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Sample records for acute neurotoxic effects

  1. From neurotoxic to chemosensory effects: new insights on acute solvent neurotoxicity exemplified by acute effects of 2-ethylhexanol.

    PubMed

    van Thriel, Christoph; Kiesswetter, Ernst; Schäper, Michael; Blaszkewicz, Meinolf; Golka, Klaus; Juran, Stephanie; Kleinbeck, Stefan; Seeber, Andreas

    2007-03-01

    Historically, acute solvent neurotoxicity was strongly related to reversible narcotic states that could be detected by neurobehavioral tests (e.g., simple reaction time). Nowadays, the occupational exposure to chemicals is markedly reduced and the avoidance of chemosensory effects is more important for the regulation of solvents. Exemplarily, this study examines if the chemosensory perception of 2-ethylhexanol is capable to distract performance in demanding neurobehavioral tasks. In two experiments three time-weighted average concentrations of 2-ethylhexanol (C(TWA): 1.5, 10, and 20 ppm) were investigated. In experiment A (n=24) variable concentrations over time (4h) were used, experiment B (n=22) investigated constant concentrations. The experiments were conducted in a 29 m3 exposure laboratory. Cross-over designs with randomized sequences of exposures were used. Among the 46 male participants 19 subjects reported enhanced chemical sensitivity; the other 27 subjects did not show this personality feature. During the exposure periods neurobehavioral tests were presented twice (beginning; end), the intensity of chemosensory perceptions were rated thrice. The intensity of chemosensory perceptions showed a clear dose-dependency. Subjects' performance in the vigilance test was not affected by the different exposures. Moreover, the results of neurobehavioral tests measuring executive function were neither affected by the C(TWA) concentration nor by the exposure peaks. With increasing C(TWA), a subgroup of the chemically sensitive subjects showed deteriorated accuracy in a divided attention task. Especially the 20 ppm conditions were very annoying. Only during the constant 10 ppm condition the time courses of the annoyance and nasal irritation ratings indicated some adaptation. In general, with the applied neurobehavioral tests distractive effects of acute 2-ethylhexanol exposures up to 20 ppm could not be confirmed. In sensitive groups such distractive effects of

  2. Aflatrem: a tremorgenic mycotoxin with acute neurotoxic effects.

    PubMed Central

    Valdes, J J; Cameron, J E; Cole, R J

    1985-01-01

    Tremorgenic mycotoxins induce neurologic symptoms ranging from mental confusion to tremors, seizures and death, and are apparently the only class of mycotoxins with significant central nervous system activity. Tremorgens have been implicated in a number of neurologic diseases of cattle collectively known as staggers syndromes, and pose significant agricultural and health problems for both cattle and humans. Although the effects of tremorgens are thought to result from transient perturbations of amino acid neurotransmitter release mechanisms, there is reason to believe that acute exposures to toxins with such synaptic effects may result in degeneration of neuronal fiber processes. To test this hypothesis, rats were given a single tremorgenic (3 mg/kg, IP) dose of aflatrem, and kinetics of amino acid neurotransmitter uptake was assessed in isolated hippocampal nerve terminals at 1 day, 1 week, and 2 weeks after injection. Results indicate a decrease in the capacity of the GABA and glutamate uptake systems, which was interpreted as a loss of nerve terminals. The affinity constants suggest a decrease in release of these transmitters as well. In addition to its transient influence on transmitter release, a single low dose of aflatrem is able to induce degeneration of neuronal processes in hippocampal neurotransmitter systems and therefore represents a long-term health threat. PMID:2867895

  3. Fish embryo toxicity test: identification of compounds with weak toxicity and analysis of behavioral effects to improve prediction of acute toxicity for neurotoxic compounds.

    PubMed

    Klüver, Nils; König, Maria; Ortmann, Julia; Massei, Riccardo; Paschke, Albrecht; Kühne, Ralph; Scholz, Stefan

    2015-06-01

    The fish embryo toxicity test has been proposed as an alternative for the acute fish toxicity test, but concerns have been raised for its predictivity given that a few compounds have been shown to exhibit a weak acute toxicity in the fish embryo. In order to better define the applicability domain and improve the predictive capacity of the fish embryo test, we performed a systematic analysis of existing fish embryo and acute fish toxicity data. A correlation analysis of a total of 153 compounds identified 28 compounds with a weaker or no toxicity in the fish embryo test. Eleven of these compounds exhibited a neurotoxic mode of action. We selected a subset of eight compounds with weaker or no embryo toxicity (cyanazine, picloram, aldicarb, azinphos-methyl, dieldrin, diquat dibromide, endosulfan, and esfenvalerate) to study toxicokinetics and a neurotoxic mode of action as potential reasons for the deviating fish embryo toxicity. Published fish embryo LC50 values were confirmed by experimental analysis of zebrafish embryo LC50 according to OECD guideline 236. Except for diquat dibromide, internal concentration analysis did not indicate a potential relation of the low sensitivity of fish embryos to a limited uptake of the compounds. Analysis of locomotor activity of diquat dibromide and the neurotoxic compounds in 98 hpf embryos (exposed for 96 h) indicated a specific effect on behavior (embryonic movement) for the neurotoxic compounds. The EC50s of behavior for neurotoxic compounds were close to the acute fish toxicity LC50. Our data provided the first evidence that the applicability domain of the fish embryo test (LC50s determination) may exclude neurotoxic compounds. However, neurotoxic compounds could be identified by changes in embryonic locomotion. Although a quantitative prediction of acute fish toxicity LC50 using behavioral assays in fish embryos may not yet be possible, the identification of neurotoxicity could trigger the conduction of a conventional fish

  4. Acute effects of tetracycline exposure in the freshwater fish Gambusia holbrooki: antioxidant effects, neurotoxicity and histological alterations.

    PubMed

    Nunes, B; Antunes, S C; Gomes, R; Campos, J C; Braga, M R; Ramos, A S; Correia, A T

    2015-02-01

    A large body of evidence was compiled in the recent decades showing a noteworthy increase in the detection of pharmaceutical drugs in aquatic ecosystems. Due to its ubiquitous presence, chemical nature, and practical purpose, this type of contaminant can exert toxic effects in nontarget organisms. Exposure to pharmaceutical drugs can result in adaptive alterations, such as changes in tissues, or in key homeostatic mechanisms, such as antioxidant mechanisms, biochemical/physiological pathways, and cellular damage. These alterations can be monitored to determine the impact of these compounds on exposed aquatic organisms. Among pharmaceutical drugs in the environment, antibiotics are particularly important because they include a variety of substances widely used in medical and veterinary practice, livestock production, and aquaculture. This wide use constitutes a decisive factor contributing for their frequent detection in the aquatic environment. Tetracyclines are the individual antibiotic subclass with the second highest frequency of detection in environmental matrices. The characterization of the potential ecotoxicological effects of tetracycline is a much-required task; to attain this objective, the present study assessed the acute toxic effects of tetracycline in the freshwater fish species Gambusia holbrooki by the determination of histological changes in the gills and liver, changes in antioxidant defense [glutathione S-transferase (GST), catalase (CAT), and lipoperoxidative damage] as well as potential neurotoxicity (acetylcholinesterase activity). The obtained results suggest the existence of a cause-and-effect relationship between the exposure to tetracycline and histological alterations (more specifically in gills) and enzymatic activity (particularly the enzyme CAT in liver and GST in gills) indicating that this compound can exert a pro-oxidative activity. PMID:25475590

  5. BIOCHEMICAL, FUNCTIONAL AND MORPHOLOGICAL INDICATORS OF NEUROTOXICITY: EFFECTS OF ACUTE ADMINISTRATION OF TRIMETHYLTIN TO THE DEVELOPING RAT

    EPA Science Inventory

    The neurotoxic organometal, trimethyltin (TMT), was administered to rats on postnatal day (PND)5. Neurotoxicity was assessed throughout subsequent development using morphological, biochemical and functional endpoints. These consisted of brain weight measures and histology (morpho...

  6. The effect of stress on the acute neurotoxicity of the organophosphate insecticide chlorpyrifos

    SciTech Connect

    Hancock, Sandra; Ehrich, Marion; Hinckley, Jonathan; Pung, Thitiya; Jortner, Bernard S. . E-mail: bjortner@vt.edu

    2007-03-15

    A study was conducted to determine if multiple exposures to several stress paradigms might affect the anticholinesterase effect of subsequently administered organophosphate insecticide chlorpyrifos. Male Sprague-Dawley rats were subject to daily periods of restraint, swimming, a combination of the two, or neither of the two (controls) (n = 8/group) for 5 days per week over a six-week period. The most profound stress, as measured by reduced body weight gain and elevated levels of plasma corticosterone, was swimming. On day 39 of the study, shortly after the daily stress episode, one half of the rats in each group was dosed with 60 mg/kg chlorpyrifos subcutaneously. This had no effect on subsequent levels of plasma corticosterone. There were no stress-related differences in the degree of chlorpyrifos-induced inhibition of brain acetylcholinesterase in animals sacrificed on day 43.

  7. Anticonvulsant and acute neurotoxic effects of imperatorin, osthole and valproate in the maximal electroshock seizure and chimney tests in mice: a comparative study.

    PubMed

    Luszczki, Jarogniew J; Wojda, Ewa; Andres-Mach, Marta; Cisowski, Wojciech; Glensk, Michal; Glowniak, Kazimierz; Czuczwar, Stanislaw J

    2009-08-01

    The aim of this study was to determine and compare the anticonvulsant and acute adverse (neurotoxic) effects of imperatorin and osthole (two natural coumarin derivatives) with valproate (a classical antiepileptic drug) in the maximal electroshock seizure and chimney tests in mice. The anticonvulsant and acute adverse effects of imperatorin, osthole and valproate were determined at 15, 30, 60 and 120 min after their systemic (i.p.) administration. The evaluation of time-course and dose-response relationships for imperatorin, osthole and valproate in the maximal electroshock seizure test revealed that the compounds produced a clear-cut antielectroshock action in mice and the experimentally derived ED(50) values for imperatorin ranged between 167 and 290 mg/kg, those for osthole ranged from 253 to 639 mg/kg, whereas the ED(50) values for valproate ranged from 189 to 255 mg/kg. The evaluation of acute neurotoxic effects in the chimney test revealed that the TD(50) values for imperatorin ranged between 329 and 443 mg/kg, the TD(50) values for osthole ranged from 531 to 648 mg/kg, while the TD(50) values for valproate ranged from 363 to 512 mg/kg. The protective index (as a ratio of TD(50) and ED(50) values) for imperatorin ranged between 1.13 and 2.60, for osthole ranged from 0.83 to 2.44, and for valproate ranged between 1.72 and 2.00. In conclusion, both natural coumarin derivatives deserve more attention from a preclinical point of view as compounds possessing some potentially favorable activities in terms of suppression of seizures, quite similar to those reported for valproate. PMID:19406619

  8. NEURON-SPECIFIC PHOSPHOPROTEINS AS BIOCHEMICAL INDICATORS OF NEUROTOXICITY: EFFECTS OF ACUTE ADMINISTRATION OF TRIMETHYLTIN TO THE ADULT RAT

    EPA Science Inventory

    The cytoarchitecture of the adult central nervous system is expressed by proteins specific to individual cell types. In this investigation, a subclass of these proteins, the neuron-specific phosphoproteins, was examined after the administration of trimethyltin (TMT), a neurotoxic...

  9. ASSESSING HIPPOCAMPAL CHANGES INDICATIVE OF NEUROTOXIC EFFECTS.

    EPA Science Inventory

    Subtle changes in cognitive function are often the earliest indication of neurotoxic effects in humans. The hippocampus is a large forebrain structure subserving specific kinds of information encoding and consolidation in humans and other animals. Because of it laminar structur...

  10. Neurotoxic effects of gasoline and gasoline constituents

    SciTech Connect

    Burbacher, T.M.

    1993-12-01

    This overview was developed as part of a symposium on noncancer end points of gasoline and key gasoline components. The specific components included are methyl tertiary butyl ether, ethyl tertiary butyl ether, tertiary amyl methyl ether, butadiene, benzene, xylene, toluene, methyl alcohol, and ethyl alcohol. The overview focuses on neurotoxic effects related to chronic low-level exposures. A few general conclusions and recommendations can be made based on the results of the studies to date. (a) All the compounds reviewed are neuroactive and, as such, should be examined for their neurotoxicity. (b) For most of the compounds, there is a substantial margin of safety between the current permissible exposure levels and levels that would be expected to cause overt signs of neurotoxicity in humans. This is not the case for xylene, toluene, and methanol, however, where neurologic effects are observed at or below the current Threshold Limit Value. (c) For most of the compounds, the relationship between chronic low-level exposure and subtle neurotoxic effects has not been studied. Studies therefore should focus on examining the dose-response relationship between chronic low-level exposure and subtle changes in central nervous system function. 96 refs., 7 tabs.

  11. ACUTE NEUROTOXIC EFFECTS OF INHALED PERCHLOROETHYLENE ON PATTERN VISUAL EVOKED POTENTIALS AS A FUNCTION OF EXPOSURE AND ESTIMATED BLOOD AND BRAIN CONCENTRATION.

    EPA Science Inventory

    Previous experiments have shown the effects of acute inhalation exposure to trichloroethylene (TCE) and toluene are related to the target tissue concentration at the time of testing. The current studies examined exposure to another volatile organic compound, perchloroethylene (P...

  12. Chronic exercise training versus acute endurance exercise in reducing neurotoxicity in rats exposed to lead acetate.

    PubMed

    Shahandeh, Mohammad; Roshan, Valiollah Dabidi; Hosseinzadeh, Somayeh; Mahjoub, Soleiman; Sarkisian, Vaginak

    2013-03-15

    After intraperitoneal injection of 20 mg/kg lead acetate, rats received 8 weeks of treadmill exercise (15-22 m/min, 25-64 minutes) and/or treadmill exercise at 1.6 km/h until exhaustion. The markers related to neurotoxicity were measured by enzyme-linked immunosorbent assay method. 8 weeks of treadmill exercise significantly increased brain-derived neurotrophic factor level in the hippocampus (P = 0.04) and plasma level of total antioxidant capacity of rats exposed to lead acetate (P < 0.001), and significantly decreased plasma level of malondialdehyde (P < 0.001). Acute exercise only decreased the hippocampal malondialdehyde level (P = 0.09) and increased brain-derived neurotrophic factor level in the hippocampus (P = 0.66). Acute exercise also enhanced the total antioxidant capacity in rats exposed to lead acetate, insignificantly (P = 0.99). These findings suggest that chronic treadmill exercise can significantly decrease neurotoxicity and alleviate oxidative stress in rats exposed to lead acetate. However, acute endurance exercise was not associated with these beneficial effects. PMID:25206718

  13. Chronic exercise training versus acute endurance exercise in reducing neurotoxicity in rats exposed to lead acetate☆

    PubMed Central

    Shahandeh, Mohammad; Roshan, Valiollah Dabidi; Hosseinzadeh, Somayeh; Mahjoub, Soleiman; Sarkisian, Vaginak

    2013-01-01

    After intraperitoneal injection of 20 mg/kg lead acetate, rats received 8 weeks of treadmill exercise (15–22 m/min, 25–64 minutes) and/or treadmill exercise at 1.6 km/h until exhaustion. The markers related to neurotoxicity were measured by enzyme-linked immunosorbent assay method. 8 weeks of treadmill exercise significantly increased brain-derived neurotrophic factor level in the hippocampus (P = 0.04) and plasma level of total antioxidant capacity of rats exposed to lead acetate (P < 0.001), and significantly decreased plasma level of malondialdehyde (P < 0.001). Acute exercise only decreased the hippocampal malondialdehyde level (P = 0.09) and increased brain-derived neurotrophic factor level in the hippocampus (P = 0.66). Acute exercise also enhanced the total antioxidant capacity in rats exposed to lead acetate, insignificantly (P = 0.99). These findings suggest that chronic treadmill exercise can significantly decrease neurotoxicity and alleviate oxidative stress in rats exposed to lead acetate. However, acute endurance exercise was not associated with these beneficial effects. PMID:25206718

  14. A Novel Antibody-Based Biomarker for Chronic Algal Toxin Exposure and Sub-Acute Neurotoxicity

    PubMed Central

    Lefebvre, Kathi A.; Frame, Elizabeth R.; Gulland, Frances; Hansen, John D.; Kendrick, Preston S.; Beyer, Richard P.; Bammler, Theo K.; Farin, Frederico M.; Hiolski, Emma M.; Smith, Donald R.; Marcinek, David J.

    2012-01-01

    The neurotoxic amino acid, domoic acid (DA), is naturally produced by marine phytoplankton and presents a significant threat to the health of marine mammals, seabirds and humans via transfer of the toxin through the foodweb. In humans, acute exposure causes a neurotoxic illness known as amnesic shellfish poisoning characterized by seizures, memory loss, coma and death. Regular monitoring for high DA levels in edible shellfish tissues has been effective in protecting human consumers from acute DA exposure. However, chronic low-level DA exposure remains a concern, particularly in coastal and tribal communities that subsistence harvest shellfish known to contain low levels of the toxin. Domoic acid exposure via consumption of planktivorous fish also has a profound health impact on California sea lions (Zalophus californianus) affecting hundreds of animals yearly. Due to increasing algal toxin exposure threats globally, there is a critical need for reliable diagnostic tests for assessing chronic DA exposure in humans and wildlife. Here we report the discovery of a novel DA-specific antibody response that is a signature of chronic low-level exposure identified initially in a zebrafish exposure model and confirmed in naturally exposed wild sea lions. Additionally, we found that chronic exposure in zebrafish caused increased neurologic sensitivity to DA, revealing that repetitive exposure to DA well below the threshold for acute behavioral toxicity has underlying neurotoxic consequences. The discovery that chronic exposure to low levels of a small, water-soluble single amino acid triggers a detectable antibody response is surprising and has profound implications for the development of diagnostic tests for exposure to other pervasive environmental toxins. PMID:22567140

  15. A novel antibody-based biomarker for chronic algal toxin exposure and sub-acute neurotoxicity

    USGS Publications Warehouse

    Lefebvre, Kathi A.; Frame, Elizabeth R.; Gulland, Frances; Hansen, John D.; Kendrick, Preston S.; Beyer, Richard P.; Bammler, Theo K.; Farin, Frederico M.; Hiolski, Emma M.; Smith, Donald R.; Marcinek, David J.

    2012-01-01

    The neurotoxic amino acid, domoic acid (DA), is naturally produced by marine phytoplankton and presents a significant threat to the health of marine mammals, seabirds and humans via transfer of the toxin through the foodweb. In humans, acute exposure causes a neurotoxic illness known as amnesic shellfish poisoning characterized by seizures, memory loss, coma and death. Regular monitoring for high DA levels in edible shellfish tissues has been effective in protecting human consumers from acute DA exposure. However, chronic low-level DA exposure remains a concern, particularly in coastal and tribal communities that subsistence harvest shellfish known to contain low levels of the toxin. Domoic acid exposure via consumption of planktivorous fish also has a profound health impact on California sea lions (Zalophus californianus) affecting hundreds of animals yearly. Due to increasing algal toxin exposure threats globally, there is a critical need for reliable diagnostic tests for assessing chronic DA exposure in humans and wildlife. Here we report the discovery of a novel DA-specific antibody response that is a signature of chronic low-level exposure identified initially in a zebrafish exposure model and confirmed in naturally exposed wild sea lions. Additionally, we found that chronic exposure in zebrafish caused increased neurologic sensitivity to DA, revealing that repetitive exposure to DA well below the threshold for acute behavioral toxicity has underlying neurotoxic consequences. The discovery that chronic exposure to low levels of a small, water-soluble single amino acid triggers a detectable antibody response is surprising and has profound implications for the development of diagnostic tests for exposure to other pervasive environmental toxins.

  16. Mitochondria: key players in the neurotoxic effects of amphetamines.

    PubMed

    Barbosa, Daniel José; Capela, João Paulo; Feio-Azevedo, Rita; Teixeira-Gomes, Armanda; Bastos, Maria de Lourdes; Carvalho, Félix

    2015-10-01

    Amphetamines are a class of psychotropic drugs with high abuse potential, as a result of their stimulant, euphoric, emphathogenic, entactogenic, and hallucinogenic properties. Although most amphetamines are synthetic drugs, of which methamphetamine, amphetamine, and 3,4-methylenedioxymethamphetamine ("ecstasy") represent well-recognized examples, the use of natural related compounds, namely cathinone and ephedrine, has been part of the history of humankind for thousands of years. Resulting from their amphiphilic nature, these drugs can easily cross the blood-brain barrier and elicit their well-known psychotropic effects. In the field of amphetamines' research, there is a general consensus that mitochondrial-dependent pathways can provide a major understanding concerning pathological processes underlying the neurotoxicity of these drugs. These events include alterations on tricarboxylic acid cycle's enzymes functioning, inhibition of mitochondrial electron transport chain's complexes, perturbations of mitochondrial clearance mechanisms, interference with mitochondrial dynamics, as well as oxidative modifications in mitochondrial macromolecules. Additionally, other studies indicate that amphetamines-induced neuronal toxicity is closely regulated by B cell lymphoma 2 superfamily of proteins with consequent activation of caspase-mediated downstream cell death pathway. Understanding the molecular mechanisms at mitochondrial level involved in amphetamines' neurotoxicity can help in defining target pathways or molecules mediating these effects, as well as in developing putative therapeutic approaches to prevent or treat the acute- or long-lasting neuropsychiatric complications seen in human abusers. PMID:25743372

  17. Delayed Neurotoxicity Associated with Therapy for Children with Acute Lymphoblastic Leukemia

    ERIC Educational Resources Information Center

    Cole, Peter D.; Kamen, Barton A.

    2006-01-01

    Most children diagnosed today with acute lymphoblastic leukemia (ALL) will be cured. However, treatment entails risk of neurotoxicity, causing deficits in neurocognitive function that can persist in the years after treatment is completed. Many of the components of leukemia therapy can contribute to adverse neurologic sequelae, including…

  18. Age-related differences in acute neurotoxicity produced by mevinphos, monocrotophos, dicrotophos, and phosphamidon

    EPA Science Inventory

    Age-related differences in the acute neurotoxicity of cholinesterase (ChE)-inhibiting pesticides have been well-studied for a few organophosphates, but not for many others. In this study, we directly compared dose-responses using brain and red blood cell (RBC) ChE measurements, a...

  19. Potential neurotoxic effects of polymethylmethacrylate during cranioplasty.

    PubMed

    Pikis, Stylianos; Goldstein, Jacob; Spektor, Sergey

    2015-01-01

    Cranioplasty for the surgical correction of cranial defects is often performed using polymethyl methacrylate (PMMA), or bone cement. Immediately prior to PMMA application, a liquid monomer form (methylacrylate) and a benzoyl peroxide accelerator are mixed resulting in polymerization, an exothermic reaction during which monomer linking and subsequent formation of solid polymer occur. The potential side effects of residual methylacrylate monomer toxicity and thermal damage of neural tissue during PMMA hardening have been described in various in vitro, animal, and cadaveric studies; however, clinically documented in vivo neurotoxicity in humans attributed to either of the above two mechanisms during PMMA cranioplasty is lacking. We present a series of four patients operated for removal of cerebellopontine angle lesions and two operated for the excision of parieto-occipital tumors who sustained cranial neuropathies and encephalopathies with transient or permanent neurological deficits that could not be attributed to surgical manipulation. We hypothesize that these complications most likely occurred due to thermal damage and/or chemical toxicity from exposure to PMMA during cranioplasty. Our case series indicates that even small volumes of PMMA used for cranioplasty may cause severe side effects related to thermal damage or to exposure of neural tissue to methylacrylate monomer. PMID:25085727

  20. Neurotoxic effects during vidarabine therapy for herpes zoster.

    PubMed Central

    Burdge, D R; Chow, A W; Sacks, S L

    1985-01-01

    Two cases of neurotoxic effects resulting from therapy with vidarabine are described. Both patients were undergoing treatment for cutaneously disseminated herpes zoster complicating therapy for solid malignant tumours. Both had normal renal function. The serum levels of hepatic enzymes were normal in one patient and slightly elevated in the other. Neurotoxicity was first manifested in both patients by the development of intention tremors that progressed to gross tremors. Obtundation, coma and death ensued in one patient and pain syndromes in the other. Vidarabine-induced neurotoxic effects, which may occur in the absence of hepatic or renal dysfunction or treatment with another drug, may be mild initially but may progress rapidly to more serious, even life-threatening, conditions. Presentation of neurotoxic effects should be considered an indication for withdrawal of vidarabine. PMID:3971255

  1. Pb Neurotoxicity: Neuropsychological Effects of Lead Toxicity

    PubMed Central

    Mason, Lisa H.; Harp, Jordan P.; Han, Dong Y.

    2014-01-01

    Neurotoxicity is a term used to describe neurophysiological changes caused by exposure to toxic agents. Such exposure can result in neurocognitive symptoms and/or psychiatric disturbances. Common toxic agents include heavy metals, drugs, organophosphates, bacterial, and animal neurotoxins. Among heavy metal exposures, lead exposure is one of the most common exposures that can lead to significant neuropsychological and functional decline in humans. In this review, neurotoxic lead exposure's pathophysiology, etiology, and epidemiology are explored. In addition, commonly associated neuropsychological difficulties in intelligence, memory, executive functioning, attention, processing speed, language, visuospatial skills, motor skills, and affect/mood are explored. PMID:24516855

  2. Neurotoxic effects induced by gammahydroxybutyric acid (GHB) in male rats.

    PubMed

    Pedraza, Carmen; García, Francisca Belén; Navarro, José Francisco

    2009-10-01

    Gammahydroxybutyric acid (GHB) is an endogenous constituent of the central nervous system that has acquired great social relevance for its use as a recreational 'club drug'. GHB, popularly known as 'liquid ecstasy', is addictive when used continuously. Although the symptoms associated with acute intoxication are well known, the effects of prolonged use remain uncertain. We examined in male rats the effect of repeated administration of GHB (10 and 100 mg/kg) on various parameters: neurological damage, working memory and spatial memory, using neurological tests, the Morris water maze and the hole-board test. The results showed that repeated administration of GHB, especially at doses of 10 mg/kg, causes neurological damage, affecting the 'grasping' reflex, as well as alteration in spatial and working memories. Stereological quantification showed that this drug produces a drastic neuronal loss in the CA1 hippocampal region and in the prefrontal cortex, two areas clearly involved in cognitive and neurological functions. No effects were noted after quantification in the periaqueductal grey matter (PAG), a region lacking GHB receptors. Moreover, NCS-382, a putative antagonist of GHB receptor, prevented both neurological damage and working- memory impairment induced by GHB. This suggests that the effects of administration of this compound may be mediated, at least partly, by specific receptors in the nervous system. The results show for the first time that the repeated administration of GHB, especially at very low doses, produces neurotoxic effects. This is very relevant because its abuse, especially by young persons, could produce considerable neurological alterations after prolonged abuse. PMID:19288974

  3. Developmental neurotoxic effects of Malathion on 3D neurosphere system

    PubMed Central

    Salama, Mohamed; Lotfy, Ahmed; Fathy, Khaled; Makar, Maria; El-emam, Mona; El-gamal, Aya; El-gamal, Mohamed; Badawy, Ahmad; Mohamed, Wael M.Y.; Sobh, Mohamed

    2015-01-01

    Developmental neurotoxicity (DNT) refers to the toxic effects induced by various chemicals on brain during the early childhood period. As human brains are vulnerable during this period, various chemicals would have significant effects on brains during early childhood. Some toxicants have been confirmed to induce developmental toxic effects on CNS; however, most of agents cannot be identified with certainty. This is because available animal models do not cover the whole spectrum of CNS developmental periods. A novel alternative method that can overcome most of the limitations of the conventional techniques is the use of 3D neurosphere system. This in-vitro system can recapitulate many of the changes during the period of brain development making it an ideal model for predicting developmental neurotoxic effects. In the present study we verified the possible DNT of Malathion, which is one of organophosphate pesticides with suggested possible neurotoxic effects on nursing children. Three doses of Malathion (0.25 μM, 1 μM and 10 μM) were used in cultured neurospheres for a period of 14 days. Malathion was found to affect proliferation, differentiation and viability of neurospheres, these effects were positively correlated to doses and time progress. This study confirms the DNT effects of Malathion on 3D neurosphere model. Further epidemiological studies will be needed to link these results to human exposure and effects data. PMID:27054080

  4. Studies on the assessment of neurotoxicity in children with acute lymphoblastic leukemia

    SciTech Connect

    Muchi, H.; Satoh, T.; Yamamoto, K.; Karube, T.; Miyao, M.

