver were investigated. SOD-Like Supreme was found to possess potent free radical scavenging activity in vitro as assessed by an oxygen radical absorbance capacity assay. Incubation with SOD-Like Supreme (0.5-3% (v/v)) was shown to protect against menadione-induced toxicity in H9c2 and AML12 cells, as evidenced by increases in cell viability. The ability of SOD-Like Supreme to protect against menadione cytotoxicity was associated with an elevation in the cellular reduced glutathione (GSH)/oxidized glutathione (GSSG) ratio in menadione-challenged cells. Consistent with the cell-based studies, pre-/post-treatment with SOD-Like Supreme (0.69 and 2.06 mL/kg, three intermittent doses per day for two consecutive days) was found to protect against isoproterenol-induced myocardial injury and carbon tetrachloride hepatotoxicity in mice. The cardio/hepatoprotection afforded by SOD-Like Supreme was also paralleled by increases in myocardial/hepatic mitochondrial GSH/GSSG ratios in the SOD-Like Supreme-treated/oxidant-challenged mice. In conclusion, incubation/treatment with SOD-Like Supreme was found to protect against oxidant-induced injury in vitro and in vivo, presumably by virtue of its free radical scavenging activity.

Evaluation of free radical scavenging capacity and antioxidative damage effect of resveratrol-nanostructured lipid carriers

NASA Astrophysics Data System (ADS)

Jin, Ju; Shi, Fan; Li, Qiu-wen; Li, Pei-shan; Chen, Tong-sheng; Wang, Yi-fei; Wang, Zhi-ping

2016-03-01

Cellular damage induced by free-radicals like reactive oxygen species has been implicated in several diseases. 2, 2-azobis(2-amidino-propane) dihydrochloride(AAPH) generates two potent ROS capable of inducing lipid peroxidation: alkoxy radical(RO-) and peroxy radical(ROO-). These radicals are similar to those that are physiologically active and thus might initiate a cascade of intracellular toxic events leading to oxidation, lipid peroxidation, DNA damage and subsequent cell death. Hence naturally anti-oxidant play a vital role in combating these conditions. In this study, resveratrol loaded nanostructured lipid carriers (Res-NLC) was prepared by hot melting and then high pressure homogenization technique. The effects of Res-NLC on free radical scavenging capacity and antioxidative damage is investigated. The particle size and zeta potential of Res-NLC were 139.3 ± 1.7 nm and -11.21 ± 0.41 mV, respectively. By free radical scavenging assays, the IC50 value of Res-NLC were 19.25, 5.29 μg/mL with DPPH, ABTS assay respectively, and 0.161 mg ferrous sulfate/1 mg Res-NLC with FRAP assay; and by AAPH-induced oxidative injury cell model assay, Res-NLC showed the strong protective effect against the human liver tumor HepG2 cell oxidative stress damage. These results indicated that the antioxidant properties of Res-NLC hold great potential used as an alternative to more toxic synthetic antioxidants as an additive in food, cosmetic and pharmaceutical preparations for the oxidative diseases treatment.

Mucuna pruriens and Its Major Constituent L-DOPA Recover Spermatogenic Loss by Combating ROS, Loss of Mitochondrial Membrane Potential and Apoptosis

PubMed Central

Singh, Akhand Pratap; Sarkar, Saumya; Tripathi, Muktanand; Rajender, Singh

2013-01-01

Background The Ayurvedic medicinal system claims Mucuna pruriens (MP) to possess pro-male fertility, aphrodisiac and adaptogenic properties. Some scientific evidence also supports its pro-male fertility properties; however, the mechanism of its action is not yet clear. The present study aimed at demonstrating spermatogenic restorative efficacy of MP and its major constituent L-DOPA (LD), and finding the possible mechanism of action thereof in a rat model. Methodology/Findings Ethinyl estradiol (EE) was administered at a rate of 3 mg/kg body weight (BW)/day for a period of 14 days to generate a rat model with compromised spermatogenesis. MP and LD were administered in two separate groups of these animals starting 15th day for a period of 56 days, and the results were compared with an auto-recovery (AR) group. Sperm count and motility, testis histo-architecture, level of reactive oxygen species (ROS), mitochondrial membrane potential (MMP), apoptosis, peripheral hormone levels and testicular germ cell populations were analysed, in all experimental groups. We observed efficient and quick recovery of spermatogenesis in MP and LD groups in comparison to the auto-recovery group. The treatment regulated ROS level, apoptosis, and mitochondrial membrane potential (MMP), recovered the hypothalamic-pituitary-gonadal axis and the number of testicular germ cells, ultimately leading to increased sperm count and motility. Conclusion/Significance M. pruriens efficiently recovers the spermatogenic loss induced due to EE administration. The recovery is mediated by reduction in ROS level, restoration of MMP, regulation of apoptosis and eventual increase in the number of germ cells and regulation of apoptosis. The present study simplified the complexity of mechanism involved and provided meaningful insights into MP/LD mediated correction of spermatogenic impairment caused by estrogens exposure. This is the first study demonstrating that L-DOPA largely accounts for pro-spermatogenic properties of M. pruriens. The manuscript bears CDRI communication number 8374. PMID:23349947

Mucuna pruriens and its major constituent L-DOPA recover spermatogenic loss by combating ROS, loss of mitochondrial membrane potential and apoptosis.

PubMed

Singh, Akhand Pratap; Sarkar, Saumya; Tripathi, Muktanand; Rajender, Singh

2013-01-01

The Ayurvedic medicinal system claims Mucuna pruriens (MP) to possess pro-male fertility, aphrodisiac and adaptogenic properties. Some scientific evidence also supports its pro-male fertility properties; however, the mechanism of its action is not yet clear. The present study aimed at demonstrating spermatogenic restorative efficacy of MP and its major constituent L-DOPA (LD), and finding the possible mechanism of action thereof in a rat model. Ethinyl estradiol (EE) was administered at a rate of 3 mg/kg body weight (BW)/day for a period of 14 days to generate a rat model with compromised spermatogenesis. MP and LD were administered in two separate groups of these animals starting 15(th) day for a period of 56 days, and the results were compared with an auto-recovery (AR) group. Sperm count and motility, testis histo-architecture, level of reactive oxygen species (ROS), mitochondrial membrane potential (MMP), apoptosis, peripheral hormone levels and testicular germ cell populations were analysed, in all experimental groups. We observed efficient and quick recovery of spermatogenesis in MP and LD groups in comparison to the auto-recovery group. The treatment regulated ROS level, apoptosis, and mitochondrial membrane potential (MMP), recovered the hypothalamic-pituitary-gonadal axis and the number of testicular germ cells, ultimately leading to increased sperm count and motility. M. pruriens efficiently recovers the spermatogenic loss induced due to EE administration. The recovery is mediated by reduction in ROS level, restoration of MMP, regulation of apoptosis and eventual increase in the number of germ cells and regulation of apoptosis. The present study simplified the complexity of mechanism involved and provided meaningful insights into MP/LD mediated correction of spermatogenic impairment caused by estrogens exposure. This is the first study demonstrating that L-DOPA largely accounts for pro-spermatogenic properties of M. pruriens. The manuscript bears CDRI communication number 8374.

Resveratrol protects against arsenic trioxide-induced oxidative damage through maintenance of glutathione homeostasis and inhibition of apoptotic progression

PubMed Central

Chen, Chengzhi; Jiang, Xuejun; Lai, Yanhao; Liu, Yuan; Zhang, Zunzhen

2014-01-01

Arsenic trioxide (As2O3) is commonly used to treat acute promyelocytic leukemia and solid tumors. However, the clinical application of the agent is limited by its cyto- and genotoxic effects on normal cells. Thus, relief of As2O3 toxicity in normal cells is essentially necessary for improvement of As2O3-mediated chemotherapy. In this study, we have identified a series of protective effects of resveratrol against As2O3-induced oxidative damage in normal human bronchial epithelial (HBE) cells. We showed that treatment of HBE cells with resveratrol significantly reduced cellular levels of DNA damage, chromosomal breakage and apoptosis induced by As2O3. The effect of resveratrol against DNA damage was associated with a decreased level of reactive oxygen species and lipid peroxidation in cells treated by As2O3, suggesting that resveratrol protects against As2O3 toxicity via a cellular anti-oxidative stress pathway. Further analysis of the roles of resveratrol demonstrated that it modulated biosynthesis, recycling and consumption of glutathione (GSH), thereby promoting GSH homeostasis in HBE cells treated by As2O3. This was further supported by results showing that resveratrol prevented an increase in the activities and levels of caspases, Fas, Fas-L and cytochrome c proteins induced by As2O3. Our study indicates that resveratrol relieves As2O3-induced oxidative damage in normal human lung cells via maintenance of GSH homeostasis and suppression of apoptosis. PMID:25339131

Evaluation of free radical scavenging and anti-oxidative capacity of polydatin-nanostructured lipid carriers

NASA Astrophysics Data System (ADS)

Meng, Xiang-Ping; Shi, Fan; Li, Hai-Jie; Yin, Li-De; Wang, Yi-Fei; Wang, Zhi-ping; Chen, Tong-sheng

2016-10-01

Cellular damage induced by free-radicals like reactive oxygen species has been implicated in several diseases. 2, 2-azobis(2-amidino-propane) dihydrochloride(AAPH) generates two potent ROS capable of inducing lipid peroxidation: alkoxy radical(RO-) and peroxy radical (ROO-). These radicals are similar to those that are physiologically active and thus might initiate a cascade of intracellular toxic events leading to oxidation, lipid peroxidation, DNA damage and subsequent cell death. Hence naturally anti-oxidant play a vital role in combating these conditions. In this study, polydatin loaded nanostructured lipid carriers (Pol-NLC) was prepared by hot melting and then high pressure homogenization technique. The effects of Pol-NLC on free radical scavenging and anti-oxidative capacity is investigated. The particle size and zeta potential of Pol-NLC were 113.9 +/- 1.1 nm and -16.3 1 +/- 0.27 mV, respectively. By free radical scavenging assays, the IC50 value of Pol-NLC were 28.71, 9.83 μg/mL with DPPH, ABTS assay respectively, and 0.143 mg ferrous sulfate/1 mg Pol-NLC with FRAP assay. These results indicated that the antioxidant properties of Pol-NLC hold great potential used as an alternative to more toxic synthetic anti-oxidants as an additive in food, cosmetic and pharmaceutical preparations for the oxidative diseases treatment.

Proteome Profiling Reveals Potential Toxicity and Detoxification Pathways Following Exposure of BEAS-2B Cells to Engineered Titanium Dioxide Nanoparticles

EPA Science Inventory

Oxidative stress is known to play important roles in engineered nanomaterial induced cellular toxicity. However, the proteins and signaling pathways associated with the engineered nanomaterial mediated oxidative stress and toxicity are largely unknown. To identify these toxicity ...

Enantioselective apoptosis and oxidative damage induced by individual isomers of profenofos in primary hippocampal neurons.

PubMed

Lu, Xian T; Ma, Yun; Zhang, Hang J; Jin, Mei Q; Tang, Jun H

2017-07-03

The purpose of this study was to investigate the apoptosis-related cytotoxic effects and molecular mechanisms of individual isomers of profenofos (PFF) on primary hippocampal neurons at 1.0 to 20 mg L -1 . The cell viability and lactate dehydrogenase (LDH) efflux indicated that (-)-PFF exposure was associated with more toxic effects than (+)-PFF above the concentration of 5 mg L -1 (P < 0.5). Flow cytometric results showed that the percentages of apoptotic cells incubated with 20 mg L -1 (-)-PFF, (+)-PFF and rac-PFF for 24 h reached 23.4%, 9.2% and 14.2% (P < 0.01), respectively. Hippocampal neurons incubated with (-)-PFF, (+)-PFF and rac-PFF exhibited a dose-dependent accumulation of intracellular reactive oxygen species (ROS) and malondialdehyde (MDA) and a dose-dependent inhibition of superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx) activity, implying that the defense system of the tests induces oxidative damage. A statistically significant difference was observed between the two enantiomers at 5 mg L -1 and above. Moreover, the results showed that (-)-PFF exposure caused a significant loss in mitochondrial transmembrane potential (MMP), an upregulation of Ca 2+ and Bax protein expression, a downregulation of Bcl-2 protein expression, and the activation of caspase-3 and caspase-9 in a dose-dependent manner; (+)-PFF and rac-PFF exhibited these effects to a lesser degree. All results suggest that PFF induced apoptosis in rat hippocampal neurons via the mitochondria-mediated pathway, and oxidative stress is one of the factors of PFF-induced apoptosis. In addition, (-)-PFF appears to play an important role in oxidative stress and apoptosis, indicating that enantioselectivity should be considered when assessing ecotoxicological effects and health risks of chiral pesticides.

Citrus Epicarp-Derived Biochar Reduced Cd Uptake and Ameliorates Oxidative Stress in Young Abelmoschus esculentus (L.) Moench (okra) Under Low Cd Stress.

PubMed

Ogunkunle, Clement O; Varun, Mayank; Ogundele, Iyanuoluwa G; Olorunmaiye, Kehinde S; Paul, Manoj S

2018-06-01

Due to the important role of biochar (BC) in reducing metal-toxicity in plants, this study was aimed at assessing the potential of citrus epicarp-derived BC in ameliorating Cd toxicity in young Abelmoschus esculentus (okra) under low Cd toxicity. Okra was grown in soil amended with BC at four treatment levels for 49 days as follows: control (A), sole 1.4 mg Cd/kg-spiked soil (B), 1.4 mg Cd/kg-spiked soil + 1% BC (C) and 1.4 mg Cd/kg-spiked soil + 3% BC (D). The results showed a dose-dependent reduction in shoot accumulation of Cd due to the BC application. In addition, compared to control and sole Cd-amended soil, BC treatments (both at 1% and 3% w/w) decreased the oxidative stress, and enhanced activities of enzymatic and non-enzymatic antioxidants in the young okra. Generally, the application of BC to the soil was effective in ameliorating the Cd-induced oxidative stress in okra with limited shoot bioaccumulation of Cd.

Differential effect of UV-B radiation on growth, oxidative stress and ascorbate-glutathione cycle in two cyanobacteria under copper toxicity.

PubMed

Singh, Vijay Pratap; Srivastava, Prabhat Kumar; Prasad, Sheo Mohan

2012-12-01

Effects of low (UV-B(L); 0.1 μmol m(-2) s(-1)) and high (UV-B(H); 1.0 μmol m(-2) s(-1)) fluence rates of UV-B radiation on growth, oxidative stress and ascorbate-glutathione cycle (AsA-GSH cycle) were investigated in two cyanobacteria viz. Phormidium foveolarum and Nostoc muscorum under copper (2 and 5 μM) toxicity after 24 and 72 h of experiments. Cu at 2 and 5 μM and UV-B(H) irradiation decreased growth in both the organisms and the effect was more pronounced in N. muscorum. Superoxide radical (SOR) and hydrogen peroxide (H(2)O(2)) productions were significantly enhanced by Cu and UV-B(H) which was accompanied by accelerated lipid peroxidation (malondialdehyde; MDA) and protein oxidation (reactive carbonyl groups; RCG). The components of AsA-GSH cycle, i.e. ascorbate peroxidase (APX), glutathione reductase (GR), monodehydroascobate reductase (MDHAR) and dehydroascorbate reductase (DHAR) activities as well as total ascorbate and glutathione contents and their reduced/oxidized ratios were decreased considerably by Cu and UV-B(H). Further, combined treatments of Cu and UV-B(H) exacerbated damaging effects in both the cyanobacteria. Unlike UV-B(H), UV-B(L) irradiation rather than damaging cyanobacteria caused alleviation in Cu-induced toxicity by down-regulating the levels of SOR, H(2)O(2), MDA and RCG due to enhanced activity of APX, GR, MDHAR and DHAR, and contents of ascorbate and glutathione. Results revealed that UV-B radiation at low fluence rate (UV-B(L)) stimulated protective responses in both the organisms under Cu toxicity while UV-B(H) irradiation caused damage alone as well as together with Cu, and the components of AsA-GSH cycle play significant role in these responses. Copyright © 2012 Elsevier Masson SAS. All rights reserved.

Oxidative stress-induced autophagy: Role in pulmonary toxicity

PubMed Central

Malaviya, Rama; Laskin, Jeffrey D.; Laskin, Debra L.