    1987-03-01

    Central nervous system (CNS) prophylaxis caused a remarkable reduction in the incidence of CNS disease, however there has evolved a growing concern regarding the immediate or late toxicities to the developing CNS. Twenty-eight children with acute lymphoblastic leukemia who survived for more than 2 years were examined for the assessment of neurotoxicity induced by CNS prophylaxis and its treatment. The patients were stratified into three groups: Stratum I, prophylaxis with methotrexate; Stratum II, prophylaxis with cranial irradiation with methotrexate; and Stratum III, with CNS leukemia. Once CNS disease developed the sequelae were frequent and severe, due to the elevated methotrexate levels in the cerebrospinal fluid. CNS prophylaxis with intermediate-dose methotrexate was less toxic to the developing CNS than prophylactic cranial irradiation, especially in children under 5 years of age. Electroencephalograms and evoked potentials are likely to find increasing application in defining the CNS sequelae of acute lymphoblastic leukemia in children and its treatment. Although the sample size was small, the findings delineate specific areas of neurotoxicity.

  5. Phthalates and neurotoxic effects on hippocampal network plasticity.

    PubMed

    Holahan, Matthew R; Smith, Catherine A

    2015-05-01

    Phthalates are synthetically derived chemicals used as plasticizers in a variety of common household products. They are not chemically bound to plastic polymers and over time, easily migrate out of these products and into the environment. Experimental investigations evaluating the biological impact of phthalate exposure on developing organisms are critical given that estimates of phthalate exposure are considerably higher in infants and children compared to adults. Extensive growth and re-organization of neurocircuitry occurs during development leaving the brain highly susceptible to environmental insults. This review summarizes the effects of phthalate exposure on brain structure and function with particular emphasis on developmental aspects of hippocampal structural and functional plasticity. In general, it appears that widespread disruptions in hippocampal functional and structural plasticity occur following developmental (pre-, peri- and post-natal) exposure to phthalates. Whether these changes occur as a direct neurotoxic effect of phthalates or an indirect effect through disruption of endogenous endocrine functions is not fully understood. Comprehensive investigations that simultaneously assess the neurodevelopmental, neurotoxic, neuroendocrine and behavioral correlates of phthalate exposure are needed to provide an opportunity to thoroughly evaluate the neurotoxic potential of phthalates throughout the lifespan. PMID:25749100

  6. Analysis of nociceptive effects of neurotoxic phospholipase A2 from Vipera nikolskii venom in mice

    PubMed Central

    Dyachenko, Igor A; Murashev, Arkadii N; Andreeva, Tatyana V; Tsetlin, Victor I; Utkin, Yuri N

    2013-01-01

    Phospholipases A2 are represented in snake venoms by several types and possess diverse biological activities including neurotoxicity. Previously, we isolated and characterized two neurotoxic phospholipases A2 (HDP-1 and HDP-2) from the venom of Nikolski's viper (Vipera nikolskii), which were heterodimers composed of two non-covalently bound subunits. Each heterodimer consisted of an enzymatically active basic subunit and an inactive acidic subunit. In this work, we studied the in vivo biological activity of HDP-2 in mice. The acute toxicity (LD50 = 0.38 μg/gm) and maximal tolerated dose (0.1 μg/gm) were determined. In the hot plate test, HDP-2 at the maximal tolerated dose, reliably prolonged the time of the mouse staying on the plate. However, taking into account the neurotoxicity of HDP-2, we believe that this effect may be explained by a general intoxication rather than specific decrease of pain sensitivity. In this respect HDP-2 differs from other heterodimeric phospholipases A2 like crotoxin, which possess analgesic activity. This difference can be explained by the dissimilarity in the structure of the acidic subunits, suggesting an important role of this subunit in analgesic activity. PMID:23577231

  7. Evaluation of Caenorhabditis elegans as an acute lethality and a neurotoxicity screening model

    SciTech Connect

    Williams, P.L.

    1988-01-01

    This investigation evaluated C. elegans as a lethality and neurotoxicity screening model. The lethality experiments were performed in both agar and an aquatic medium. The salts of 8 metals (Hg, Be, Al, Cu, Zn, Pb, Cd, and Sr) were used in the agar studies and the salts of 14 metals (Ag, Hg, Cu, Be, Al, Pb, Cr, As, Tl, Zn, Cd, Ni, Sr, and Sb) were used in the aquatic tests. In each of these tests an LC50 value was determined. The data from the agar plates were compared to the published mammalian oral LD50 values for salts of the same metals. Within this set of chemicals C. elegans was found to be a predictor of mammalian acute lethality, generating LC50 values parallel to the rat and mouse LD50 values. The aquatic data were compared to data from EPA Ambient Water Quality Criteria documents. C. elegans was found to be less sensitive than Daphnia but generally more sensitive than the other invertebrate organisms that are presently used. The neurotoxicity testing also was performed in both agar and an aquatic media. The testing in agar was conducted with the salts of 4 metals (Cu, Be, Pb, and Hg) and 2 organophosphate pesticides (malathion and vapona). The studies in an aquatic medium tested the salts of 4 metals (Cu, Be, Pb, and Hg).

  8. Genetic or pharmacological blockade of noradrenaline synthesis enhances the neurochemical, behavioural, and neurotoxic effects of methamphetamine

    PubMed Central

    Weinshenker, David; Ferrucci, Michela; Busceti, Carla L.; Biagioni, Francesca; Lazzeri, Gloria; Liles, L. Cameron; Lenzi, Paola; Murri, Luigi; Paparelli, Antonio; Fornai, Francesco

    2008-01-01

    N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4) lesions of the locus coeruleus (LC), the major brain noradrenergic nucleus, exacerbate the damage to nigrostriatal dopamine (DA) terminals caused by the psychostimulant methamphetamine (METH). However, because noradrenergic terminals contain other neuromodulators and the noradrenaline (NA) transporter, which may act as a neuroprotective buffer, it was unclear whether this enhancement of METH neurotoxicity was caused by the loss of noradrenergic innervation or the loss of NA itself. We addressed the specific role of NA by comparing the effects of METH in mice with noradrenergic lesions (DSP-4) and those with intact noradrenergic terminals but specifically lacking NA (genetic or acute pharmacological blockade of the NA biosynthetic enzyme dopamine β-hydroxylase; DBH). We found that genetic deletion of DBH (DBH −/− mice) and acute treatment of wild-type mice with a DBH inhibitor (fusaric acid) recapitulated the effects of DSP-4 lesions on METH responses. All three methods of NA depletion enhanced striatal DA release, extracellular oxidative stress (as measured by in vivo microdialysis of DA and 2,3-dihydroxybenzoic acid), and behavioural stereotypies following repeated METH administration. These effects accompanied a worsening of the striatal DA neuron terminal damage and ultrastructural changes to medium spiny neurons. We conclude that NA itself is neuroprotective and plays a fundamental role in the sensitivity of striatal DA terminals to the neurochemical, behavioural, and neurotoxic effects of METH. PMID:18042179

  9. Neurotoxicity and reactive astrogliosis in the anterior cingulate cortex in acute ciguatera poisoning.

    PubMed

    Zhang, Xu; Cao, Bing; Wang, Jun; Liu, Jin; Tung, Vivian Oi Vian; Lam, Paul Kwan Sing; Chan, Leo Lai; Li, Ying

    2013-06-01

    Ciguatoxins (CTXs) cause long-term disturbance of cerebral functions. The primary mechanism of neurotoxicity is related to their interaction with voltage-gated sodium channels. However, until now, the neurological targets for CTXs in the brain of intact animals have not been described. In our study, 1 day following oral exposure to 0.26 ng/g of Pacific ciguatoxin 1 (P-CTX-1), we performed in vivo electrophysiological recordings in the rat anterior cingulate cortex (ACC) and identified the increase in spontaneous firings and enhanced responses to visceral noxious stimulation. Local field recordings characterized the P-CTX-1-induced synaptic potentiation and blockage of the induction of electrical stimulation-induced long-term potentiation in the medial thalamus (MT)-ACC pathway. Furthermore, intracerebroventricular administration of P-CTX-1 at doses of 1.0, 5.0, and 10 nM produced a dose-dependent increase in ACC neuronal firings and MT-ACC synaptic transmission. Further studies showed upregulated Na(+) channel expression in astrocytes under pathological conditions. We hypothesized that the astrocytes might have been activated in the ciguatera poisoning in vivo. Increases in glial fibrillary acid protein expression were detected in reactive astrocytes in the rat ACC. The activation of astroglia was further indicated by activation of the gap junction protein connexin 43 and upregulation of excitatory amino acid transporter 2 expression suggesting that glutamate was normally rapidly cleared from the synaptic cleft during acute ciguatera poisoning. However, neurotoxicity and reactive astrogliosis were not detected in the ACC after 7 days of P-CTX-1 exposure. The present results are the first characterization of P-CTX-1-invoked brain cortex neuronal excitotoxicity in vivo and supported the theme that neuron and astroglia signals might play roles in acute ciguatera poisoning. PMID:23494292

  10. Effects of rutin on acrylamide-induced neurotoxicity

    PubMed Central

    2014-01-01

    Background Rutin is an important flavonoid that is consumed in the daily diet. The cytoprotective effects of rutin, including antioxidative, and neuroprotective have been shown in several studies. Neurotoxic effects of acrylamide (ACR) have been established in humans and animals. In this study, the protective effects of rutin in prevention and treatment of neural toxicity of ACR were studied. Results Rutin significantly reduced cell death induced by ACR (5.46 mM) in time- and dose-dependent manners. Rutin treatment decreased the ACR-induced cytotoxicity significantly in comparison to control (P <0.01, P < 0.001). Rutin (100 and 200 mg/kg) could prevent decrease of body weight in rats. In combination treatments with rutin (50, 100 and 200 mg/kg), vitamin E (200 mg/kg) and ACR, gait abnormalities significantly decreased in a dose-dependent manner (P < 0.01 and P < 0.001). The level of malondialdehyde significantly decreased in the brain tissue of rats in both preventive and therapeutic groups that received rutin (100 and 200 mg/kg). Conclusion It seems that rutin could be effective in reducing neurotoxicity and the neuroprotective effect of it might be mediated via antioxidant activity. PMID:24524427

  11. Subacute methotrexate neurotoxicity and cerebral venous sinus thrombosis in a 12-year-old with acute lymphoblastic leukemia and methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism: homocysteine-mediated methotrexate neurotoxicity via direct endothelial injury.

    PubMed

    Mahadeo, Kris M; Dhall, Girish; Panigrahy, Ashok; Lastra, Carlos; Ettinger, Lawrence J

    2010-02-01

    From as early as the 1970s methotrexate has been associated with disseminated necrotizing leukoencephalopathy and other neurotoxic sequelae. Yet, a clear mechanism for methotrexate-induced neurotoxicity has not been established. The authors describe the case of a 12-year-old male with acute lymphoblastic leukemia and a homozygous methylenetetrahydrofolate reductase C677T mutation, who developed subacute methotrexate-induced toxicity and cerebral venous thrombosis after receiving intrathecal methotrexate. The role of homocysteine as a possible mediator in methotrexate-induced neurotoxicity via direct endothelial injury is discussed. PMID:20121554

  12. Neurotoxic Effects and Biomarkers of Lead Exposure: A Review

    PubMed Central

    Sanders, Talia; Liu, Yiming; Buchner, Virginia; Tchounwou, Paul B.

    2010-01-01

    Biological monitoring techniques are useful for risk assessment of toxic agents in the field of environmental health. Lead, a systemic toxicant affecting virtually every organ system, primarily affects the central nervous system, particularly the developing brain. Consequently, children are at a greater risk than adults of suffering from the neurotoxic effects of lead. The ability of lead to pass through the blood-brain barrier is due in large part to its ability to substitute for calcium ions. Within the brain, lead-induced damage in the prefrontal cerebral cortex, hippocampus, and cerebellum can lead to a variety of neurological disorders, such as brain damage, mental retardation, behavioral problems, nerve damage, and possibly Alzheimer’s disease, Parkinson’s disease, and schizophrenia. At the molecular level, lead interferes with the regulatory action of calcium on cell functions and disrupts many intracellular biological activities. Experimental studies have also shown that lead exposure may have genotoxic effects, especially in the brain, bone marrow, liver, and lung cells. This paper presents an overview of biomarkers of lead exposure and discusses the neurotoxic effects of lead with regard to children, adults, and experimental animals, updated to January 2009. PMID:19476290

  13. Acetylcholinesterase in zebrafish embryos as a tool to identify neurotoxic effects in sediments.

    PubMed

    Kais, Britta; Stengel, Daniel; Batel, Annika; Braunbeck, Thomas

    2015-11-01

    In order to clarify the suitability of zebrafish (Danio rerio) embryos for the detection of neurotoxic compounds, the acetylcholinesterase assay was adapted and validated with a series of priority pollutants listed as relevant for the European water policy (Aroclor 1254, 2,3-benzofuran, bisphenol A, chlorpyrifos, paraoxon-methyl, quinoline, and methyl mercury chloride) as well as acetonic extracts from three sediments of known contamination. The acute toxicities of the model substances and the sediment extracts were determined by means of the fish embryo test as specified in OECD TG 236, and concentrations as low as the effective concentration at 10% inhibition (EC10) were used as the highest test concentration in the acetylcholinesterase test in order to avoid nonspecific systemic effects mimicking neurotoxicity. Among the model compounds, only the known acetylcholinesterase inhibitors paraoxon-methyl and chlorpyrifos produced a strong inhibition to about 20 and 33%, respectively, of the negative controls. For the sediment extracts, a reduction of acetylcholinesterase activity to about 60% could only be shown for the Vering Canal sediment extracts; this could be correlated to high contents of acetylcholinesterase-inhibiting polycyclic aromatic hydrocarbons (PAHs) as identified by chemical analyses. Co-incubation of the Vering Canal sediment extracts with chlorpyrifos at EC10 concentrations each did not significantly increase the inhibitory effect of chlorpyrifos, indicating that the mode of action of acetylcholinesterase inhibition by the sediment-borne PAHs is different to that of the typical acetylcholinesterase blocker chlorpyrifos. Overall, the study documents that zebrafish embryos represent a suitable model not only to reveal acetylcholinesterase inhibition, but also to investigate various modes of neurotoxic action. PMID:25567057

  14. EFFECTS OF PYRETHROIDS ON VOLTAGE-SENSITIVE CALCIUM CHANNELS: A CRITICAL EVALUATION OF STRENGTHS, WEAKNESSES, DATA NEEDS, AND RELATIONSHIP TO ASSESSMENT OF CUMULATIVE NEUROTOXICITY.

    EPA Science Inventory

    A recently published review (Soderlund et al., 2002, Toxicology 171, 3-59.) of the mechanisms of acute neurotoxicity of pyrethroid compounds postulated that voltage-sensitive calcium channels (VSCC) may be a target of some pyrethroid compounds and that effects on VSCC may contrib...

  15. Predicting the acute neurotoxicity of diverse organic solvents using probabilistic neural networks based QSTR modeling approaches.

    PubMed

    Basant, Nikita; Gupta, Shikha; Singh, Kunwar P

    2016-03-01

    Organic solvents are widely used chemicals and the neurotoxic properties of some are well established. In this study, we established nonlinear qualitative and quantitative structure-toxicity relationship (STR) models for predicting neurotoxic classes and neurotoxicity of structurally diverse solvents in rodent test species following OECD guideline principles for model development. Probabilistic neural network (PNN) based qualitative and generalized regression neural network (GRNN) based quantitative STR models were constructed using neurotoxicity data from rat and mouse studies. Further, interspecies correlation based quantitative activity-activity relationship (QAAR) and global QSTR models were also developed using the combined data set of both rodent species for predicting the neurotoxicity of solvents. The constructed models were validated through deriving several statistical coefficients for the test data and the prediction and generalization abilities of these models were evaluated. The qualitative STR models (rat and mouse) yielded classification accuracies of 92.86% in the test data sets, whereas, the quantitative STRs yielded correlation (R(2)) of >0.93 between the measured and model predicted toxicity values in both the test data (rat and mouse). The prediction accuracies of the QAAR (R(2) 0.859) and global STR (R(2) 0.945) models were comparable to those of the independent local STR models. The results suggest the ability of the developed QSTR models to reliably predict binary neurotoxicity classes and the endpoint neurotoxicities of the structurally diverse organic solvents. PMID:26721664

  16. An overview of butanol-induced developmental neurotoxicity and the potential mechanisms related to these observed effects.

    PubMed

    Bale, Ambuja S; Lee, Janice S

    2016-01-01

    The purpose of this article is to briefly review the published literature on the developmental neurotoxic effects, including potential mechanisms, of four butanols: n-butanol, sec-butanol, tert-butanol, isobutanol, and identify data gaps and research needs for evaluation of human health risks in this area. Exposure potential to these four butanols is considerable given the high production volume (>1 billion lb) of n- and tert-butanol and moderate production volumes (100-500 million lb) of sec- and isobutanol. With the impetus to derive cleaner gasoline blends, butanols are being considered for use as fuel oxygenates. Notable signs of neurotoxicity and developmental neurotoxicity have been observed in some studies where laboratory animals (rodents) were gestationally exposed to n- or tert-butanol. Mechanistic data relevant to the observed developmental neurotoxicity endpoints were also reviewed to hypothesize potential mechanisms associated with the developmental neurotoxicity outcome. Data from the related and highly characterized alcohol, ethanol, were included to examine consistencies between this compound and the four butanols. It is widely known that alcohols, including butanols, interact with several ion channels and modulate the function of these targets following both acute and chronic exposures. In addition, n- and sec-butanol have been demonstrated to inhibit fetal rat brain astroglial cell proliferation. Further, rat pups exposed to n-butanol in utero were also reported to have significant increases in brain levels of dopamine and serotonin, but decreases in serotonin levels were noted with gestational exposure to tert-butanol. tert-Butanol was reported to inhibit muscarinic receptor-stimulated phosphoinositide metabolism which has been hypothesized to be a possible target for the neurotoxic effects of ethanol during brain development. The mechanistic data for the butanols support developmental neurotoxicity that has been observed in some of the rodent

  17. Platinum Neurotoxicity Pharmacogenetics

    PubMed Central

    McWhinney, Sarah R.; Goldberg, Richard M.; McLeod, Howard L.

    2009-01-01

    Cisplatin, carboplatin, and oxaliplatin anticancer drugs are commonly used to treat lung, colorectal, ovarian, breast, head/neck, and genitourinary cancers. However, the efficacy of platinum-based drugs is often compromised because of the substantial risk for severe toxicities, including neurotoxicity. Neurotoxicity can result in both acute and chronic debilitation. Moreover, colorectal cancer patients treated with oxaliplatin more often discontinue therapy due to peripheral neuropathy than for tumor progression, potentially compromising patient benefit. Numerous methods to prevent neurotoxicity have so far proven unsuccessful. In order to circumvent this life-altering side effect, while taking advantage of the antitumor activities of the platinum agents, efforts to identify mechanism-based biomarkers are underway. In this review, we detail findings from the current literature for genetic markers associated with neurotoxicity induced by single agent and combination platinum chemotherapy. These data have the potential for broad clinical implications if mechanistic associations lead to the development of toxicity modulators to minimize the noxious sequelae of platinum chemotherapy. PMID:19139108

  18. EVALUATING THE HUMAN HEALTH EFFECTS OF HAZARDOUS WASTES: REPRODUCTION AND DEVELOPMENT, NEUROTOXICITY, GENETIC TOXICITY AND CANCER

    EPA Science Inventory

    Several approaches are available for characterizing potential toxicity of wastes. his paper describes biological tests which are appropriate for identifying waste as neurotoxic, genotoxic, or likely to produce developmental or reproductive effects. he tests recommended are, for n...

  19. Age-related differences in neurotoxicity produced by organophosphorus and N-methyl carbamate pesticides

    EPA Science Inventory

    Potential pesticide effects in infants and toddlers have received much attention in the scientific literature and the public media, including the concern for increased response to acute or shortterm exposures. Age-related differences in the acute neurotoxicity of acetylcholinest...

  20. Recovery study of cholinesterases and neurotoxic signs in the non-target freshwater invertebrate Chilina gibbosa after an acute exposure to an environmental concentration of azinphos-methyl.

    PubMed

    Cossi, Paula Fanny; Beverly, Boburg; Carlos, Luquet; Kristoff, Gisela

    2015-10-01

    lethality (30%) was registered in treated snails. C. gibbosa is a very sensitive organism to azinphos-methyl. These snails play an important role in the structure and function of aquatic food webs in this region. Thus, a decline of this species' population would probably have an impact on aquatic and non-aquatic communities. Our results show that C. gibbosa is a relevant sentinel species for studying exposure and effects of azinphos-methyl using behavioral and biochemical biomarkers. Neurotoxic behavioral signs are very sensitive, non-destructive biomarkers, which can be easily detected for about one week after acute exposure. Cholinesterse activity is a very useful biomarker showing a high sensitivity and a slow recovery capacity increasing the possibility to indirectly detect organophosphates for long periods after a contaminant event. PMID:26364254

  1. Development of NMDAR Antagonists with Reduced Neurotoxic Side Effects: a Study on GK11

    PubMed Central

    Teigell, Marisa; Prieto-Cappellini, Monica; Vignon, Jacques; Privat, Alain; Perez-Polo, Regino; Nesic, Olivera; Hirbec, Helene

    2013-01-01

    The NMDAR glutamate receptor subtype mediates various vital physiological neuronal functions. However, its excessive activation contributes to neuronal damage in a large variety of acute and chronic neurological disorders. NMDAR antagonists thus represent promising therapeutic tools that can counteract NMDARs’ overactivation. Channel blockers are of special interest since they are use-dependent, thus being more potent at continuously activated NMDARs, as may be the case in pathological conditions. Nevertheless, it has been established that NMDAR antagonists, such as MK801, also have unacceptable neurotoxic effects. Presently only Memantine is considered a safe NMDAR antagonist and is used clinically. It has recently been speculated that antagonists that preferentially target extrasynaptic NMDARs would be less toxic. We previously demonstrated that the phencyclidine derivative GK11 preferentially inhibits extrasynaptic NMDARs. We thus anticipated that this compound would be safer than other known NMDAR antagonists. In this study we used whole-genome profiling of the rat cingulate cortex, a brain area that is particularly sensitive to NMDAR antagonists, to compare the potential adverse effects of GK11 and MK801. Our results showed that in contrast to GK11, the transcriptional profile of MK801 is characterized by a significant upregulation of inflammatory and stress-response genes, consistent with its high neurotoxicity. In addition, behavioural and immunohistochemical analyses confirmed marked inflammatory reactions (including astrogliosis and microglial activation) in MK801-treated, but not GK11-treated rats. Interestingly, we also showed that GK11 elicited less inflammation and neuronal damage, even when compared to Memantine, which like GK11, preferentially inhibits extrasynaptic NMDAR. As a whole, our study suggests that GK11 may be a more attractive therapeutic alternative in the treatment of CNS disorders characterized by the overactivation of glutamate

  2. Acute Cerebrovascular Radiation Syndrome: Radiation Neurotoxicity , mechanisms of CNS radiation injury, advanced countermeasures for Radiation Protection of Central Nervous System.

    NASA Astrophysics Data System (ADS)

    Popov, Dmitri; Jones, Jeffrey; Maliev, Slava

    Key words: Cerebrovascular Acute Radiation Syndrome (Cv ARS), Radiation Neurotoxins (RNT), Neurotransmitters, Radiation Countermeasures, Antiradiation Vaccine (ArV), Antiradiation Blocking Antibodies, Antiradiation Antidote. Psychoneuroimmunology, Neurotoxicity. ABSTRACT: To review the role of Radiation Neurotoxins in triggering, developing of radiation induced central nervous system injury. Radiation Neurotoxins - rapidly acting blood toxic lethal agent, which activated after irradiation and concentrated, circulated in interstitial fluid, lymph, blood with interactions with cell membranes, receptors and cell compartments. Radiation Neurotoxins - biological molecules with high enzymatic activity and/or specific lipids and activated or modified after irradiation. The Radiation Neurotoxins induce increased permeability of blood vessels, disruption of the blood-brain barrier, blood-cerebrospinal fluid (CSF) barrier and developing severe disorder of blood macro- and micro-circulation. Principles of Radiation Psychoneuro-immunology and Psychoneuro-allergology were applied for determination of pathological processes developed after irradiation or selective administration of Radiation Neurotoxins to radiation naïve mammals. Effects of radiation and exposure to radiation can develop severe irreversible abnormalities of Central Nervous System, brain structures and functions. Antiradiation Vaccine - most effective, advanced methods of protection, prevention, mitigation and treatment and was used for of Acute Radiation Syndromes and elaboration of new technology for immune-prophylaxis and immune-protection against ϒ, Heavy Ion, Neutron irradiation. Results of experiments suggested that blocking, antitoxic, antiradiation antibodies can significantly reduce toxicity of Radiation Toxins. New advanced technology include active immune-prophylaxis with Antiradiation Vaccine and Antiradiation therapy that included specific blocking antibodies to Radiation Neurotoxins

  3. 1,3-Dinitrobenzene neurotoxicity - Passage effect in immortalized astrocytes.

    PubMed

    Maurer, Laura L; Latham, Jackelyn D; Landis, Rory W; Song, Dong Hoon; Epstein, Tamir; Philbert, Martin A

    2016-03-01

    Age-related disturbances in astrocytic mitochondrial function are linked to loss of neuroprotection and decrements in neurological function. The immortalized rat neocortical astrocyte-derived cell line, DI-TNC1, provides a convenient model for the examination of cellular aging processes that are difficult to study in primary cell isolates from aged brain. Successive passages in culture may serve as a surrogate of aging in which time-dependent adaptation to culture conditions may result in altered responses to xenobiotic challenge. To investigate the hypothesis that astrocytic mitochondrial homeostatic function is decreased with time in culture, low passage DI-TNC1 astrocytes (LP; #2-8) and high passage DI-TNC1 astrocytes (HP; #17-28) were exposed to the mitochondrial neurotoxicant 1,3-dinitrobenzene (DNB). Cells were exposed in either monoculture or in co-culture with primary cortical neurons. Astrocyte mitochondrial membrane potential, morphology, ATP production and proliferation were monitored in monoculture, and the ability of DI-TNC1 cells to buffer K(+)-induced neuronal depolarization was examined in co-cultures. In HP DI-TNC1 cells, DNB exposure decreased proliferation, reduced mitochondrial membrane potential and significantly decreased mitochondrial form factor. Low passage DI-TNC1 cells effectively attenuated K(+)-induced neuronal depolarization in the presence of DNB whereas HP counterparts were unable to buffer K(+) in DNB challenge. Following DNB challenge, LP DI-TNC1 cells exhibited greater viability in co-culture than HP. The data provide compelling evidence that there is an abrupt phenotypic change in DI-TNC1 cells between passage #9-16 that significantly diminishes the ability of DI-TNC1 cells to compensate for neurotoxic challenge and provide neuroprotective spatial buffering. Whether or not these functional changes have an in vivo analog in aging brain remains to be determined. PMID:26769196

  4. TIME-COURSE OF ACUTE NEUROTOXICITY PRODUCED BY N-METHYL CARBAMATES IN PREWEANLING RATS.

    EPA Science Inventory

    N-methyl carbamate insecticides are reversible inhibitors of central and peripheral acetylcholinesterease (ChE). Despite their widespread and long-term use, we could find no studies of a systematic comparison of neurotoxicity in young animals across this group of chemicals. To ...

  5. Neurotoxic effects of methylene chloride: are they long lasting in humans?

    PubMed Central

    Lash, A A; Becker, C E; So, Y; Shore, M

    1991-01-01

    The neurotoxicity of methylene chloride (MC) is of special interest because of its acute effects on the central nervous system (CNS) and its metabolic conversion to carbon monoxide. A cohort study of retired airline mechanics was conducted to examine the hypothesis that long term exposure to MC results in lasting effects on the CNS. Retirees were studied to eliminate effects of current occupational exposures. The total retiree population (n = 1758) was surveyed to identify mechanics who met specific occupational, demographic, and medical criteria. A group of eligible retirees having long term exposure to MC and another group with low probability of exposure to solvents were given a comprehensive battery of physiological and psychological tests. The exposure groups were similar for all potential confounders that were measured. No statistically significant differences between groups were detected on outcome measures, although subtle differences in attention and memory were identified. Thus no firm evidence was found to support the hypothesis of lasting CNS effects in retired mechanics with long term exposure to MC. PMID:2064980

  6. Environmental enrichment does not reduce the rewarding and neurotoxic effects of methamphetamine.

    PubMed

    Thiriet, Nathalie; Gennequin, Benjamin; Lardeux, Virginie; Chauvet, Claudia; Decressac, Mickael; Janet, Thierry; Jaber, Mohamed; Solinas, Marcello

    2011-01-01

    Abuse of amphetamine analogues, such as methamphetamine (METH), represents an important health problem because of their powerful addictive and neurotoxic effects. Abuse of METH induces dopamine neuron terminals loss and cell death in the striatum similar to what is found in other neurodegenerative processes. Exposing mice and rats to enriched environments (EE) has been shown to produce significant protective effects against drug-induced reward as well as against neurodegenerative processes. Here, we investigated whether exposure to EE could reduce the METH-induced reward and neurotoxicity. For this, we reared mice for 2 months during early stages of life in standard environments or EE and then, at adulthood, we tested the ability of METH to induce conditioned place preference and neurotoxicity. We found that, contrary to what we found with other drugs such as cocaine and heroin, EE was unable to reduce the rewarding effects of METH. In addition, contrary to what we found with other toxins such as MPTP, EE did not diminish the striatal neurotoxicity induced by METH (4 x 10 mg/kg) as measured by dopamine content, tyrosine hydroxylase protein levels and apoptosis. Our results demonstrate that the rewarding and neurotoxic effects of METH are not reduced by EE and highlight the great risks associated with the increased popularity of this drug amongst the young population. PMID:20143198

  7. Neurotoxicity following acute inhalation of aerosols generated during resistance spot weld-bonding of carbon steel.

    PubMed

    Sriram, Krishnan; Jefferson, Amy M; Lin, Gary X; Afshari, Aliakbar; Zeidler-Erdely, Patti C; Meighan, Terence G; McKinney, Walter; Jackson, Mark; Cumpston, Amy; Cumpston, Jared L; Leonard, Howard D; Frazer, David G; Antonini, James M

    2014-10-01

    divulge the differential effects of LM and HM aerosols in the brain and suggest that exposure to weld-bonding aerosols can potentially elicit neurotoxicity following a short-term exposure. However, further investigations are warranted to determine if the aerosols generated by weld-bonding can contribute to persistent long-term neurological deficits and/or neurodegeneration. PMID:25265048

  8. Neurotoxicity following acute inhalation of aerosols generated during resistance spot weld-bonding of carbon steel

    PubMed Central

    Sriram, Krishnan; Jefferson, Amy M.; Lin, Gary X.; Afshari, Aliakbar; Zeidler-Erdely, Patti C.; Meighan, Terence G.; McKinney, Walter; Jackson, Mark; Cumpston, Amy; Cumpston, Jared L.; Leonard, Howard D.; Frazer, David G.; Antonini, James M.

    2015-01-01

    divulge the differential effects of LM and HM aerosols in the brain and suggest that exposure to weld-bonding aerosols can potentially elicit neurotoxicity following a short-term exposure. However, further investigations are warranted to determine if the aerosols generated by weld-bonding can contribute to persistent long-term neurological deficits and/or neurodegeneration. PMID:25265048

  9. The in vitro protective effect of salicylic acid against paclitaxel and cisplatin-induced neurotoxicity.

    PubMed

    Cetin, Damla; Hacımuftuoglu, Ahmet; Tatar, Abdulgani; Turkez, Hasan; Togar, Basak

    2016-08-01

    Paclitaxel (PAC) and cisplatin (CIS) are two established chemotherapeutic drugs used in combination for the treatment of various solid tumors. However, the usage of PAC and CIS are limited because of the incidence of their moderate or severe neurotoxic side effects. In this study, we aimed to assess the protective role of salicylic acid (SA) against neurotoxicity caused by PAC and CIS. For this purpose, newborn Sprague Dawley rats were decapitated in sterile atmosphere and primary cortex neuron cultures were established. On the 10th day SA was added into culture plates. PAC and CIS were added on the 12th day. The cytotoxicity was determined by using the MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assay. Oxidative alterations were assessed using total antioxidant capacity and total oxidative stress assays in rat primary neuron cell cultures. It was shown that both concentrations of PAC and CIS treatments caused neurotoxicity. Although SA decreased the neurotoxicity by CIS and PAC, it was more effective against the toxicity caused by CIS rather than the toxicity caused by PAC. In conclusion it was clearly revealed that SA decreased the neurotoxic effect of CIS and PAC in vitro. PMID:26199062

  10. Expression of heat shock protein (HSP 72 kD) during acute methamphetamine intoxication depends on brain hyperthermia: neurotoxicity or neuroprotection?

    PubMed Central

    Kiyatkin, Eugene A.; Sharma, Hari S.

    2011-01-01

    In the present study, light and electron microscopy were used to examine heat shock protein (HSP 72kD) expression during acute methamphetamine (METH) intoxication in rats and evaluate its relationships with brain temperature and alterations in a number of other histochemical and morphological parameters. Freely moving rats received METH at the same dose (9 mg/kg, sc) but at different ambient temperatures (23 and 29°C), showing a wide range of brain temperature elevations (37.6–42.5°C); brains were taken for histochemical and morphological evaluations at peak of brain temperature increase. We found that acute METH intoxication induces massive and wise-spread HSP expression in neural and glial cells examined in details in the cortex, hippocampus, thalamus, and hypothalamus. In each of these structures, the number of HSP-positive cells tightly correlated with brain temperature elevation. The changes in HSP immunoreactivity were also tightly related to alterations in permeability of the blood-brain barrier, acute glial activation and brain edema assessed by albumin and GFAP immunoreactivity and measuring tissue water content, respectively. While robust and generalized HSP production normally appears to be the part of an adaptive brain response associated with METH-induced metabolic activation, activation of this protective mechanism has its natural limits and could not counteract the damaging effects of oxidative stress, high temperature and edema – the leading factors of METH-induced neurotoxicity. PMID:20931246

  11. Protective effects of a Chotosan Fraction and its active components on β-amyloid-induced neurotoxicity.

    PubMed

    Wei, Menglin; Chen, Lei; Liu, Jiazhuo; Zhao, Jiaojiao; Liu, Wenyuan; Feng, Feng

    2016-03-23

    Chotosan (CTS) is a traditional Kampo prescription used to treat chronic headache and hypertension. Recent clinical studies demonstrated that CTS has ameliorative effects on dementia. This study aims to identify the anti-Alzheimer components in CTS. β-amyloid (Aβ) is considered to play a central role in the pathophysiology of Alzheimer's disease. CTS-E, a fraction of CTS, showed significant protective effects on Aβ-induced neurotoxicity. High-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry was used for the qualitative analysis of it. Among the identified constituents, neuroprotective effects against Aβ25-35-induced neurotoxicity of 10 major compounds were tested by MTT assay. Their inhibitory action on Aβ1-42 self-induced aggregation was measured by Thioflavin T-binding assay. The results showed that caffeic acid, chlorogenic acid, 1,5-dicaffeoylquinic acid, 3,5-dicaffeoylquinic acid and 4,5-dicaffeoylquinic acid had significant neuroprotective effects on Aβ25-35-induced neurotoxicity. Besides these phenolic acids, nobiletin and hesperidin could also inhibit Aβ1-42 self-induced aggregation. In conclusion, the neuroprotective fraction, CTS-E, could protect PC12 cells from Aβ-induced neurotoxicity. Anti-oxidative effects may at least partly mediate the neuroprotective effects of it. Phenolic acids from Chrysanthemi Flos and flavonoids from Citri Reticulatae Pericarpium might be the effective constituents in CTS-E. PMID:26876445

  12. Chemotherapy-Related Neurotoxicity.

    PubMed

    Taillibert, Sophie; Le Rhun, Emilie; Chamberlain, Marc C

    2016-09-01

    Chemotherapy may have detrimental effects on either the central or peripheral nervous system. Central nervous system neurotoxicity resulting from chemotherapy manifests as a wide range of clinical syndromes including acute, subacute, and chronic encephalopathies, posterior reversible encephalopathy, acute cerebellar dysfunction, chronic cognitive impairment, myelopathy, meningitis, and neurovascular syndromes. These clinical entities vary by causative agent, degree of severity, evolution, and timing of occurrence. In the peripheral nervous system, chemotherapy-induced peripheral neuropathy (CIPN) and myopathy are the two main complications of chemotherapy. CIPN is the most common complication, and the majority manifest as a dose-dependent length-dependent sensory axonopathy. In severe cases of CIPN, the dose of chemotherapy is reduced, the administration delayed, or the treatment discontinued. Few treatments are available for CIPN and based on meta-analysis, duloxetine is the preferred symptomatic treatment. Myopathy due to corticosteroid use is the most frequent cause of muscle disorders in patients with cancer. PMID:27443648

  13. Neurotoxic and Cytotoxic Effects of Venom from Different Populations of the Egyptian Scorpio Maurus Palmatus

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Neurotoxic and cytotoxic effects of venoms from Scorpio maurus palmatus taken from different populations were assessed for geographic based variability in toxicity and to evaluate their insecticidal potency. Scorpions were collected from four regions. Three locations were mutually isolated pockets i...

  14. NEUROTOXIC EFFECTS OF ENVIRONMENTAL AGENTS: DATA GAPS THAT CHALLENGE DOSE-RESPONSE ESTIMATION

    EPA Science Inventory

    Neurotoxic effects of environmental agents: Data gaps that challenge dose-response estimation
    S Gutter*, P Mendola+, SG Selevan**, D Rice** (*UNC Chapel Hill; +US EPA, NHEERL; **US EPA, NCEA)

    Dose-response estimation is a critical feature of risk assessment. It can be...

  15. Local effects and global impact in neurotoxicity and neurodegeneration: The Xi’an International Neurotoxicology Conference

    EPA Science Inventory

    Neurotoxicity and Neurodegeneration: Local Effect and Global Impact” was the theme of the Xi’an International Neurotoxicology Conference (XINC), held in Xi’an, June 2011. The Conference was a joint event of the 13th Biennal Meeting of the International Neurotoxicology Associatio...

  16. Possible long-term effects of γ-hydroxybutyric acid (GHB) due to neurotoxicity and overdose.

    PubMed

    van Amsterdam, Jan G C; Brunt, Tibor M; McMaster, Minni T B; Niesink, Raymond J M

    2012-04-01

    In several countries, including the Netherlands, the use of GHB seems to be rising. GHB is regarded by recreational users as an innocent drug without any side effects. Recently, the number of patients in treatment due to GHB addiction sharply increased. In addition, various studies report incidents following risky GHB use or GHB overdosing. Other sedative drugs, like ketamine and alcohol have been shown to result in unintended neurotoxic harm at the level of memory and cognitive function. As outlined in the present review, GHB and ketamine have a common mode of action, which suggests that GHB may also lead to similar neurotoxicity as ketamine. GHB overdosing, as well as binge drinking (and high ketamine doses), induce profound coma which is probably neurotoxic for the brain especially in the maturing brain of young adults. It is therefore advocated to investigate possible long-term neurotoxic effects in recreational GHB users e.g. by studying the residual effects on cognition and memory. PMID:22342779

  17. [Acute vincristine neurotoxicity in a non-Hodgkin's lymphoma patient with Charcot-Marie-Tooth disease].

    PubMed

    Uno, S; Katayama, K; Dobashi, N; Hirano, A; Ogihara, A; Yamazaki, H; Usui, N; Kobayashi, T; Inoue, K; Kuraishi, Y

    1999-05-01

    A 44-year-old, previously healthy man with a diagnosis of non-Hodgkin's lymphoma (NHL, diffuse large B-cell type, stage IIA) was treated with combination chemotherapy including vincristine (VCR). After receiving a cumulative dose of VCR, he experienced rapid and marked weakening which progressed to quadriplegia and bulbar palsy. Prior to this therapy, the patient had no neurological problems, and his siblings were asymptomatic. Physical examination identified pes cavus (hollow foot), and electrodiagnostic studies showed markedly slower nerve conduction velocity of myelinated fibers, with abundant "onion bulb" formations. Chromosomal analysis detected 17p11.2-12 duplication, thus yielding a diagnosis of Charcot-Marie-Tooth (CMT) 1A. CMT disease is a familial neuromuscular disorder, and the incidence is approximately 1 in 2,500. We concluded that if CMT disease is diagnosed, vincristine should be avoided due to the potential severity of neurotoxicity to small doses. PMID:10390891

  18. Acute neurotoxicity associated with recreational use of methylmethaqualone confirmed by liquid chromatography tandem mass spectrometry.

    PubMed

    Ceschi, A; Giardelli, G; Müller, D M; Elavumkudy, S; Manini, A F; Rauber-Lüthy, C; Hofer, K E

    2013-01-01

    Methylmethaqualone is a sedative designer drug created by adding a methyl group to the 3-phenyl ring of methaqualone, and is at present not subject to restrictive regulation in many countries. To our knowledge, no case of methylmethaqualone abuse has been published to date in the scientific literature, and the only sources of information are users' reports on Web discussion forums and data from preclinical animal studies. We report a case of oral methylmethaqualone abuse confirmed by liquid chromatography tandem mass spectrometry in a 24-year-old previously healthy Caucasian male. Observed symptoms and signs such as central nervous system depression alternating with excitation, psychomotor agitation, muscle hyperactivity, and tachycardia were compatible with methaqualone-induced adverse effects. Except for the mild tachycardia (115 beats/min), other vital signs were normal: blood pressure 134/89 mmHg, body temperature 36.2°C (97.16°F), and peripheral oxygen saturation 99% while breathing room air. The ECG showed no prolongation of the QT interval and the QRS duration was normal. Laboratory analysis revealed a slight increase in creatine kinase (368 U/L) and alanine aminotransferase (90 U/L) serum concentrations. Blood alcohol concentration was 0.32 g/L. Methylmethaqualone was identified in a serum sample collected on admission which was analyzed by a liquid chromatography tandem mass spectrometry toxicological screening method using turbulent flow online extraction. After a few days the patient ingested the same amount of substance with identical symptoms. Based on the chemical structure and animal data, and according to this case report and users' Web reports, methylmethaqualone appears to have a similar acute toxicity profile to methaqualone, with marked psychomotor stimulation. Symptoms of acute toxicity can be expected to resolve with supportive care. PMID:23298217

  19. Effect of Gene-Mercury Interactions on Mercury Toxicokinetics and Neurotoxicity.

    PubMed

    Llop, Sabrina; Ballester, Ferran; Broberg, Karin

    2015-06-01

    Individuals differ in susceptibility to mercury neurotoxicity, in part, due to underlying genetic differences. This review aims to evaluate the state-of-the-art of the effect of (1) genetics on mercury toxicokinetics and (2) gene-mercury interactions on neurodevelopment and neurotoxicity. We conducted a PubMed search in September 2014 and retrieved 14 studies on the influence of genetics on mercury toxicokinetics and ten on neurological effects of gene-mercury interactions. Genes frequently studied for their influence on mercury toxicokinetics were mainly related to the metabolism of glutathione, but the results were contradictory for most of the genes. The gene-mercury interactions on child neurodevelopment and adult neurotoxicity reported were too few to draw any definite conclusion. So far, candidate gene approaches have not identified any major gene/s modifying the kinetics or toxicity of mercury, suggesting that these might be polygenic traits. More research is highly warranted to clarify if there are vulnerable subgroups to mercury neurotoxicity in humans. PMID:26231367

  20. The delayed neurotoxic effect of some organophosphorus compounds. Identification of the phosphorylation site as an esterase

    PubMed Central

    Johnson, M. K.

    1969-01-01

    1. Organophosphorus compounds that produce a delayed neurotoxic effect in hens phosphorylate a specific site in the brain soon after administration. 2. Phosphorylation of the specific site by di-isopropyl [32P]phosphorofluoridate in vitro is blocked by the prior addition of phenyl phenylacetate. 3. A small proportion of the total activity of hen brain hydrolysing phenyl phenylacetate in vitro was shown to be due to an enzyme different from two others previously described. 4. This enzyme is only slightly inhibited in vitro by concentrations of tetraethyl pyrophosphate and paraoxon (diethyl 4-nitrophenyl phosphate) up to 64μm and is completely inhibited by 6μm-di-isopropyl phosphorofluoridate and 128μm-mipafox. 5. It is also inhibited in vivo by effective doses of neurotoxic organophosphorus compounds but not by high doses of non-neurotoxic analogues. 6. It is deduced that the active site of this enzyme is the phosphorylation site associated with the genesis of delayed neurotoxicity. PMID:4310054

  1. Effects of chelators on mercury, iron, and lead neurotoxicity in cortical culture.

    PubMed

    Rush, Travis; Hjelmhaug, Julie; Lobner, Doug

    2009-01-01

    Chelation therapy for the treatment of acute, high dose exposure to heavy metals is accepted medical practice. However, a much wider use of metal chelators is by alternative health practitioners for so called "chelation therapy". Given this widespread and largely unregulated use of metal chelators it is important to understand the actions of these compounds. We tested the effects of four commonly used metal chelators, calcium disodium ethylenediaminetetraacetate (CaNa2EDTA), D-penicillamine (DPA), 2,3 dimercaptopropane-1-sulfonate (DMPS), and dimercaptosuccinic acid (DMSA) for their effects on heavy metal neurotoxicity in primary cortical cultures. We studied the toxicity of three forms of mercury, inorganic mercury (HgCl2), methyl mercury (MeHg), and ethyl mercury (thimerosal), as well as lead (PbCl2) and iron (Fe-citrate). DPA had the worst profile of effects, providing no protection while potentiating HgCl2, thimerosal, and Fe-citrate toxicity. DMPS and DMSA both attenuated HgCl2 toxicity and potentiated thimerosal and Fe toxicity, while DMPS also potentiated PbCl2 toxicity. CaNa2EDTA attenuated HgCl2 toxicity, but caused a severe potentiation of Fe-citrate toxicity. The ability of these chelators to attenuate the toxicity of various metals is quite restricted, and potentiation of toxicity is a serious concern. Specifically, protection is provided only against inorganic mercury, while it is lacking against the common form of mercury found in food, MeHg, and the form found in vaccines, thimerosal. The potentiation of Fe-citrate toxicity is of concern because of iron's role in oxidative stress in the body. Potentiation of iron toxicity could have serious health consequences when using chelation therapy. PMID:19027035

  2. Comparative non-cholinergic neurotoxic effects of paraoxon and diisopropyl fluorophosphate (DFP) on human neuroblastoma and astrocytoma cell lines

    SciTech Connect

    Qian Yongchang; Venkatraj, Jijayanagaram; Barhoumi, Rola; Pal, Ranadip; Datta, Aniruddha; Wild, James R.; Tiffany-Castiglioni, Evelyn . E-mail: ecastiglioni@cvm.tamu.edu

    2007-03-15

    The objective of this study was to evaluate the comparative non-cholinergic neurotoxic effects of paraoxon, which is acutely neurotoxic, and diisopropyl fluorophosphate (DFP), which induces OPIDN, in the human neuroblastoma SY5Y and the human astrocytoma cell line CCF-STTG1. SY5Y cells have been studied extensively as a model for OP-induced neurotoxicity, but CCF cells have not previously been studied. We conducted a preliminary human gene array assay of OP-treated SY5Y cells in order to assess at the gene level whether these cells can distinguish between OP compounds that do and do not cause OPIDN. Paraoxon and DFP induced dramatically different profiles of gene expression. Two genes were upregulated and 13 downregulated by at least 2-fold in paraoxon-treated cells. In contrast, one gene was upregulated by DFP and none was downregulated at the 2-fold threshold. This finding is consistent with current and previous observations that SY5Y cells can distinguish between OPs that do or do not induce OPIDN. We also examined gene array results for possible novel target proteins or metabolic pathways for OP neurotoxicity. Protein levels of glucose regulated protein 78 (GRP78) revealed that paraoxon exposure at 3 {mu}M for 24 h significantly reduced GRP78 levels by 30% in neuroblastoma cells, whereas DFP treatment had no effect. In comparison with SY5Y neuroblastoma cells, paraoxon and DFP (3 {mu}M for 24 h) each significantly increased GRP78 levels by 23-24% in CCF astrocytoma cells. As we have previously evaluated intracellular changes in Ca{sup 2+} levels in SY5Y cells, we investigated the effects of paraoxon and DFP on cellular Ca{sup 2+} homeostasis in CCF by studying cytosolic and mitochondrial basal calcium levels. A significant decrease in the ratio of mitochondrial to cytosolic Ca{sup 2+} fluorescence was detected in CCF cultures treated for either 1 or 3 days with 1, 3, 10, or 30 {mu}M paraoxon. In contrast, treatment with DFP for 1 day had no significant effect

  3. Protective effect of Bajijiasu against β-amyloid-induced neurotoxicity in PC12 cells.

    PubMed

    Chen, Di-Ling; Zhang, Peng; Lin, Li; Shuai, Ou; Zhang, He-Ming; Liu, Song-Hao; Wang, Jin-Yu

    2013-08-01

    Beta-amyloid peptide (Aβ), a major protein component of senile plaques associated with Alzheimer's disease (AD), is also directly neurotoxic. Mitigation of Aβ-induced neurotoxicity is thus a possible therapeutic approach to delay or prevent onset and progression of AD. This study evaluated the protective effect of Bajijiasu (β- D-fructofuranosyl (2-2) β- D-fructofuranosyl), a dimeric fructose isolated from the Chinese herb Radix Morinda officinalis, on Aβ-induced neurotoxicity in pheochromocytoma (PC12) cells. Bajijiasu alone had no endogenous neurotoxicity up to 200 μM. Brief pretreatment with 10-40 μM Bajijiasu (2 h) significantly reversed the reduction in cell viability induced by subsequent 24 h exposure to Aβ25-35 (21 μM) as measured by MTT and LDH assays, and reduced Aβ25-35-induced apoptosis as indicated by reduced annexin V-EGFP staining. Bajijiasu also decreased the accumulation of intracellular reactive oxygen species and the lipid peroxidation product malondialdehyde in PC12 cells, upregulated expression of glutathione reductase and superoxide dismutase, prevented depolarization of the mitochondrial membrane potential (Ψm), and blocked Aβ25-35-induced increases in [Ca(2+)] i . Furthermore, Bajijiasu reversed Aβ25-35-induced changes in the expression levels of p21, CDK4, E2F1, Bax, NF-κB p65, and caspase-3. Bajijiasu is neuroprotective against Aβ25-35-induced neurotoxicity in PC12 cells, likely by protecting against oxidative stress and ensuing apoptosis. PMID:23812758

  4. Neurotoxicity following acute inhalation exposure to the oil dispersant COREXIT EC9500A.

    PubMed

    Sriram, Krishnan; Lin, Gary X; Jefferson, Amy M; Goldsmith, William T; Jackson, Mark; McKinney, Walter; Frazer, David G; Robinson, Victor A; Castranova, Vincent

    2011-01-01

    Consequent to the 2010 Deepwater Horizon oil spill in the Gulf of Mexico, there is an emergent concern about the short- and long-term adverse health effects of exposure to crude oil, weathered-oil products, and oil dispersants among the workforce employed to contain and clean up the spill. Oil dispersants typically comprise of a mixture of solvents and surfactants that break down floating oil to micrometer-sized droplets within the water column, thus preventing it from reaching the shorelines. As dispersants are generally sprayed from the air, workers are at risk for exposure primarily via inhalation. Such inhaled fractions might potentially permeate or translocate to the brain via olfactory or systemic circulation, producing central nervous system (CNS) abnormalities. To determine whether oil dispersants pose a neurological risk, male Sprague-Dawley rats were exposed by whole-body inhalation exposure to a model oil dispersant, COREXIT EC9500A (CE; approximately 27 mg/m(3) × 5 h/d × 1 d), and various molecular indices of neural dysfunction were evaluated in discrete brain areas, at 1 or 7 d postexposure. Exposure to CE produced partial loss of olfactory marker protein in the olfactory bulb. CE also reduced tyrosine hydroxylase protein content in the striatum. Further, CE altered the levels of various synaptic and neuronal intermediate filament proteins in specific brain areas. Reactive astrogliosis, as evidenced by increased expression of glial fibrillary acidic protein, was observed in the hippocampus and frontal cortex following exposure to CE. Collectively, these findings are suggestive of disruptions in olfactory signal transduction, axonal function, and synaptic vesicle fusion, events that potentially result in an imbalance in neurotransmitter signaling. Whether such acute molecular aberrations might persist and produce chronic neurological deficits remains to be ascertained. PMID:21916746

  5. NEUROTOXICITY FOLLOWING ACUTE INHALATION EXPOSURE TO THE OIL DISPERSANT COREXIT EC9500A

    PubMed Central

    Sriram, Krishnan; Lin, Gary X.; Jefferson, Amy M.; Goldsmith, William T.; Jackson, Mark; McKinney, Walter; Frazer, David G.; Robinson, Victor A.; Castranova, Vincent

    2015-01-01

    Consequent to the 2010 Deepwater Horizon oil spill in the Gulf of Mexico, there is an emergent concern about the short- and long-term adverse health effects of exposure to crude oil, weathered-oil products, and oil dispersants among the workforce employed to contain and clean up the spill. Oil dispersants typically comprise of a mixture of solvents and surfactants that break down floating oil to micrometer-sized droplets within the water column, thus preventing it from reaching the shorelines. As dispersants are generally sprayed from the air, workers are at risk for exposure primarily via inhalation. Such inhaled fractions might potentially permeate or translocate to the brain via olfactory or systemic circulation, producing central nervous system (CNS) abnormalities. To determine whether oil dispersants pose a neurological risk, male Sprague-Dawley rats were exposed by whole-body inhalation exposure to a model oil dispersant, COREXIT EC9500A (CE; approximately 27 mg/m3 × 5 h/d × 1 d), and various molecular indices of neural dysfunction were evaluated in discrete brain areas, at 1 or 7 d postexposure. Exposure to CE produced partial loss of olfactory marker protein in the olfactory bulb. CE also reduced tyrosine hydroxylase protein content in the striatum. Further, CE altered the levels of various synaptic and neuronal intermediate filament proteins in specific brain areas. Reactive astrogliosis, as evidenced by increased expression of glial fibrillary acidic protein, was observed in the hippocampus and frontal cortex following exposure to CE. Collectively, these findings are suggestive of disruptions in olfactory signal transduction, axonal function, and synaptic vesicle fusion, events that potentially result in an imbalance in neurotransmitter signaling. Whether such acute molecular aberrations might persist and produce chronic neurological deficits remains to be ascertained. PMID:21916746

  6. Neurotoxic and cytotoxic effects of venom from different populations of the Egyptian Scorpio maurus palmatus.

    PubMed

    Abdel-Rahman, Mohamed A; Omran, Mohamed Alaa A; Abdel-Nabi, Ismail M; Nassier, Omimah A; Schemerhorn, Brandon J

    2010-01-01

    Neurotoxic and cytotoxic effects of venoms from Scorpio maurus palmatus taken from different populations were assessed for geographic based variability in toxicity, and to evaluate their insecticidal potency. Scorpions were collected from four regions. Three locations were mutually isolated pockets in the arid area of Southern Sinai. The fourth sample was collected from a population inhabiting the semi-arid environment of Western Mediterranean Coastal Desert. The neurotoxic (paralytic) effect of the venom from each population was assayed by its ability to induce permanent disability in adult cockroaches within 3h. Venom was applied using microinjection techniques through an intersegmental membrane. Probit analysis was used to calculate the Paralytic Effective Dose (PED(50), ng/100mg). Levels of glutathione, lipid peroxidation, protein carbonyl content and nitric oxide, as well as the activities of superoxide dismutase, catalase and cholinesterase, were measured to assess the cytotoxicity of the venom. The results show that the injected venom from each population induced obvious spasticity, followed by flaccid paralysis. All the tested biochemical parameters, except glutathione content, revealed significant differences in toxicity in venom taken from the different scorpion populations. We conclude that (i) the venom of this scorpion has significant neurotoxic and cytotoxic effects on insect cells, (ii) its efficacy, as assessed by the PED(50) unit, exhibited variation across its geographic range, and (iii) components in the venom may have the potential for being developed into effective and environmentally friendly bioinsecticides. PMID:19682484

  7. Acute ammonia neurotoxicity in vivo involves increase in cytoplasmic protein P53 without alterations in other markers of apoptosis.