2015-01-01

Autophagy is an evolutionarily conserved catabolic process important in regulating the turnover of essential proteins and in elimination of damaged organelles and protein aggregates. Autophagy is observed in the lung in response to oxidative stress generated as a consequence of exposure to environmental toxicants. Whether autophagy plays role in promoting cell survival or cytotoxicity is unclear. In this article recent findings on oxidative stress-induced autophagy in the lung are reviewed; potential mechanisms initiating autophagy are also discussed. A better understanding of autophagy and its role in pulmonary toxicity may lead to the development of new strategies to treat lung injury associated with oxidative stress. PMID:24398106

Oxidative stress in MeHg-induced neurotoxicity

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

Farina, Marcelo, E-mail: farina@ccb.ufsc.br; Aschner, Michael; Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN

2011-11-15

Methylmercury (MeHg) is an environmental toxicant that leads to long-lasting neurological and developmental deficits in animals and humans. Although the molecular mechanisms mediating MeHg-induced neurotoxicity are not completely understood, several lines of evidence indicate that oxidative stress represents a critical event related to the neurotoxic effects elicited by this toxicant. The objective of this review is to summarize and discuss data from experimental and epidemiological studies that have been important in clarifying the molecular events which mediate MeHg-induced oxidative damage and, consequently, toxicity. Although unanswered questions remain, the electrophilic properties of MeHg and its ability to oxidize thiols have beenmore » reported to play decisive roles to the oxidative consequences observed after MeHg exposure. However, a close examination of the relationship between low levels of MeHg necessary to induce oxidative stress and the high amounts of sulfhydryl-containing antioxidants in mammalian cells (e.g., glutathione) have led to the hypothesis that nucleophilic groups with extremely high affinities for MeHg (e.g., selenols) might represent primary targets in MeHg-induced oxidative stress. Indeed, the inhibition of antioxidant selenoproteins during MeHg poisoning in experimental animals has corroborated this hypothesis. The levels of different reactive species (superoxide anion, hydrogen peroxide and nitric oxide) have been reported to be increased in MeHg-exposed systems, and the mechanisms concerning these increments seem to involve a complex sequence of cascading molecular events, such as mitochondrial dysfunction, excitotoxicity, intracellular calcium dyshomeostasis and decreased antioxidant capacity. This review also discusses potential therapeutic strategies to counteract MeHg-induced toxicity and oxidative stress, emphasizing the use of organic selenocompounds, which generally present higher affinity for MeHg when compared to the classically studied agents.« less

Role of Mitochondria in Methamphetamine-Induced Dopaminergic Neurotoxicity: Involvement in Oxidative Stress, Neuroinflammation, and Pro-apoptosis-A Review.

PubMed

Shin, Eun-Joo; Tran, Hai-Quyen; Nguyen, Phuong-Tram; Jeong, Ji Hoon; Nah, Seung-Yeol; Jang, Choon-Gon; Nabeshima, Toshitaka; Kim, Hyoung-Chun

2018-01-01

Methamphetamine (MA), an amphetamine-type psychostimulant, is associated with dopaminergic toxicity and has a high abuse potential. Numerous in vivo and in vitro studies have suggested that impaired mitochondria are critical in dopaminergic toxicity induced by MA. Mitochondria are important energy-producing organelles with dynamic nature. Evidence indicated that exposure to MA can disturb mitochondrial energetic metabolism by inhibiting the Krebs cycle and electron transport chain. Alterations in mitochondrial dynamic processes, including mitochondrial biogenesis, mitophagy, and fusion/fission, have recently been shown to contribute to dopaminergic toxicity induced by MA. Furthermore, it was demonstrated that MA-induced mitochondrial impairment enhances susceptibility to oxidative stress, pro-apoptosis, and neuroinflammation in a positive feedback loop. Protein kinase Cδ has emerged as a potential mediator between mitochondrial impairment and oxidative stress, pro-apoptosis, or neuroinflammation in MA neurotoxicity. Understanding the role and underlying mechanism of mitochondrial impairment could provide a molecular target to prevent or alleviate dopaminergic toxicity induced by MA.

Moderate treadmill exercise prevents oxidative stress-induced anxiety-like behavior in rats.

PubMed

Salim, Samina; Sarraj, Nada; Taneja, Manish; Saha, Kaustuv; Tejada-Simon, Maria Victoria; Chugh, Gaurav

2010-04-02

Recent work has suggested correlation of oxidative stress with anxiety-like behavior. There also is evidence for anxiolytic effects of physical exercise. However, a direct role of oxidative stress in anxiety is not clear and a protective role of physical exercise in oxidative stress-mediated anxiety has never been addressed. In this study, we have utilized rats to test direct involvement of oxidative stress with anxiety-like behavior and have identified oxidative stress mechanisms likely involved in anxiolytic effects of physical exercise. Intraperitoneal injections at non-toxic dose of l-buthionine-(S,R)-sulfoximine (BSO), an agent that increases oxidative stress markers, increased anxiety-like behavior of rats compared to vehicle-treated control rats. Prior 2 weeks treatment with the antioxidant, tempol attenuated BSO-induced anxiety-like behavior of rats suggesting a role of oxidative stress in this phenomenon. Moreover, moderate treadmill exercise prevented BSO-induced anxiety-like behavior of rats and also prevented BSO-mediated increase in oxidative stress markers in serum, urine and brain tissue homogenates from hippocampus, amygdala and locus coeruleus. Thus increasing oxidative stress increases anxiety-like behavior of rats. Moreover, antioxidant or treadmill exercise training both reduce oxidative stress in the rat brain regions implicated in anxiety response and prevent anxiety-like behavior of rats. Published by Elsevier B.V.

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

Lajmanovich, Rafael C., E-mail: lajmanovich@hotmail.com; Faculty of Biochemistry and Biological Sciences; Junges, Celina M.

The effects of commercial formulations of Bacillus thuringiensisvar.israelensis (Bti) on non-target organisms are still a matter of debate; in amphibians, the risks of Bti are little known. To evaluate the toxicity of a commercial liquid (aqueous suspension, AS) formulation of Bti (Introban{sup ®}) on Leptodactylus latrans tadpoles, including median lethal concentration (LC{sub 50}) and no-and lowest–observed-effect concentrations (NOEC and LOEC, respectively), as well as the possible effects of Bti on oxidative responses, erythrocytes genotoxicity, and histology of the intestines. In the laboratory, tadpoles were exposed to nominal concentrations of 0 (control), 2.5, 5, 10, 20 and 40 mg/L of formulatedmore » Bti-AS. Glutathione S-transferase (GST) and catalase (CAT) activities, as well as formation of erythrocyte nuclear abnormalities (ENAs), and histological effect were measured in tadpoles displaying survival rates >85%. L. latrans tadpoles were sensitive to exposure to Bti-AS, reaching 100% mortality after 48 h of exposure at the highest concentration. Bti-AS induced GST and CAT enzymes and genotoxicity (erythrocyte's nuclear abnormalities), and caused intestine's histopathology. Our results demonstrate that toxicity of Bti-AS is dose-dependent for L. latrans tadpoles and that sublethal exposure alters enzymes of oxidative stress, induces genotoxicity, and causes intestine damage. Further research is needed to evaluate the ecotoxicological risk of the massive use of Bti formulations on amphibian populations that commonly used suburban wastewater or urban waterbodies to reproduce and where this biopesticide is frequently applied. - Highlights: • An ecotoxicological evaluation of a Bti formulation on amphibian was conducted. • Toxicity of Bti-AS was dose-dependent for Leptodactylus latrans tadpoles. • Sublethal exposure altered the enzymes of oxidative stress (GST and CAT). • Bti-AS was genotoxic because increased MN frequencies (CO: 0.82–2.74‰). • Bti-AS caused the inflammatory infiltration in the lamina propria of intestine.« less

In vitro toxicity of zinc oxide nanoparticles: a review

NASA Astrophysics Data System (ADS)

Pandurangan, Muthuraman; Kim, Doo Hwan

2015-03-01

The toxic effect of ZnO nanoparticles is due to their solubility. ZnO nanoparticles dissolve in the extracellular region, which in turn increases the intracellular [Zn2+] level. The mechanism for increased intracellular [Zn2+] level and ZnO nanoparticles dissolution in the medium is still unclear. Cytotoxicity, increased oxidative stress, increased intracellular [Ca2+] level, decreased mitochondrial membrane potential, and interleukin-8 productions occur in the BEAS-2B bronchial epithelial cells and A549 alveolar adenocarcinoma cells following the exposure of ZnO nanoparticles. Confluent C2C12 cells are more resistant to ZnO nanoparticles compared to the sparse monolayer. Loss of 3T3-L1 cell viability, membrane leakage, and morphological changes occurs due to exposure of ZnO nanoparticles. ZnO nanoparticle induces cytotoxicity and mitochondrial dysfunction in RKO colon carcinoma cells. The occurrence of apoptosis, increased ROS level, reduced mitochondrial activity and formation of tubular intracellular structures are reported following exposure of ZnO nanoparticles in skin cells. Macrophages, monocytes, and dendritic cells are affected by ZnO nanoparticles. In addition, genotoxicity is also induced. The present review summarizes the literature on in vitro toxicity of ZnO nanoparticles (10-100 nm) on various cell lines.

Neuroprotective effect of cannabidiol, a non-psychoactive component from Cannabis sativa, on beta-amyloid-induced toxicity in PC12 cells.

PubMed

Iuvone, Teresa; Esposito, Giuseppe; Esposito, Ramona; Santamaria, Rita; Di Rosa, Massimo; Izzo, Angelo A

2004-04-01

Abstract Alzheimer's disease is widely held to be associated with oxidative stress due, in part, to the membrane action of beta-amyloid peptide aggregates. Here, we studied the effect of cannabidiol, a major non-psychoactive component of the marijuana plant (Cannabis sativa) on beta-amyloid peptide-induced toxicity in cultured rat pheocromocytoma PC12 cells. Following exposure of cells to beta-amyloid peptide (1 micro g/mL), a marked reduction in cell survival was observed. This effect was associated with increased reactive oxygen species (ROS) production and lipid peroxidation, as well as caspase 3 (a key enzyme in the apoptosis cell-signalling cascade) appearance, DNA fragmentation and increased intracellular calcium. Treatment of the cells with cannabidiol (10(-7)-10(-4)m) prior to beta-amyloid peptide exposure significantly elevated cell survival while it decreased ROS production, lipid peroxidation, caspase 3 levels, DNA fragmentation and intracellular calcium. Our results indicate that cannabidiol exerts a combination of neuroprotective, anti-oxidative and anti-apoptotic effects against beta-amyloid peptide toxicity, and that inhibition of caspase 3 appearance from its inactive precursor, pro-caspase 3, by cannabidiol is involved in the signalling pathway for this neuroprotection.

The aflatoxin B1 -fumonisin B1 toxicity in BRL-3A hepatocytes is associated to induction of cytochrome P450 activity and arachidonic acid metabolism.

PubMed

Mary, Verónica S; Arias, Silvina L; Otaiza, Santiago N; Velez, Pilar A; Rubinstein, Héctor R; Theumer, Martín G

2017-06-01

Human oral exposure to aflatoxin B 1 (AFB 1 ) and fumonisin B 1 (FB 1 ) is associated with increased hepatocellular carcinoma. Although evidence suggested interactive AFB 1 -FB 1 hepatotoxicity, the underlying mechanisms remain mostly unidentified. This work was aimed at evaluating the possible AFB 1 -FB 1 interplay to induce genetic and cell cycle toxicities in BRL-3A rat hepatocytes, reactive oxygen species (ROS) involvement, and the AFB 1 metabolizing pathways cytochrome P450 (CYP) and arachidonic acid (ArAc) metabolism as ROS contributors. Flow cytometry of stained BRL-3A hepatocytes was used to study the cell cycle (propidium iodide), ROS intracellular production (DCFH-DA, HE, DAF-2 DA), and phospholipase A activity (staining with bis-BODIPY FL C11-PC). The CYP1A activity was assessed by the 7-ethoxyresorufin-O-deethylase (EROD) assay. Despite a 48-h exposure to FB 1 (30 μM) not being genotoxic, the AFB 1 (20 μM)-induced micronucleus frequency was overcome by the AFB 1 -FB 1 mixture (MIX), presumably showing toxin interaction. The mycotoxins blocked G1/S-phase, but only MIX caused cell death. Overall, the oxidative stress led these alterations as the pretreatment with N-acetyl-l-cysteine reduced such toxic effects. While AFB 1 had a major input to the MIX pro-oxidant activity, with CYP and ArAc metabolism being ROS contributors, these pathways were not involved in the FB 1 -elicited weak oxidative stress. The MIX-induced micronucleus frequency in N-acetyl-l-cysteine pretreated cells was greater than that caused by AFB 1 without antioxidants, suggesting enhanced AFB 1 direct genotoxicity probably owing to the higher CYP activity and ArAc metabolism found in MIX. The metabolic pathways modulation by AFB 1 -FB 1 mixtures could raise its hepatocarcinogenic properties. © 2017 Wiley Periodicals, Inc.

Toxicity of 11 Metal Oxide Nanoparticles to Three Mammalian Cell Types In Vitro.

PubMed

Ivask, Angela; Titma, Tiina; Visnapuu, Meeri; Vija, Heiki; Kakinen, Aleksandr; Sihtmae, Mariliis; Pokhrel, Suman; Madler, Lutz; Heinlaan, Margit; Kisand, Vambola; Shimmo, Ruth; Kahru, Anne

2015-01-01

The knowledge on potential harmful effects of metallic nanomaterials lags behind their increased use in consumer products and therefore, the safety data on various nanomaterials applicable for risk assessment are urgently needed. In this study, 11 metal oxide nanoparticles (MeOx NPs) prepared using flame pyrolysis method were analyzed for their toxicity against human alveolar epithelial cells A549, human epithelial colorectal cells Caco2 and murine fibroblast cell line Balb/c 3T3. The cell lines were exposed for 24 h to suspensions of 3-100 μg/mL MeOx NPs and cellular viability was evaluated using. Neutral Red Uptake (NRU) assay. In parallel to NPs, toxicity of soluble salts of respective metals was analyzed, to reveal the possible cellular effects of metal ions shedding from the NPs. The potency of MeOx to produce reactive oxygen species was evaluated in the cell-free assay. The used three cell lines showed comparable toxicity responses to NPs and their metal ion counterparts in the current test setting. Six MeOx NPs (Al2O3, Fe3O4, MgO, SiO2, TiO2, WO3) did not show toxic effects below 100 µg/mL. For five MeOx NPs, the averaged 24 h IC50 values for the three mammalian cell lines were 16.4 µg/mL for CuO, 22.4 µg/mL for ZnO, 57.3 µg/mL for Sb2O3, 132.3 µg/mL for Mn3O4 and 129 µg/mL for Co3O4. Comparison of the dissolution level of MeOx and the toxicity of soluble salts allowed to conclude that the toxicity of CuO, ZnO and Sb2O3 NPs was driven by release of metal ions. The toxic effects of Mn3O4 and Co3O4 could be attributed to the ROS-inducing ability of these NPs. All the NPs were internalized by the cells according to light microscopy studies but also proven by TEM, and internalization of Co3O4 NPs seemed to be most prominent in this aspect. In conclusion, this work provides valuable toxicological data for a library of 11 MeOx NPs. Combining the knowledge on toxic or non-toxic nature of nanomaterials may be used for safe-by-design approach.

N-Methyl, N-propynyl-2-phenylethylamine (MPPE), a Selegiline Analog, Attenuates MPTP-induced Dopaminergic Toxicity with Guaranteed Behavioral Safety: Involvement of Inhibitions of Mitochondrial Oxidative Burdens and p53 Gene-elicited Pro-apoptotic Change.

PubMed

Shin, Eun-Joo; Nam, Yunsung; Lee, Ji Won; Nguyen, Phuong-Khue Thi; Yoo, Ji Eun; Tran, The-Vinh; Jeong, Ji Hoon; Jang, Choon-Gon; Oh, Young J; Youdim, Moussa B H; Lee, Phil Ho; Nabeshima, Toshitaka; Kim, Hyoung-Chun

2016-11-01

Selegiline is a monoamine oxidase-B (MAO-B) inhibitor with anti-Parkinsonian effects, but it is metabolized to amphetamines. Since another MAO-B inhibitor N-Methyl, N-propynyl-2-phenylethylamine (MPPE) is not metabolized to amphetamines, we examined whether MPPE induces behavioral side effects and whether MPPE affects dopaminergic toxicity induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Multiple doses of MPPE (2.5 and 5 mg/kg/day) did not show any significant locomotor activity and conditioned place preference, whereas selegiline (2.5 and 5 mg/kg/day) significantly increased these behavioral side effects. Treatment with MPPE resulted in significant attenuations against decreases in mitochondrial complex I activity, mitochondrial Mn-SOD activity, and expression induced by MPTP in the striatum of mice. Consistently, MPPE significantly attenuated MPTP-induced oxidative stress and MPPE-mediated antioxidant activity appeared to be more pronounced in mitochondrial-fraction than in cytosolic-fraction. Because MPTP promoted mitochondrial p53 translocation and p53/Bcl-xL interaction, it was also examined whether mitochondrial p53 inhibitor pifithrin-μ attenuates MPTP neurotoxicity. MPPE, selegiline, or pifithrin-μ significantly attenuated mitochondrial p53/Bcl-xL interaction, impaired mitochondrial transmembrane potential, cytosolic cytochrome c release, and cleaved caspase-3 in wild-type mice. Subsequently, these compounds significantly ameliorated MPTP-induced motor impairments. Neuroprotective effects of MPPE appeared to be more prominent than those of selegiline. MPPE or selegiline did not show any additional protective effects against the attenuation by p53 gene knockout, suggesting that p53 gene is a critical target for these compounds. Our results suggest that MPPE possesses anti-Parkinsonian potentials with guaranteed behavioral safety and that the underlying mechanism of MPPE requires inhibition of mitochondrial oxidative stress, mitochondrial translocation of p53, and pro-apoptotic process.

Radionecrosis versus disease progression in brain metastasis. Value of (18)F-DOPA PET/CT/MRI.

PubMed

Hernández Pinzón, J; Mena, D; Aguilar, M; Biafore, F; Recondo, G; Bastianello, M

2016-01-01

The use of (18)F-DOPA PET/CT with magnetic resonance imaging fusion and the use of visual methods and quantitative analysis helps to differentiate between changes post-radiosurgery vs. suspicion of disease progression in a patient with brain metastases from melanoma, thus facilitating taking early surgical action. Copyright © 2016 Elsevier España, S.L.U. y SEMNIM. All rights reserved.

Neurotoxicity of fungal volatile organic compounds in Drosophila melanogaster.

PubMed

Inamdar, Arati A; Masurekar, Prakash; Bennett, Joan Wennstrom

2010-10-01

Many volatile organic compounds (VOCs) are found in indoor environment as products of microbial metabolism. In damp indoor environments, fungi are associated with poor air quality. Some epidemiological studies have suggested that microbial VOCs have a negative impact on human health. Our study was designed to provide a reductionist approach toward studying fungal VOC-mediated toxicity using the inexpensive model organism, Drosophila melanogaster, and pure chemical standards of several important fungal VOCs. Low concentrations of the following known fungal VOCs, 0.1% of 1-octen-3-ol and 0.5% of 2-octanone; 2,5 dimethylfuran; 3-octanol; and trans-2-octenal, caused locomotory defects and changes in green fluorescent protein (GFP)- and antigen-labeled dopaminergic neurons in adult D. melanogaster. Locomotory defects could be partially rescued with L-DOPA. Ingestion of the antioxidant, vitamin E, improved the survival span and delayed the VOC-mediated changes in dopaminergic neurons, indicating that the VOC-mediated toxicity was due, in part, to generation of reactive oxygen species.

Toxicological and chemical assessment of arsenic-contaminated groundwater after electrochemical and advanced oxidation treatments.

PubMed

Radić, Sandra; Crnojević, Helena; Vujčić, Valerija; Gajski, Goran; Gerić, Marko; Cvetković, Želimira; Petra, Cvjetko; Garaj-Vrhovac, Vera; Oreščanin, Višnja

2016-02-01

Owing to its proven toxicity and mutagenicity, arsenic is regarded a principal pollutant in water used for drinking. The objective of this study was the toxicological and chemical evaluation of groundwater samples obtained from arsenic enriched drinking water wells before and after electrochemical and ozone-UV-H2O2-based advanced oxidation processes (EAOP). For this purpose, acute toxicity test with Daphnia magna and chronic toxicity test with Lemna minor L. were employed as well as in vitro bioassays using human peripheral blood lymphocytes (HPBLs). Several oxidative stress parameters were estimated in L.minor. Physicochemical analysis showed that EAOP treatment was highly efficient in arsenic but also in ammonia and organic compound removal from contaminated groundwater. Untreated groundwater caused only slight toxicity to HPBLs and D. magna in acute experiments. However, 7-day exposure of L. minor to raw groundwater elicited genotoxicity, a significant growth inhibition and oxidative stress injury. The observed genotoxicity and toxicity of raw groundwater samples was almost completely eliminated by EAOP treatment. Generally, the results obtained with L. minor were in agreement with those obtained in the chemical analysis suggesting the sensitivity of the model organism in monitoring of arsenic-contaminated groundwater. In parallel to chemical analysis, the implementation of chronic toxicity bioassays in a battery is recommended in the assessment of the toxic and genotoxic potential of such complex mixtures. Copyright © 2015 Elsevier B.V. All rights reserved.

Toxic effects of combined effects of anthracene and UV radiation on Brachionus plicatilis

NASA Astrophysics Data System (ADS)

Gao, Ceng; Zhang, Xinxin; Xu, Ningning; Tang, Xuexi

2017-05-01

Anthracene is a typical polycyclic aromatic hydrocarbon, with photo activity, can absorb ultraviolet light a series of chemical reactions, aquatic organisms in the ecosystem has a potential light induced toxicity. In this paper, the effects of anthracene and UV radiation on the light-induced toxicity of Brachionus plicatilis were studied. The main methods and experimental results were as follows: (1) The semi-lethal concentration of anthracene in UV light was much lower than that in normal light, The rotifers have significant light-induced acute toxicity. (2) Under UV irradiation, anthracene could induce the increase of ROS and MDA content in B. plicatilis, and the activity of antioxidant enzymes in B. plicatilis significantly changed, Where SOD, GPx activity was induced within 24 hours of the beginning of the experiment. And the content of GPX and CAT was inhibited after 48 hours. Therefore, the anthracite stress induced by UV radiation could more strongly interfere with the ant oxidative metabolism of B. plicatilis, and more seriously cause oxidative damage, significant light-induced toxicity.

Effects of the pharmaceuticals gemfibrozil and diclofenac on the marine mussel (Mytilus spp.) and their comparison with standardized toxicity tests.

PubMed

Schmidt, Wiebke; O'Rourke, Kathleen; Hernan, Robert; Quinn, Brian

2011-07-01

Human pharmaceuticals, like the lipid lowering agent gemfibrozil and the non-steroidal anti-inflammatory drug diclofenac are causing environmental concern. In this study, the marine mussel (Mytilus spp.) was exposed by injection to environmentally relevant and elevated (1 μg/L and 1000 μg/L) concentrations of both compounds and biomarker expression was observed. Gemfibrozil exposure induced biomarkers of stress (glutathione S-transferase and metallothionein) at both concentrations 24h and 96 h after exposure, respectively. Biomarkers of damage (lipid peroxidation (LPO) and DNA damage) were significantly affected, as well as the biomarker for reproduction, alkali-labile phosphate assay, indicating the potential oxidative stress and endocrine disrupting effect of gemfibrozil. Diclofenac significantly induced LPO after 96 h indicating tissue damage. Additionally standard toxicity tests using the marine species Vibrio fischeri, Skeletonema costatum and Tisbe battagliai showed differences in sensitivity to both drugs in the mg/L range. Results indicate a suite of tests should be used to give accurate information for regulation. Copyright © 2011 Elsevier Ltd. All rights reserved.

Berberis vulgaris L. effects on oxidative stress and liver injury in lead-intoxicated mice.

PubMed

Laamech, Jawhar; El-Hilaly, Jaouad; Fetoui, Hamadi; Chtourou, Yassine; Gouitaa, Hanane; Tahraoui, Adel; Lyoussi, Badiaa

2017-03-01

Background Berberis vulgaris L. (BV), commonly known as "Aghriss" in Moroccan pharmacopoeia, is used to cure liver disorders and other diseases. The present study aimed to investigate the protective effect of BV aqueous extract against lead-induced toxicity in mice liver. Methods Sixty IOPS mice were divided into six groups and were treated as follows: group 1 (normal control) received double distilled water; group 2 (toxic control) received lead acetate (5 mg/kg body weight/day) in double distilled water for 40 days; groups 3-6 received BV aqueous extract at doses of 25, 50, 100 and 150 mg/kg body weight , respectively, once daily for 30 days from 11 day after beginning of lead acetate exposure to the end of the experiment. Results Toxic control group showed a significant alteration of serum alanine-aminotransferase (ALT), aspartate-aminotransferase (AST), total cholesterol (TC), total bilirubin (TB), catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GPx) and reduced glutathione (GSH). Histological assessment of lead-intoxicated mice liver revealed alterations in hepatocytes and focal necrosis. BV treatment significantly prevented lead accumulation, increased ALT, AST, TC, and TB, inhibited lipid peroxidation and protein carbonyls(PCO) formation. Additionally, BV extract normalized the antioxidant enzymes (CAT, SOD and GPx), GSH and architecture of liver tissues. Conclusions BV aqueous extract exerts significant hepatoprotective effects against lead-induced oxidative stress and liver dysfunction. The BV effect may be mediated through the enhancement of antioxidant status, lead-chelating abilities and free radicals quenching.

Phosphate alleviation of glyphosate-induced toxicity in Hydrocharis dubia (Bl.) Backer.

PubMed

Zhong, Guidi; Wu, Zhonghua; Liu, Nian; Yin, Jun

2018-05-30

Glyphosate, as a broad-spectrum herbicide, is frequently detected in water, and phosphorus widely enters the water due to the extensive use of phosphorus-containing substances in agriculture, industries and daily life. Thus, aquatic ecosystems are exposed to both glyphosate and phosphorus, which may affect aquatic organisms. In the present research, we studied the physiological responses of the floating aquatic plant species H. dubia to different concentrations of glyphosate (0, 1, 5, 15 mg/L) with different levels of phosphate (0, 50, 100 mg/L) after 14 days (d) of treatment. We explored glyphosate toxicity in H. dubia and investigated whether phosphate addition mitigates glyphosate toxicity in this species, which will provide a theoretical basis for the ecotoxicological study of aquatic plants. The results show that glyphosate significantly reduced the chlorophyll content, leaf number and root length of H. dubia, while it significantly increased the malondialdehyde (MDA), hydrogen peroxide (H 2 O 2 ), shikimate, proline, and soluble protein content and enzyme activities (superoxide dismutase (SOD), catalase (CAT), guaiacol peroxidase (POD), ascorbate peroxidase (APX) and polyphenol oxidase (PPO)) in H. dubia. After phosphate supplement, the MDA, H 2 O 2 , proline, and soluble protein contents and enzyme activities in the plants treated with glyphosate decreased. These results indicate that the concentration of glyphosate investigated in our study can cause oxidative stress and affect the growth of H. dubia. Phosphate can alleviate glyphosate-induced oxidative stress in H. dubia. Copyright © 2018 Elsevier B.V. All rights reserved.

Acetyl-L-carnitine prevents total body hydroxyl free radical and uric acid production induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in the rat.

PubMed

Loots, Du Toit; Mienie, Lodewyk J; Bergh, Jacobus J; Van der Schyf, Cornelis J

2004-07-23

Acetyl-L-carnitine (ALCAR) is intimately involved in the transport of long chain fatty acids across the inner mitochondrial membrane during oxidative phosphorylation. ALCAR also has been reported to attenuate the occurrence of parkinsonian symptoms associated with 1-methyl-1,2,3,6-tetrahydropyridine (MPTP) in vivo, and protects in vitro against the toxicity of the neurotoxic 1-methyl-4-phenylpyridinium (MPP+) metabolite of MPTP. The mechanism for these protective effects remains unclear. ALCAR may attenuate hydroxyl (HO*) free radical production in the MPTP/MPP+ neurotoxic pathway through several mechanisms. Most studies on MPTP/MPP+ toxicity and protection by ALCAR have focused on in vivo brain chemistry and in vitro neuronal culture studies. The present study investigates the attenuative effects of ALCAR on whole body oxidative stress markers in the urine of rats treated with MPTP. In a first study, ALCAR totally prevented the MPTP-induced formation of HO* measured by salicylate radical trapping. In a second study, the production of uric acid after MPTP administration-a measure of oxidative stress mediated through xanthine oxidase-was also prevented by ALCAR. Because ALCAR is unlikely to be a potent radical scavenger, these studies suggest that ALCAR protects against MPTP/MPP+-mediated oxidative stress through other mechanisms. We speculate that ALCAR may operate through interference with organic cation transporters such as OCTN2 and/or carnitine-acylcarnitine translocase (CACT), based partly on the above findings and on semi-empirical electronic similarity calculations on ALCAR, MPP+, and two other substrates for these transporters.

Zinc-induced differential oxidative stress and antioxidant responses in Chlorella sorokiniana and Scenedesmus acuminatus.

PubMed

Hamed, Seham M; Zinta, Gaurav; Klöck, Gerd; Asard, Han; Selim, Samy; AbdElgawad, Hamada

2017-06-01

Algae are frequently exposed to toxic metals, and zinc (Zn) is one of the major toxicants present. We exposed two green microalgae, Chlorella sorokiniana and Scenedesmus acuminatus, to sub-lethal concentrations (1.0 and 0.6mM) of Zn for seven days. Algal responses were analysed at the level of growth, oxidative stress, and antioxidants. Growth parameters such as cell culture yield and pigment content were less affected by Zn in C. sorokiniana, despite the fact that this alga accumulated more zinc than S. acuminatus. Also, C. sorokiniana, but not S. acuminatus, was able to acclimatize during long-term exposure to toxic concentrations of the test metals (specific growth rate (µ) was 0.041/day and total chlorophyll was 14.6mg/mL). Although, Zn induced oxidative stress in both species, C. sorokiniana experienced less stress than S. acuminatus. This could be explained by a higher accumulation of antioxidants in C. sorokiniana, where flavonoids, polyphenols, tocopherols, glutathione (GSH) and ascorbate (ASC) content increased. Moreover, antioxidant enzymes glutathione S transferase (GST), glutathione reductase (GR), superoxide dismutase (SOD), peroxidase (POX) and ascorbate peroxidase (APX), showed increased activities in C. sorokiniana. In addition to, and probably also underlying, the higher Zn tolerance in C. sorokiniana, this alga also showed higher Zn biosorption capacity. Use of C. sorokiniana as a bio-remediator, could be considered. Copyright © 2017 Elsevier Inc. All rights reserved.

Dopamine effects on evidence gathering and integration

PubMed Central

Andreou, Christina; Schneider, Brooke C.; Braun, Vivien; Kolbeck, Katharina; Gallinat, Jürgen; Moritz, Steffen

2015-01-01

Background Disturbances in evidence gathering and disconfirmatory evidence integration have been associated with the presence of or propensity for delusions. Previous evidence suggests that these 2 types of reasoning bias might be differentially affected by antipsychotic medication. We aimed to investigate the effects of a dopaminergic agonist (L-dopa) and a dopaminergic antagonist (haloperidol) on evidence gathering and disconfirmatory evidence integration after single-dose administration in healthy individuals. Methods The study used a randomized, double-blind, placebo-controlled, 3-way crossover design. Participants were healthy individuals aged 18–40 years. We administered a new data-gathering task designed to increase sensitivity to change compared with traditional tasks. The Bias Against Disconfirmatory Evidence (BADE) task was used as a measure of disconfirmatory evidence integration. Results We included 30 individuals in our study. In the data-gathering task, dopaminergic modulation had no significant effect on the amount of evidence gathered before reaching a decision. In contrast, the ability of participants to integrate disconfirmatory evidence showed a significant linear dopaminergic modulation pattern (highest with haloperidol, intermediate with placebo, lowest with L-dopa), with the difference between haloperidol and L-dopa marginally reaching significance. Limitations Although the doses used for haloperidol and L-dopa were similar to those used in previous studies, drug plasma level measurements would have added to the validity of findings. Conclusion Evidence gathering and disconfirmatory evidence integration might be differentially influenced by dopaminergic agents. Our findings are in support of a dual-disturbance account of delusions and provide a plausible neurobiological basis for the use of interventions targeted at improving reasoning biases as an adjunctive treatment in patients with psychotic disorders. PMID:26197302

Social intentions in Parkinson's disease patients: A kinematic study.