    PubMed

    Kosenko, Elena; Kaminsky, Yuri; Solomadin, Ilia; Marov, Nikolay; Venediktova, Natalia; Felipo, Vicente; Montoliu, Carmina

    2007-08-15

    Acute intoxication with large ammonia doses leads to activation of NMDA receptors in the brain, resulting in oxidative stress and disturbance of mitochondrial function. Altered mitochondrial function is a crucial step in some mechanisms of cellular apoptosis. This study assesses whether ammonia intoxication in vivo leads to induction of apoptotic markers such as permeability transition pore (PTP) formation, caspase-3, and caspase-9 activation, changes in p53 protein, or cytochrome c release. Acute ammonia intoxication did not affect caspase-9 or caspase-3 activities. The mitochondrial membrane potential also remained unaltered in non-synaptic brain mitochondria after injection of ammonia, indicating that ammonia did not induce PTP formation in brain in vivo. The nuclear level of p53 did not change, whereas its cytoplasmic level increased approximately two-fold. In agreement with the theory that translocation of the p53 from cytosol to nuclei is an essential step for induction of apoptosis we did not find apoptotic nuclei in brain of rats injected with ammonia. This supports the idea that ammonia neurotoxicity does not involve apoptosis and points to impaired p53 transfer from cytoplasm to nuclei as a possible preventer of apoptosis. We did not find any release of cytochrome c from mitochondria to cytosol after ammonia injection. Cytochrome c content was significantly reduced (30%) in brain mitochondria from rats injected with ammonia. This decrease may contribute to the reduced state 3 respiration, decreased respiratory control index, and disturbances in the mitochondrial electron transport chain in brain mitochondria from rats injected with ammonia. PMID:17551980

  8. Brain Function in Young Patients Receiving Methotrexate for Acute Lymphoblastic Leukemia

    ClinicalTrials.gov

    2016-04-08

    Childhood B Acute Lymphoblastic Leukemia; Childhood T Acute Lymphoblastic Leukemia; Cognitive Side Effects of Cancer Therapy; Long-Term Effects Secondary to Cancer Therapy in Children; Neurotoxicity Syndrome; Psychological Impact of Cancer; Untreated Childhood Acute Lymphoblastic Leukemia

  9. Protective effects of ginsenoside Rg2 against glutamate-induced neurotoxicity in PC12 cells.

    PubMed

    Li, Na; Liu, Bin; Dluzen, Dean E; Jin, Yi

    2007-05-22

    We investigated the effect of ginsenoside Rg2 on neurotoxic activities induced by glutamate in PC12 cells. The cells were incubated with glutamate (1 mmol/L), glutamate and ginsenoside Rg2 (0.05, 0.1, 0.2 mmol/L) or nimodipine (5 micromol/L) for 24 h. The cellular viability was assessed by MTT assay. The lipid peroxidation products malondialdehyde (MDA) and nitrogen oxide (NO) were measured by a spectrophotometric method. Fura-2/AM, as a cell permeable fluorescent probe for Ca2+, was used to detect intracellular Ca2+ concentration ([Ca2+]i) using a monespectrofluorometer. Immunocytochemical techniques were employed to check the protein expression levels of calpain II, caspase-3 and beta-amyloid (Abeta)1-40 in PC12 cells. The results showed that glutamate decreased the cell viability, increased [Ca2+]i, lipid peroxidation (the excessive production of MDA, NO) and the protein expression levels of calpain II, caspase-3 and Abeta1-40 in PC12 cells. Ginsenoside Rg2 significantly attenuated glutamate-induced neurotoxic effects upon these parameters at all doses tested. Our study suggests that ginsenoside Rg2 has a neuroprotective effect against glutamate-induced neurotoxicity through mechanisms related to anti-oxidation and anti-apoptosis. In addition, the inhibitory effect of ginsenoside Rg2 against the formation of Abeta1-40 suggests that ginsenoside Rg2 may also represent a potential treatment strategy for Alzheimer's disease. PMID:17257792

  10. Effect of repeated ('binge') dosing of MDMA to rats housed at normal and high temperature on neurotoxic damage to cerebral 5-HT and dopamine neurones.

    PubMed

    Sanchez, Veronica; O'shea, Esther; Saadat, Kathryn S; Elliott, J Martin; Colado, M Isabel; Green, A Richard

    2004-09-01

    The technique of 'binge' dosing (several doses in one session) by recreational users of 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) requires evaluation in terms of its consequences on the acute hyperthermic response and long-term neurotoxicity. We examined the neurotoxic effects of this dosing schedule on 5-HT and dopamine neurones in the rat brain. When repeated (three) doses of MDMA (2, 4 and 6 mg/kg i.p.) were given 3 h apart to rats housed at 19 degrees C, a dose-dependent acute hyperthermia and long-term loss of 5-HT was observed in several brain regions (hippocampus, cortex and striatum), with an approximate 50% loss following 3 x 4 mg/kg and 65% decrease following 3 x 6 mg/kg. No decrease in striatal dopamine content was detected. When MDMA (4 mg/kg i.p.) was given repeatedly to rats housed at 30 degrees C, a larger acute hyperthermic response than that observed in rats treated at 19 degrees C environment was seen (maximum response 2.6 +/- 0.1 degrees C versus 1.3 +/- 0.2 degrees C). A long-term cerebral 5-HT loss of approximately 65% was also detected in both the cortex and hippocampus, but no loss in striatal dopamine content occurred. These data emphasize the increased acute hyperthermic response and neurotoxicity which occurs when MDMA is administered in a hot room environment compared to normal room temperature conditions, and support the view that MDMA is a selective 5-HT neurotoxin, even when a binge dosing schedule is employed and the rats are present in a hot environment. PMID:15358986

  11. The Protective Effects of Nigella sativa and Its Constituents on Induced Neurotoxicity.

    PubMed

    Khazdair, Mohammad Reza

    2015-01-01

    Nigella sativa (N. sativa) is an annual plant and widely used as medicinal plant throughout the world. The seeds of the plant have been used traditionally in various disorders and as a spice to ranges of Persian foods. N. sativa has therapeutic effects on tracheal responsiveness (TR) and lung inflammation on induced toxicity by Sulfur mustard. N. sativa has been widely used in treatment of various nervous system disorders such as Alzheimer disease, epilepsy, and neurotoxicity. Most of the therapeutic properties of this plant are due to the presence of some phenolic compounds especially thymoquinone (TQ), which is major bioactive component of the essential oil. The present review is an effort to provide a comprehensive study of the literature on scientific researches of pharmacological activities of the seeds of this plant on induced neurotoxicity. PMID:26604923

  12. The Protective Effects of Nigella sativa and Its Constituents on Induced Neurotoxicity

    PubMed Central

    Khazdair, Mohammad Reza

    2015-01-01

    Nigella sativa (N. sativa) is an annual plant and widely used as medicinal plant throughout the world. The seeds of the plant have been used traditionally in various disorders and as a spice to ranges of Persian foods. N. sativa has therapeutic effects on tracheal responsiveness (TR) and lung inflammation on induced toxicity by Sulfur mustard. N. sativa has been widely used in treatment of various nervous system disorders such as Alzheimer disease, epilepsy, and neurotoxicity. Most of the therapeutic properties of this plant are due to the presence of some phenolic compounds especially thymoquinone (TQ), which is major bioactive component of the essential oil. The present review is an effort to provide a comprehensive study of the literature on scientific researches of pharmacological activities of the seeds of this plant on induced neurotoxicity. PMID:26604923

  13. Amphetamine- and methamphetamine-induced hyperthermia: Implications of the effects produced in brain vasculature and peripheral organs to forebrain neurotoxicity

    PubMed Central

    Bowyer, John F; Hanig, Joseph P

    2014-01-01

    The adverse effects of amphetamine- (AMPH) and methamphetamine- (METH) induced hyperthermia on vasculature, peripheral organs and peripheral immune system are discussed. Hyperthermia alone does not produce amphetamine-like neurotoxicity but AMPH and METH exposures that do not produce hyperthermia (≥40°C) are minimally neurotoxic. Hyperthermia likely enhances AMPH and METH neurotoxicity directly through disruption of protein function, ion channels and enhanced ROS production. Forebrain neurotoxicity can also be indirectly influenced through the effects of AMPH- and METH- induced hyperthermia on vasculature. The hyperthermia and the hypertension produced by high doses amphetamines are a primary cause of transient breakdowns in the blood-brain barrier (BBB) resulting in concomitant regional neurodegeneration and neuroinflammation in laboratory animals. This BBB breakdown can occur in the amygdala, thalamus, striatum, sensory and motor cortex and hippocampus. Under these conditions, repetitive seizures greatly enhance neurodegeneration in hippocampus, thalamus and amygdala. Even when the BBB is less disrupted, AMPH- or METH- induced hyperthermia effects on brain vasculature may play a role in neurotoxicity. In this case, striatal and cortical vascular function are adversely affected, and even greater ROS, immune and damage responses are seen in the meninges and cortical surface vasculature. Finally, muscle and liver damage and elevated cytokines in blood can result when amphetamines produce hyperthermia. Proteins, from damaged muscle may activate the peripheral immune system and exacerbate liver damage. Liver damage can further increase cytokine levels, immune system activation and increase ammonia levels. These effects could potentially enhance vascular damage and neurotoxicity.

  14. Combination Chemotherapy in Treating Young Patients With Newly Diagnosed High-Risk Acute Lymphoblastic Leukemia

    ClinicalTrials.gov

    2016-08-23

    B Acute Lymphoblastic Leukemia; Bone Necrosis; Central Nervous System Leukemia; Cognitive Side Effects of Cancer Therapy; Neurotoxicity Syndrome; Pain; Testicular Leukemia; Therapy-Related Toxicity; Untreated Adult Acute Lymphoblastic Leukemia; Untreated Childhood Acute Lymphoblastic Leukemia

  15. NEUROTOXICITY STUDIES

    EPA Science Inventory

    The neurotoxicity of DBPs in general has not been well characterized. The literature provides reports of neurotoxicity of DCA following exposures to relatively high doses. Studies completed at EPA, however, have shown that relatively low doses of DCA (as low as 16 mg/kg/day; simi...

  16. ELECTROPHYSIOLOGICAL DETECTION OF SUBLETHAL NEUROTOXIC EFFECTS IN INTACT EARTHWORMS

    EPA Science Inventory

    The nervous system of earthworms is a logical site for studying the deleterious effects of many toxic substances because neural functions are often more sensitive to disruption than other physiological processes. However, the sublethal effects of toxicants on neural and behaviora...

  17. Neurotoxicity in Snakebite—The Limits of Our Knowledge

    PubMed Central

    Ranawaka, Udaya K.; Lalloo, David G.; de Silva, H. Janaka

    2013-01-01

    Snakebite is classified by the WHO as a neglected tropical disease. Envenoming is a significant public health problem in tropical and subtropical regions. Neurotoxicity is a key feature of some envenomings, and there are many unanswered questions regarding this manifestation. Acute neuromuscular weakness with respiratory involvement is the most clinically important neurotoxic effect. Data is limited on the many other acute neurotoxic manifestations, and especially delayed neurotoxicity. Symptom evolution and recovery, patterns of weakness, respiratory involvement, and response to antivenom and acetyl cholinesterase inhibitors are variable, and seem to depend on the snake species, type of neurotoxicity, and geographical variations. Recent data have challenged the traditional concepts of neurotoxicity in snake envenoming, and highlight the rich diversity of snake neurotoxins. A uniform system of classification of the pattern of neuromuscular weakness and models for predicting type of toxicity and development of respiratory weakness are still lacking, and would greatly aid clinical decision making and future research. This review attempts to update the reader on the current state of knowledge regarding this important issue. PMID:24130909

  18. Neurotoxic effects of AZT on developing and adult neurogenesis

    PubMed Central

    Demir, Meryem; Laywell, Eric D.

    2015-01-01

    Azidothymidine (AZT) is a synthetic, chain-terminating nucleoside analog used to treat HIV-1 infection. While AZT is not actively transported across the blood brain barrier, it does accumulate at high levels in cerebrospinal fluid, and subsequently diffuses into the overlying parenchyma. Due to the close anatomical proximity of the neurogenic niches to the ventricular system, we hypothesize that diffusion from CSF exposes neural stem/progenitor cells and their progeny to biologically relevant levels of AZT sufficient to perturb normal cell functions. We employed in vitro and in vivo models of mouse neurogenesis in order to assess the effects of AZT on developing and adult neurogenesis. Using in vitro assays we show that AZT reduces the population expansion potential of neural stem/progenitor cells by inducing senescence. Additionally, in a model of in vitro neurogenesis AZT severely attenuates neuroblast production. These effects are mirrored in vivo by clinically-relevant animal models. We show that in utero AZT exposure perturbs both population expansion and neurogenesis among neural stem/progenitor cells. Additionally, a short-term AZT regimen in adult mice suppresses subependymal zone neurogenesis. These data reveal novel negative effects of AZT on neural stem cell biology. Given that the sequelae of HIV infection often include neurologic deficits—subsumed under AIDS Dementia Complex (Brew, 1999)—it is important to determine to what extent AZT negatively affects neurological function in ways that contribute to, or exacerbate, ADC in order to avoid attributing iatrogenic drug effects to the underlying disease process, and thereby skewing the risk/benefit analysis of AZT therapy. PMID:25852464

  19. Effective suppression of acrylamide neurotoxicity by lithium in mouse.

    PubMed

    Song, Lingzhen; Wang, Jiutao; Zhang, Wei; Yan, Runchuan; Hu, Xinde; Chen, Shulin; Zhao, Shanting

    2014-11-01

    The primary objective of this investigation was to assess the neuroprotective efficacy of lithium in an acrylamide (ACR)-induced neuropathy model in mice. In this study, Kunming male mice were administered ACR (25 mg/kg bw, i.p. once a day) with or without lithium (25 mg/kg bw, i.p. once a day) for 2 weeks. All ACR-administered mice exhibited severe symptoms of neuropathy. We found that treatment with lithium effectively alleviated behavioral deficits in animals elicited by acrylamide. Interestingly, the reduction of hippocampal neurogenesis resulting from ACR injection was promoted by administration of lithium. Further, lithium treatment significantly offset ACR-induced depletion in p-GSK-3β (Ser9) levels in hippocampus. Collectively our findings suggest the propensity of lithium to attenuate ACR-induced neuropathy. Further studies are necessary to understand the precise molecular mechanism by which the lithium attenuates neuropathy. Nevertheless, our data clearly demonstrate the beneficial effects of lithium on ACR-induced neuropathy in mice and suggest its possible therapeutic application as an adjuvant in the management of other forms of neuropathy in humans. PMID:25146901

  20. Neurotoxic effects of solvent exposure on sewage treatment workers

    SciTech Connect

    Kraut, A.; Lilis, R.; Marcus, M.; Valciukas, J.A.; Wolff, M.S.; Landrigan, P.J.

    1988-07-01

    Nineteen Sewage Treatment Workers (STWs) exposed to industrial sewage that contained benzene, toluene, and other organic solvents at a primary sewage treatment plant in New York City (Plant A) were examined for evidence of solvent toxicity. Fourteen (74%) complained of central nervous system (CNS) symptoms consistent with solvent exposure, including lightheadedness, fatigue, increased sleep requirement, and headache. The majority of these symptoms resolved with transfer from the plant. Men working less than 1 yr at Plant A were more likely to complain of two or more CNS symptoms than men who were working there longer than 1 yr (p = .055). Objective abnormalities in neurobehavioral testing were found in all 4 men working longer than 9 yr at this plant, but in only 5 of 15 employed there for a shorter period (p = .03). These results are consistent with the known effects of solvent exposure. Occupational health personnel must be aware that STWs can be exposed to solvents and other industrial wastes.

  1. Cyclooxygenase-independent neuroprotective effects of aspirin against dopamine quinone-induced neurotoxicity.

    PubMed

    Asanuma, Masato; Miyazaki, Ikuko; Kikkawa, Yuri; Kimoto, Naotaka; Takeshima, Mika; Murakami, Shinki; Miyoshi, Ko

    2012-09-01

    Prostaglandin H synthase exerts not only cyclooxygenase activity but also peroxidase activity. The latter activity of the enzyme is thought to couple with oxidation of dopamine to dopamine quinone. Therefore, it has been proposed that cyclooxygenase inhibitors could suppress dopamine quinone formation. In the present study, we examined effects of various cyclooxygenase inhibitors against excess methyl L-3,4-dihydroxyphenylalanine (L-DOPA)-induced quinoprotein (protein-bound quinone) formation and neurotoxicity using dopaminergic CATH.a cells. The treatment with aspirin inhibited excess methyl L-DOPA-induced quinoprotein formation and cell death. However, acetaminophen did not show protective effects, and indomethacin and meloxicam rather aggravated these methyl L-DOPA-induced changes. Aspirin and indomethacin did not affect the level of glutathione that exerts quenching dopamine quinone in dopaminergic cells. In contrast with inhibiting effects of higher dose in the previous reports, relatively lower dose of aspirin that affected methyl L-DOPA-induced quinoprotein formation and cell death failed to prevent cyclooxygenase-induced dopamine chrome generation in cell-free system. Furthermore, aspirin but not acetaminophen or meloxicam showed direct dopamine quinone-scavenging effects in dopamine-semiquinone generating systems. The present results suggest that cyclooxygenase shows little contribution to dopamine oxidation in dopaminergic cells and that protective effects of aspirin against methyl L-DOPA-induced dopamine quinone neurotoxicity are based on its cyclooxygenase-independent property. PMID:22674083

  2. In vitro neurotoxic effects of 1 GeV/n iron particles assessed in retinal explants.

    PubMed

    Vazquez, M E; Kirk, E

    2000-01-01

    The heavy ion component of the cosmic radiation remains problematic to the assessment of risk in manned space flight. The biological effectiveness of HZE particles has yet to be established, particularly with regard to nervous tissue. Using heavy ions accelerated at the AGS of Brookhaven National Laboratory, we study the neurotoxic effects of iron particles. We exposed retinal explants, taken from chick embryos, to determine the dose response relationships for neurite outgrowth. Morphometric techniques were used to evaluate the in vitro effects of 1 GeV/a iron particles (LET 148 keV/micrometer). Iron particles produced a dose-dependent reduction of neurite outgrowth with a maximal effect achieved with a dose of 100 cGy. Doses as low as 10-50 cGy were able to induce reductions of the neurite outgrowth as compared to the control group. Neurite generation is a more sensitive parameter than neurite elongation, suggesting different mechanism of radiation damage in our model. These results showed that low doses/fluences of iron particles could impair the retinal ganglion cells' capacity to generate neurites indicating the highly neurotoxic capability of this heavy charged particle. PMID:11542855

  3. Inhibitory effects of pain relief drugs on neurological enzymes: implications on their potential neurotoxicity to aquatic animals.

    PubMed

    Wu, Jui-Pin; Li, Mei-Hui

    2015-03-01

    Pain relief medications commonly occur in the aquatic environment at measurable levels. While the neurotoxicity of pain relievers to higher vertebrates is currently known, little is known about their effects on aquatic animals. This study investigated the neurotoxicity of pain relievers to aquatic animals. We used three neurological enzymes, cholinesterase (ChE), adenosine triphosphatase (ATPase), and monoamine oxidase (MAO), from a freshwater planarian (Dugesia japonica) and green neon shrimp (Neocaridina denticulata) as biomarkers to examine the effects of pain relievers on in vitro activity. The activity of MAO and ChE, but not ATPase, was significantly inhibited by acetaminophen, but not by other pain relievers examined. It was likely that the inhibitory effects of acetaminophen on shrimp neurological enzymes were more severe than on the planarian. These findings suggest that acetaminophen is potentially neurotoxic to aquatic animals, at least in terms of neurotransmission disturbance. PMID:25801321

  4. Quantification of neurotoxic effects on individual neuron cells using optical diffraction tomography (Conference Presentation)

    NASA Astrophysics Data System (ADS)

    Yoon, Jonghee; Yang, Su-a.; Kim, Kyoohyun; Park, YongKeun

    2016-03-01

    Parkinson's disease (PD) is a common neurodegenerative disease that causes symptoms of postural instability and slowness of movement. Neurodegeneration in dopaminergic neurons at the substantia nigra has been reported as pathologic features, however, detailed mechanisms underlying neurodegeneration are still remain unclear. To investigate a neurodegenerative process, various imaging tools including phase contrast microscopy, electron microscopy, and fluorescence microscopy are utilized. However, these imaging methods provide qualitative information and require invasive approaches such as the use of fluorescence agents or chemical fixation procedures that disturb normal physiological conditions of neuron cells. In order to quantify the neurodegenerative process in a non-invasive manner, we exploited optical diffraction tomography (ODT). ODT is a 3D quantitative phase imaging method that measures 3D refractive index (RI) distributions of a sample which provide quantitative structural (volume, surface area, sphericity) and biochemical (protein concentration, total cellular dry mass) information. We investigated neurotoxic effects of MPP+ on SH-SY5Y cells by using quantitative information obtained from 3D RI distributions. We also performed temporal measurements of 3D RI distributions of an individual SH-SY5Y cell to analyze neurotoxic effects on intracellular vesicle dynamics.

  5. Neurotoxic effects induced by endosulfan exposure during pregnancy and lactation in female and male rat striatum.

    PubMed

    Lafuente, Anunciación; Pereiro, Natividad

    2013-09-01

    Possible neurotoxic effects induced by endosulfan exposure during pregnancy and lactation in striatum of Sprague-Dawley female and male offspring rats have been evaluated. Dams were treated orally with 0.61 or 6.12mg of endosulfan/kg/day from the beginning of gestation until weaning. At postnatal day 60 offspring were sacrificed. We studied variations of norepinephrine, dopamine and serotonin content in striatum by High Performance Liquid Chromatography (HPLC) in these animals. Dopamine and serotonin metabolism was also determined. Endosulfan inhibits the striatal aminergic systems in adult male rats by decreasing norepinephrine and serotonin concentration and dopamine and serotonin metabolism. However, in adult female rats, only a diminution of norepinephrine content and an increase of dopamine and serotonin content were observed after endosulfan administration at the dose of 6.12mg/kg/day, whereas the concentration and the metabolism of these biogenic amines were not with the dose of 0.61mg/kg/day. Gender differences emerge in the striatal aminergic system susceptibility to endosulfan exposure during the early life stages, being the neurotoxic effects of this organochlorine insecticide higher in male than in female rats. PMID:23702353

  6. Protective effects of pinostrobin on β-amyloid-induced neurotoxicity in PC12 cells.

    PubMed

    Xian, Yan-Fang; Ip, Siu-Po; Lin, Zhi-Xiu; Mao, Qing-Qiu; Su, Zi-Ren; Lai, Xiao-Ping

    2012-11-01

    Beta-Amyloid peptide (Aβ), a major protein component of brain senile plaques in Alzheimer's disease (AD), has been considered as a critical cause in the pathogenesis of AD. Pinostrobin, a potent flavonoid inducer, is the major and most active ingredient of Folium cajani. The present study aimed to investigate whether pinostrobin could provide protective effect against Aβ(25-35)-induced neurotoxicity in cultured rat pheochromocytoma (PC12) cells. The PC12 cells were pretreated with different concentrations of pinostrobin for 2 h, followed by the challenge with 20 μM Aβ(25-35) for 24 h. The results showed that pretreatment with pinostrobin significantly elevated cell viability, decreased the lactate dehydrogenase activity, the levels of intracellular reactive oxygen species and calcium, and mitochondrial membrane potential in Aβ(25-35)-treated PC12 cells. In addition, pinostrobin significantly suppressed the formation of DNA fragmentation and increased the ratio of Bcl-2/Bax. These results indicate that pinostrobin was able to exert a neuroprotective effect against Aβ(25-35)-induced neurotoxicity in PC12 cells, at least in part, via inhibiting oxidative damage and calcium overload, as well as suppressing the mitochondrial pathway of cellular apoptosis. PMID:22565301

  7. Protective effect of arctigenin against MPP+ and MPTP-induced neurotoxicity.

    PubMed

    Li, Dongwei; Liu, Qingping; Jia, Dong; Dou, Deqiang; Wang, Xiaofei; Kang, Tingguo

    2014-01-01

    The potential protective effects of arctigenin on 1-methyl-4-phenylpyridinium ion and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyride-induced neurotoxicity were examined, and the results indicated that arctigenin could improve the movement behaviors and upregulate dopamine and γ-aminobutyric acid levels in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyride-induced neurotoxicity mouse model. A further in vitro experiment showed that the pretreatment with arctigenin on cultured human neuroblastoma SH-SY5Y cells could obviously attenuate the decrease of cell survival rates caused by treatment with 1-methyl-4-phenylpyridinium ion by way of acting against cell apoptosis through the decrease of Bax/Bcl-2 and caspase-3, and by antioxidative action through reduction of the surplus reactive oxygen species production and downregulation of mitochondrial membrane potential. It is for the first time that a neuroprotective activity of arctigenin in both in vitro and in vivo experiments was reported, enlightening that arctigenin could be useful as a potential therapeutic agent for Parkinson's disease. PMID:24414307

  8. Neurotoxic effects of bisphenol AF on calcium-induced ROS and MAPKs.

    PubMed

    Lee, Soyoung; Kim, Yoo Kyeong; Shin, Tae-Yong; Kim, Sang-Hyun

    2013-04-01

    Bisphenol AF (BPAF), a newly introduced chemical structurally related to bisphenol A, is used extensively in fluoroelastomers and polyesters, and has been known to induce estrogen-dependent responses. However, the toxicity of BPAF is largely unknown except for its endocrine-related effects. In this study, we investigated the neurotoxicity of BPAF and underlying mechanisms of action using hippocampal cell line (HT-22) and mouse primary neuronal cells. We found that BPAF induced apoptosis in both HT-22 and primary neuronal cells. In order to clarify the underlying mechanisms of BPAF-induced apoptosis, various signaling molecules were evaluated. BPAF increased the level of intracellular calcium, followed by the generation of reactive oxygen species (ROS). BPAF upregulated the phosphorylation of mitogen-activated protein kinase: extracellular signal-regulated kinase, p38 and c-Jun N-terminal kinase (JNK), and nuclear translocation of nuclear factor-κB. Using specific inhibitors, we confirmed that calcium, ROS, p38, and JNK mediated the BPAF-induced apoptosis. In addition, BPAF inhibited microglial activation in a microglia/neuroblastoma coculture model by the reduction of nitric oxide production. We found that BPAF interrupted the normal physiologic functions of microglia at non-toxic levels. Taken together, our results suggest that BPAF, the substitute of BPA, also have neurotoxic properties. PMID:22996013

  9. Combination Chemotherapy in Treating Young Patients With Newly Diagnosed High-Risk B Acute Lymphoblastic Leukemia and Ph-Like TKI Sensitive Mutations

    ClinicalTrials.gov

    2016-09-14

    B Acute Lymphoblastic Leukemia; Bone Necrosis; Central Nervous System Leukemia; Cognitive Side Effects of Cancer Therapy; Neurotoxicity Syndrome; Pain; Testicular Leukemia; Therapy-Related Toxicity; Untreated Adult Acute Lymphoblastic Leukemia; Untreated Childhood Acute Lymphoblastic Leukemia

  10. Evaluating the human-health effects of hazardous wastes: Reproduction and development, neurotoxicity, genetic toxicity, and cancer

    SciTech Connect

    Dyer, R.S.; Houk, V.S.; Reiter, L.W.