PubMed

Straulino, Elisa; Scaravilli, Tomaso; Castiello, Umberto

2015-09-01

Dysfunction of the dopaminergic system leads to motor, cognitive and motivational symptoms in brain disorders such as Parkinson's disease (PD). Moreover, the dopaminergic system plays an important role in social interactions. The dopaminergic input to the basal ganglia (BG) thought to integrate social cues during the planning and execution of voluntary movements remains, however, largely unexplored. Since PD provides a model to assess this function in humans, our study aimed to investigate the effects of social intentions on actions in non-demented PDpatients receiving dopamine replacement therapy (Levodopa = l-Dopa) and in neurologically healthy control participants. Patients' ability to modulate motor patterning depending on the intention motivating the action to be performed was evaluated both in "on" (with l-Dopa) and "off" (without l-Dopa) states. Participants were instructed to reach for and to grasp an object; they were then told to hand it to another person (social condition) or to place it on a concave frame (individual condition). A 'passive-observer' condition, which was similar to the 'individual' condition except for the presence of an onlooker who simply observed the scene, was also assessed to exclude the possibility that differences might be due to the presence of another person. Movement kinematics were recorded using a three-dimensional motion analysis system. Study results demonstrated that the controls and the PD patients in an 'on' state adopted different kinematic patterning for the 'social' and the 'individual' conditions; the PD patients in the 'off' state, instead, were unable to kinematically differentiate between the two conditions. These results suggest that l-Dopa treatment has positive effects on translating social intentions into specific motor patterns in PD patients. Copyright © 2015 Elsevier Ltd. All rights reserved.

Clinical improvement of the aggressive neurobehavioral phenotype in a patient with a deletion of PITX3 and the absence of L-DOPA in the cerebrospinal fluid.

PubMed

Derwińska, Katarzyna; Mierzewska, Hanna; Goszczańska, Alicja; Szczepanik, Elżbieta; Xia, Zhilian; Kuśmierska, Katarzyna; Tryfon, Jolanta; Kutkowska-Kaźmierczak, Anna; Bocian, Ewa; Mazurczak, Tadeusz; Obersztyn, Ewa; Stankiewicz, Paweł

2012-03-01

The development of midbrain dopamine (DA) neurons is regulated by several transcription factors, including Nurr1, Wnt1, Lmx1a/1b, En1, En2, Foxa1, Foxa2, and Pitx3. PITX3 is an upstream co-activator of the TH (tyrosine hydroxylase) promoter. Pitx3(-/-) mice have a selective loss of dopaminergic neurons in the substantia nigra and ventral tegmental area, leading to the significantly reduced DA levels in the nigrostriatal pathway and in the dorsal striatum and manifest anomalous striatum-dependent cognitive impairment and neurobehavioral activity. Treatment with L-DOPA, dopamine, or dopamine receptor agonists in these mice reversed several of their sensorimotor impairments. Heterozygous missense mutations in PITX3 have been reported in patients with autosomal dominant congenital cataract and anterior segment (ocular) mesenchymal dysgenesis (ASMD) whereas homozygous missense mutations have been found in patients with microphthalmia and neurological impairment. Using a clinical oligonucleotide array comparative genomic hybridization (aCGH), we have identified an ∼317 kb hemizygous deletion in 10q24.32, involving PITX3 in a 17-year-old male with a Smith-Magenis syndrome-like phenotype, including mild intellectual impairment, sleep disturbance, hyperactivity, and aggressive and self-destructive behavior. Interestingly, no eye anomalies were found in our patient. Analysis of neurotransmitters in his cerebrospinal fluid revealed an absence of L-DOPA and significantly decreased levels of catecholamine metabolites. Importantly, L-DOPA treatment of our patient has led to mild mitigation of his aggressive behavior and mild improvement of his attention span, extended time periods of concentration, and better sleep. Copyright © 2012 Wiley Periodicals, Inc.

Brain catecholamine depletion and motor impairment in a Th knock-in mouse with type B tyrosine hydroxylase deficiency.

PubMed

Korner, Germaine; Noain, Daniela; Ying, Ming; Hole, Magnus; Flydal, Marte I; Scherer, Tanja; Allegri, Gabriella; Rassi, Anahita; Fingerhut, Ralph; Becu-Villalobos, Damasia; Pillai, Samyuktha; Wueest, Stephan; Konrad, Daniel; Lauber-Biason, Anna; Baumann, Christian R; Bindoff, Laurence A; Martinez, Aurora; Thöny, Beat

2015-10-01

Tyrosine hydroxylase catalyses the hydroxylation of L-tyrosine to l-DOPA, the rate-limiting step in the synthesis of catecholamines. Mutations in the TH gene encoding tyrosine hydroxylase are associated with the autosomal recessive disorder tyrosine hydroxylase deficiency, which manifests phenotypes varying from infantile parkinsonism and DOPA-responsive dystonia, also termed type A, to complex encephalopathy with perinatal onset, termed type B. We generated homozygous Th knock-in mice with the mutation Th-p.R203H, equivalent to the most recurrent human mutation associated with type B tyrosine hydroxylase deficiency (TH-p.R233H), often unresponsive to l-DOPA treatment. The Th knock-in mice showed normal survival and food intake, but hypotension, hypokinesia, reduced motor coordination, wide-based gate and catalepsy. This phenotype was associated with a gradual loss of central catecholamines and the serious manifestations of motor impairment presented diurnal fluctuation but did not improve with standard l-DOPA treatment. The mutant tyrosine hydroxylase enzyme was unstable and exhibited deficient stabilization by catecholamines, leading to decline of brain tyrosine hydroxylase-immunoreactivity in the Th knock-in mice. In fact the substantia nigra presented an almost normal level of mutant tyrosine hydroxylase protein but distinct absence of the enzyme was observed in the striatum, indicating a mutation-associated mislocalization of tyrosine hydroxylase in the nigrostriatal pathway. This hypomorphic mouse model thus provides understanding on pathomechanisms in type B tyrosine hydroxylase deficiency and a platform for the evaluation of novel therapeutics for movement disorders with loss of dopaminergic input to the striatum. © The Author (2015). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Graphene oxide sheets-based platform for induced pluripotent stem cells culture: toxicity, adherence, growth and application

NASA Astrophysics Data System (ADS)

Durán, Marcela; Andrade, Patricia F.; Durán, Nelson; Luzo, Angela C. M.; Fávaro, Wagner J.

2015-05-01

It was prepared the graphene oxide (GO) sheets by suspension of GO in ultrapure deionized water or in Pluronic F-68 using a ultrasonicator bath. Total characterization of GO sheets was carried out. The results on suspension of GO in water showed excellent growth and cell adhesion. GO/Pluronic F-68 platform for the growth and adhesion of adipose-derived stem cells (ASCs) that exhibits excellent properties for these processes. GO in water suspension exhibited an inhibition of the cell growth over 5 μg/mL In vivo study with GO suspended in water (100 μg/mL) on Fisher 344 rats via i.p. administration showed low toxicity. Despite GO particle accumulates in the intraperitoneal cavity, this fact did not interfere with the final absorption of GO. The AST (aspartate aminotransferase) and ALT (alanine aminotransferase) levels (liver function) did not differ statistically in all experimental groups. Also, creatinine and urea levels (renal function) did not differ statistically in all experimental groups. Taking together, the data suggest the great potential of graphene oxide sheets as platform to ACSs, as well as, new material for treatment several urological diseases.

Effects of isoquinoline alkaloid berberine on lipid peroxidation, antioxidant defense system, and liver damage induced by lead acetate in rats.

PubMed

Hasanein, Parisa; Ghafari-Vahed, Masumeh; Khodadadi, Iraj

2017-01-01

Liver is considered a target organ affected by lead toxicity. Oxidative stress is among the mechanisms involved in liver damage. Here we investigated the effects of the natural alkaloid berberine on oxidative stress and hepatotoxicity induced by lead in rats. Animals received an aqueous solution of lead acetate (500 mg Pb/l in the drinking water) and/or daily oral gavage of berberine (50 mg/kg) for 8 weeks. Rats were then weighed and used for the biochemical, molecular, and histological evaluations. Lead-induced oxidative stress, shown by increasing lipid peroxidation along with a concomitant decrease in hepatic levels of thiol groups, total antioxidant capacity, the activities of superoxide dismutase, catalase, glutathione peroxidase, and glutathione-S-transferase, and reduced versus oxidized glutathione ratio. Berberine corrected all the disturbances in oxidative stress markers induced by lead administration. Berberine also prevented the elevated levels of enzymes (alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase) and the decrease in body weight and albumin. The protective effects of berberine were comparable with silymarin. Furthermore, berberine attenuated liver damage, shown by decreased necrosis and inflammatory cell infiltration. Berberine represents a potential therapeutic option against lead-induced hepatotoxicity through inhibiting lipid peroxidation and enhancing antioxidant defenses. Berberine exerted protective effects on lead-induced oxidative stress and hepatotoxicity in rats.

Accumulation and developmental toxicity of hexabromocyclododecanes (HBCDs) on the marine copepod Tigriopus japonicus.

PubMed

Shi, Dalin; Lv, Dongmei; Liu, Wanxin; Shen, Rong; Li, Dongmei; Hong, Haizheng

2017-01-01

The brominated flame retardants hexabromocyclododecanes (HBCDs) are ubiquitous environmental contaminants, widely distributed in aquatic systems including the marine environment and marine organisms. HBCDs are toxic to the development of both freshwater and marine fish. However, the impacts of HBCDs on marine invertebrates are not well known. In this study, the marine copepod, Tigriopus japonicus, was used to assess the bioaccumulation and developmental toxicity of technical HBCD (tHBCD) through water-borne exposure. The uptake rate constant of tHBCD by T. japonicus was high, which resulted in high bioaccumulation potential. The bioconcentration factors of tHBCD were 8.73 × 10 4 and 6.34 × 10 4  L kg -1 in T. japonicus, calculated using the kinetic and steady-state methods, respectively. Exposure of T. japonicus nauplii to tHBCD caused significant growth delay. The lowest-observable-effect-concentrations of tHBCD induced developmental delay were 30 and 8 μg L -1 for the F0 and F1 generations, respectively, which suggested that the F1 generation was more sensitive to tHBCD than the F0 generation and warranted multiple-generation toxicity tests for future studies. Furthermore, exposure of the adult copepods to tHBCD induced the transcription of oxidative stress response genes and apoptotic genes, e.g., SOD,CAT, GST, OGG1, P53 and Caspase-3. It was therefore speculated that tHBCD exposure induced the generation of reactive oxygen species in T. japonicus, which activated the oxidative stress defense genes and meanwhile resulted in oxidative DNA damage. The damaged DNA activated the transcription of p53 and triggered the caspase-mediated apoptosis pathway, which may be the reason for the tHBCD induced developmental delay in T. japonicus nauplii. Copyright © 2016 Elsevier Ltd. All rights reserved.

Dissolved organic matter and aluminum oxide nanoparticles synergistically cause cellular responses in freshwater microalgae.

PubMed

Ye, Nan; Wang, Zhuang; Wang, Se; Fang, Hao; Wang, Degao

2018-06-07

This study investigated the impact of dissolved organic matters (DOM) on the ecological toxicity of aluminum oxide nanoparticles (Al 2 O 3 NPs) at a relatively low exposure concentration (1 mg L -1 ). The unicellular green alga Scenedesmus obliquus was exposed to Al 2 O 3 NP suspensions in the presence of DOM (fulvic acid) at various concentrations (1, 10, and 40 mg L -1 ). The results show that the presence of DOM elevated the growth inhibition toxicity of Al 2 O 3 NPs towards S. obliquus in a dose-dependent manner. Moreover, the combination of DOM at 40 mg L -1 and Al 2 O 3 NPs resulted in a synergistic effect. The relative contribution of Al-ions released from Al 2 O 3 NPs to toxicity was lower than 5%, indicating that the presence of the particles instead of the dissolved ions in the suspensions was the major toxicity sources, regardless of the presence of DOM. Furthermore, DOM at 10 and 40 mg L -1 and Al 2 O 3 NPs synergistically induced the upregulation of intercellular reactive oxygen species levels and superoxide dismutase activities. Analysis of the plasma malondialdehyde concentrations and the observation of superficial structures of S. obliquus indicated that the mixtures of DOM and Al 2 O 3 NPs showed no significant effect on membrane lipid peroxidation damage. In addition, the presence of both DOM and Al 2 O 3 NPs contributed to an enhancement in both the mitochondrial membrane potential and the cell membrane permeability (CMP) in S. obliquus. In particular, Al 2 O 3 NPs in the presence of 10 and 40 mg L -1 DOM caused a greater increase in CMP compared to Al 2 O 3 NPs and DOM alone treatments. In conclusion, these findings suggest that DOM at high concentrations and Al 2 O 3 NPs synergistically interrupted cell membrane functions and triggered subsequent growth inhibition toxicity.

Mequindox-Induced Kidney Toxicity Is Associated With Oxidative Stress and Apoptosis in the Mouse.

PubMed

Liu, Qianying; Lei, Zhixin; Guo, Jingchao; Liu, Aimei; Lu, Qirong; Fatima, Zainab; Khaliq, Haseeb; Shabbir, Muhammad A B; Maan, Muhammad Kashif; Wu, Qinghua; Dai, Menghong; Wang, Xu; Pan, Yuanhu; Yuan, Zonghui

2018-01-01

Mequindox (MEQ), belonging to quinoxaline-di- N -oxides (QdNOs), is a synthetic antimicrobial agent widely used in China. Previous studies found that the kidney was one of the main toxic target organs of the QdNOs. However, the mechanisms underlying the kidney toxicity caused by QdNOs in vivo still remains unclear. The present study aimed to explore the molecular mechanism of kidney toxicity in mice after chronic exposure to MEQ. MEQ led to the oxidative stress, apoptosis, and mitochondrial damage in the kidney of mice. Meanwhile, MEQ upregulated Bax/Bcl-2 ratio, disrupted mitochondrial permeability transition pores, caused cytochrome c release, and a cascade activation of caspase, eventually induced apoptosis. The oxidative stress mediated by MEQ might led to mitochondria damage and apoptosis in a mitochondrial-dependent apoptotic pathway. Furthermore, upregulation of the Nrf2-Keap1 signaling pathway was also observed. Our findings revealed that the oxidative stress, mitochondrial dysfunction, and the Nrf2-Keap1 signaling pathway were associated with the kidney apoptosis induced by MEQ in vivo .

Mequindox-Induced Kidney Toxicity Is Associated With Oxidative Stress and Apoptosis in the Mouse

PubMed Central

Liu, Qianying; Lei, Zhixin; Guo, Jingchao; Liu, Aimei; Lu, Qirong; Fatima, Zainab; Khaliq, Haseeb; Shabbir, Muhammad A. B.; Maan, Muhammad Kashif; Wu, Qinghua; Dai, Menghong; Wang, Xu; Pan, Yuanhu; Yuan, Zonghui

2018-01-01

Mequindox (MEQ), belonging to quinoxaline-di-N-oxides (QdNOs), is a synthetic antimicrobial agent widely used in China. Previous studies found that the kidney was one of the main toxic target organs of the QdNOs. However, the mechanisms underlying the kidney toxicity caused by QdNOs in vivo still remains unclear. The present study aimed to explore the molecular mechanism of kidney toxicity in mice after chronic exposure to MEQ. MEQ led to the oxidative stress, apoptosis, and mitochondrial damage in the kidney of mice. Meanwhile, MEQ upregulated Bax/Bcl-2 ratio, disrupted mitochondrial permeability transition pores, caused cytochrome c release, and a cascade activation of caspase, eventually induced apoptosis. The oxidative stress mediated by MEQ might led to mitochondria damage and apoptosis in a mitochondrial-dependent apoptotic pathway. Furthermore, upregulation of the Nrf2-Keap1 signaling pathway was also observed. Our findings revealed that the oxidative stress, mitochondrial dysfunction, and the Nrf2-Keap1 signaling pathway were associated with the kidney apoptosis induced by MEQ in vivo. PMID:29765325

Nano-Se attenuates cyclophosphamide-induced pulmonary injury through modulation of oxidative stress and DNA damage in Swiss albino mice.

PubMed

Bhattacharjee, Arin; Basu, Abhishek; Biswas, Jaydip; Bhattacharya, Sudin

2015-07-01

Chemotherapy is an integral part of modern day treatment regimen but anticancer drugs fail to demarcate between cancerous and normal cells thereby causing severe form of systemic toxicity. Among which pulmonary toxicity is a dreadful complication developed in cancer patients upon cyclophosphamide (CP) therapy. Oxidative stress, fibrosis, and apoptosis are the major patho-mechanisms involved in CP-induced pulmonary toxicity. In the present study, we have synthesized Nano-Se, nanotechnology-based new form of elemental selenium which has significantly lower toxicity and acceptable bioavailability. In order to meet the need of effective drugs against CP-induced adverse effects, nano selenium (Nano-Se) was tested for its possible protective efficacy on CP-induced pulmonary toxicity and bone marrow toxicity. CP intoxication resulted in structural and functional lung impairment which was revealed by massive histopathological changes. Lung injury was associated with oxidative stress/lipid peroxidation as evident by increased in reactive oxygen species, nitric oxide level, and malondialdehyde (MDA) formation with decreased in level of antioxidants such as reduced glutathione, glutathione-S-transferase, glutathione peroxidase, superoxide dismutase, and catalase. Furthermore, CP at a dose of 25 mg/kg b.w. increased pulmonary DNA damage ('comet tail') and triggered DNA fragmentation and apoptosis in mouse bone marrow cells. On the other hand, Nano-Se at a dose of 2 mg Se/kg b.w., significantly inhibited CP-induced DNA damage in bronchoalveolar lavage cells, and decreased the apoptosis and percentage of DNA fragmentation in bone marrow cells and also antagonized the reduction of the activities of antioxidant enzymes and the increase level of MDA. Thus, our results suggest that Nano-Se in pre- and co-administration may serve as a promising preventive strategy against CP-induced pulmonary toxicity.