    1991-01-01

    Several approaches are available for characterizing potential toxicity of wastes. The paper describes biological tests which are appropriate for identifying waste as neurotoxic, genotoxic, or likely to produce developmental or reproductive effects. The tests recommended are, for neurotoxicity a functional observational battery, coupled with a measure of motor (bodily movement) activity; for genetic toxicity, the 'Ames' test of mutagenicity in Salmonella and a test of clastogenicity (DNA damage); and for developmental and reproductive toxicity, the Chernoff-Kavlock assay and a multigenerational reproductive assay. In addition, the paper identifies several generic factors which must be considered in performing any evaluations of hazardous wastes.

  11. EVALUATION OF HUMAN NEURAL PROGENITOR CELLS FOR DEVELOPMENTAL NEUROTOXICITY SCREENING: TIME COURSE OF EFFECTS ON CELL PROLIFERATION AND VIABILITY.

    EPA Science Inventory

    Current testing methods for developmental neurotoxicity (DNT) make evaluation of the effects of large numbers of chemicals impractical and prohibitively expensive. As such, we are evaluating human neural progenitor cells (NPCs) as a screen for DNT. ReNcell CX (ReN CX) cells are a...

  12. A developmental neurotoxicity evaluation of the effects of prenatal exposure to fluoxetine in rats.

    PubMed

    Vorhees, C V; Acuff-Smith, K D; Schilling, M A; Fisher, J E; Moran, M S; Buelke-Sam, J

    1994-08-01

    Fluoxetine is a widely used serotonin reuptake inhibitor effective in the treatment of depression. This experiment assessed the potential developmental neurotoxicity of fluoxetine. Sprague-Dawley CD rats were treated once per day on Days 7-20 of gestation with 0, 1, 5, or 12 mg/kg of fluoxetine (free base) dissolved in distilled water. One control group received water by gavage; animals in this group were provided food and water ad libitum. The second control group (PF) also received water by gavage; animals in this group had their food and water restricted by pair-feeding and watering them to the 12 mg/kg fluoxetine group. Litters were culled to 12 after birth and offspring (male/female pairs) were tested neurobehaviorally at three developmental stages (preweaning, juvenile, and adult). At each stage, two pairs per litter received tests of locomotor activity, acoustic startle, and startle after administration of one of two pharmacological challenges (one pair each receiving fluoxetine or apomorphine). Two pairs were also tested for spontaneous alternation, passive avoidance, and complex learning in a water maze. At the highest dose, fluoxetine caused maternal weight loss during pregnancy, reduced litter sizes at birth, and increased neonatal mortality. No effects on long-term growth or survival were seen. Prenatal fluoxetine exposure produced no significant effects on locomotor activity, spontaneous alternation, passive avoidance, or water maze performance. A few scattered interactions involving treatment group were obtained on startle, but no pattern of treatment-related changes was evident. Regional wet and dry brain weights taken at each stage were not affected by prenatal fluoxetine exposure. The data suggest that fluoxetine is not developmentally neurotoxic in the rat. PMID:7982528

  13. Maternal milk as methylmercury source for suckling mice: neurotoxic effects involved with the cerebellar glutamatergic system.

    PubMed

    Manfroi, C B; Schwalm, F D; Cereser, V; Abreu, F; Oliveira, A; Bizarro, L; Rocha, J B T; Frizzo, M E S; Souza, D O; Farina, M

    2004-09-01

    Methylmercury (MeHg) is a highly neurotoxic compound and several studies have reported intoxication signs in children whose mothers were exposed to this environmental toxicant. Although it is well established that the in utero exposure to MeHg causes neurological deficits in animals and humans, there is no evidence of the exclusive contribution of lactational exposure to MeHg as a possible cause of neurotoxicity in the offspring. In this study, we investigated the exclusive contribution of MeHg exposure through maternal milk on biochemical parameters related to the glutamatergic homeostasis (glutamate uptake by slices) and to the oxidative stress (total and nonprotein sulfhydryl groups, nonprotein hydroperoxides, glutathione peroxidase and catalase activities) in the cerebellum of suckling mice (Swiss albino). The same parameters were also evaluated in the cerebellum of mothers. Our results showed, for the first time, that lactational exposure to MeHg caused a high percent of inhibition (50%) on glutamate uptake by cerebellar slices in pups. Contrarily, this effect was not observed in mothers, which were submitted to a direct oral exposure to MeHg (15 mg/l in drinking water). In addition, behavioral/functional changes were observed in the weaning mice exposed to MeHg. It was observed an increase in the levels of nonprotein hydroperoxides in cerebellum, and this increase was negatively correlated to the glutamate uptake by cerebellar slices. This study indicates that (1) the exposure of lactating mice to MeHg causes inhibition of the glutamate uptake by cerebellar slices in the offspring; (2) this inhibitory effect seems to be related to increased levels of hydroperoxide. PMID:15201443

  14. The protective effect of Physalis peruviana L. against cadmium-induced neurotoxicity in rats.

    PubMed

    Abdel Moneim, Ahmed E; Bauomy, Amira A; Diab, Marwa M S; Shata, Mohamed Tarek M; Al-Olayan, Ebtesam M; El-Khadragy, Manal F

    2014-09-01

    The present study was carried out to investigate the protective effect of Physalis peruviana L. (family Solanaceae) against cadmium-induced neurotoxicity in rats. Adult male Wistar rats were randomly divided into four groups. Group 1 was used as control. Group 2 was intraperitoneally injected with 6.5 mg/kg bwt of cadmium chloride for 5 days. Group 3 was treated with 200 mg/kg bwt of methanolic extract of Physalis (MEPh). Group 4 was pretreated with MEPh 1 h before cadmium for 5 days. Cadmium treatment induced marked disturbances in neurochemical parameters as indicating by significant (p < 0.05) reduction in dopamine (DA), serotonin (5-HT), and 5-hydroxyindoleacetic acid (5-HIAA) in cerebellum, hippocampus, and cerebral cortex and enhanced significantly (p < 0.05) the levels of lipid peroxidation and nitric oxide in the brain. Cadmium treatment also decreased the amount of nonenzymatic and enzymatic antioxidants significantly (p < 0.05). Pretreatment with MEPh resulted in significant (p < 0.05) decreases in lipid peroxidation and nitric oxide levels and restored the amount of glutathione successfully. Although, preadministration of MEPh also brought the activities of cellular antioxidant enzymes, namely superoxide dismutase, catalase, glutathione peroxidase, and glutathione reductase significantly (p < 0.05) to the control levels, as well as the levels of Ca(2+), Cl(-), DA, 5-HT, and serotonin metabolite, 5-HIAA. These data indicated that Physalis has a beneficial effect in ameliorating the cadmium-induced oxidative neurotoxicity in the brain of rats. PMID:25022246

  15. Delayed application of the anesthetic propofol contrasts the neurotoxic effects of kainate on rat organotypic spinal slice cultures.

    PubMed

    Bajrektarevic, Dzejla; Nistri, Andrea

    2016-05-01

    Excitotoxicity due to hyperactivation of glutamate receptors is thought to underlie acute spinal injury with subsequent strong deficit in spinal network function. Devising an efficacious protocol of neuroprotection to arrest excitotoxicity might, therefore, spare a substantial number of neurons and allow later recovery. In vitro preparations of the spinal cord enable detailed measurement of spinal damage evoked by the potent glutamate analogue kainate. Any clinically-relevant neuroprotective treatment should start after the initial lesion and spare networks for at least 24h when cell damage plateaus. Using this strategy, we have observed that the gas anesthetic methoxyflurane provided strong, delayed neuroprotection. It is unclear if this beneficial effect was due to the mechanism of action by methoxyflurane, or it was the consequence of anesthetic depression. To test this hypothesis, we investigated the effect by propofol (commonly injected i.v. for general anesthesia) after kainate excitotoxicity induced on organotypic spinal slices. At 5μM concentration, propofol significantly attenuated cell death, including neuronal losses and, especially, damage to the highly vulnerable motoneurons. The action by propofol was fully prevented when co-applied with the GABAA antagonist bicuculline, indicating that neuroprotection required intact GABAA receptor function. Although bicuculline per se was not neurotoxic, it largely enhanced the lesional effects of kainate, suggesting that GABAA receptor activity could limit excitotoxicity. Our data might offer an explanation for the beneficial clinical outcome of neurosurgery performed as soon as possible after spinal lesion: we posit that general anesthesia contributes to this outcome, regardless of the type of anesthetic used. PMID:26947011

  16. Inhibitory effects of imidazoline receptor ligands on basal and kainic acid-induced neurotoxic signalling in mice.

    PubMed

    Keller, Benjamin; García-Sevilla, Jesús A

    2016-09-01

    This in vivo study assessed the potential of the imidazoline receptor (IR) ligands moxonidine (selective I1-IR), BU224 (selective I2-IR) and LSL61122 (mixed I1/I2-IR) to dampen excitotoxic signalling induced by kainic acid (KA; 45 mg/kg) in the mouse brain (hippocampus and cerebral cortex). KA triggered a strong behavioural syndrome (seizures; maximal at 60-90 minutes) and sustained stimulation (at 72 hours with otherwise normal mouse behaviour) of pro-apoptotic c-Jun-N-terminal kinases (JNK) and calpain with increased cleavage of p35 into neurotoxic p25 (cyclin-dependent kinase 5 [Cdk5] activators) in mouse hippocampus. Pretreatment (five days) with LSL61122 (10 mg/kg), but not moxonidine (1 mg/kg) or BU224 (20 mg/kg), attenuated the KA-induced behavioural syndrome, and all three IR ligands inhibited JNK and calpain activation, as well as p35/p25 cleavage after KA in the hippocampus (effects also observed after acute IR drug treatments). Efaroxan (I1-IR, 10 mg/kg) and idazoxan (I2-IR, 10 mg/kg), postulated IR antagonists, did not antagonise the effects of moxonidine and LSL61122 on KA targets (these IR ligands showed agonistic properties inhibiting pro-apoptotic JNK). Brain subcellular preparations revealed reduced synaptosomal postsynaptic density-95 protein contents (a mediator of JNK activation) and indicated increased p35/Cdk5 complexes (with pro-survival functions) after treatment with moxonidine, BU224 and LSL61122. These results showed that I1- and I2-IR ligands (moxonidine and BU224), and especially the mixed I1/I2-IR ligand LSL61122, are partly neuroprotective against KA-induced excitotoxic signalling. These findings suggest a therapeutic potential of IR drugs in disorders associated with glutamate-mediated neurodegeneration. PMID:27302941

  17. Piperine Enhances the Protective Effect of Curcumin Against 3-NP Induced Neurotoxicity: Possible Neurotransmitters Modulation Mechanism.

    PubMed

    Singh, Shamsher; Jamwal, Sumit; Kumar, Puneet

    2015-08-01

    3-Nitropropionic acid (3-NP) is a fungal toxin well established model used for inducing symptoms of Huntington's disease. Curcumin a natural polyphenol has been reported to possess neuroprotective activity by decreasing oxidative stress. The aim of present study was to investigate neuroprotective effect of curcumin with piperine (bioavailability enhancer) against 3-NP induced neurotoxicity in rats. Administration of 3-NP (10 mg/kg for 21 days) showed loss in body weight, declined motor function and changes in biochemical (LPO, nitrite and glutathione level), neuroinflammatory (TNF-α and IL-1β level) and neurochemical (DA, NE, 5-HT, DOPAC, 5-HIAA and HVA). Chronic treatment with curcumin (25 and 50 mg/kg) and curcumin (25 mg/kg) with piperine (2.5 mg/kg) once daily for 21 days prior to 3-NP administration. All the behavioral parameters were studied at 1st, 7th, 14th, and 21st day. On 22nd day all the animals was scarified and striatum was separated. Curcumin alone and combination (25 mg/kg) with piperine (2.5 mg/kg) showed beneficial effect against 3-NP induced motor deficit, biochemical and neurochemical abnormalities in rats. Piperine (2.5 mg/kg) with curcumin (25 mg/kg) significantly enhances its protective effect as compared with curcumin alone treated group. The results of the present study indicate that protective effect of curcumin potentiated in the presence of piperine (bioavailability enhancer) against 3-NP-induced behavioral and molecular alteration. PMID:26160706

  18. The similar neurotoxic effects of nanoparticulate and ionic silver in vivo and in vitro.

    PubMed

    Hadrup, Niels; Loeschner, Katrin; Mortensen, Alicja; Sharma, Anoop K; Qvortrup, Klaus; Larsen, Erik H; Lam, Henrik R

    2012-06-01

    We compared the neurotoxic effects of 14 nm silver nanoparticles (AgNPs) and ionic silver, in the form of silver acetate (AgAc), in vivo and in vitro. In female rats, we found that AgNPs (4.5 and 9 mg AgNP/kg bw/day) and ionic silver (9 mg Ag/kg bw/day) increased the dopamine concentration in the brain following 28 days of oral administration. The concentration of 5-hydroxytryptamine (5-HT) in the brain was increased only by AgNP at a dose of 9 mg Ag/kg bw/day. Only AgAc (9 mg Ag/kg bw/day) was found to increase noradrenaline concentration in the brain. In contrast to the results obtained from a 28-day exposure, the dopamine concentration in the brain was decreased by AgNPs (2.25 and 4.5mg/kg bw/day) following a 14-day exposure. These data suggest that there are differential effects of silver on dopamine depending on the length of exposure. In vitro, AgNPs, AgAc and a 12 kDa filtered sub-nano AgNP fraction were used to investigate cell death mechanisms in neuronal-like PC12 cells. AgNPs and the 12 kDa filtered fraction decreased cell viability to a similar extent, whereas AgAc was relatively more potent. AgNPs did not induce necrosis. However, apoptosis was found to be equally increased in cells exposed to AgNPs and the 12kDa filtered fraction, with AgAc showing a greater potency. Both the mitochondrial and the death receptor pathways were found to be involved in AgNP- and AgAc-induced apoptosis. In conclusion, 14 nm AgNPs and AgAc affected brain neurotransmitter concentrations. AgNP affected 5-HT, AgAc affected noradrenaline, whereas both silver formulations affected dopamine. Furthermore, apoptosis was observed in neuronal-like cells exposed to AgNPs, a 12 kDa filtered fraction of AgNP, and AgAc. These findings suggest that ionic silver and a 14 nm AgNP preparation have similar neurotoxic effects; a possible explanation for this could be the release and action of ionic silver from the surface of AgNPs. PMID:22531227

  19. N-methyl-D-aspartate receptor-mediated mitochondrial Ca(2+) overload in acute excitotoxic motor neuron death: a mechanism distinct from chronic neurotoxicity after Ca(2+) influx.

    PubMed

    Urushitani, M; Nakamizo, T; Inoue, R; Sawada, H; Kihara, T; Honda, K; Akaike, A; Shimohama, S

    2001-03-01

    Mitochondrial uptake of Ca(2+) has recently been found to play an important role in glutamate-induced neurotoxicity (GNT) as well as in the activation of Ca(2+)-dependent molecules, such as calmodulin and neuronal nitric oxide synthase (nNOS), in the cytoplasm. Prolonged exposure to glutamate injures motor neurons predominantly through the activation of Ca(2+)/calmodulin-nNOS, as previously reported, and is, in part, associated with the pathogenesis of amyotrophic lateral sclerosis (ALS). In the present study, we investigated how mitochondrial uptake of Ca(2+) is involved in GNT in spinal motor neurons. Acute excitotoxicity induced by exposure to 0.5 mM glutamate for 5 min was found in both motor and nonmotor neurons in cultured spinal cords from rat embryos and was dependent on extracellular Ca(2+) and on N-methyl-D-aspartate (NMDA) receptor activation. Mitochondrial uncouplers markedly blocked acute excitotoxicity, and membrane-permeable superoxide dismutase mimics attenuated acute excitotoxicity induced by glutamate and NMDA but not by alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) or kainate. Fluorimetric analysis showed that mitochondrial Ca(2+) was elevated promptly with subsequent accumulation of reactive oxygen species (ROS) in the mitochondria. An NMDA receptor antagonist and a mitochondrial uncoupler eliminated the increase in fluorescence of mitochondrial Ca(2+) and ROS indicators. These data indicate that acute excitotoxicity in spinal neurons is mediated by mitochondrial Ca(2+) overload and ROS generation through the activation of NMDA receptors. This mechanism is different from that of chronic GNT. PMID:11223912

  20. CM156, a high affinity sigma ligand, attenuates the stimulant and neurotoxic effects of methamphetamine in mice

    PubMed Central

    Kaushal, Nidhi; Seminerio, Michael J.; Shaikh, Jamaluddin; Medina, Mark A.; Mesangeau, Christophe; Wilson, Lisa L.; McCurdy, Christopher R.; Matsumoto, Rae R.

    2012-01-01

    Methamphetamine (METH) is a highly addictive psychostimulant drug of abuse. Low and high dose administration of METH leads to locomotor stimulation, and dopaminergic and serotonergic neurotoxicity, respectively. The behavioral stimulant and neurotoxic effects of METH can contribute to addiction and other neuropsychiatric disorders, thus necessitating the identification of potential pharmacotherapeutics against these effects produced by METH. METH binds to σ receptors at physiologically relevant concentrations. Also, σ receptors are present on and can modulate dopaminergic and serotonergic neurons. Therefore, σ receptors provide a viable target for the development of pharmacotherapeutics against the adverse effects of METH. In the present study, CM156, a σ receptor ligand with high affinity and selectivity for σ receptors over 80 other non-σ binding sites, was evaluated against METH-induced stimulant, hyperthermic, and neurotoxic effects. Pretreatment of male, Swiss Webster mice with CM156 dose dependently attenuated the locomotor stimulation, hyperthermia, striatal dopamine and serotonin depletions, and striatal dopamine and serotonin transporter reductions produced by METH, without significant effects of CM156 on its own. These results demonstrate the ability of a highly selective σ ligand to mitigate the effects of METH. PMID:21762711

  1. [Acyclovir-induced neurotoxicity and acute kidney injury in an elderly diabetic patient treated with valacyclovir: report of a case].

    PubMed

    Sagawa, Naoko; Tsurutani, Yuya; Nomura, Kazushi; Okuyama, Tomoko; Kondo, Mai; Sata, Akira; Miyao, Mariko; Mizuno, Yuzo

    2014-01-01

    An 83-year-old Japanese man had a 29-year history of well-controlled diabetes mellitus. His HbA1c level was approximately 6.0%, with no microalbuminuria and a serum creatinine level seven days before admission of 0.8 mg/dl (eGFR: 69.67 ml/min/1.73 m(2)). Five days before admission, he visited an ophthalmologist with inflammation of the right palpebra and conjunctiva and began taking valacyclovir at a dose of 3,000 mg for the treatment of herpes zoster. Two days before admission, he was prescribed loxoprofen at a dose of 180 mg for a headache. One day prior to admission, he developed dysarthria, wandering and loss of appetite. He was subsequently admitted to our hospital with progressive deterioration of consciousness (Japan Coma Scale: II-20). On admission, he exhibited renal dysfunction, with a serum creatinine level of 5.11 mg/dl (eGFR: 9.16 ml/min/1.73 m(2)). Based on his diverse symptoms and current treatment with valacyclovir, the patient was diagnosed with acyclovir-induced neurotoxicity and his symptoms rapidly improved after hemodialysis. The serum acyclovir level on admission was found to be 9.25 μg/ml. Although acyclovir-induced neurotoxicity is commonly seen in elderly patients with renal dysfunction, there are also reports of this condition in patients with a normal renal function. Valacyclovir is frequently prescribed to the elderly to treat diseases such as herpes zoster. As valacyclovir induces renal dysfunction, which raises the serum acyclovir level to the toxic range, special attention must be paid when administering this drug in elderly subjects. PMID:25749332

  2. Neurotoxic Weapons and Syndromes.

    PubMed

    Carota, Antonio; Calabrese, Pasquale; Bogousslavsky, Julien

    2016-01-01

    The modern era of chemical and biological warfare began in World War I with the large-scale production and use of blistering and choking agents (chlorine, phosgene and mustard gases) in the battlefield. International treaties (the 1925 Geneva Protocol, the 1975 Biological and Toxin Weapons Convention and the 1993 Chemical Weapons Convention) banned biological and chemical weapons. However, several countries are probably still engaged in their development. Hence, there is risk of these weapons being used in the future. This chapter will focus on neurotoxic weapons (e.g. nerve agents, chemical and biological neurotoxins, psychostimulants), which act specifically or preeminently on the central nervous system and/or the neuromuscular junction. Deeply affecting the function of the nervous system, these agents either have incapacitating effects or cause clusters of casualties who manifest primary symptoms of encephalopathy, seizures, muscle paralysis and respiratory failure. The neurologist should be prepared both to notice patterns of symptoms and signs that are sufficiently consistent to raise the alarm of neurotoxic attacks and to define specific therapeutic interventions. Additionally, extensive knowledge on neurotoxic syndromes should stimulate scientific research to produce more effective antidotes and antibodies (which are still lacking for most neurotoxic weapons) for rapid administration in aerosolized forms in the case of terrorist or warfare scenarios. PMID:27035576

  3. Local infusion of interleukin-6 attenuates the neurotoxic effects of NMDA on rat striatal cholinergic neurons.

    PubMed

    Toulmond, S; Vige, X; Fage, D; Benavides, J

    1992-09-14

    The potential neuroprotective effects of IL-6 against the excitotoxic neuronal loss induced by N-methyl-D-aspartate (NMDA) have been studied. Infusion into the rat striatum of excitotoxic amounts (250 nmol) of NMDA resulted in a 45% decrease in striatal choline acetyl transferase activity (ChAT; a marker of cholinergic neurons) and glutamate decarboxylase (GAD, a marker of GABAergic neurons) at 2 days post-injection. Co-infusion of 10 U of IL-6 reduced the loss of ChAT activity to 21% but failed to prevent the loss of GAD activity. IL-6 per se, up to the dose of 500 U, failed to affect ChAT or GAD activities. The in vivo effects of IL-6 are not mediated by a direct antagonism of NMDA toxicity, since IL-6 (up to a concentration of 500 and 5000 U/ml, respectively) did not antagonize either the increase in cyclic GMP levels resulting from NMDA receptor activation in cerebellar slices or the glutamate-induced release of lactate dehydrogenase, an index of neurotoxicity, by cultured cortical neurons. These results suggest that the increase in IL-6 levels observed in experimental brain lesions may play a role in the protection and regeneration of cholinergic neurons. PMID:1331914

  4. Development of an animal model to study the potential neurotoxic effects associated with welding fume inhalation.

    PubMed

    Antonini, James M; O'Callaghan, James P; Miller, Diane B

    2006-09-01

    Serious questions have been raised regarding a possible causal association between neurological effects in welders and the presence of manganese in welding fume. An experimental model is needed that could examine the potential neurotoxic effect of manganese after pulmonary exposure to welding fume. The National Institute for Occupational Safety and Health (NIOSH) has recently finished construction of a completely automated, computer controlled welding fume generation and inhalation exposure system for laboratory animals. The system is comprised of a programmable six-axis robotic welding arm and a water-cooled arc welding torch. A flexible trunk has been attached to the robotic arm of the welder and is used to collect and transport fume from the vicinity of the arc to the animal exposure chamber. Preliminary fume characterization studies have indicated that particle morphology, size, and chemical composition were comparable to welding fume generated in the workplace. Animal inhalation studies are currently underway. With the development of this novel system, an animal model has been established using controlled welding exposures to investigate the possible mechanisms by which welding fume may affect the central nervous system. PMID:16546258

  5. Protective effect of fangchinoline on cyanide-induced neurotoxicity in cultured rat cerebellar granule cells.

    PubMed

    Cho, Soon Ok; Seong, Yeon Hee

    2002-06-01

    The present study was performed to examine the effect of fangchinoline, a bis- benzylisoquinoline alkaloid, which exhibits the characteristics of a Ca2+ channel blocker, on cyanide-induced neurotoxicity using cultured rat cerebellar granule neurons. NaCN produced a concentration-dependent reduction of cell viability, which was blocked by MK-801, an N-methyl-D-aspartate (NMDA) receptor antagonist, verapamil, L-type Ca2+ channel blocker, and L-NAME, a nitric oxide synthase inhibitor. Pretreatment with fangchinoline over a concentration range of 0.1 to 10 microM significantly decreased the NaCN-induced neuronal cell death, glutamate release into medium, and elevation of [Ca2+]i and oxidants generation. These results suggest that fangchinoline may mitigate the harmful effects of cyanide-induced neuronal cell death by interfering with [Ca2+]i influx, due to its function as a Ca2+ channel blocker, and then by inhibiting glutamate release and oxidants generation. PMID:12135109

  6. Protective effects of ebselen (Ebs) and para-aminosalicylic acid (PAS) against manganese (Mn)-induced neurotoxicity

    SciTech Connect

    Marreilha dos Santos, A.P.; Lucas, Rui L.; Andrade, Vanda; Mateus, M. Luísa; Milatovic, Dejan; Aschner, Michael; Batoreu, M. Camila

    2012-02-01

    Chronic, excessive exposure to manganese (Mn) may induce neurotoxicity and cause an irreversible brain disease, referred to as manganism. Efficacious therapies for the treatment of Mn are lacking, mandating the development of new interventions. The purpose of the present study was to investigate the efficacy of ebselen (Ebs) and para-aminosalicylic acid (PAS) in attenuating the neurotoxic effects of Mn in an in vivo rat model. Exposure biomarkers, inflammatory and oxidative stress biomarkers, as well as behavioral parameters were evaluated. Co-treatment with Mn plus Ebs or Mn plus PAS caused a significant decrease in blood and brain Mn concentrations (compared to rats treated with Mn alone), concomitant with reduced brain E{sub 2} prostaglandin (PGE{sub 2}) and enhanced brain glutathione (GSH) levels, decreased serum prolactin (PRL) levels, and increased ambulation and rearing activities. Taken together, these results establish that both PAS and Ebs are efficacious in reducing Mn body burden, neuroinflammation, oxidative stress and locomotor activity impairments in a rat model of Mn-induced toxicity. -- Highlights: ► The manuscript is unique in its approach to the neurotoxicity of Mn. ► The manuscript incorporates molecular, cellular and functional (behavioral) analyses. ► Both PAS and Ebs are effective in restoring Mn behavioral function. ► Both PAS and Ebs are effective in reducing Mn-induced oxidative stress. ► Both PAS and Ebs led to a decrease in Mn-induced neuro-inflammation.

  7. Macrophages-mediated neurotoxic effects of intra-nigral manganese administration are attenuated by minocycline.

    PubMed

    Ponzoni, Silvia

    2012-01-01

    The present study was designed to address the role of macrophages in Mn-induced neurotoxicity and to test the hypothesis that minocycline, a tetracycline derivative, attenuates the biochemical and morphological sequelae of Mn. Mn was unilaterally microinjected into rat nigra followed by systemic minocycline or saline administration 24h later, daily for 3 days. At 72h after the intranigral Mn microinjection, tyrosine hydroxylase immunostaining (TH-IS) was evaluated in the striatum, along with the number of macrophages (as indicated by CD11b immunostaining) in the substantia nigra. Mn significantly reduced striatal TH-IS, and causes an increased macrophage number at the lesion site when compared with the control group. The effects of Mn on striatal TH-IS and the number of macrophages at the lesion site were concentration dependent. Consistent with the stated hypothesis, minocycline significantly reduced the macrophage number in the lesion site and minimized the TH-IS striatal loss induced by Mn. These results indicate that an inflammatory response mediated by macrophages is induced by intranigral Mn microinjection, which is fully attenuated by minocycline treatment, suggesting that suppression of macrophage infiltration provides neuroprotection to dopaminergic neurons. PMID:22085690

  8. Cytotoxic, Genotoxic, and Neurotoxic Effects of Mg, Pb, and Fe on Pheochromocytoma (PC-12) Cells

    PubMed Central

    Sanders, Talia; Liu, Yi-Ming; Tchounwou, Paul B.

    2014-01-01

    Metals such as lead (Pb), magnesium (Mg), and iron (Fe) are ubiquitous in the environment as a result of natural occurrence and anthropogenic activities. Although Mg, Fe and others are considered essential elements, high level of exposure has been associated with severe adverse health effects including cardiovascular, hematological, nephrotoxic, hepatotoxic, and neurologic abnormalities in humans. In the present study we hypothesized that Mg, Pb, and Fe are cytotoxic, genotoxic and neurotoxic, and their toxicity is mediated through oxidative stress and alteration in protein expression. To test the hypothesis, we used the pheochromocytoma (PC-12) cell line as a neuro cell model and performed the LDH assay for cell viability, Comet assay for DNA damage, Western blot for oxidative stress, and HPLC-MS to assess the concentration levels of neurological biomarkers such as glutamate, dopamine (DA), and 3-methoxytyramine (3-MT). The results of this study clearly show that Mg, Pb, and Fe, respectively in the form of MgSO4, Pb(NO3)2, FeCl2, and FeCl3 induce cytotoxicity, oxidative stress, and genotoxicity in PC-12 cells. In addition, exposure to these metallic compounds caused significant changes in the concentration levels of glutamate, dopamine, and 3-MT in PC-12 cells. Taken together the findings suggest that MgSO4, Pb(NO3)2, FeCl2, and FeCl3 have the potential to induce substantial toxicity to PC-12 cells. PMID:24942330

  9. The effects of concurrent cannabis use among ecstasy users: neuroprotective or neurotoxic?

    PubMed

    Fisk, John E; Montgomery, Catharine; Wareing, Michelle; Murphy, Philip N

    2006-08-01

    The research evidence regarding the potential effects of ecstasy suggests that it may be neurotoxic and that its use is associated with cognitive impairment. In recent years evidence has emerged suggesting that cannabinoids, the active ingredients in cannabis, can be neuroprotective under certain conditions. Given that many ecstasy users also consume cannabis at the same time, the possibility emerges that these individuals might be less susceptible to ecstasy-related impairment. The present paper reanalyses the data from a number of previous studies, contrasting the performance of those individuals who generally consume cannabis and ecstasy at the same time with those who generally consume ecstasy on its own. The two ecstasy-using groups are compared with non-ecstasy users on a range of measures including processing speed, random letter generation, verbal and visuo-spatial working memory span, reasoning and associative learning. The two ecstasy user groups did not differ significantly from each other on any of the measures. Both user groups were significantly worse than non-ecstasy users on measures of associative learning, verbal and visuo-spatial working memory and reasoning. The results suggest that consuming cannabis at the same time as ecstasy does not reduce the likelihood of cognitive impairment. PMID:16915582

  10. Presynaptic Mechanisms of Lead Neurotoxicity: Effects on Vesicular Release, Vesicle Clustering and Mitochondria Number

    PubMed Central

    McGlothan, Jennifer L.; Stansfield, Kirstie H.; Stanton, Patric K.; Guilarte, Tomás R.

    2015-01-01

    Childhood lead (Pb2+) intoxication is a global public health problem and accounts for 0.6% of the global burden of disease associated with intellectual disabilities. Despite the recognition that childhood Pb2+ intoxication contributes significantly to intellectual disabilities, there is a fundamental lack of knowledge on presynaptic mechanisms by which Pb2+ disrupts synaptic function. In this study, using a well-characterized rodent model of developmental Pb2+ neurotoxicity, we show that Pb2+ exposure markedly inhibits presynaptic vesicular release in hippocampal Schaffer collateral-CA1 synapses in young adult rats. This effect was associated with ultrastructural changes which revealed a reduction in vesicle number in the readily releasable/docked vesicle pool, disperse vesicle clusters in the resting pool, and a reduced number of presynaptic terminals with multiple mitochondria with no change in presynaptic calcium influx. These studies provide fundamental knowledge on mechanisms by which Pb2+ produces profound inhibition of presynaptic vesicular release that contribute to deficits in synaptic plasticity and intellectual development. PMID:26011056

  11. Presynaptic mechanisms of lead neurotoxicity: effects on vesicular release, vesicle clustering and mitochondria number.

    PubMed

    Zhang, Xiao-Lei; Guariglia, Sara R; McGlothan, Jennifer L; Stansfield, Kirstie H; Stanton, Patric K; Guilarte, Tomás R

    2015-01-01

    Childhood lead (Pb2+) intoxication is a global public health problem and accounts for 0.6% of the global burden of disease associated with intellectual disabilities. Despite the recognition that childhood Pb2+ intoxication contributes significantly to intellectual disabilities, there is a fundamental lack of knowledge on presynaptic mechanisms by which Pb2+ disrupts synaptic function. In this study, using a well-characterized rodent model of developmental Pb2+ neurotoxicity, we show that Pb2+ exposure markedly inhibits presynaptic vesicular release in hippocampal Schaffer collateral-CA1 synapses in young adult rats. This effect was associated with ultrastructural changes which revealed a reduction in vesicle number in the readily releasable/docked vesicle pool, disperse vesicle clusters in the resting pool, and a reduced number of presynaptic terminals with multiple mitochondria with no change in presynaptic calcium influx. These studies provide fundamental knowledge on mechanisms by which Pb2+ produces profound inhibition of presynaptic vesicular release that contribute to deficits in synaptic plasticity and intellectual development. PMID:26011056

  12. A phosphorylation site in brain and the delayed neurotoxic effect of some organophosphorus compounds

    PubMed Central

    Johnson, M. K.

    1969-01-01

    1. It is proposed that part of a neurotoxic dose of di-isopropyl phosphorofluoridate will be covalently bound in vivo to a specific component in the brain and spinal cord as the initial biochemical event in the genesis of the lesion. 2. A test system in vitro was devised that removes many di-isopropyl phosphorofluoridate-binding sites and indicates that the specific component may be a protein present in brain at a concentration comparable with that of the cholinesterases. 3. The site was found to be present and capable of binding di-isopropyl phosphorofluoridate in vitro in brain samples taken from either normal hens or those dosed with organophosphorus esterase inhibitors that are not neurotoxic. 4. Very little of the specific binding activity was found in brain samples from hens pre-dosed with a variety of neurotoxic organophosphorus compounds. 5. A solubilized preparation of the active brain component was obtained, suitable for further purification and study. PMID:5774473

  13. Neurotoxicity effects of atrazine-induced SH-SY5Y human dopaminergic neuroblastoma cells via microglial activation.

    PubMed

    Ma, Kun; Wu, Hao-Yu; Zhang, Bo; He, Xi; Li, Bai-Xiang

    2015-11-01

    Atrazine (2-chloro-4-ethytlamino-6-isopropylamine-1,3,5-triazine; ATR) is a broad-spectrum herbicide with a wide range of applications worldwide. However, ATR is neurotoxic; it reduces dopamine levels in the substantia nigra and corpus striatum in the midbrain, affects the absorption of synaptic vesicles and synaptic bodies, and interferes with dopamine storage and uptake in synaptic vesicles, leading to neurodegenerative disorders. Microglia are resident immunocompetent and phagocytic cells that regulate and participate in the microenvironment in the central nervous system. They demonstrate macrophage characteristics after activation by releasing inflammatory cytokines and neurotoxic substances to increase the inflammatory response, and are thus involved in neurodegeneration. The aim of this study was to investigate the neurotoxic effects of ATR-activated microglia-mediated neuronal damage in terms of human dopaminergic neuroblastoma SH-SY5Y cell death. ATR was administered to BV-2 microglial cells at 12.5, 25, and 50 μM for 1, 6, 12, 24 and 48 h, respectively. ATR increased activated-microglia-induced overexpression of reactive oxygen species, inducible nitric oxide synthase, nitric oxide, gp91(phox), p47(phox), and the inflammatory cytokines tumor necrosis factor α and interleukin-1β, thus reducing SH-SY5Y cell viability. These results suggest that activated microglia may play a critical role in inflammation-mediated dopaminergic neuronal death, and provide the basis for further studies on the mechanisms of ATR-induced dopaminergic system toxicity. PMID:26256823

  14. Opiate Addiction Therapies and HIV-1 Tat: Interactive Effects on Glial [Ca2+]i, Oxyradical and Neuroinflammatory Chemokine Production and Correlative Neurotoxicity

    PubMed Central

    Fitting, Sylvia; Zou, Shiping; El-Hage1, Nazira; Suzuki, Masami; Paris, Jason J.; Schier, Christina J.; Rodríguez, José W.; Rodriguez, Myosotys; Knapp, Pamela E.; Hauser, Kurt F.

    2014-01-01

    Few preclinical studies have compared the relative therapeutic efficacy of medications used to treat opiate addiction in relation to neuroAIDS. Here we compare the ability of methadone and buprenorphine, and the prototypic opiate morphine, to potentiate the neurotoxic and proinflammatory ([Ca2+]i, ROS, H2O2, chemokines) effects of HIV-1 Tat in neuronal and/or mixed-glial co-cultures. Repeated observations of neurons during 48 h exposure to combinations of Tat, equimolar concentrations (500 nM) of morphine, methadone, or buprenorphine exacerbated neurotoxicity significantly above levels seen with Tat alone. Buprenorphine alone displayed marked neurotoxicity at 500 nM, prompting additional studies of its neurotoxic effects at 5 nM and 50 nM concentrations ± Tat. In combination with Tat, buprenorphine displayed paradoxical, concentration-dependent, neurotoxic and neuroprotective actions. Buprenorphine neurotoxicity coincided with marked elevations in [Ca2+]i, but not increases in glial ROS or chemokine release. Tat by itself elevated the production of CCL5/RANTES, CCL4/MIP-1β, and CCL2/MCP-1. Methadone and buprenorphine alone had no effect, but methadone interacted with Tat to further increase production of CCL5/RANTES. In combination with Tat, all drugs significantly increased glial [Ca2+]i, but ROS was only significantly increased by co-exposure with morphine. Taken together, the increases in glial [Ca2+]i, ROS, and neuroinflammatory chemokines were not especially accurate predictors of neurotoxicity. Despite similarities, opiates displayed differences in their neurotoxic and neuroinflammatory interactions with Tat. Buprenorphine, in particular, was partially neuroprotective at a low concentration, which may result from its unique pharmacological profile at multiple opioid receptors. Overall, the results reveal differences among addiction medications that may impact neuroAIDS. PMID:25760046

  15. Effects of Cymbopogon citratus and Ferula assa-foetida extracts on glutamate-induced neurotoxicity.

    PubMed

    Tayeboon, Ghazaleh S; Tavakoli, Fatemeh; Hassani, Shokoufeh; Khanavi, Mahnaz; Sabzevari, Omid; Ostad, S Nasser

    2013-10-01

    Many of CNS diseases can lead to a great quantity of release of glutamate and the extreme glutamate induces neuronal cell damage and death. Here, we wanted to investigate the effects of Cymbopogon citratus essential oil and Ferula assa-foetida extracts treatment on glutamate-induced cell damage in a primary culture of rat cerebellar granule neurons. Cerebellums were collected from 7-d rat brains and cerebellar granule neurons were obtained after 8-d culture. CGN cells were treated with C. citratus essential oil and F. assa-foetida extracts at concentration of 100 μg/ml before, after, and during exposure to 30 μM glutamate. The cellular viability was evaluated by 3-(4, 5-dimethytthiazol-2-yl)-2, 5-diphenyltetrazoliumbromide (MTT) staining. The flow cytometry assay was used to examine cell cycle and apoptosis. MTT assay showed a glutamate-induced reduction in cellular viability while treatment with C. citratus essential oil and F. assa-foetida extracts before, during, and after exposure to glutamate was increased. Flow cytometric analysis indicated that F. assa-foetida extracts treatment significantly (p < 0.001) attenuated glutamate-induced apoptotic/necrotic cell death and the necrotic rate was decreased by C. citratus essential oil treatment compared to glutamate group, significantly (p < 0.001). The results show that C. citratus essential oil and F. assa-foetida extracts display neuroprotective effects in glutamate-induced neurotoxicity. These extracts exert antiapoptotic activity in cerebellar granule neurons due to cell cycle arrest in G0G1 phase, which explain the beneficial effects of C. citratus essential oil and F. assa-foetida extracts as therapies for neurologic disorders. PMID:23949776

  16. Behavioural and neurotoxic long-lasting effects of MDMA plus cocaine in adolescent mice.

    PubMed

    Daza-Losada, M; Rodríguez-Arias, M; Maldonado, C; Aguilar, M A; Miñarro, J

    2008-08-20

    The poly-drug pattern is the most common among MDMA users, with cocaine being a frequently associated drug. The aim of the present work was to evaluate the behavioural and neurotoxic long-term effects of exposure during adolescence to MDMA alone or plus cocaine. Mice of 28 to 30 days of age received a treatment of two daily injections of an identical dose of MDMA (5, 10 or 20 mg/kg), alone or plus cocaine (25 mg/kg), for 3 days (6 administrations). Three weeks after receiving MDMA, an increase in the time dedicated by the animals to social contacts with their conspecifics was observed, whilst their behaviour in the elevated plus maze showed no differences from that of non-treated mice. After being exposed to MDMA plus cocaine, mice spent more time in social contacts during the interaction test, as well as exhibiting an anxiolytic profile in the elevated plus maze, with an increase in the time and number of entries in the open arms. The activity of mice treated with cocaine alone or plus MDMA remained constant; the decrease observed among the rest of the animals after the second hour was absent in their case. The level of dopamine in the striatum was diminished in mice treated with 20 mg/kg of MDMA, but this neurotransmitter was not affected in animals exposed to the same dose plus cocaine. The present results highlight pronounced alterations in the behaviour of adult mice after exposure to MDMA and cocaine during adolescence, and demonstrate that these long-term effects can occur without the dopaminergic system becoming affected. PMID:18585379

  17. Long-term effects of neonatal methamphetamine exposure in rats on spatial learning in the Barnes maze and on cliff avoidance, corticosterone release, and neurotoxicity in adulthood.

    PubMed

    Williams, Michael T; Blankenmeyer, Tracy L; Schaefer, Tori L; Brown, Carrie A; Gudelsky, Gary A; Vorhees, Charles V

    2003-12-30

    Methamphetamine (MA) is a commonly abused stimulant and because of its addictive properties, abusers may not cease use during pregnancy, thereby exposing the fetus to the drug. The consequences of such exposure remain largely unknown however data from animal models show that long-term deficits in spatial learning and memory in the Morris water maze (MWM) occur. In this study we explored the spatial learning ability of rats treated four times daily with MA (5 mg/kg/dose) during the sensitive period for induction of MWM deficits, postnatal days (P) 11-20, using a different maze. In adulthood the animals were tested in a non-swimming spatial task, the Barnes maze, using either aversive (bright light) or appetitive (food reward) motivation. Approximately 30 days after behavioral testing, the pituitary and adrenal response to forced swim was assessed and susceptibility to MA-induced neurotoxicity measured. MA-treated animals tested in the aversive, but not the appetitive, version of the Barnes maze demonstrated spatial learning deficits. An attenuated corticosterone response in MA-treated animals was observed following forced swimming, however no differences in ACTH were found. Following acute MA administration in adulthood to all animals, the neonatally MA-treated animals displayed longer latencies to fall from a cliff than neonatally saline-treated rats given the same acute MA dose. This effect supports previous data showing hypoactivity in neonatally MA-treated animals. Acute MA treatment caused comparable striatal monoamine depletions in all groups, although females treated with MA as neonates displayed increased basal levels of corticosterone three days after the acute dose. These data demonstrate that MA administration during the neonatal period impairs spatial learning in an aversive non-swimming task and alters the adrenal response to a forced swim stressor, suggesting that the adrenal output during learning may contribute to the spatial learning deficits. PMID

  18. Neuroprotective effect of caffeic acid phenethyl ester in 3-nitropropionic acid-induced striatal neurotoxicity.

    PubMed

    Bak, Jia; Kim, Hee Jung; Kim, Seong Yun; Choi, Yun-Sik

    2016-05-01

    Caffeic acid phenethyl ester (CAPE), derived from honeybee hives, is a bioactive compound with strong antioxidant activity. This study was designed to test the neuroprotective effect of CAPE in 3-nitropropionic acid (3NP)-induced striatal neurotoxicity, a chemical model of Huntington's disease (HD). Initially, to test CAPE's antioxidant activity, a 2,2'-azino-bis-3-ethylbenzthiazoline-6-sulfonic acid (ABTS) antioxidant assay was employed, and CAPE showed a strong direct radical-scavenging eff ect. In addition, CAPE provided protection from 3NP-induced neuronal cell death in cultured striatal neurons. Based on these observations, the in vivo therapeutic potential of CAPE in 3NP-induced HD was tested. For this purpose, male C57BL/6 mice were repeatedly given 3NP to induce HD-like pathogenesis, and 30 mg/kg of CAPE or vehicle (5% dimethyl sulfoxide and 95% peanut oil) was administered daily. CAPE did not cause changes in body weight, but it reduced mortality by 29%. In addition, compared to the vehicle-treated group, robustly reduced striatal damage was observed in the CAPE-treated animals, and the 3NP-induced behavioral defi cits on the rotarod test were signifi cantly rescued after the CAPE treatment. Furthermore, immunohistochemical data showed that immunoreactivity to glial fibrillary acidic protein (GFAP) and CD45, markers for astrocyte and microglia activation, respectively, were strikingly reduced. Combined, these data unequivocally indicate that CAPE has a strong antioxidant eff ect and can be used as a potential therapeutic agent against HD. PMID:27162482

  19. Neuroprotective effect of caffeic acid phenethyl ester in 3-nitropropionic acid-induced striatal neurotoxicity

    PubMed Central

    Bak, Jia; Kim, Hee Jung; Kim, Seong Yun

    2016-01-01

    Caffeic acid phenethyl ester (CAPE), derived from honeybee hives, is a bioactive compound with strong antioxidant activity. This study was designed to test the neuroprotective effect of CAPE in 3-nitropropionic acid (3NP)-induced striatal neurotoxicity, a chemical model of Huntington's disease (HD). Initially, to test CAPE's antioxidant activity, a 2,2'-azino-bis-3-ethylbenzthiazoline-6-sulfonic acid (ABTS) antioxidant assay was employed, and CAPE showed a strong direct radical-scavenging eff ect. In addition, CAPE provided protection from 3NP-induced neuronal cell death in cultured striatal neurons. Based on these observations, the in vivo therapeutic potential of CAPE in 3NP-induced HD was tested. For this purpose, male C57BL/6 mice were repeatedly given 3NP to induce HD-like pathogenesis, and 30 mg/kg of CAPE or vehicle (5% dimethyl sulfoxide and 95% peanut oil) was administered daily. CAPE did not cause changes in body weight, but it reduced mortality by 29%. In addition, compared to the vehicle-treated group, robustly reduced striatal damage was observed in the CAPE-treated animals, and the 3NP-induced behavioral defi cits on the rotarod test were signifi cantly rescued after the CAPE treatment. Furthermore, immunohistochemical data showed that immunoreactivity to glial fibrillary acidic protein (GFAP) and CD45, markers for astrocyte and microglia activation, respectively, were strikingly reduced. Combined, these data unequivocally indicate that CAPE has a strong antioxidant eff ect and can be used as a potential therapeutic agent against HD. PMID:27162482

  20. A Drosophila model to investigate the neurotoxic side effects of radiation exposure.

    PubMed

    Sudmeier, Lisa J; Howard, Steven P; Ganetzky, Barry

    2015-07-01

    Children undergoing cranial radiation therapy (CRT) for pediatric central nervous system malignancies are at increased risk for neurological deficits later in life. We have developed a model of neurotoxic damage in adult Drosophila following irradiation during the juvenile stages with the goal of elucidating underlying neuropathological mechanisms and of ultimately identifying potential therapeutic targets. Wild-type third-instar larvae were irradiated with single doses of γ-radiation, and the percentage that survived to adulthood was determined. Motor function of surviving adults was examined with a climbing assay, and longevity was assessed by measuring lifespan. Neuronal cell death was assayed by using immunohistochemistry in adult brains. We also tested the sensitivity at different developmental stages by irradiating larvae at various time points. Irradiating late third-instar larvae at a dose of 20 Gy or higher impaired the motor activity of surviving adults. A dose of 40 Gy or higher resulted in a precipitous reduction in the percentage of larvae that survive to adulthood. A dose-dependent decrease in adult longevity was paralleled by a dose-dependent increase in activated Death caspase-1 (Dcp1) in adult brains. Survival to adulthood and adult lifespan were more severely impaired with decreasing larval age at the time of irradiation. Our initial survey of the Drosophila Genetic Reference Panel demonstrated that differences in genotype can confer phenotypic differences in radio-sensitivity for developmental survival and motor function. This work demonstrates the usefulness of Drosophila to model the toxic effects of radiation during development, and has the potential to unravel underlying mechanisms and to facilitate the discovery of novel therapeutic interventions. PMID:26092528

  1. Transcriptomic analyses of neurotoxic effects in mouse brain after intermittent neonatal administration of thimerosal.

    PubMed

    Li, Xiaoling; Qu, Fengqin; Xie, Wenjuan; Wang, Fengli; Liu, Hongmei; Song, Shuhui; Chen, Tingting; Zhang, Yang; Zhu, Shu; Wang, Yun; Guo, Caixia; Tang, Tie-Shan

    2014-06-01

    Thimerosal is a vaccine antimicrobial preservative which has long been suspected an iatrogenic factor possibly contributing to neurodevelopmental disorders including autism. The association between infant vaccine thimerosal exposure and autism remains an open question. Although thimerosal has been removed from mandatory childhood vaccines in the United States, thimerosal-preserved vaccines are still widely used outside of the United States especially in developing countries. Notably, thimerosal-containing vaccines are being given to the newborns within the first 12-24 h after birth in some countries. To examine the possible neurotoxic effects of early neonatal exposure to a higher level of thimerosal, FVB mice were subcutaneously injected with thimerosal-mercury at a dose which is 20× higher than that used for regular Chinese infant immunization during the first 4 months of life. Thimerosal-treated mice exhibited neural development delay, social interaction deficiency, and inclination of depression. Apparent neuropathological changes were also observed in adult mice neonatally treated with thimerosal. High-throughput RNA sequencing of autistic-behaved mice brains revealed the alternation of a number of canonical pathways involving neuronal development, neuronal synaptic function, and the dysregulation of endocrine system. Intriguingly, the elevation of anterior pituitary secreting hormones occurred exclusively in male but not in female thimerosal-treated mice, demonstrating for the first time the gender bias of thimerosal-mercury toxicity with regard to endocrine system. Our results indicate that higher dose of neonatal thimerosal-mercury (20× higher than that used in human) is capable of inducing long-lasting substantial dysregulation of neurodevelopment, synaptic function, and endocrine system, which could be the causal involvements of autistic-like behavior in mice. PMID:24675092

  2. [Neurotoxicity of radiation].

    PubMed

    Suzuki, Keiji

    2015-01-01

    It is well-known that the central nervous system is thoroughly resistant to ionizing radiation as high-dose radiation exposure is required for causing neuronal death. In contrast, recent studies have revealed that the hippocampus, which could be the main organ involved in disorder of higher brain functions after radiation therapy, contains radiation-sensitive cell fractions. In this paper, the basics of radiation effects and the molecular mechanism of neurotoxicity of radiation have been reviewed and discussed. PMID:25585436

  3. CORRELATION BETWEEN NEUROTOXIC ESTERASE INHIBITION AND MIPAFOX-INDUCED NEUROPATHIC DAMAGE IN RATS

    EPA Science Inventory

    The correlation between neuropathic damage and inhibition of neurotoxic esterase or neuropathy target enzyme (NTE) was examined in rats acutely exposed to Mipafox (N, N'-diisopropylphosphorodiamidofluoridate), a neurotoxic organophospate. Brain and spinal cord NTE activities were...

  4. Neuroprotective effect of curcumin-loaded lactoferrin nano particles against rotenone induced neurotoxicity.

    PubMed

    Bollimpelli, V Satish; Kumar, Prashant; Kumari, Sonali; Kondapi, Anand K

    2016-05-01

    Curcumin is known to have neuroprotective role and possess antioxidant, anti-inflammatory activities. Rotenone, a flavonoid induced neurotoxicity in dopaminergic cells is being widely studied in Parkinson's Disease (PD) research. In the present study, curcumin loaded lactoferrin nano particles prepared by sol-oil chemistry were used to protect dopaminergic cell line SK-N-SH against rotenone induced neurotoxicity. These curcumin loaded nano particles were of 43-60 nm diameter size and around 100 nm hydrodynamic size as assessed by transmission electron microscopy, atomic force microscopy and dynamic light scattering analysis respectively. The encapsulation efficiency was 61.3% ± 2.4%. Cellular uptake of curcumin through these nano particles was confirmed by confocal imaging and spectrofluorimetric analysis. The curcumin loaded lactoferrin nanoparticles showed greater intracellular drug uptake, sustained retention and greater neuroprotection than soluble counterpart. Neuroprotective activity was characterized through viability assays and by estimating ROS levels. Furthermore rotenone induced PD like features were characterized by decrease in tyrosine hydroxylase expression and increase in α-synuclein expression. Taken together curcumin loaded lactoferrin nanoparticles could be a promising drug delivery strategy against neurotoxicity in dopaminergic neurons. PMID:26826319

  5. EFFECTS OF ACUTE PYRETHROID EXPOSURE ON THERMOREGULATION IN RATS.

    EPA Science Inventory

    Pyrethroid insecticides produce acute neurotoxicity in mammals. According to the FQPA mandate, the USEPA is required to consider the risk of cumulative toxicity posed to humans through exposure to pyrethroid mixtures. Thermoregulatory response (TR) is being used to determine if t...

  6. Effects of environmentally relevant concentrations of metallic compounds on the flatfish Scophthalmus maximus: biomarkers of neurotoxicity, oxidative stress and metabolism.