Rasagiline (TVP-1012): a new selective monoamine oxidase inhibitor for Parkinson's disease.

PubMed

Guay, David R P

2006-12-01

This article reviews the chemistry, pharmacodynamics, pharmacokinetics, clinical efficacy, tolerability, drug-interaction potential, indications, dosing, and potential role of rasagiline mesylate, a new selective monoamine oxidase (MAO) type B (MAO-B) inhibitor, in the treatment of Parkinson's disease. A MEDLINE/PUBMED search (1986 through September 2006) was conducted to identify studies involving rasagiline written in English. Additional references were obtained from the bibliographies of these studies. All studies evaluating any aspect of rasagiline, including in vitro, in vivo (animal), and human studies, were reviewed. Rasagiline mesylate was developed with the goal of producing a selective MAO-B inhibitor that is not metabolized to (presumed) toxic metabolites (eg, amphetamine and methamphetamine, which are byproducts of the metabolism of selegiline, another selective MAO-B inhibitor). In vitro and in vivo data have confirmed the drug's selectivity for MAO-B. Rasagiline is almost completely eliminated by oxidative metabolism (catalyzed by cytochrome P-450 [CYP] isozyme 1A2) followed by renal excretion of conjugated parent compound and metabolites. Drug clearance is sufficiently slow to allow once-daily dosing. Several studies have documented its efficacy as monotherapy for early-stage disease and as adjunctive therapy in L-dopa recipients with motor fluctuations. As monotherapy, rasagiline is well tolerated with an adverse-effect profile similar to that of placebo. As adjunctive therapy, it exhibits the expected adverse effects of dopamine excess, which can be ameliorated by reducing the L-dopa dosage. CYP1A2 inhibitors slow the elimination of rasagiline and mandate dosage reduction. Hepatic impairment has an analogous effect. The recommended dosage regimens for monotherapy and adjunctive therapy are 1 and 0.5 mg PO QD, respectively. Despite the well-documented selectivity of rasagiline, the manufacturer recommends virtually all of the dietary (vis-à-vis tyramine) and drug restrictions of the nonselective MAO inhibitors. Although useful, selective MAO-B inhibitors have a limited role in Parkinson's disease. Of greater interest is the potential neuroprotective effect of rasagiline and its major metabolite, 1(R)-aminoindan, which may have great utility in a wide variety of neurodegenerative disorders of aging. In addition, bifunctional molecules combining selective MAO-B inhibition (based on the active moiety of rasagiline) with acetylcholinesterase inhibition or iron chelation may eventually be useful in Alzheimer's disease.

Enhancement of DMNQ-induced hepatocyte toxicity by cytochrome P450 inhibition.

PubMed

Ishihara, Yasuhiro; Shiba, Dai; Shimamoto, Norio

2006-07-15

Two mechanisms have been proposed to explain quinone cytotoxicity: oxidative stress via the redox cycle and the arylation of intracellular nucleophiles. As the redox cycle is catalyzed by NADPH cytochrome P450 reductase, cytochrome P450 systems are expected to be related to the cytotoxicity induced by redox-cycling quinones. Thus, we investigated the relationship between cytochrome P450 systems and quinone toxicity for rat primary hepatocytes using an arylator, 1,4-benzoquinone (BQ), and a redox cycler, 2,3-dimethoxy-1,4-naphthoquinone (DMNQ). The hepatocyte toxicity of both BQ and DMNQ increased in a time- and dose-dependent manner. Pretreatment with cytochrome P450 inhibitors, such as SKF-525A (SKF), ketoconazole and 2-methy-1,2-di-3-pyridyl-1-propanone, enhanced the hepatocyte toxicity induced by DMNQ but did not affect BQ-induced hepatocyte toxicity. The production of superoxide anion and the levels of glutathione disulfide and thiobarbituric-acid-reactive substances were increased by treatment with DMNQ, and SKF pretreatment further enhanced their increases. In addition, NADPH oxidation in microsomes was increased by treatment with DMNQ and further augmented by pretreatment with SKF, and a NADPH cytochrome P450 reductase inhibitor, diphenyleneiodonium chloride completely suppressed NADPH oxidations increased by treatment with either DMNQ- or DMNQ + SKF. Pretreatment with antioxidants, such as alpha-tocopherol, reduced glutathione, N-acetyl cysteine or an iron ion chelator deferoxamine, totally suppressed DMNQ- and DMNQ + SKF-induced hepatocyte toxicity. These results indicate that the hepatocyte toxicity of redox-cycling quinones is enhanced under cytochrome P450 inhibition, and that this enhancement is caused by the potentiation of oxidative stress.

Tualang Honey Protects the Rat Midbrain and Lung against Repeated Paraquat Exposure

PubMed Central

Sulaiman, Siti Amrah

2017-01-01

Paraquat (PQ) is a dopaminergic neurotoxin and a well-known pneumotoxicant that exerts its toxic effect via oxidative stress-mediated cellular injuries. This study investigated the protective effects of Tualang honey against PQ-induced toxicity in the midbrain and lungs of rats. The rats were orally treated with distilled water (2 mL/kg/day), Tualang honey (1.0 g/kg/day), or ubiquinol (0.2 g/kg/day) throughout the experimental period. Two weeks after the respective treatments, the rats were injected intraperitoneally with saline (1 mL/kg/week) or PQ (10 mg/kg/week) once per week for four consecutive weeks. After four weekly exposures to PQ, the glutathione peroxidase activity and the number of tyrosine-hydroxylase immunopositive neurons in the midbrain were significantly decreased in animals from group PQ (p < 0.05). The lungs of animals from group PQ showed significantly decreased activity of superoxide dismutase and glutathione-S-transferase. Treatment with Tualang honey ameliorated the toxic effects observed in the midbrain and lungs. The beneficial effects of Tualang honey were comparable to those of ubiquinol, which was used as a positive control. These findings suggest that treatment with Tualang honey may protect against PQ-induced toxicity in the rat midbrain and lung. PMID:28127418

Tualang Honey Protects the Rat Midbrain and Lung against Repeated Paraquat Exposure.

PubMed

Tang, Suk Peng; Kuttulebbai Nainamohamed Salam, Sirajudeen; Jaafar, Hasnan; Gan, Siew Hua; Muzaimi, Mustapha; Sulaiman, Siti Amrah

2017-01-01

Paraquat (PQ) is a dopaminergic neurotoxin and a well-known pneumotoxicant that exerts its toxic effect via oxidative stress-mediated cellular injuries. This study investigated the protective effects of Tualang honey against PQ-induced toxicity in the midbrain and lungs of rats. The rats were orally treated with distilled water (2 mL/kg/day), Tualang honey (1.0 g/kg/day), or ubiquinol (0.2 g/kg/day) throughout the experimental period. Two weeks after the respective treatments, the rats were injected intraperitoneally with saline (1 mL/kg/week) or PQ (10 mg/kg/week) once per week for four consecutive weeks. After four weekly exposures to PQ, the glutathione peroxidase activity and the number of tyrosine-hydroxylase immunopositive neurons in the midbrain were significantly decreased in animals from group PQ ( p < 0.05). The lungs of animals from group PQ showed significantly decreased activity of superoxide dismutase and glutathione-S-transferase. Treatment with Tualang honey ameliorated the toxic effects observed in the midbrain and lungs. The beneficial effects of Tualang honey were comparable to those of ubiquinol, which was used as a positive control. These findings suggest that treatment with Tualang honey may protect against PQ-induced toxicity in the rat midbrain and lung.

Oxidized starch solutions for environmentally friendly aircraft deicers.

PubMed

Plahuta, Joseph M; Teel, Amy L; Ahmad, Mushtaque; Beutel, Mark W; Rentz, Jeremy A; Watts, Richard J

2011-09-01

Deicers currently used for aircraft deicing, including ethylene glycol and propylene glycol, pose significant threats to surface waters, as a result of high biochemical oxygen demand (BOD) and toxicity to aquatic organisms. Oxidized starch may provide a less toxic deicer with lower BOD. The freezing point depression of starch formulations oxidized using hydrogen peroxide and catalysts (i.e., catalyzed hydrogen peroxide [H2O2] propagations-CHP) was 28 degrees C, and viscosities similar to those of commercial deicers were achieved after post-treatment with granular activated carbon. The most effective oxidized starch formulation exerted a 5-day BOD up to 6 times lower than glycol deicers (103 versus 400 to 800 g O2/L). Toxicity to Ceriodaphnia dubia for this formulation (48-hour lethal concentration, 50% [LC50] of 2.73 g/L) was greater than pure propylene glycol (13.1 g/ L), but lower than propylene glycol deicer formulations (1.02 g/L). Organic acids were identified by gas chromatography/mass spectrometry as the primary constituents in the oxidized starch solution. The proposed deicing system would provide effective deicing while exerting minimal environmental effects (e.g., lower toxicity to aquatic organisms and lower BOD). Furthermore, these deicers could be made from waste starch, promoting sustainability.

Antiparkinsonian effects of aqueous methanolic extract of Hyoscyamus niger seeds result from its monoamine oxidase inhibitory and hydroxyl radical scavenging potency.

PubMed

Sengupta, T; Vinayagam, J; Nagashayana, N; Gowda, B; Jaisankar, P; Mohanakumar, K P

2011-01-01

Hyoscyamus species is one of the four plants used in Ayurveda for the treatment of Parkinson's disease (PD). Since Hyoscyamus niger was found to contain negligible levels of L-DOPA, we evaluated neuroprotective potential, if any, of characterized petroleum ether and aqueous methanol extracts of its seeds in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of PD in mice. Air dried authenticated H. niger seeds were sequentially extracted using petroleum ether and aqueous methanol and were characterized employing HPLC-electrochemistry and LCMS. Parkinsonian mice were treated daily twice with the extracts (125-500 mg/kg, p.o.) for two days and motor functions and striatal dopamine levels were assayed. Administration of the aqueous methanol extract (containing 0.03% w/w of L-DOPA), but not petroleum ether extract, significantly attenuated motor disabilities (akinesia, catalepsy and reduced swim score) and striatal dopamine loss in MPTP treated mice. Since the extract caused significant inhibition of monoamine oxidase activity and attenuated 1-methyl-4-phenyl pyridinium (MPP+)-induced hydroxyl radical (·OH) generation in isolated mitochondria, it is possible that the methanolic extract of Hyoscyamus niger seeds protects against parkinsonism in mice by means of its ability to inhibit increased ·OH generated in the mitochondria.

Pain processing in atypical Parkinsonisms and Parkinson disease: A comparative neurophysiological study.

PubMed

Avenali, Micol; Tassorelli, Cristina; De Icco, Roberto; Perrotta, Armando; Serrao, Mariano; Fresia, Mauro; Pacchetti, Claudio; Sandrini, Giorgio

2017-10-01

Pain is a frequent non-motor feature in Parkinsonism but mechanistic data on the alteration of pain processing are insufficient to understand the possible causes and to define specifically-targeted treatments. we investigated spinal nociception through the neurophysiological measure of the threshold (TR) of nociceptive withdrawal reflex (NWR) and its temporal summation threshold (TST) comparatively in 12 Progressive Supranuclear Palsy (PSP) subjects, 11 Multiple System Atrophy (MSA) patients, 15 Parkinson's disease (PD) subjects and 24 healthy controls (HC). We also investigated the modulatory effect of L-Dopa in these three parkinsonian groups. We found a significant reduction in the TR of NWR and in the TST of NWR in PSP, MSA and PD patients compared with HC. L-Dopa induced an increase in the TR of NWR in the PSP group while TST of NWR increased in both PSP and PD. Our neurophysiological findings identify a facilitation of nociceptive processing in PSP that is broadly similar to that observed in MSA and PD. Specific peculiarities have emerged for PSP. Our data advance the knowledge of the neurophysiology of nociception in the advanced phases of parkinsonian syndromes and on the role of dopaminergic pathways in the control on pain processing. Copyright © 2017 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.

CrII Reactivity of Taurine/α-Ketoglutarate Dioxygenase

PubMed Central

Grzyska, Piotr K.; Hausinger, Robert P.

2008-01-01

The interaction of CrII with taurine/α-ketoglutarate (αKG) dioxygenase (TauD) was examined. CrII replaces FeII and binds stoichiometrically with αKG to the FeII/αKG-binding site of the protein, with additional CrII used to generate a chromophore attributed to a CrIII-semiquinone in a small percentage of the sample. Formation of the latter oxygen -sensitive species requires the dihydroxyphenylalanine (DOPA) quinone form of Tyr-73. This pre-formed side chain is generated by intracellular self-hydroxylation of Tyr-73 to form DOPA, which is subsequently oxidized to the quinone. No chromophore is generated when using NaBH4-treated sample, protein isolated from anaerobically grown cells, inactive TauD variants that are incapable of self-hydroxylation, or the Y73F active mutant of TauD. A CrIII-DOPA semiquinone also was observed in the herbicide hydroxylase SdpA. PMID:17973473

Cr(II) reactivity of taurine/alpha-ketoglutarate dioxygenase.

PubMed

Grzyska, Piotr K; Hausinger, Robert P

2007-11-26

The interaction of CrII with taurine/alpha-ketoglutarate (alphaKG) dioxygenase (TauD) was examined. CrII replaces FeII and binds stoichiometrically with alphaKG to the FeII/alphaKG binding site of the protein, with additional CrII used to generate a chromophore attributed to a CrIII-semiquinone in a small percentage of the sample. Formation of the latter oxygen-sensitive species requires the dihydroxyphenylalanine (DOPA) quinone form of Tyr-73. This preformed side chain is generated by intracellular self-hydroxylation of Tyr-73 to form DOPA, which is subsequently oxidized to the quinone. No chromophore is generated when using NaBH4-treated sample, protein isolated from anaerobically grown cells, inactive TauD variants that are incapable of self-hydroxylation, or the Y73F active mutant of TauD. A CrIII-DOPA semiquinone also was observed in the herbicide hydroxylase SdpA.

Dose- dependent ameliorative effects of quercetin and l-Carnitine against atrazine- induced reproductive toxicity in adult male Albino rats.

PubMed

Abdel Aziz, Rabie L; Abdel-Wahab, Ahmed; Abo El-Ela, Fatma I; Hassan, Nour El-Houda Y; El-Nahass, El-Shaymaa; Ibrahim, Marwa A; Khalil, Abdel-Tawab A Y

2018-06-01

This study aimed to determine the protective effects of co-administration of Quercetin (QT) or l-Carnitine (LC) against the oxidative stress induced by Atrazine (ATZ) in the reproductive system of intact male Albino rats. 36 rats were divided equally into 6 groups. Rats in the control negative "CNT" group received 1.5 ml distilled water for 21 days. All rats in the other groups received ATZ (120 mg/kg bw) through gavage. Groups 3 and 4 were co-administered with either low or high dose of QT (10 "ATZLQT" and 50 "ATZHQT" mg/kg bw, respectively). Groups 5 and 6 were co-administered with either low or high dose of LC (200 "ATZLLC" and 400 "ATZHLC" mg/kg bw, respectively). At the end of the experiment, animals were sacrificed and all samples were collected. ATZ significantly increased serum level of malondialdehyde (MDA) and decreased total antioxidant capacity (TAC). Also, ATZ increased significantly the sperm cell abnormalities and reduced both testicular IgA and serum testosterone levels. Testicular DNA laddering % and CYP17A1 mRNA expression were significantly reduced in ATZ group. Interestingly, co-administration with low dose QT or different doses of LC succeeded to counteract the negative toxic effects of ATZ on serum oxidative stress indicators, serum testosterone levels, testicular IgA level and improved testicular CYP17A1 mRNA expression. In conclusion, QT in low dose and LC in both low and high doses exerted a significant protective action against the reproductive toxicity of ATZ, while higher dose of QT failed induce immune-stimulant effect against ATZ in adult male Albino rats. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

Unlabeled multi tumor marker detection system based on bioinitiated light addressable potentiometric sensor.

PubMed

Jia, Yun-Fang; Gao, Chun-Ying; He, Jia; Feng, Dao-Fu; Xing, Ke-Li; Wu, Ming; Liu, Yang; Cai, Wen-Sheng; Feng, Xi-Zeng

2012-08-21

Multi biomarkers' assays are of great significance in clinical diagnosis. A label-free multi tumor markers' parallel detection system was proposed based on a light addressable potentiometric sensor (LAPS). Arrayed LAPS chips with basic structure of Si(3)N(4)-SiO(2)-Si were prepared on silicon wafers, and the label-free parallel detection system for this component was developed with user friendly controlling interfaces. Then the l-3,4-dihydroxyphenyl-alanine (L-Dopa) hydrochloric solution was used to initiate the surface of LAPS. The L-Dopa immobilization state was investigated by the theoretical calculation. L-Dopa initiated LAPS' chip was biofunctionalized respectively by the antigens and antibodies of four tumor markers, α-fetoprotein (AFP), carcinoembryonic antigen (CEA), cancer antigen 19-9 (CA19-9) and Ferritin. Then unlabeled antibodies and antigens of these four biomarkers were detected by the proposed detection systems. Furthermore physical and measuring principles in this system were described, and qualitative understanding for experimental data were given. The measured response ranges were compared with their clinical cutoff values, and sensitivities were calculated by OriginLab. The results indicate that this bioinitiated LAPS based label-free detection system may offer a new choice for the realization of unlabeled multi tumor markers' clinical assay.

Monoamine Reuptake Inhibitors in Parkinson's Disease

PubMed Central

Huot, Philippe; Fox, Susan H.; Brotchie, Jonathan M.

2015-01-01

The motor manifestations of Parkinson's disease (PD) are secondary to a dopamine deficiency in the striatum. However, the degenerative process in PD is not limited to the dopaminergic system and also affects serotonergic and noradrenergic neurons. Because they can increase monoamine levels throughout the brain, monoamine reuptake inhibitors (MAUIs) represent potential therapeutic agents in PD. However, they are seldom used in clinical practice other than as antidepressants and wake-promoting agents. This review article summarises all of the available literature on use of 50 MAUIs in PD. The compounds are divided according to their relative potency for each of the monoamine transporters. Despite wide discrepancy in the methodology of the studies reviewed, the following conclusions can be drawn: (1) selective serotonin transporter (SERT), selective noradrenaline transporter (NET), and dual SERT/NET inhibitors are effective against PD depression; (2) selective dopamine transporter (DAT) and dual DAT/NET inhibitors exert an anti-Parkinsonian effect when administered as monotherapy but do not enhance the anti-Parkinsonian actions of L-3,4-dihydroxyphenylalanine (L-DOPA); (3) dual DAT/SERT inhibitors might enhance the anti-Parkinsonian actions of L-DOPA without worsening dyskinesia; (4) triple DAT/NET/SERT inhibitors might exert an anti-Parkinsonian action as monotherapy and might enhance the anti-Parkinsonian effects of L-DOPA, though at the expense of worsening dyskinesia. PMID:25810948

Prophylactic role of coenzyme Q10 and Cynara scolymus L on doxorubicin-induced toxicity in rats: Biochemical and immunohistochemical study.

PubMed

Mustafa, Hesham N; El Awdan, Sally A; Hegazy, Gehan A; Abdel Jaleel, Gehad A

2015-01-01

The study aims to evaluate the protective effects of coenzyme Q10 (CoQ10) and Cynara scolymus L (CS) on doxorubicin (dox)-induced toxicity. Sixty male rats were divided into six groups. Group 1 as a control. Group 2 received dox (10 mg/kg) intraperitoneally. Group 3 received CoQ10 (200 mg/kg). Group 4 received CS (500 mg/kg). Group 5 received CoQ10 (200 mg/kg) and dox (10 mg/kg). Group 6 received CS (500 mg/kg) and dox (10 mg/kg). The rats were then evaluated biochemically and immunohistochemically. Dox produced a significant deterioration of hepatic and renal functional parameters. Moreover, an upsurge of oxidative stress and nitrosative stress markers. The expression of alpha-smooth muscle actin (α-SMA) was increased and proliferating cell nuclear antigen (PCNA) expression was decreased. Administration of CoQ10 and CS resulted in a significant improvement of hepatic and renal functional parameters, and an improvement of both α-SMA and PCNA. It is concluded that pretreatment with CoQ10 and CS is associated with up-regulation of favorable protective enzymes and down-regulation of oxidative stress. That can be advised as a supplement to dox-treated patients.

Prophylactic role of coenzyme Q10 and Cynara scolymus L on doxorubicin-induced toxicity in rats: Biochemical and immunohistochemical study

PubMed Central

Mustafa, Hesham N.; El Awdan, Sally A.; Hegazy, Gehan A.; Abdel Jaleel, Gehad A.

2015-01-01

Objective: The study aims to evaluate the protective effects of coenzyme Q10 (CoQ10) and Cynara scolymus L (CS) on doxorubicin (dox)-induced toxicity. Materials and Methods: Sixty male rats were divided into six groups. Group 1 as a control. Group 2 received dox (10 mg/kg) intraperitoneally. Group 3 received CoQ10 (200 mg/kg). Group 4 received CS (500 mg/kg). Group 5 received CoQ10 (200 mg/kg) and dox (10 mg/kg). Group 6 received CS (500 mg/kg) and dox (10 mg/kg). The rats were then evaluated biochemically and immunohistochemically. Results: Dox produced a significant deterioration of hepatic and renal functional parameters. Moreover, an upsurge of oxidative stress and nitrosative stress markers. The expression of alpha-smooth muscle actin (α-SMA) was increased and proliferating cell nuclear antigen (PCNA) expression was decreased. Administration of CoQ10 and CS resulted in a significant improvement of hepatic and renal functional parameters, and an improvement of both α-SMA and PCNA. Conclusion: It is concluded that pretreatment with CoQ10 and CS is associated with up-regulation of favorable protective enzymes and down-regulation of oxidative stress. That can be advised as a supplement to dox-treated patients. PMID:26729958

Relationship between genotoxicity and oxidative stress induced by mercury on common carp (Cyprinus carpio) tissues.

PubMed

García-Medina, Sandra; Galar-Martínez, Marcela; Gómez-Oliván, Leobardo Manuel; Ruiz-Lara, Karina; Islas-Flores, Hariz; Gasca-Pérez, Eloy

2017-11-01

Mercury is one of the most toxic metals in aquatic systems since it is able to induce neurobehavioral disorders as well as renal and gastrointestinal tract damage. The common carp Cyprinus carpio is an important species from both an ecological and economic viewpoint as it is consumed in many countries, the top producers being Mexico, China, India and Japan. The present study aimed to evaluate the relation between Hg-induced oxidative stress and genotoxicity in diverse tissues of C. carpio. Specimens were exposed to 0.01mgHg/L (the maximum permissible limit for aquatic life protection), and lipid peroxidation, protein carbonyl content and the activity of antioxidant enzymes were evaluated at 96h. Micronuclei frequency and DNA damage by comet assay were determined at 12, 24, 48, 72 and 96h. Hg induced oxidative stress and genotoxicity on exposed fish, since inhibition of antioxidant enzymes activity and increases in lipid peroxidation, DNA damage and micronuclei frequency occurred. Blood, gill and liver were more susceptible to oxidative stress, while blood were more sensitive to genotoxicity. In conclusion, Hg at concentrations equal to the maximum permissible limit for aquatic life protection induced oxidative stress and genotoxicity on C. carpio, and these two effects prove to be correlated. Copyright © 2017 Elsevier B.V. All rights reserved.

Effect of exogenous nitric oxide on antioxidative system and S-nitrosylation in leaves of Boehmeria nivea (L.) Gaud under cadmium stress.

PubMed

Wang, Dafei; Liu, Yunguo; Tan, Xiaofei; Liu, Hongyu; Zeng, Guangming; Hu, Xinjiang; Jian, Hao; Gu, Yanling

2015-03-01

Cadmium (Cd)-induced growth inhibition is one of the primary factors limiting phytoremediation effect of Boehmeria nivea (L.) Gaud in contaminated soil. Sodium nitroprusside (SNP), a donor of nitric oxide (NO), has been evidenced to alleviate Cd toxicity in many plants. However, as an important mechanism of NO in orchestrating cellular functions, S-nitrosylation is still poorly understood in its relation with Cd tolerance of plants. In this study, higher exogenous NO levels were found to coincide with higher S-nitrosylation level expressed as content of S-nitrosothiols (SNO). The addition of low concentration (100 μM) SNP increased the SNO content, and it simultaneously induced an alleviating effect against Cd toxicity by enhancing the activities of superoxide dismutase (SOD), ascorbate peroxidase (APX), and glutathione reductase (GR) and reduced the accumulation of H2O2 as compared with Cd alone. Application of S-nitrosoglutathione reductase (GSNOR) inhibitors dodecanoic acid (DA) in 100 μM SNP group brought in an extra elevation in S-nitrosylation level and further reinforced the effect of SNP. While the additions of 400 μM SNP and 400 μM SNP + 50 μM DA further elevated the S-nitrosylation level, it markedly weakened the alleviating effect against Cd toxicity as compared with the addition of 100 μM SNP. This phenomenon could be owing to excess consumption of glutathione (GSH) to form SNO under high S-nitrosylation level. Therefore, the present study indicates that S-nitrosylation is involved in the ameliorating effect of SNP against Cd toxicity. This involvement exhibited a concentration-dependent property.

D-tyrosine negatively regulates melanin synthesis by competitively inhibiting tyrosinase activity.

PubMed

Park, Jisu; Jung, Hyejung; Kim, Kyuri; Lim, Kyung-Min; Kim, Ji-Young; Jho, Eek-Hoon; Oh, Eok-Soo

2018-05-01

Although L-tyrosine is well known for its melanogenic effect, the contribution of D-tyrosine to melanin synthesis was previously unexplored. Here, we reveal that, unlike L-tyrosine, D-tyrosine dose-dependently reduced the melanin contents of human MNT-1 melanoma cells and primary human melanocytes. In addition, 500 μM of D-tyrosine completely inhibited 10 μM L-tyrosine-induced melanogenesis, and both in vitro assays and L-DOPA staining MNT-1 cells showed that tyrosinase activity is reduced by D-tyrosine treatment. Thus, D-tyrosine appears to inhibit L-tyrosine-mediated melanogenesis by competitively inhibiting tyrosinase activity. Furthermore, we found that D-tyrosine inhibited melanogenesis induced by α-MSH treatment or UV irradiation, which are the most common environmental factors responsible for melanin synthesis. Finally, we confirmed that D-tyrosine reduced melanin synthesis in the epidermal basal layer of a 3D human skin model. Taken together, these data suggest that D-tyrosine negatively regulates melanin synthesis by inhibiting tyrosinase activity in melanocyte-derived cells. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Computer assisted CT-guided stereotactic transplantation of foetal ventral mesencephalon to the caudate nucleus and putamen in Parkinson's disease.

PubMed

Molina, H; Quiñones, R; Ortega, I; Alvarez, L; Muñoz, J; Gonzalez, C; Suárez, C

1993-01-01

We report our preliminary results related to CT-guided stereotactic transplantation of foetal ventral mesencephalic cell suspension into the striatum of five patients with idiopathic Parkinson's disease. The mean age was 51 years, the evolution time of the disease ranged from 7 to 14 years, and all of them had motor complications associated with chronic L-dopa therapy. The patients were evaluated according to the Core Assessment Program for Intracerebral Transplantations (CAPIT) for one year before and three months after surgery. The postoperative clinical assessment demonstrated significant improvement of neurological symptoms and reduction of daily L-dopa dosage.

Cytotoxic effects of Urtica dioica radix on human colon (HT29) and gastric (MKN45) cancer cells mediated through oxidative and apoptotic mechanisms.

PubMed

Ghasemi, S; Moradzadeh, M; Mousavi, S H; Sadeghnia, H R

2016-10-15

Defects in the apoptotic pathways are responsible for both the colorectal cancer pathogenesis and resistance to therapy. In this study, we examined the level of cellular oxidants, cytotoxicity and apoptosis induced by hydroalcoholic extract of U. dioica radix (0-2000 µg/mL) and oxaliplatin (0-1000 µg/mL, as positive control) in human gastric (MKN45) and colon (HT29) cancer, as well as normal human foreskin fibroblast (HFF) cells. Exposure to U. dioica or oxaliplatin showed a concentration dependent suppression in cell survival with IC50 values of 24.7, 249.9 and 857.5 µg/mL for HT29, MKN45 and HFF cells after 72 h treatment, respectively. ROS formation and lipid peroxidation were also concentration-dependently increased following treatment with U. dioica, similar to oxaliplatin. In addition, the number of apoptotic cells significantly increased concomitantly with concentration of U. dioica as compared with control cells, which is similar to oxaliplatin and serum-deprived cancer cells. In conclusion, the present study demonstrated that U. dioica inhibited proliferation of gastric and colorectal cancer cells while posing no significant toxic effect on normal cells. U. dioica not only increased levels of oxidants, but also induced concomitant increase of apoptosis. The precise signaling pathway by which U. dioica induce apoptosis needs further research.

DAT1 Polymorphism Determines L-DOPA Effects on Learning about Others’ Prosociality

PubMed Central

Rieskamp, Jörg; Zehnder, Christian; Ebstein, Richard; Fehr, Ernst; Knoch, Daria

2013-01-01

Despite that a wealth of evidence links striatal dopamine to individualś reward learning performance in non-social environments, the neurochemical underpinnings of such learning during social interaction are unknown. Here, we show that the administration of 300 mg of the dopamine precursor L-DOPA to 200 healthy male subjects influences learning about a partners’ prosocial preferences in a novel social interaction task, which is akin to a repeated trust game. We found learning to be modulated by a well-established genetic marker of striatal dopamine levels, the 40-bp variable number tandem repeats polymorphism of the dopamine transporter (DAT1 polymorphism). In particular, we found that L-DOPA improves learning in 10/10R genoype subjects, who are assumed to have lower endogenous striatal dopamine levels and impairs learning in 9/10R genotype subjects, who are assumed to have higher endogenous dopamine levels. These findings provide first evidence for a critical role of dopamine in learning whether an interaction partner has a prosocial or a selfish personality. The applied pharmacogenetic approach may open doors to new ways of studying psychiatric disorders such as psychosis, which is characterized by distorted perceptions of others’ prosocial attitudes. PMID:23861813

The safety of istradefylline for the treatment of Parkinson's disease.

PubMed

Müller, Thomas

2015-05-01

Antagonism of the A2A receptor improves motor behavior in patients with Parkinson's disease (PD), according to results of clinical studies which confirm findings of previous experimental research. The xanthine derivative, istradefylline , has the longest half-life out of the available A2A receptor antagonists. Istradefylline easily crosses the blood-brain barrier and shows a high affinity to the human A2A receptor. This narrative review aims to discuss the safety and tolerability of istradefylline against the background of the currently available drug portfolio for the treatment of PD patients. Istradefylline was safe and well tolerated in clinical trials, which have focused on l-DOPA-treated PD patients. The future of istradefylline as a complementary drug for modulation of the dopaminergic neurotransmission also relies on its potential to act like an l-DOPA plus dopamine agonist sparing future treatment alternative and to reduce the risk of predominant l-DOPA-related onset of motor complications in addition to its direct ameliorating effect on motor symptoms. Dopamine-substituting drugs may dose-dependently produce systemic side effects, particularly onset of hypotension and nausea by peripheral dopamine receptor stimulation. Istradefylline does not interfere with these peripheral receptors and therefore shows a good safety and tolerability profile.

Trapping of cis-2-butene-1,4-dial to measure furan metabolism in human liver microsomes by cytochrome P450 enzymes.