    PubMed

    Nunes, Bruno; Brandão, Fátima; Sérgio, Tânia; Rodrigues, Sara; Gonçalves, Fernando; Correia, Alberto Teodorico

    2014-06-01

    Flatfish species, such as the turbot (Scophthalmus maximus), are common targets for toxic effects, since they are exposed through the food chain (ingestion of contaminated preys) and are in direct contact with the waterborne contaminant and sediments. Furthermore, these fish species live in close proximity to interstitial water that frequently dissolves high amounts of contaminants, including metals. Despite this significant set of characteristics, the present knowledge concerning flatfish contamination and toxicity by metals is still scarce. To attain the objective of assessing the effects of metals on a flatfish species, S. maximus specimens were chronically exposed to lead, copper and zinc, at ecologically relevant concentrations, and biochemical (oxidative stress: catalase and glutathione S-transferases activities, and lipid peroxidation; neurotoxicity: cholinesterase activity) parameters were assessed on selected tissues (gills and liver). Copper had no significant effects on all tested parameters; lead was causative of significant increases in liver GSTs activities and also in lipoperoxidation of gill tissue; exposure to zinc caused a significant increase in catalase activity of gill tissue. None of the tested metals elicited noteworthy effects in terms of neurotoxicity. The obtained results showed that only the metal lead is of some environmental importance, since it was able to cause deleterious modifications of oxidative nature at relevant concentrations. PMID:24595748

  7. Neurotoxicity of metals.

    PubMed

    Caito, Samuel; Aschner, Michael

    2015-01-01

    Metals are frequently used in industry and represent a major source of toxin exposure for workers. For this reason governmental agencies regulate the amount of metal exposure permissible for worker safety. While essential metals serve physiologic roles, metals pose significant health risks upon acute and chronic exposure to high levels. The central nervous system is particularly vulnerable to metals. The brain readily accumulates metals, which under physiologic conditions are incorporated into essential metalloproteins required for neuronal health and energy homeostasis. Severe consequences can arise from circumstances of excess essential metals or exposure to toxic nonessential metal. Herein, we discuss sources of occupational metal exposure, metal homeostasis in the human body, susceptibility of the nervous system to metals, detoxification, detection of metals in biologic samples, and chelation therapeutic strategies. The neurologic pathology and physiology following aluminum, arsenic, lead, manganese, mercury, and trimethyltin exposures are highlighted as classic examples of metal-induced neurotoxicity. PMID:26563789

  8. Lack of delayed neurotoxic effect after tri-o-cresyl phosphate treatment in male Fischer 344 rats: biochemical, neurobehavioral, and neuropathological studies.

    PubMed

    Somkuti, S G; Tilson, H A; Brown, H R; Campbell, G A; Lapadula, D M; Abou-Donia, M B

    1988-02-01

    Tri-o-cresyl phosphate (TOCP), which produces a delayed neurotoxic syndrome in humans and some animal species, was given to Fischer 344 (F344) male (18 week old) rats to determine if it causes biochemical, sensorimotor, and neuropathological effects. Animals were given TOCP by gavage in doses ranging from 10 to 100 mg of TOCP/kg daily for a period of 63 days. The rats were subjected to a series of neurobehavioral tests including fore- and hindlimb grip strength, motor activity, tremor, and latency to respond to a thermal stimulus. Central and peripheral nervous tissues were examined for damage characteristic of organophosphorous compound-induced delayed neurotoxicity (OPIDN). Brain neurotoxic esterase and acetylcholinesterase activities were inhibited in a dose-dependent fashion. A group of three chickens treated with 100 mg of TOCP/kg/day for 18 days was included as the positive control for enzymatic and histopathological alterations associated with OPIDN. Rats showed no consistent neurobehavioral changes or evidence of neuropathological damage in nervous tissues associated with treatment. In contrast, chickens treated with TOCP developed delayed neurotoxicity characterized by ataxia, which progressed to paralysis. These neurological changes included swelling, fragmentation, and degeneration of the axon and myelin in both central and peripheral nervous tissues. This study concludes that the F344 rat is not sensitive to the delayed neurotoxic effects of TOCP. When studying OPIDN in rats, care must be exercised in choosing the experimental animal since some strains, e.g., F344, are not sensitive. PMID:3356306

  9. Assessment of neurotoxic effects of mercury in beluga whales (Delphinapterus leucas), ringed seals (Pusa hispida), and polar bears (Ursus maritimus) from the Canadian Arctic.

    PubMed

    Krey, Anke; Ostertag, Sonja K; Chan, Hing Man

    2015-03-15

    Marine mammals are indicator species of the Arctic ecosystem and an integral component of the traditional Inuit diet. The potential neurotoxic effects of increased mercury (Hg) in beluga whales (Delphinapterus leucas), ringed seals (Pusa hispida), and polar bears (Ursus maritimus) are not clear. We assessed the risk of Hg-associated neurotoxicity to these species by comparing their brain Hg concentrations with threshold concentrations for toxic endpoints detected in laboratory animals and field observations: clinical symptoms (>6.75 mg/kg wet weight (ww)), neuropathological signs (>4 mg/kg ww), neurochemical changes (>0.4 mg/kg ww), and neurobehavioral changes (>0.1mg/kg ww). The total Hg (THg) concentrations in the cerebellum and frontal lobe of ringed seals and polar bears were <0.5mg/kg ww, whereas the average concentration in beluga whale brain was >3mg/kg ww. Our results suggest that brain THg levels in polar bears are below levels that induce neurobehavioral effects as reported in the literature, while THg concentrations in ringed seals are within the range that elicit neurobehavioral effects and individual ringed seals exceed the threshold for neurochemical changes. The relatively high THg concentration in beluga whales exceeds all of the neurotoxicity thresholds assessed. High brain selenium (Se):Hg molar ratios were observed in all three species, suggesting that Se could protect the animals from Hg-associated neurotoxicity. This assessment was limited by several factors that influence neurotoxic effects in animals, including: animal species; form of Hg in the brain; and interactions with modifiers of Hg-associated toxicity, such as Se. Comparing brain Hg concentrations in wildlife with concentrations of appropriate laboratory studies can be used as a tool for risk characterization of the neurotoxic effects of Hg in Arctic marine mammals. PMID:24958011

  10. Neuroprotective effects of lotus seedpod procyanidins on extremely low frequency electromagnetic field-induced neurotoxicity in primary cultured hippocampal neurons.

    PubMed

    Yin, Chunchun; Luo, Xiaoping; Duan, Yuqing; Duan, Wenyi; Zhang, Haihui; He, Yuanqing; Sun, Guibo; Sun, Xiaobo

    2016-08-01

    The present study investigated the protective effects of lotus seedpod procyanidins (LSPCs) on extremely low frequency electromagnetic field (ELF-EMF)-induced neurotoxicity in primary cultured rat hippocampal neurons and the underlying molecular mechanism. The results of MTT, morphological observation, superoxide dismutase (SOD) and malondialdehyde (MDA) assays showed that compared with control, incubating neurons under ELF-EMF exposure significantly decreased cell viability and increased the number of apoptotic cells, whereas LSPCs evidently protected the hippocampal neurons against ELF-EMF-induced cell damage. Moreover, a certain concentration of LSPCs inhibited the elevation of intracellular reactive oxygen species (ROS) and Ca(2+) level, as well as prevented the disruption of mitochondrial membrane potential induced by ELF-EMF exposure. In addition, supplementation with LSPCs could alleviate DNA damage, block cell cycle arrest at S phase, and inhibit apoptosis and necrosis of hippocampal neurons under ELF-EMF exposure. Further study demonstrated that LSPCs up-regulated the activations of Bcl-2, Bcl-xl proteins and suppressed the expressions of Bad, Bax proteins caused by ELF-EMF exposure. In conclusion, these findings revealed that LSPCs protected against ELF-EMF-induced neurotoxicity through inhibiting oxidative stress and mitochondrial apoptotic pathway. PMID:27470406

  11. Neuroprotective effect of Allium cepa L. in aluminium chloride induced neurotoxicity.

    PubMed

    Singh, Tanveer; Goel, Rajesh Kumar

    2015-07-01

    The present study was envisaged to investigate the neuroprotective potential of Allium cepa (A. cepa) in aluminium chloride induced neurotoxicity. Aluminium chloride (50 mg/kg/day) was administered orally in mice supplemented with different doses of A. cepa hydroethanolic extract for a period of 60 days. Various behavioural, biochemical and histopathological parameters were estimated in aluminium exposed animals. Chronic aluminium administration resulted in significant motor incoordination and memory deficits, which were also endorsed biochemically as there was increased oxidative stress as well as elevated acetylcholinesterase (AChE) and aluminium levels in the brain. Supplementation with A. cepa in aluminium exposed animals significantly improved muscle coordination and memory deficits as well as reduced oxidative stress, AChE and decreased abnormal aluminium deposition in the brain. Histopathologically, there was marked deterioration visualized as decreased vacuolated cytoplasm as well as decreased pyramidal cells in the hippocampal area of mice brain which were found to be reversed with A. cepa supplementation. Administration of BADGE (PPARγ antagonist) in aluminium exposed animals reversed the neuroprotective potential of A. cepa as assessed with various behavioural, biochemical, neurochemical and histopathological estimations. In conclusion, finding of this study suggested significant neuroprotective potential of A. cepa in aluminium induced neurotoxicity. Further, the role of PPARγ receptor agonism has also been suggested as a putative neuroprotective mechanism of A. cepa, which needs further studies for confirmation. PMID:25940660

  12. Effects of impaired membrane interactions on α-synuclein aggregation and neurotoxicity

    PubMed Central

    Ysselstein, Daniel; Joshi, Mehul; Mishra, Vartika; Griggs, Amy M.; Asiago, Josephat M.; McCabe, George P.; Stanciu, Lia A.; Post, Carol Beth; Rochet, Jean-Christophe

    2015-01-01

    The post-mortem brains of individuals with Parkinson’s disease (PD) and other synucleinopathy disorders are characterized by the presence of aggregated forms of the presynaptic protein α-synuclein (aSyn). Understanding the molecular mechanism of aSyn aggregation is essential for the development of neuroprotective strategies to treat these diseases. In this study, we examined how interactions between aSyn and phospholipid vesicles influence the protein’s aggregation and toxicity to dopaminergic neurons. Two-dimensional NMR data revealed that two familial aSyn mutants, A30P and G51D, populated an exposed, membrane-bound conformer in which the central hydrophobic region was dissociated from the bilayer to a greater extent than in the case of wild-type aSyn. A30P and G51D had a greater propensity to undergo membrane-induced aggregation and elicited greater toxicity to primary dopaminergic neurons compared to the wild-type protein. In contrast, the non-familial aSyn mutant A29E exhibited a weak propensity to aggregate in the presence of phospholipid vesicles or to elicit neurotoxicity, despite adopting a relatively exposed membrane-bound conformation. Our findings suggest that the aggregation of exposed, membrane-bound aSyn conformers plays a key role in the protein’s neurotoxicity in PD and other synucleinopathy disorders. PMID:25931201

  13. Existence of glia mitigated ketamine-induced neurotoxicity in neuron-glia mixed cultures of neonatal rat cortex and the glia-mediated protective effect of 2-PMPA.

    PubMed

    Zuo, Daiying; Wang, Chengna; Li, Zengqiang; Lin, Li; Duan, Zhenfang; Qi, Huan; Li, Lin; Sun, Feng; Wu, Yingliang

    2014-09-01

    The present study compared ketamine-induced neurotoxicity in the neuron-glia mixed cultures and neuronal cultures and further explored the neuroprotective effect of the NAAG peptidase inhibitor 2-(phosphonomethyl) pentanedioic acid (2-PMPA). Firstly, Rosenfeld's staining and immunofluorescence staining of microtubule-associated protein 2 (MAP2) and glial fibrillary acidic protein (GFAP) were used to address the difference of morphology in the mixed cultures and neuronal cultures. Our results showed that neurons and astrocytes grew in good conditions. The ratio of neurons and astrocytes in the mixed cultures was around 1:1, and the purity of neurons in the neuronal cultures is 91.3%. Furthermore, ketamine was used to test the hypothesis that the presence of a higher proportion of glia in the mixed cultures would be protective against ketamine-induced neurotoxicity in the mixed cultures compared with neuronal cultures. The results showed that ketamine-induced morphological changes, cell viability decrease and lactate dehydrogenase (LDH) levels increase were significantly mitigated in neuron-glia mixed cultures compared with neuronal cultures. Furthermore, 2-PMPA was included to further explore efficient protective drug for ketamine-induced neurotoxicity. Our results showed that 2-PMPA reduced ketamine-induced decrease of cell viability and increase of LDH levels in the mixed cultures but not in the neuronal cultures. Further morphological changes of neurons and astrocytes also indicated that 2-PMPA could improve ketamine damaged neurons in the mixed cultures instead of neuronal cultures. These results indicate that glia protect neurons from ketamine-induced neurotoxicity. These data further suggest that glia mediate the neuroprotective effect of 2-PMPA and 2-PMPA has the potential to treat ketamine-induced neurotoxicity in vivo. Delineating the mechanisms underlying the communication between neurons and glia and the neuroprotective effects of 2-PMPA in the mixed

  14. RNAi-mediated silencing of hepatic Alas1 effectively prevents and treats the induced acute attacks in acute intermittent porphyria mice

    PubMed Central

    Yasuda, Makiko; Gan, Lin; Chen, Brenden; Kadirvel, Senkottuvelan; Yu, Chunli; Phillips, John D.; New, Maria I.; Liebow, Abigail; Fitzgerald, Kevin; Querbes, William; Desnick, Robert J.

    2014-01-01

    The acute hepatic porphyrias are inherited disorders of heme biosynthesis characterized by life-threatening acute neurovisceral attacks. Factors that induce the expression of hepatic 5-aminolevulinic acid synthase 1 (ALAS1) result in the accumulation of the neurotoxic porphyrin precursors 5-aminolevulinic acid (ALA) and porphobilinogen (PBG), which recent studies indicate are primarily responsible for the acute attacks. Current treatment of these attacks involves i.v. administration of hemin, but a faster-acting, more effective, and safer therapy is needed. Here, we describe preclinical studies of liver-directed small interfering RNAs (siRNAs) targeting Alas1 (Alas1-siRNAs) in a mouse model of acute intermittent porphyria, the most common acute hepatic porphyria. A single i.v. dose of Alas1-siRNA prevented the phenobarbital-induced biochemical acute attacks for approximately 2 wk. Injection of Alas1-siRNA during an induced acute attack significantly decreased plasma ALA and PBG levels within 8 h, more rapidly and effectively than a single hemin infusion. Alas1-siRNA was well tolerated and a therapeutic dose did not cause hepatic heme deficiency. These studies provide proof-of-concept for the clinical development of RNA interference therapy for the prevention and treatment of the acute attacks of the acute hepatic porphyrias. PMID:24821812

  15. LONG-LASTING LITHIUM NEUROTOXICITY IN AN ADOLESECENT

    PubMed Central

    Khanna, Rakesh; Sethi, Sujata

    1993-01-01

    SUMMARY Acute lithium intoxication is well known. A case of long tasting lithium neurotoxicity in an adolescent male is reported, who showed signs of cerebellar as well as brain stem involvement. Persistent lithium neurotoxicity is discussed and the recommendation made that this condition be considered irreversible only if no substantial recovery occurs in the first six months. PMID:21743620

  16. Glucose Effect in the Acute Porphyrias

    MedlinePlus

    ... You are here Home Diet and Nutrition The glucose effect in acute porphyrias The disorders Acute Intermittent ... are treated initially with the administration of carbohydrate/glucose. This therapy has its basis in the ability ...

  17. Effects of glucose administered with lidocaine solution on spinal neurotoxicity in rats

    PubMed Central

    Ma, Hanxiang; Xu, Tingting; Xiong, Xiangsheng; Mao, Jingjing; Yang, Fan; Zhang, Yonghai; Bai, Zhixia; Chen, Xuexin

    2015-01-01

    To investigate whether intrathecal administration of 10% glucose increases functional impairment and histologic damage in rats when mixed with 5% lidocaine. After implanted intrathecal catheter, 32 male Sprague-Dawley rats were randomly assigned to one of four groups: lidocaine group (Group L, n=8) received 5% lidocaine 20 µL, lidocaine with glucose group (Group LG, n=8) received 5% lidocaine with 10% glucose 20 µL, glucose group (Group G, n=8) received 10% glucose 20 µL and normal saline group received normal saline 20 µL (Group NS, n=8). Four days after intrathecal injection, sensory impairments of rats in the four groups were evaluated by using the tail-flick test. The histologic changes of spinal cord and nerve roots were observed by electron microscopy and light microscopy. There was no significant difference in baseline tail-flick latencies between the four groups (P=0.284). On the 4th day after intrathecal injection, the assessment result of sensory function was similar to baseline (P=0.217) in saline-treated animals. Sensory impairment occurred after intrathecal administration of 5% lidocaine, and 10% glucose with 5% lidocaine worsen this satiation (P=0.0001); histologic changes in 10% glucose with 5% lidocaine-treated group has differ significantly from lidocaine-treated group (P=0.001). Sensory function after intrathecal administration of 10% glucose was similar to baseline and did not differ from the saline group (P=0.995); histologic changes in 10% glucose-treated rats did not differ significantly from saline controls (P=0.535). These results suggest that 5% lidocaine can induce spinal neurotoxicity and 10% glucose with 5% lidocaine could worsen spinal neurotoxicity. PMID:26884984

  18. Integration of in vitro neurotoxicity data with biokinetic modelling for the estimation of in vivo neurotoxicity.

    PubMed

    Forsby, Anna; Blaauboer, Bas

    2007-04-01

    Risk assessment of neurotoxicity is mainly based on in vivo exposure, followed by tests on behaviour, physiology and pathology. In this study, an attempt to estimate lowest observed neurotoxic doses after single or repeated dose exposure was performed. Differentiated human neuroblastoma SH-SY5Y cells were exposed to acrylamide, lindane, parathion, paraoxon, phenytoin, diazepam or caffeine for 72 hours. The effects on protein synthesis and intracellular free Ca2+ concentration were studied as physiological endpoints. Voltage operated Ca2+ channel function, acetylcholine receptor function and neurite degenerative effects were investigated as neurospecific endpoints for excitability, cholinergic signal transduction and axonopathy, respectively. The general cytotoxicity, determined as the total cellular protein levels after the 72 hours exposure period, was used for comparison to the specific endpoints and for estimation of acute lethality. The lowest concentration that induced 20% effect (EC20) obtained for each compound, was used as a surrogate for the lowest neurotoxic level (LOEL) at the target site in vivo. The LOELs were integrated with data on adsorption, distribution, metabolism and excretion of the compounds in physiologically-based biokinetic (PBBK) models of the rat and the lowest observed effective doses (LOEDs) were estimated for the test compounds. A good correlation was observed between the estimated LOEDs and experimental LOEDs found in literature for rat for all test compounds, except for diazepam. However, when using in vitro data from the literature on diazepam's effect on gamma-amino butyric acid (GABA)A receptor function for the estimation of LOED, the correlation between the estimated and experimental LOEDs was improved from a 10,000-fold to a 10-fold difference. Our results indicate that it is possible to estimate LOEDs by integrating in vitro toxicity data as surrogates for lowest observed target tissue levels with PBBK models, provided that

  19. The neurotoxic effects of N-methyl-N-nitrosourea on the electrophysiological property and visual signal transmission of rat's retina

    SciTech Connect

    Tao, Ye; Chen, Tao; Liu, Bei; Yang, Guo Qing; Peng, Guanghua; Zhang, Hua; Huang, Yi Fei

    2015-07-01

    The neurotoxic effects of N-methyl-N-nitrosourea (MNU) on the inner retinal neurons and related visual signal circuits have not been described in any animal models or human, despite ample morphological evidences about the MNU induced photoreceptor (PR) degeneration. With the helping of MEA (multielectrode array) recording system, we gained the opportunity to systemically explore the neural activities and visual signal pathways of MNU administrated rats. Our MEA research identified remarkable alterations in the electrophysiological properties and firstly provided instructive information about the neurotoxicity of MNU that affects the signal transmission in the inner retina. Moreover, the spatial electrophysiological functions of retina were monitored and found that the focal PRs had different vulnerabilities to the MNU. The MNU-induced PR dysfunction exhibited a distinct spatial- and time-dependent progression. In contrast, the spiking activities of both central and peripheral RGCs altered synchronously in response to the MNU administration. Pharmacological tests suggested that gap junctions played a pivotal role in this homogeneous response of RGCs. SNR analysis of MNU treated retina suggested that the signaling efficiency and fidelity of inner retinal circuits have been ruined by this toxicant, although the microstructure of the inner retina seemed relatively consolidated. The present study provided an appropriate example of MEA investigations on the toxicant induced pathological models and the effects of the pharmacological compounds on neuron activities. The positional MEA information would enrich our knowledge about the pathology of MNU induced RP models, and eventually be instrumental for elucidating the underlying mechanism of human RP. - Highlights: • We systemically explored the neural activities and visual signal pathways of MNU administrated retinas. • The focal photoreceptors had different vulnerabilities to the MNU administration.

  20. DEVELOPING AN EXPOSURE-DOSE-RESPONSE MODEL FOR THE ACUTE NEUROTOXICITY OF ORGANIC SOLVENTS: OVERVIEW AND PROGRESS ON IN VITRO MODELS AND DOSIMETRY.

    EPA Science Inventory

    This article provides an overview of the current status of an exposure-dose-response (EDR) model for the volatile organic compound toluene. This model is being developed as a vehicle for understanding the neurotoxicity of organic solvents and will be used to support risk assessme...

  1. ANALYSIS OF THE MOTOR NEUROTOXICITY INDUCED BY ACUTE ORAL EXPOSURE TO MULTIPLE PYRETHROID COMPOUNDS IN THE RAT USING AN ADDITIVITY MODEL.

    EPA Science Inventory

    Use of pyrethroids has increased in the last decade, and co-exposure to multiple pyrethroids has been reported in humans. Pyrethroids produce neurotoxicity in mammals at dosages far below those producing lethality. The Food Quality Protection Act requires the EPA to consider cumu...

  2. Effects of prenatal exposure to antipsychotic risperidone on developmental neurotoxicity, apoptotic neurodegeneration and neurobehavioral sequelae in rat offspring.

    PubMed

    Singh, K P; Singh, Manoj Kr; Singh, Manish

    2016-08-01

    A tremendous increase has been documented in the recent past in prescribing second generation atypical antipsychotic drugs (AAPDs) to the pregnant women with psychosis, considering their reproductive and teratogenic safety. Among AAPDs, risperidone (RIS) ranked third after olanzapine (OLZ) and quetiapine (QUE) used during pregnancy, as OLZ is associated to substantial weight gain in adults and offspring. Although teratogenic safety of RIS has been established, its potential role in developmental neurotoxicity and related neurobehavioral impairments in adolescents has not been documented so far. Therefore, present study has been undertaken to elucidate the effect of prenatal exposure to risperidone (RIS) on developmental neurotoxicity and apoptotic neurodegeneration in neocortical region of fetal brain; and related functional sequelae in young rat offspring. The pregnant Wistar rats were exposed to RIS at 0.8, 1.0 and 2.0mg/kg, at equivalent therapeutic doses, orally from GD 6 to 21. Half of the pregnant rats were sacrificed and their brains were collected, weighed, and processed for neurohistopathological and apoptotic neurodegenerative evaluation. The remaining dams were allowed to deliver naturally, and their offspring were reared up to 10 weeks for neurobehavioral study. Prenatal exposure to RIS induced significant stunting of fetal body and brain weight, substantial reduction in the thickness of neocortical layers and apoptotic neurodegeneration in fetal brains, and delayed postnatal development and growth of the offspring; as well as long- lasting impact on anxiety like impaired behavioral responses on explorative mazes. Therefore, health care providers should be careful in prescribing atypical antipsychotics in general and RIS in particular, to the pregnant psychotic population. PMID:27184437

  3. DEVELOPMENTAL NEUROTOXICITY OF PYRETHROID INSECTICIDES: CRITICAL REVIEW.

    EPA Science Inventory

    Pyrethroids are widely utilized insecticides whose primary action is the disruption of voltage-sensitive sodium channels (VSSC). Although these compounds have been in use for over 30 years and their acute neurotoxicity has been well characterized, there is considerably less info...

  4. Neurotoxic Profiles of HIV, Psychostimulant Drugs of Abuse, and their Concerted Effect on the Brain: Current Status of Dopamine System Vulnerability in NeuroAIDS

    PubMed Central

    Ferris, Mark J.; Mactutus, Charles F.; Booze, Rosemarie M.

    2008-01-01

    There are roughly 30 to 40 million HIV infected individuals in the world as of December 2007, and drug abuse directly contributes to one-third of all HIV-infections in the United States. Antiretroviral therapy has increased the lifespan of HIV-seropositives, but CNS function often remains diminished, effectively decreasing quality of life. A modest proportion may develop HIV-associated dementia, the severity and progression of which is increased with drug abuse. HIV and drugs of abuse in the CNS target subcortical brain structures and DA systems in particular. This toxicity is mediated by a number of neurotoxic mechanisms, including but not limited to, aberrant immune response and oxidative stress. Therefore, novel therapeutic strategies must be developed that can address a wide variety of disparate neurotoxic mechanisms and apoptotic cascades. This paper reviews the research pertaining to the where, what, and how of HIV and cocaine/methamphetamine toxicity in the CNS. Specifically, where these toxins most affect the brain, what aspects of the virus are neurotoxic, and how these toxins mediate neurotoxicity. PMID:18430470

  5. What is microglia neurotoxicity (Not)?

    PubMed

    Biber, Knut; Owens, Trevor; Boddeke, Erik

    2014-06-01

    Microglia most likely appeared early in evolution as they are not only present in vertebrates, but are also found in nervous systems of various nonvertebrate organisms. Mammalian microglia are derived from a specific embryonic, self-renewable myeloid cell population that is throughout lifetime not replaced by peripheral myeloid cells. These phylogenic and ontogenic features suggest that microglia serve vital functions. Yet, microglia often are described as neurotoxic cells, that actively kill (healthy) neurons. Since it is from an evolutionary point of view difficult to understand why an important and vulnerable organ like the brain should host numerous potential killers, we here review the concept of microglia neurotoxicity. On one hand it is discussed that most of our understanding about how microglia kill neurons is based on in vitro experiments or correlative staining studies that suffer from the difficulty to discriminate microglia and peripheral myeloid cells in the diseased brain. On the other hand it is described that a more functional approach by mutating, inactivating or deleting microglia is seldom associated with a beneficial outcome in an acute injury situation, suggesting that microglia are normally important protective elements in the brain. This might change in chronic disease or the aged brain, where; however, it remains to be established whether microglia simply lose their protective capacities or whether microglia become truly neurotoxic cells. PMID:24590682

  6. In vitro neurotoxic hazard characterisation of dinitrophenolic herbicides.

    PubMed

    Heusinkveld, Harm J; van Vliet, Arie C; Nijssen, Peter C G; Westerink, Remco H S

    2016-06-11

    Dinitrophenolic compounds are powerful toxicants with a long history of use in agriculture and industry. While (high) human exposure levels are not uncommon, in particular for agricultural workers during the spraying season, the neurotoxic mechanism(s) that underlie the human health effects are largely unknown. We therefore investigated the in vitro effects of two dinitrophenolic herbicides (DNOC and dinoseb) on a battery of neurotoxicity endpoints in (dopaminergic) rat PC12 cells. Cell viability, mitochondrial activity, oxidative stress and caspase activation were assessed using fluorescence-based bioassays (CFDA, alamar Blue, H2DCFDA and Ac-DEVD-AMC, respectively), whereas changes in intracellular [Ca(2+)]i were assessed using single-cell fluorescence microscopy with Fura-2AM. The combined results demonstrate that exposure to both DNOC and dinoseb is linked to calcium release from the endoplasmic reticulum and activation of caspase-mediated apoptotic pathways. In subsequent experiments, immunofluorescent labelling with specific antibodies was used to determine changes in intracellular α-synuclein levels, demonstrating that both DNOC and dinoseb increase levels of intracellular α-synuclein. The combined results indicate that in vitro exposure to DNOC and dinoseb activates pathways that are not only involved in acute neurotoxicity but also in long-term effects as seen in neurodegeneration. PMID:27106277

  7. Behavioural and neurotoxic effects of ayahuasca infusion (Banisteriopsis caapi and Psychotria viridis) in female Wistar rat.