PubMed

Gates, Leah A; Lu, Ding; Peterson, Lisa A

2012-03-01

Furan is a liver toxicant and carcinogen in rodents. It is classified as a possible human carcinogen, but the human health effects of furan exposure remain unknown. The oxidation of furan by cytochrome P450 (P450) enzymes is necessary for furan toxicity. The product of this reaction is the reactive α,β-unsaturated dialdehyde, cis-2-butene-1,4-dial (BDA). To determine whether human liver microsomes metabolize furan to BDA, a liquid chromatography/tandem mass spectrometry method was developed to detect and quantify BDA by trapping this reactive metabolite with N-acetyl-l-cysteine (NAC) and N-acetyl-l-lysine (NAL). Reaction of NAC and NAL with BDA generates N-acetyl-S-[1-(5-acetylamino-5-carboxypentyl)-1H-pyrrol-3-yl]-l-cysteine (NAC-BDA-NAL). Formation of NAC-BDA-NAL was quantified in 21 different human liver microsomal preparations. The levels of metabolism were comparable to that observed in F-344 rat and B6C3F1 mouse liver microsomes, two species known to be sensitive to furan-induced toxicity. Studies with recombinant human liver P450s indicated that CYP2E1 is the most active human liver furan oxidase. The activity of CYP2E1 as measured by p-nitrophenol hydroxylase activity was correlated to the extent of NAC-BDA-NAL formation in human liver microsomes. The formation of NAC-BDA-NAL was blocked by CYP2E1 inhibitors but not other P450 inhibitors. These results suggest that humans are capable of oxidizing furan to its toxic metabolite, BDA, at rates comparable to those of species sensitive to furan exposure. Therefore, humans may be susceptible to furan's toxic effects.

Trapping of cis-2-Butene-1,4-dial to Measure Furan Metabolism in Human Liver Microsomes by Cytochrome P450 Enzymes

PubMed Central

Gates, Leah A.; Lu, Ding

2012-01-01

Furan is a liver toxicant and carcinogen in rodents. It is classified as a possible human carcinogen, but the human health effects of furan exposure remain unknown. The oxidation of furan by cytochrome P450 (P450) enzymes is necessary for furan toxicity. The product of this reaction is the reactive α,β-unsaturated dialdehyde, cis-2-butene-1,4-dial (BDA). To determine whether human liver microsomes metabolize furan to BDA, a liquid chromatography/tandem mass spectrometry method was developed to detect and quantify BDA by trapping this reactive metabolite with N-acetyl-l-cysteine (NAC) and N-acetyl-l-lysine (NAL). Reaction of NAC and NAL with BDA generates N-acetyl-S-[1-(5-acetylamino-5-carboxypentyl)-1H-pyrrol-3-yl]-l-cysteine (NAC-BDA-NAL). Formation of NAC-BDA-NAL was quantified in 21 different human liver microsomal preparations. The levels of metabolism were comparable to that observed in F-344 rat and B6C3F1 mouse liver microsomes, two species known to be sensitive to furan-induced toxicity. Studies with recombinant human liver P450s indicated that CYP2E1 is the most active human liver furan oxidase. The activity of CYP2E1 as measured by p-nitrophenol hydroxylase activity was correlated to the extent of NAC-BDA-NAL formation in human liver microsomes. The formation of NAC-BDA-NAL was blocked by CYP2E1 inhibitors but not other P450 inhibitors. These results suggest that humans are capable of oxidizing furan to its toxic metabolite, BDA, at rates comparable to those of species sensitive to furan exposure. Therefore, humans may be susceptible to furan's toxic effects. PMID:22187484

TiO2, SiO2 and ZrO2 Nanoparticles Synergistically Provoke Cellular Oxidative Damage in Freshwater Microalgae

PubMed Central

Liu, Yinghan; Ye, Nan; Fang, Hao; Wang, Degao

2018-01-01

Metal-based nanoparticles (NPs) are the most widely used engineered nanomaterials. The individual toxicities of metal-based NPs have been plentifully studied. However, the mixture toxicity of multiple NP systems (n ≥ 3) remains much less understood. Herein, the toxicity of titanium dioxide (TiO2) nanoparticles (NPs), silicon dioxide (SiO2) NPs and zirconium dioxide (ZrO2) NPs to unicellular freshwater algae Scenedesmus obliquus was investigated individually and in binary and ternary combination. Results show that the ternary combination systems of TiO2, SiO2 and ZrO2 NPs at a mixture concentration of 1 mg/L significantly enhanced mitochondrial membrane potential and intracellular reactive oxygen species level in the algae. Moreover, the ternary NP systems remarkably increased the activity of the antioxidant defense enzymes superoxide dismutase and catalase, together with an increase in lipid peroxidation products and small molecule metabolites. Furthermore, the observation of superficial structures of S. obliquus revealed obvious oxidative damage induced by the ternary mixtures. Taken together, the ternary NP systems exerted more severe oxidative stress in the algae than the individual and the binary NP systems. Thus, our findings highlight the importance of the assessment of the synergistic toxicity of multi-nanomaterial systems. PMID:29419775

In vitro toxicological assessment of iron oxide, aluminium oxide and copper nanoparticles in prokaryotic and eukaryotic cell types.

PubMed

Sadiq, Rakhshinda; Khan, Qaiser Mahmood; Mobeen, Ameena; Hashmat, Amer Jamal

2015-04-01

Metallic nanoparticles (NPs) have a variety of applications in different industries including pharmaceutical industry where these NPs are used mainly for image analysis and drug delivery. The increasing interest in nanotechnology is largely associated with undefined risks to the human health and to the environment. Therefore, in the present study cytotoxic and genotoxic effects of iron oxide, aluminium oxide and copper nanoparticles were evaluated using most commonly used assays i.e. Ames assay, in vitro cytotoxicity assay, micronucleus assay and comet assay. Cytotoxicity to bacterial cells was assessed in terms of colony forming units by using Escherichia coli (gram negative) and Bacillus subtilis (gram positive). Ames assay was carried out using two bacterial strains of Salmonella typhimurium TA98 and TA100. Genotoxicity of these NPs was evaluated following exposure to monkey kidney cell line, CHS-20. No cytotoxic and genotoxic effects were observed for iron oxide, and aluminium oxide NPs. Copper NPs were found mutagenic in TA98 and in TA100 and also found cytotoxic in dose dependent manner. Copper NPs induced significant (p < 0.01) increase in number of binucleated cells with micronuclei (96.6 ± 5.40) at the highest concentration (25 µg/mL). Copper NPs also induced DNA strand breaks at 10 µg/mL and oxidative DNA damage at 5 and 10 µg/mL. We consider these findings very useful in evaluating the genotoxic potential of NPs especially because of their increasing applications in human health and environment with limited knowledge of their toxicity and genotoxicity.

The chemoprotection of a blueberry anthocyanin extract against the acrylamide-induced oxidative stress in mitochondria: unequivocal evidence in mice liver.

PubMed

Zhao, Mengyao; Wang, Pengpu; Zhu, Yuchen; Liu, Xin; Hu, Xiaosong; Chen, Fang

2015-09-01

Acrylamide (AA) is one of the most important contaminants occurring in heated food products. Accumulating evidence indicates that AA-induced toxicity is associated with oxidative stress and long-term exposure to AA induced mitochondria collapse and finally leads to apoptosis. Whereas anthocyanins are natural antioxidants and have a strong ability to reduce oxidative damage in vivo. This study investigates the protection of a blueberry anthocyanin extract (BAE) against AA-induced mitochondrial oxidative stress in mice models. The activities of electron transport chain complexes, oxidative status, and the structure and function of mitochondria were measured. Results showed that pretreatment with BAE markedly inhibited reactive oxygen species (ROS) formation, and prevented the successive events associated with the mitochondrial damage and dysfunction, including recovered activities of electron transport chain, ATPase and superoxide dismutase, ameliorated depolarization of mitochondrial membrane potential and membrane lipid peroxidation, reduced release of cytochrome c and protection of mitochondria against swelling. In a word, mitochondria are a key target at the organelle level for the protective effect of BAE against AA toxicity. These results will be helpful to provide new clues for a better understanding of the AA toxicity intervention mechanism and for exploring effective dietary constituents for intervention of AA toxicity.

Novel approach on the risk assessment of oxidized fats and oils for perspectives of food safety and quality. I. Oxidized fats and oils induces neurotoxicity relating pica behavior and hypoactivity.

PubMed

Gotoh, N; Watanabe, H; Osato, R; Inagaki, K; Iwasawa, A; Wada, S

2006-04-01

Food poisoning caused by deteriorated fat and oil in instant noodles was first reported in Japan approximately 40 years ago. In these cases, many people developed neurotoxic symptoms such as emesis and discomfort. The degree of oxidation of the fat and oil in the instant noodles that induced food poisoning was at least 100 meq/kg in peroxide value (PV). No general toxicity studies with animals, however, have examined the toxicity of fat and oil oxidized to that extent. In this study, pica behavior, a behavior characterized by eating a nonfood material such as kaolin and that relates to the degree of discomfort in animals, and alterations of locomotor activity of rats eating deteriorated fat and oil were measured. The groups fed fat and oil with at least 138.5 meq/kg PV consumed significantly more kaolin compared to the control group. Furthermore, rats that ate deteriorated fat and oil with at least 107.2 meq/kg PV had significantly decreased locomotor activity compared to control rats. These phenomena suggest that oxidized fat and oil with at least 100 meq/kg PV induce neurotoxicity. The toxicity of oxidized fat and oil has only been addressed using general toxicity tests, but the present results reveal the importance of evaluating toxicity by using other measures.

Alterations in primary motor cortex neurotransmission and gene expression in hemi-parkinsonian rats with drug-induced dyskinesia.

PubMed

Lindenbach, D; Conti, M M; Ostock, C Y; Dupre, K B; Bishop, C

2015-12-03

Treatment of Parkinson's disease (PD) with dopamine replacement relieves symptoms of poverty of movement, but often causes drug-induced dyskinesias. Accumulating clinical and pre-clinical evidence suggests that the primary motor cortex (M1) is involved in the pathophysiology of PD and that modulating cortical activity may be a therapeutic target in PD and dyskinesia. However, surprisingly little is known about how M1 neurotransmitter tone or gene expression is altered in PD, dyskinesia or associated animal models. The present study utilized the rat unilateral 6-hydroxydopamine (6-OHDA) model of PD/dyskinesia to characterize structural and functional changes taking place in M1 monoamine innervation and gene expression. 6-OHDA caused dopamine pathology in M1, although the lesion was less severe than in the striatum. Rats with 6-OHDA lesions showed a PD motor impairment and developed dyskinesia when given L-DOPA or the D1 receptor agonist, SKF81297. M1 expression of two immediate-early genes (c-Fos and ARC) was strongly enhanced by either L-DOPA or SKF81297. At the same time, expression of genes specifically involved in glutamate and GABA signaling were either modestly affected or unchanged by lesion and/or treatment. We conclude that M1 neurotransmission and signal transduction in the rat 6-OHDA model of PD/dyskinesia mirror features of human PD, supporting the utility of the model to study M1 dysfunction in PD and the elucidation of novel pathophysiological mechanisms and therapeutic targets. Copyright © 2015 IBRO. Published by Elsevier Ltd. All rights reserved.

Naringin Ameliorates HIV-1 Nucleoside Reverse Transcriptase Inhibitors- Induced Mitochondrial Toxicity.

PubMed

Oluwafeyisetan, Adebiyi; Olubunmi, Adebiyi; Peter, Owira

2016-01-01

Mitochondrial reactive oxygen species (ROS) generation and defective oxidative phosphorylation (OXPHOS) have been proposed as possible mechanisms underlying the development of nucleoside reverse transcriptase inhibitors (NRTIs)-induced mitochondrial toxicities. Available options in managing these complications have, so far, produced controversial results, thus necessitating further research into newer agents with promise. Antioxidant and free-radical scavenging effects of naringin, a plant-derived flavonoid, have previously been demonstrated. This study was designed to investigate the effects of naringin on NRTIs-induced mitochondrial toxicity. Wistar rats were randomly divided into Zidovudine (AZT)-only (100 mg/kg body weight BW); AZT+Naringin (100+50 mg/kg BW); AZT+Vitamin E (100+100 mg/kg BW); Stavudine (d4T)- only (50 mg/kg BW); d4T+Naringin (50+50 mg/kg BW); d4T+Vitamin E (50+100 mg/kg BW) and Vehicle (3.0 mL/kg BW)-treated groups, respectively. After 56 days of oral daily dosing, rats were euthanized by halothane overdose, blood collected by cardiac puncture and livers promptly excised for further biochemical and ultrastructural analyses. </p> Results: AZT- or d4T-only caused significant mitochondrial dysfunction and mitochondrial ultrastructural damage compared to controls, while either naringin or vitamin E reversed indices of mitochondrial dysfunction evidenced by significantly reduced mitochondrial malondialdehyde (MDA) and blood lactate concentrations, increased liver manganese superoxide dismutase (MnSOD) activity and upregulate expression of mitochondrial-encoded subunit of electron transport chain (ETC) complex IV protein compared to AZT- or d4T-only treated rats. Furthermore, naringin or vitamin E, respectively, ameliorated mitochondrial damage observed in AZT- or d4T-only treated rats. Naringin ameliorated oxidative stress and NRTI-induced mitochondrial damage and might, therefore, be beneficial in managing toxicities and complications arising from NRTI use.

Biomimetic Oxygen-Evolving Photobacteria Based on Amino Acid and Porphyrin Hierarchical Self-Organization.

PubMed

Liu, Kai; Zhang, Han; Xing, Ruirui; Zou, Qianli; Yan, Xuehai

2017-12-26

Biomimetic organization provides a promising strategy to develop functional materials and understand biological processes. However, how to mimic complex biological systems using simple biomolecular units remains a great challenge. Herein, we design and fabricate a biomimetic cyanobacteria model based on self-integration of small bioinspired molecules, including amphiphilic amino acid, 3,4-dihydroxyphenylalanine (DOPA), and metalloporphyrin and cobalt oxide nanoparticles (Co 3 O 4 NPs), with the assistance of chemical conjugation and molecular self-assembly. The assembled amino acid fiber can be modified by DOPA to form covalently bound DOPA melanin containing hydroxyl and quinone species via Schiff base reaction. The adhering template can further tune the self-assembly of metalloporphyrin and Co 3 O 4 NPs into J-aggregation and dispersive distribution, respectively, mainly via coordination binding. Metalloporphyrin molecules in the resulting hybrid fibers capture light; quinone species accept the excited electrons, and Co 3 O 4 NPs catalyze water oxidation. Thus, the essential components of the photosystem-II protein complex in cyanobacteria are simplified and engineered into a simple framework, still retaining a similar photosynthetic mechanism. In addition, this architecture leads to efficient coupling of antenna, quinone-type reaction center, and photocatalyst, which increases the flux of light energy from antenna to reaction center for charge separation, resulting in enhanced oxygen evolution rate with excellent sustainability.

Cerebrospinal fluid biomarkers of central dopamine deficiency predict Parkinson's disease.

PubMed

Goldstein, David S; Holmes, Courtney; Lopez, Grisel J; Wu, Tianxia; Sharabi, Yehonatan

2018-05-01

Consistent with nigrostriatal dopamine depletion, low cerebrospinal fluid (CSF) concentrations of 3,4-dihydroxyphenylacetic acid (DOPAC), the main neuronal metabolite of dopamine, characterize Parkinson's disease (PD) even in recently diagnosed patients. Whether low CSF levels of DOPAC or DOPA, the precursor of dopamine, identify pre-clinical PD in at-risk healthy individuals has been unknown. Participants in the intramural NINDS PDRisk study entered information about family history of PD, olfactory dysfunction, dream enactment behavior, and orthostatic hypotension at a protocol-specific website. After at least 3 risk factors were confirmed by on-site screening, 26 subjects had CSF sampled for levels of catechols and were followed for at least 3 years. Of 26 PDRisk subjects, 4 were diagnosed with PD (Pre-Clinical PD group); 22 risk-matched (mean 3.2 risk factors) subjects remained disease-free after a median of 3.7 years (No-PD group). The Pre-Clinical PD group had lower initial DOPA and DOPAC levels than did the No-PD group (p = 0.0302, p = 0.0190). All 3 subjects with both low DOPA (<2.63 pmol/mL) and low DOPAC (<1.22 pmol/mL) levels, based on optimum cut-off points using the minimum distance method, developed PD, whereas none of 14 subjects with both normal DOPA and DOPAC levels did so (75% sensitivity at 100% specificity, p = 0.0015 by 2-tailed Fisher's exact test). In people with multiple PD risk factors, those with low CSF DOPA and low CSF DOPAC levels develop clinical disease during follow-up. We suggest that neurochemical biomarkers of central dopamine deficiency identify the disease in a pre-clinical phase. Published by Elsevier Ltd.

Structural and functional correlations in stable renal allografts.

PubMed

Fulladosa, Xavier; Moreso, Francesc; Torras, Joan; Hueso, Miquel; Grinyó, Josep M; Serón, Daniel

2003-05-01

Renal functional reserve (RFR) has been proposed as a surrogate marker of renal mass, but its significance in well-functioning renal transplants is controversial. Thus, we used early protocol biopsies to analyze structural and functional correlations in stable grafts. We studied 32 cyclosporine (CsA)-treated stable cadaveric transplants at 5 months. Biopsies were evaluated according to Banff criteria and histomorphometry. Inulin and p-aminohippurate clearances were used to calculate glomerular filtration rate (GFR) and effective renal plasma flow (ERPF). RFR after an amino acid infusion (RFR-AA) and after a combined amino acid and dopamine infusion (RFR-AA-DOPA) was evaluated. Baseline GFR was 54 +/- 16 mL/min/1.73 m2, and ERPF was 219 +/- 55 mL/min/1.73 m2. RFR-AA was 9% +/- 13%, and RFR-AA-DOPA was 22% +/- 20%. RFR-AA correlated with CsA dose (R = 0.39; P = 0.02), whereas RFR-AA-DOPA correlated with CsA dose (R = 0.36; P = 0.04) and CsA levels (R = 0.40; P = 0.02). The only histological parameter associated with RFR was the presence of arteriolar hyalinosis (AH). Patients showing an AH score of 1 or greater (n = 7) had lower RFR-AA (0% +/- 9% versus 11% +/- 13%; P = 0.02) and lower RFR-AA-DOPA (9% +/- 17% versus 26% +/- 19%; P = 0.03). Multivariate analysis showed that an AH score of 1 or greater, but not CsA dose or levels, was associated with RFR-AA (R = 0.42; P = 0.01). RFR-AA-DOPA was associated with hyaline arteriolar damage (R = 0.43; P = 0.01), as well as CsA levels (R = 0.54; P = 0.006). The presence of AH is the only histological parameter associated with impaired RFR in well-functioning grafts.

Galloyl-RGD as a new cosmetic ingredient

PubMed Central

2014-01-01

Background The cosmetics market has rapidly increased over the last years. For example, in 2011 it reached 242.8 billion US dollars, which was a 3.9% increase compared to 2010. There have been many recent trials aimed at finding the functional ingredients for new cosmetics. Gallic acid is a phytochemical derived from various herbs, and has anti-fungal, anti-viral, and antioxidant properties. Although phytochemicals are useful as cosmetic ingredients, they have a number of drawbacks, such as thermal stability, residence time in the skin, and permeability through the dermal layer. To overcome these problems, we considered conjugation of gallic acid with a peptide. Results We synthesized galloyl-RGD, which represents a conjugate of gallic acid and the peptide RGD, purified it by HPLC and characterized by MALDI-TOF with the aim of using it as a new cosmetic ingredient. Thermal stability of galloyl-RGD was tested at alternating temperatures (consecutive 4°C, 20°C, or 40°C for 8 h each) on days 2, 21, 41, and 61. Galloyl-RGD was relatively safe to HaCaT keratinocytes, as their viability after 48 h incubation with 500 ppm galloyl-RGD was 93.53%. In the group treated with 50 ppm galloyl-RGD, 85.0% of free radicals were removed, whereas 1000 ppm galloyl-RGD suppressed not only L-DOPA formation (43.8%) but also L-DOPA oxidation (54.4%). Conclusions Galloyl-RGD is a promising candidate for a cosmetic ingredient. PMID:25103826

Galloyl-RGD as a new cosmetic ingredient.

PubMed

Park, Dae-Hun; Jung, Dae Hyun; Kim, Soo Jung; Kim, Sung Han; Park, Kyung Mok

2014-08-08

The cosmetics market has rapidly increased over the last years. For example, in 2011 it reached 242.8 billion US dollars, which was a 3.9% increase compared to 2010. There have been many recent trials aimed at finding the functional ingredients for new cosmetics. Gallic acid is a phytochemical derived from various herbs, and has anti-fungal, anti-viral, and antioxidant properties. Although phytochemicals are useful as cosmetic ingredients, they have a number of drawbacks, such as thermal stability, residence time in the skin, and permeability through the dermal layer. To overcome these problems, we considered conjugation of gallic acid with a peptide. We synthesized galloyl-RGD, which represents a conjugate of gallic acid and the peptide RGD, purified it by HPLC and characterized by MALDI-TOF with the aim of using it as a new cosmetic ingredient. Thermal stability of galloyl-RGD was tested at alternating temperatures (consecutive 4°C, 20°C, or 40°C for 8 h each) on days 2, 21, 41, and 61. Galloyl-RGD was relatively safe to HaCaT keratinocytes, as their viability after 48 h incubation with 500 ppm galloyl-RGD was 93.53%. In the group treated with 50 ppm galloyl-RGD, 85.0% of free radicals were removed, whereas 1000 ppm galloyl-RGD suppressed not only L-DOPA formation (43.8%) but also L-DOPA oxidation (54.4%). Galloyl-RGD is a promising candidate for a cosmetic ingredient.

Prospective trial evaluating the sensitivity and specificity of 3,4-dihydroxy-6-[18F]-fluoro-L-phenylalanine (18F-DOPA) PET and MRI in patients with recurrent gliomas.

PubMed

Youland, Ryan S; Pafundi, Deanna H; Brinkmann, Debra H; Lowe, Val J; Morris, Jonathan M; Kemp, Bradley J; Hunt, Christopher H; Giannini, Caterina; Parney, Ian F; Laack, Nadia N

2018-05-01

Treatment-related changes can be difficult to differentiate from progressive glioma using MRI with contrast (CE). The purpose of this study is to compare the sensitivity and specificity of 18F-DOPA-PET and MRI in patients with recurrent glioma. Thirteen patients with MRI findings suspicious for recurrent glioma were prospectively enrolled and underwent 18F-DOPA-PET and MRI for neurosurgical planning. Stereotactic biopsies were obtained from regions of concordant and discordant PET and MRI CE, all within regions of T2/FLAIR signal hyperintensity. The sensitivity and specificity of 18F-DOPA-PET and CE were calculated based on histopathologic analysis. Receiver operating characteristic curve analysis revealed optimal tumor to normal (T/N) and SUVmax thresholds. In the 37 specimens obtained, 51% exhibited MRI contrast enhancement (M+) and 78% demonstrated 18F-DOPA-PET avidity (P+). Imaging characteristics included M-P- in 16%, M-P+ in 32%, M+P+ in 46% and M+P- in 5%. Histopathologic review of biopsies revealed grade II components in 16%, grade III in 43%, grade IV in 30% and no tumor in 11%. MRI CE sensitivity for recurrent tumor was 52% and specificity was 50%. PET sensitivity for tumor was 82% and specificity was 50%. A T/N threshold > 2.0 altered sensitivity to 76% and specificity to 100% and SUVmax > 1.36 improved sensitivity and specificity to 94 and 75%, respectively. 18F-DOPA-PET can provide increased sensitivity and specificity compared with MRI CE for visualizing the spatial distribution of recurrent gliomas. Future studies will incorporate 18F-DOPA-PET into re-irradiation target volume delineation for RT planning.

Neuromolecular imaging, a nanobiotechnology for Parkinson's disease: advancing pharmacotherapy for personalized medicine.

PubMed

Broderick, P A; Wenning, L; Li, Y-S

2017-01-01

Evaluating each patient and animal as its own control achieves personalized medicine, which honors the hippocratic philosophy, explaining that "it is far more important to know what person has the disease than what disease the person has." Similarly, individualizing molecular signaling directly from the patient's brain in real time is essential for providing prompt, patient-based treatment as dictated by the point of care. Fortunately, nanotechnology effectively treats many neurodegenerative diseases. In particular, the new medicinal frontier for the discovery of therapy for Parkinson's disease is nanotechnology and nanobiotechnology. Indeed, the unique nanotechnology of neuromolecular imaging combined with the series of nanobiosensors enables continuous videotracking of molecular neurotransmitters in both the normal physiologic and disease states with long-term electrochemical operational stability. This nanobiotechnology is able to track a signal in real time with excellent temporal and spatial resolution directly from each patient's brain to a computer as subjects are behaving during movement, normal and/or dysfunctional including prion-like Parkinson's behavioral biometrics. Moreover, the molecular signaling performed by these nanobiosensors live streams directly online and originates from precise neuroanatomic brain sites such as, in this case, the dorsal striatum in basal ganglia. Thus, the nanobiotechnology studies discussed herein imaged neuromolecules with and without L-3,4-dihydroxyphenylalanine (L-DOPA) in dorsal striatal basal ganglia neurons. Parkinsonian and non-Parkinsonian animals were video-tracked, and images were readily seen on a laptop via a potentiostat using a semiderivative electrical circuit. Administered L-DOPA doses were 50 and 100 mg/kg intraperitoneally (ip); the same experimental paradigm was used to image and then contrast data. Results showed that the baseline release of biogenic amine molecules was significantly above detection limits in non-Parkinsonian animals. After administration of L-DOPA, biogenic amines significantly increased in these non-Parkinson's animals. Nevertheless, it is intriguing to see that L-DOPA could not enable synaptic dopamine release in Parkinson's animals, thereby demonstrating that biogenic amines are biomarkers for Parkinson's disease. Biomarkers are biochemical, genetic, or molecular measures of biological reactions. Importantly, there were other significant biomarkers present in Parkinsonian animals and absent in non-Parkinsonian animals; these were peptide neurotransmitters that include dynorphin and somatostatin in the brain with detection limits of 40 nM for dynorphin and 37 nM for somatostatin (see Table 1). Furthermore, L-DOPA significantly increased these peptide biomarkers, dynorphin and somatostatin, in Parkinson's animals. Targeting biomarkers enables new diagnostic devices and treatments for Parkinson's disease through nanotechnology and nanobiotechnology.

The Mechanism of Trichloroethylene Oxidation by Toluene Dioxygenase: Implications for Bioremediation

DTIC Science & Technology

1991-09-15

2312 Dr Lwrene P WacettTA - A4 1pJWV ORGANIZTION NAMI(S) ANO AOORESS(ES) L. PIRFORM ORGNIZATION University of Minnesota AEPORT NUMBER Gray Freshwater ...IMPLICATIONS FOR BIOREMEDIATION Lawrence P. Wackett University of Minnesota Gray Freshwater Biological Institute P.O. Box 100 Navarre, MN 55392 15...tetrahydrofuran, are highly water soluble and relatively non-toxic. They might thus be eligible to be used as gratuitous inducers of toluene dioxygenase in

Low-concentration exposure to BPA, BPF and BPAF induces oxidative DNA bases lesions in human peripheral blood mononuclear cells.

PubMed

Mokra, Katarzyna; Woźniak, Katarzyna; Bukowska, Bożena; Sicińska, Paulina; Michałowicz, Jaromir

2018-06-01

Because bisphenol A (BPA) and some of its analogs have been supposed to influence development of cancer, we have assessed the effect of BPA, bisphenol S (BPS), bisphenol F (BPF) and bisphenol AF (BPAF) on DNA bases oxidation, which is a key process in cancer initiation. The analysis was conducted on human peripheral blood mononuclear cells (PBMCs), which are very useful model to assess genotoxic potential of various toxicants in different cell types. In order to determine oxidative damage to DNA pyrimidines and purines, alkaline version of the comet assay with DNA glycosylases, i.e. endonuclease III (Nth) and human 8-oxoguanine DNA glycosylase (hOGG1) was used. PBMCs were exposed to BPA or its analogs in the concentrations of 0.01, 0.1 and 1 μg/mL for 4 h and 0.001, 0.01 and 0.1 μg/mL for 48 h. We have observed that BPA, BPS, BPF and particularly BPAF caused oxidative damage to DNA pyrimidines and more strongly to purines in human PBMCs. The results have also shown that BPS, which is the most commonly used as a substitute for BPA in the manufacture induced definitely the smallest oxidative DNA bases lesions in PBMCs. Moreover, we have noticed that BPA, BPF and BPAF caused DNA damage at very low concentration of 1 ng/mL. Copyright © 2018 Elsevier Ltd. All rights reserved.

The protective role of quercetin and arginine on gold nanoparticles induced hepatotoxicity in rats.

PubMed

Abdelhalim, Mohamed Anwar K; Moussa, Sherif A Abdelmottaleb; Qaid, Huda Abdo Yahya

2018-01-01

The aim of the study was to confirm the hepatotoxicity induced by small-sized gold nanoparticles (GNPs) and evaluate the role of quercetin (Qur) and arginine (Arg) against hepatotoxicity caused by GNPs. Twenty-five healthy male Wistar-Kyoto rats were used. GNPs were administered intraperitoneally to these rats at the dose of 50 μL for seven consecutive days. The role of Qur and Arg antioxidants against toxicity induced by GNPs was detected through the measurement of serum liver function and oxidative stress biomarkers in the liver tissues. Coadministration of Qur and Arg along with GNPs significantly induced dramatic alterations in the biochemical parameters. Levels of malondialdehyde, gamma-glutamyl transferase, alanine aminotransferase, alkaline phosphatase, and total protein increased significantly in the GNPs injected group than in the control group, while reduced glutathione was greatly reduced in the GNPs group than in the control group. It also significantly decreased liver enzymes and the oxidative stress, therefore improving the liver damage and hepatotoxicity induced by GNPs. This study demonstrated that Qur and Arg antioxidants effectively improved the hepatic oxidative damage induced by GNPs. It also substantiates the application of Qur and Arg as protecting stand-in against GNPs' hepatotoxicity.

Loss of 5-lipoxygenase activity protects mice against paracetamol-induced liver toxicity.

PubMed

Pu, Shiyun; Ren, Lin; Liu, Qinhui; Kuang, Jiangying; Shen, Jing; Cheng, Shihai; Zhang, Yuwei; Jiang, Wei; Zhang, Zhiyong; Jiang, Changtao; He, Jinhan

2016-01-01

Paracetamol (acetaminophen) is the most widely used over-the-counter analgesic and overdosing with paracetamol is the leading cause of hospital admission for acute liver failure. 5-Lipoxygenase (5-LO) catalyses arachidonic acid to form LTs, which lead to inflammation and oxidative stress. In this study, we examined whether deletion or pharmacological inhibition of 5-LO could protect mice against paracetamol-induced hepatic toxicity. Both genetic deletion and pharmacological inhibition of 5-LO in C57BL/6J mice were used to study the role of this enzyme in paracetamol induced liver toxicity. Serum and tissue biochemistry, H&E staining, and real-time PCR were used to assess liver toxicity. Deletion or pharmacological inhibition of 5-LO in mice markedly ameliorated paracetamol-induced hepatic injury, as shown by decreased serum alanine transaminase and aspartate aminotransferase levels and hepatic centrilobular necrosis. The hepatoprotective effect of 5-LO inhibition was associated with induction of the antitoxic phase II conjugating enzyme, sulfotransferase2a1, suppression of the pro-toxic phase I CYP3A11 and reduction of the hepatic transporter MRP3. In 5-LO(-/-) mice, levels of GSH were increased, and oxidative stress decreased. In addition, PPAR α, a nuclear receptor that confers resistance to paracetamol toxicity, was activated in 5-LO(-/-) mice. The activity of 5-LO may play a critical role in paracetamol-induced hepatic toxicity by regulating paracetamol metabolism and oxidative stress. © 2015 The British Pharmacological Society.

Characterization of free and alginate-polylysine-alginate microencapsulated Erwinia herbicola for the conversion of ammonia, pyruvate, and phenol into L-tyrosine

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

Lloyd-George, I.; Chang, T.M.S.

1995-12-20

The whole cell tyrosine phenol-lyase activity of Erwinia herbicola was microencapsulated. The authors studied the use of this for the conversion of ammonia and pyruvate along with phenol or catechol, respectively, into L-tyrosine or dihydroxyphenyl-L-alanine (L-dopa). The reactions are relevant to the development of new methods for the production of L-tyrosine and L-dopa. The growth of E. herbicola at temperatures from 22 C to 32 C is stable, since at these temperatures the cells grow up to the stationary phase and remain there for at least 10 h. At 37 C the cells grow rapidly, but they also enter themore » death phase rapidly. There is only limited growth of E. herbicola at 42 C. Whole cells of E. herbicola were encapsulated within alginate-polylysine-alginate microcapsules (916 {+-} 100 {micro}m, mean {+-} std. dev.). The TPL activity of the cells catalyzed the production of L-tyrosine or dihydroxyphenol-L-alanine (L-dopa) from ammonia, pyruvate, and phenol or catechol, respectively. In the production of tyrosine, an integrated equation based on an ordered ter-uni rapid equilibrium mechanism can be used to find the kinetic parameters of TPL. In an adequately stirred system, the apparent values of the kinetic parameters of whole cell TPL are equal whether the cells are free or encapsulated. The apparent K{sub M} of tyrosine varies with the amount of whole cells in the system, ranging from 0.2 to 0.3 mM. The apparent K{sub M} for phenol is 0.5 mM. The apparent K{sub M} values for pyruvate and ammonia are an order of magnitude greater for whole cells than they are for the cell free enzyme.« less