    PubMed

    Pic-Taylor, Aline; da Motta, Luciana Gueiros; de Morais, Juliana Alves; Junior, Willian Melo; Santos, Alana de Fátima Andrade; Campos, Leandro Ambrósio; Mortari, Marcia Renata; von Zuben, Marcus Vinicius; Caldas, Eloisa Dutra

    2015-09-01

    Ayahuasca, a psychoactive beverage used by indigenous and religious groups, is generally prepared by the coction of Psychotria viridis and Banisteriopsis caapi plants containing N,N-dimethyltryptamine (DMT) and β-carboline alkaloids, respectively. To investigate the acute toxicity of ayahuasca, the infusion was administered by gavage to female Wistar rats at doses of 30X and 50X the dose taken during a religious ritual, and the animals observed for 14 days. Behavioural functions were investigated one hour after dosing at 15X and 30X using the open field, elevated plus maze, and forced swimming tests. Neuronal activation (c-fos marked neurons) and toxicity (Fluoro-Jade B and Nissl/Cresyl staining) were investigated in the dorsal raphe nuclei (DRN), amygdaloid nucleus, and hippocampal formation brain areas of rats treated with a 30X ayahuasca dose. The actual lethal oral dose in female Wistar rats could not be determined in this study, but was shown to be higher than the 50X (which corresponds to 15.1mg/kg bw DMT). The ayahuasca and fluoxetine treated groups showed a significant decrease in locomotion in the open field and elevated plus-maze tests compared to controls. In the forced swimming test, ayahuasca treated animals swam more than controls, a behaviour that was not significant in the fluoxetine group. Treated animals showed higher neuronal activation in all brain areas involved in serotoninergic neurotransmission. Although this led to some brain injury, no permanent damage was detected. These results suggest that ayahuasca has antidepressant properties in Wistar female at high doses, an effect that should be further investigated. PMID:26049017

  8. Biomarkers of adult and developmental neurotoxicity

    SciTech Connect

    Slikker, William

    2005-08-07

    Neurotoxicity may be defined as any adverse effect on the structure or function of the central and/or peripheral nervous system by a biological, chemical, or physical agent. A multidisciplinary approach is necessary to assess adult and developmental neurotoxicity due to the complex and diverse functions of the nervous system. The overall strategy for understanding developmental neurotoxicity is based on two assumptions: (1) significant differences in the adult versus the developing nervous system susceptibility to neurotoxicity exist and they are often developmental stage dependent; (2) a multidisciplinary approach using neurobiological, including gene expression assays, neurophysiological, neuropathological, and behavioral function is necessary for a precise assessment of neurotoxicity. Application of genomic approaches to developmental studies must use the same criteria for evaluating microarray studies as those in adults including consideration of reproducibility, statistical analysis, homogenous cell populations, and confirmation with non-array methods. A study using amphetamine to induce neurotoxicity supports the following: (1) gene expression data can help define neurotoxic mechanism(s) (2) gene expression changes can be useful biomarkers of effect, and (3) the site-selective nature of gene expression in the nervous system may mandate assessment of selective cell populations.

  9. Mitochondrial Electron Transport Chain in Heavy Metal-Induced Neurotoxicity: Effects of Cadmium, Mercury, and Copper

    PubMed Central

    Belyaeva, Elena A.; Sokolova, Tatyana V.; Emelyanova, Larisa V.; Zakharova, Irina O.

    2012-01-01

    To clarify the role of mitochondrial electron transport chain (mtETC) in heavy-metal-induced neurotoxicity, we studied action of Cd2+, Hg2+, and Cu2+ on cell viability, intracellular reactive oxygen species formation, respiratory function, and mitochondrial membrane potential of rat cell line PC12. As found, the metals produced, although in a different way, dose- and time-dependent changes of all these parameters. Importantly, Cd2+ beginning from 10 [mu]M and already at short incubation time (3 h) significantly inhibited the FCCP-uncoupled cell respiration; besides, practically the complete inhibition of the respiration was reached after 3 h incubation with 50 [mu]M Hg2+ or 500 [mu]M Cd2+, whereas even after 48 h exposure with 500 [mu]M Cu2+, only a 50% inhibition of the respiration occurred. Against the Cd2+-induced cell injury, not only different antioxidants and mitochondrial permeability transition pore inhibitors were protective but also such mtETC effectors as FCCP and stigmatellin (complex III inhibitor). However, all mtETC effectors used did not protect against the Hg2+- or Cu2+-induced cell damage. Notably, stigmatellin was shown to be one of the strongest protectors against the Cd2+-induced cell damage, producing a 15–20% increase in the cell viability. The mechanisms of the mtETC involvement in the heavy-metal-induced mitochondrial membrane permeabilization and cell death are discussed. PMID:22619586

  10. Organophosphate-induced delayed neurotoxicity of triarylphosphates.

    PubMed

    Weiner, M L; Jortner, B S

    1999-08-01

    This paper reviews the characteristics of organophosphate-induced delayed neurotoxicity, its mechanism, lesions, species sensitivities and structure activity-relationships as they relate to the class of compounds known as triaryl phosphates. The triaryl phosphates have been widely used in commerce for over thirty years as flame retardants in fluids and plastics. Concern has been raised regarding their potential to cause organophosphate-induced delayed neurotoxicity (OPIDN), due to structural similarities to the potent neurotoxicant, tri-ortho cresyl phosphate (TOCP). Based on research on many pure isomers, Johnson (1975a, 1975b) found that certain structural features are required for a triaryl phosphate to react with the enzyme, neuropathy target enzyme (NTE), in a manner which induces OPIDN. Results of acute hen OPIDN studies, the experimental model of choice, support his findings as regards the structure-activity relationships for commercial triaryl phosphates. Thus, standard acute hen OPIDN studies on triphenyl phosphate and butylated triaryl phosphates fail to demonstrate a potential to elicit OPIDN by these products after a single dose. Studies on the mixed isopropyl phenyl phosphates indicate that, while some are neurotoxic, they are much less potent than tricresyl phosphate (TCP) and TOCP in the induction of OPIDN. Most commercial isopropylated triaryl phosphates lacked the potential to induce acute OPIDN using a limit dose of 2000 mg/kg. Although in early studies these compounds appeared to be neurotoxic, they were generally tested at excessively high doses, often exceeding 10,000 mg/kg in acute hen OPIDN studies. In contrast to the isopropylated and butylated triaryl phosphate products, TCP, and especially its ortho substituted isomer, TOCP, were found to be neurotoxic in both acute and subchronic hen OPIDN studies. Recent advances in the synthesis of commercial TCP products have resulted in products with reduced neurotoxic potential (McCormick et al, 1993

  11. EVALUATION OF POTENTIAL DEVELOPMENTAL NEUROTOXICITY OF ORGANOTINS.

    EPA Science Inventory

    Organotins, including monomethyltin (MMT), dimethyltin (DMT), and dibutyltin (DBT), are widely used as heat stabilizers in PVC and CPVC piping, which results in their presence in drinking water supplies. Concern for developmental neurotoxic effects were raised by published findi...

  12. Colistin-mediated neurotoxicity

    PubMed Central

    Wadia, Subeer; Tran, Betty

    2014-01-01

    We describe a 51-year-old man who developed renal and neural toxicity after the administration of colistin. He developed respiratory apnoea, neuromuscular blockade and severe comatose encephalopathy with the lack of brainstem reflexes. After discontinuation of the antibiotic, he made a prompt recovery to his baseline neurological function. The case illustrates the importance of recognising the toxicities associated with colistin. Although recent literature details its nephrotoxicity, current data have been discordant with the rare cases of respiratory apnoea or neuromuscular blockade once cited over 30 years ago. Additionally, no cases have ever described the profound encephalopathy with lack of brainstem function described here. The awareness of colistin's potentially fatal effects must be kept in mind when administering this antibiotic. Vigilance of the encephalopathic picture can also facilitate the diagnosis of colistin-mediated neurotoxicity in a patient with altered mental status of otherwise unknown aetiology. PMID:25199193

  13. GLIA AND METHYLMERCURY NEUROTOXICITY

    PubMed Central

    Ni, Mingwei; Li, Xin; Rocha, João B. T.; Farina, Marcelo; Aschner, Michael

    2014-01-01

    Methylmercury (MeHg) is a global environmental pollutant with significant adverse effects on human health. As the major target of MeHg, the central nervous system (CNS) exhibits the most recognizable poisoning symptoms. The role of the two major nonneuronal cell types, astrocytes and microglia, in response to MeHg exposure was recently compared. These two cell types share several common features in MeHg toxicity, but interestingly, these cells types also exhibit distinct response kinetics, indicating a cell-specific role in mediating MeHg-induced neurotoxicity. The aim of this study was to review the most recent literature and summarize key features of glial responses to this organometal. PMID:22852858

  14. Neurotoxicity of industrial and commercial chemicals

    SciTech Connect

    O'Donoghue, J.L.

    1985-01-01

    This book presents a collection of information on the neurotoxicity of chemicals used in industry or having commercial value. Chemicals reported to cause a variety of effects on the nervous system are thoroughly reviewed. Exposure data, clinical manifestations, pathology, experimental neurology, metabolism, and structure activity correlates are integrated and presented by the anatomical and functional areas of the nervous systems affected, and also by chemical classes with neurotoxic effects. Much of the information is presented in tabular format.

  15. Inhibitory effect of fangchinoline on excitatory amino acids-induced neurotoxicity in cultured rat cerebellar granule cells.

    PubMed

    Kim, S D; Oh, S K; Kim, H S; Seong, Y H

    2001-04-01

    Glutamate receptors-mediated excitotoxicity is believed to play a role in the pathophysiology of neurodegenerative diseases. The present study was performed to evaluate the inhibitory effect of fangchinoline, a bis-benzylisoquinoline alkaloid, which has a characteristic as a Ca2+ channel blocker, on excitatory amino acids (EAAs)-induced neurotoxicity in cultured rat cerebellar granule neuron. Fangchinoline (1 and 5 microM) inhibited glutamate (1 mM), N-methyl-D-aspartate (NMDA; 1 mM) and kainate (100 microM)-induced neuronal cell death which was measured by trypan blue exclusion test. Fangchinoline (1 and 5 microM) inhibited glutamate release into medium induced by NMDA (1 mM) and kainate (100 microM), which was measured by HPLC. And fangchinoline (5 microM) inhibited glutamate (1 mM)-induced elevation of intracellular calcium concentration. These results suggest that inhibition of Ca2+ influx by fangchinoline may contribute to the beneficial effects on neurodegenerative effect of glutamate in pathophysiological conditions. PMID:11339637

  16. Effects of chronic exposure to benzalkonium chloride in Oncorhynchus mykiss: cholinergic neurotoxicity, oxidative stress, peroxidative damage and genotoxicity.

    PubMed

    Antunes, S C; Nunes, B; Rodrigues, S; Nunes, R; Fernandes, J; Correia, A T

    2016-07-01

    Benzalkonium chloride (BAC) is one of the most used conservatives in pharmaceutical preparations. However, its use is limited to a small set of external use formulations, due to its high toxicity. Benzalkonium chloride effects are related to the potential exertion of deleterious effects, mediated via oxidative stress and through interaction with membrane enzymes, leading to cellular damage. To address the ecotoxicity of this specific compound rainbow trouts were chronically exposed to BAC at environmental relevant concentrations (ranging from 0.100 to 1.050mg/L), and the biological response of cholinergic neurotoxicity, modulation of the antioxidant defense, phase II metabolism, lipid peroxidation and genotoxicity was studied. The obtained results showed a dual pattern of antioxidant response, with significant alterations in catalase activity (starting at 0.180mg/L), and lipid peroxidation, for intermediate (0.180 and 0.324mg/L) concentrations. No significant alterations occurred for glutathione-S-transferases activity. An unexpected increased of the acetylcholinesterase activity was also recorded for the individuals exposed to higher concentrations of BAC (starting at 0.180mg/L). Furthermore, exposure to BAC resulted in the establishment of genotoxic alterations, observable (for the specific case of the comet assay results) for all tested BAC concentrations. However, and considering that the oxidative response was not devisable, other mechanisms may be involved in the genotoxic effects reported here. PMID:27280532

  17. Toxicological screening for organophosphorous-induced delayed neurotoxicity: complications in toxicity testing

    SciTech Connect

    Not Available

    1983-01-01

    Organophosphorus-induced delayed neurotoxicity (OPIDN) is discussed. The clinical signs of OPIDN are temporally distinct from the acute anti/acetylcholinesterase (AChE) effect and the syndrome of motor end plate inhibition. OPIDN occurs 6 to 21 days after oral, inhalation, or dermal exposure and its development is independent of an acute cholinergic reaction. The clinical signs include progressive weakness and ataxia beginning distally in the hind or lower limbs and may evolve into a flaccid paralysis that may also extend to the forelimbs. The role of toxicology and possible addenda to current screening procedures for detecting OPIDN are discussed. It is concluded that the range and prevalence of neurotoxic effects of organophosphorus pesticides are greater than expected, when considered from the standpoint of current regulatory and surveillance efforts. As a minimum, every organophosphorus ester that is in commercial use should be characterized as to its ability to induce OPIDN.

  18. The effects of aqueous extract of Lavandula angustifolia flowers in glutamate-induced neurotoxicity of cerebellar granular cell culture of rat pups.

    PubMed

    Büyükokuroğlu, Mehmet Emin; Gepdiremen, Akçahan; Hacimüftüoğlu, Ahmet; Oktay, Münir

    2003-01-01

    In the present study, neuroprotective effect of Lavandula angustifolia flower aqueous extract in glutamate-induced neurotoxicity in rat pups cerebellar granular cell culture was investigated. The extract at doses of 10 microg ml(-1), 100 microg ml(-1), 1 mg ml(-1) and 10 mg ml(-1) was applied to culture flasks. The extract at doses of 100 microg ml(-1) and 1 mg ml(-1) significantly blocked glutamate-induced neurotoxicity, with the most effective dose being 1 mg ml(-1). On the other hand, 10 mg ml(-1) dose of extract increased the dead cell with respect to glutamate group, despite being found insignificant statistically. As a result, L. angustifolia protected the neurons against glutamate toxicity. PMID:12499081

  19. An animal model to study toxicity of central nervous system therapy for childhood acute lymphoblastic leukemia: Effects on behavior

    SciTech Connect

    Mullenix, P.J.; Kernan, W.J.; Tassinari, M.S.; Schunior, A.; Waber, D.P.; Howes, A.; Tarbell, N.J. )

    1990-10-15

    Central nervous system prophylactic therapy used in the treatment of acute lymphoblastic leukemia can reduce intelligence quotient scores and impair memory and attention in children. Cranial irradiation, intrathecal methotrexate, and steroids are commonly utilized in acute lymphoblastic leukemia therapy. How they induce neurotoxicity is unknown. This study employs an animal model to explore the induction of neurotoxicity. Male and female Sprague-Dawley rats at 17 and 18 days of age were administered 18 mg/kg prednisolone, 2 mg/kg methotrexate, and 1000 cGy cranial irradiation. Another 18-day-old group was administered 1000 cGy cranial irradiation but no drugs. Matching controls received saline and/or a sham exposure to radiation. All animals at 6 weeks and 4 months of age were tested for alterations in spontaneous behavior. A computer pattern recognition system automatically recorded and classified individual behavioral acts displayed during exploration of a novel environment. Measures of behavioral initiations, total time, and time structure were used to compare treated and control animals. A permanent sex-specific change in the time structure of behavior was induced by the prednisolone, methotrexate, and radiation treatment but not by radiation alone. Unlike hyperactivity, the effect consisted of abnormal clustering and dispersion of acts in a pattern indicative of disrupted development of sexually dimorphic behavior. This study demonstrates the feasibility of an animal model delineating the agent/agents responsible for the neurotoxicity of central nervous system prophylactic therapy.

  20. Protective effects of apigenin against 1-methyl-4-phenylpyridinium ion‑induced neurotoxicity in PC12 cells.

    PubMed

    Liu, Weihai; Kong, Songzhi; Xie, Qingfeng; Su, Jiyan; Li, Wenjie; Guo, Huizhen; Li, Shanshan; Feng, Xuexuan; Su, Ziren; Xu, Yang; Lai, Xiaoping

    2015-03-01

    Parkinson's disease is recognized as the second most common neurodegenerative disorder after Alzheimer's disease, characterized by the loss of dopominergic neurons in the substantia nigra pars compacta and can be experimentally mimicked by the use of the neurotoxin, 1‑methyl‑4‑phenylpyridinium ion (MPP(+)), in in vitro models. In this study, we investigated the potential protective effects of apigenin (AP), galangin and genkwanin, naturally occurring plant flavonoids, on the MPP(+)‑induced cytotoxicity in cultured rat adrenal pheochromocytoma cells (PC12 cells). The PC12 cells were pre-treated with various concentrations of the test compounds for 4 h, followed by the challenge with 1,000 µM MPP(+) for 48 h. We found that only pre-treatment with AP (3, 6 and 12 µM) before injury significantly increased cell viability, decreased the release of lactate dehydrogenase, reduced the level of intracellular reactive oxygen species and elevated mitochondrial membrane potential in the MPP(+)‑treated PC12 cells. In addition, AP markedly suppressed the increased rate of apoptosis and the reduced Bcl‑2/Bax ratio induced by MPP(+) in the PC12 cells. Taken together, the findings of this study demonstrate that AP exerts neuroprotective effects against MPP(+)‑induced neurotoxicity in PC12 cells, at least in part, through the inhibition of oxidative damage and the suppression of apoptosis through the mitochondrial pathway. PMID:25573459

  1. The Neuroprotective Effect of Erythropoietin on Rotenone-Induced Neurotoxicity in SH-SY5Y Cells Through the Induction of Autophagy.

    PubMed

    Jang, Wooyoung; Kim, Hee Ju; Li, Huan; Jo, Kwang Deog; Lee, Moon Kyu; Yang, Hyun Ok

    2016-08-01

    Currently, the autophagy pathway is thought to be important for the pathogenesis of Parkinson's disease (PD), and the modulation of autophagy may be a novel strategy for the treatment of this disease. Erythropoietin (EPO) has been reported to have neuroprotective effects through anti-oxidative, anti-apoptotic, and anti-inflammatory mechanisms, and it has also been shown to modulate autophagy signaling in an oxygen toxicity model. Therefore, we investigated the effects of EPO on autophagy markers and evaluated its neuroprotective effect on rotenone-induced neurotoxicity. We adapted the rotenone-induced neurotoxicity model to SH-SY5Y cells as an in vitro model of PD. We measured cell viability using MTT and annexin V/propidium iodide assays and measured intracellular levels of reactive oxygen species. Immunofluorescence analysis was performed to measure the expression of LC3 and α-synuclein. Intracellular signaling proteins associated with autophagy were examined by immunoblot analysis. EPO mono-treatment increased the levels of mammalian target of rapamycin (mTOR)-independent/upstream autophagy markers, including Beclin-1, AMPK, and ULK-1. Rotenone treatment of SH-SY5Y cells reduced their viability, increased reactive oxygen species levels, and induced apoptosis and α-synuclein expression, and simultaneous exposure to EPO significantly reduced these effects. Rotenone enhanced mTOR expression and suppressed Beclin-1 expression, indicating suppression of the autophagy system. However, combined treatment with EPO restored Beclin-1 expression and decreased mTOR expression. EPO protects against rotenone-induced neurotoxicity in SH-SY5Y cells by enhancing autophagy-related signaling pathways. The experimental evidence for the EPO-induced neuroprotection against rotenone-induced dopaminergic neurotoxicity may significantly impact the development of future PD treatment strategies. PMID:26156288

  2. Platinum-induced neurotoxicity and preventive strategies: past, present, and future.

    PubMed

    Avan, Abolfazl; Postma, Tjeerd J; Ceresa, Cecilia; Avan, Amir; Cavaletti, Guido; Giovannetti, Elisa; Peters, Godefridus J

    2015-04-01

    Neurotoxicity is a burdensome side effect of platinum-based chemotherapy that prevents administration of the full efficacious dosage and often leads to treatment withdrawal. Peripheral sensory neurotoxicity varies from paresthesia in fingers to ataxic gait, which might be transient or irreversible. Because the number of patients being treated with these neurotoxic agents is still increasing, the need for understanding the pathogenesis of this dramatic side effect is critical. Platinum derivatives, such as cisplatin and carboplatin, harm mainly peripheral nerves and dorsal root ganglia neurons, possibly because of progressive DNA-adduct accumulation and inhibition of DNA repair pathways (e.g., extracellular signal-regulated kinase 1/2, c-Jun N-terminal kinase/stress-activated protein kinase, and p38 mitogen-activated protein kinass), which finally mediate apoptosis. Oxaliplatin, with a completely different pharmacokinetic profile, may also alter calcium-sensitive voltage-gated sodium channel kinetics through a calcium ion immobilization by oxalate residue as a calcium chelator and cause acute neurotoxicity. Polymorphisms in several genes, such as voltage-gated sodium channel genes or genes affecting the activity of pivotal metal transporters (e.g., organic cation transporters, organic cation/carnitine transporters, and some metal transporters, such as the copper transporters, and multidrug resistance-associated proteins), can also influence drug neurotoxicity and treatment response. However, most pharmacogenetics studies need to be elucidated by robust evidence. There are supportive reports about the effectiveness of several neuroprotective agents (e.g., vitamin E, glutathione, amifostine, xaliproden, and venlafaxine), but dose adjustment and/or drug withdrawal seem to be the most frequently used methods in the management of platinum-induced peripheral neurotoxicity. To develop alternative options in the treatment of platinum-induced neuropathy, studies on in vitro

  3. Platinum-Induced Neurotoxicity and Preventive Strategies: Past, Present, and Future

    PubMed Central

    Avan, Abolfazl; Postma, Tjeerd J.; Ceresa, Cecilia; Avan, Amir; Cavaletti, Guido; Giovannetti, Elisa

    2015-01-01

    Neurotoxicity is a burdensome side effect of platinum-based chemotherapy that prevents administration of the full efficacious dosage and often leads to treatment withdrawal. Peripheral sensory neurotoxicity varies from paresthesia in fingers to ataxic gait, which might be transient or irreversible. Because the number of patients being treated with these neurotoxic agents is still increasing, the need for understanding the pathogenesis of this dramatic side effect is critical. Platinum derivatives, such as cisplatin and carboplatin, harm mainly peripheral nerves and dorsal root ganglia neurons, possibly because of progressive DNA-adduct accumulation and inhibition of DNA repair pathways (e.g., extracellular signal-regulated kinase 1/2, c-Jun N-terminal kinase/stress-activated protein kinase, and p38 mitogen-activated protein kinass), which finally mediate apoptosis. Oxaliplatin, with a completely different pharmacokinetic profile, may also alter calcium-sensitive voltage-gated sodium channel kinetics through a calcium ion immobilization by oxalate residue as a calcium chelator and cause acute neurotoxicity. Polymorphisms in several genes, such as voltage-gated sodium channel genes or genes affecting the activity of pivotal metal transporters (e.g., organic cation transporters, organic cation/carnitine transporters, and some metal transporters, such as the copper transporters, and multidrug resistance-associated proteins), can also influence drug neurotoxicity and treatment response. However, most pharmacogenetics studies need to be elucidated by robust evidence. There are supportive reports about the effectiveness of several neuroprotective agents (e.g., vitamin E, glutathione, amifostine, xaliproden, and venlafaxine), but dose adjustment and/or drug withdrawal seem to be the most frequently used methods in the management of platinum-induced peripheral neurotoxicity. To develop alternative options in the treatment of platinum-induced neuropathy, studies on in vitro

  4. Molecular and cellular mechanisms of ecstasy-induced neurotoxicity: an overview.

    PubMed

    Capela, João Paulo; Carmo, Helena; Remião, Fernando; Bastos, Maria Lourdes; Meisel, Andreas; Carvalho, Félix

    2009-06-01

    "Ecstasy" [(+/-)-3,4-methylenedioxymethamphetamine, MDMA, XTC, X, E] is a psychoactive recreational hallucinogenic substance and a major worldwide drug of abuse. Several reports raised the concern that MDMA has the ability to induce neurotoxic effects both in laboratory animals and humans. Despite more than two decades of research, the mechanisms by which MDMA is neurotoxic are still to be fully elucidated. MDMA induces serotonergic terminal loss in rats and also in some mice strains, but also a broader neuronal degeneration throughout several brain areas such as the cortex, hippocampus, and striatum. Meanwhile, in human "ecstasy" abusers, there are evidences for deficits in seronergic biochemical markers, which correlate with long-term impairments in memory and learning. There are several factors that contribute to MDMA-induced neurotoxicity, namely, hyperthermia, monoamine oxidase metabolism of dopamine and serotonin, dopamine oxidation, the serotonin transporter action, nitric oxide, and the formation of peroxinitrite, glutamate excitotoxicity, serotonin 2A receptor agonism, and, importantly, the formation of MDMA neurotoxic metabolites. The present review covered the following topics: history and epidemiology, pharmacological mechanisms, metabolic pathways and the influence of isoenzyme genetic polymorphisms, as well as the acute effects of MDMA in laboratory animals and humans, with a special focus on MDMA-induced neurotoxic effects at the cellular and molecular level. The main aim of this review was to contribute to the understanding of the cellular and molecular mechanisms involved in MDMA neurotoxicity, which can help in the development of therapeutic approaches to prevent or treat the long-term neuropsychiatric complications of MDMA abuse in humans. PMID:19373443

  5. Neuroprotective effect of Decalepis hamiltonii in paraquat-induced neurotoxicity in Drosophila melanogaster: biochemical and behavioral evidences.

    PubMed

    Jahromi, Samaneh Reiszadeh; Haddadi, Mohammad; Shivanandappa, T; Ramesh, S R

    2013-12-01

    In this paper, we have demonstrated for the first time, the antioxidant and neuroprotective effects of Decalepis hamiltonii (Dh) root extract against paraquat (PQ)-induced oxidative stress and neurotoxicity in Drosophila melanogaster. Exposure of adult D. melanogaster (Oregon K) to PQ induced oxidative stress as evidenced by glutathione depletion, lipid peroxidation and enhanced activities of antioxidant enzymes such as catalase, superoxide dismutase as well as elevated levels of acetylcholine esterase. Pretreatment of flies by feeding with Dh extract (0.1, 0.5 %) for 14 days boosted the activities of antioxidant enzymes and prevented the PQ-induced oxidative stress. Dietary feeding of Dh extract prior to PQ exposure showed a lower incidence of mortality and enhanced motor activities of flies in a negative geotaxis assay; both suggesting the neuroprotective potential of Dh. Based on the results, we contemplate that the roots of Dh might prevent and ameliorate the human diseases caused by oxidative stress. The neuroprotective action of Dh can be attributed to the antioxidant constituents while the precise mechanism of its action needs further investigations. PMID:24173775

  6. SPECIES AND STRAIN COMPARISON OF ACUTE NEUROTOXIC EFFECTS OF TRIMETHYLTIN IN MICE AND RATS

    EPA Science Inventory

    Pathological changes in the central nervous system in two strains of mice (BALB/c and C57BL/6) and two strains of rats as a result of trimethyltin (TMT) intoxication were compared. Both strains of mice were administered with trimethyltin chloride at a dosage of 3.0 mg TMT-C1/kg b...

  7. Beneficial effect of a novel pentadecapeptide BPC 157 on gastric lesions induced by restraint stress, ethanol, indomethacin, and capsaicin neurotoxicity.

    PubMed

    Sikirić, P; Seiwerth, S; Grabarević, Z; Rucman, R; Petek, M; Jagić, V; Turković, B; Rotkvić, I; Mise, S; Zoricić, I; Gjurasin, M; Konjevoda, P; Separović, J; Ljubanović, D; Artuković, B; Bratulić, M; Tisljar, M; Jurina, L; Buljat, G; Miklić, P; Marović, A

    1996-08-01

    Very recently, the integrity of capsaicin somatosensory neurons and their protection were suggested to be related to the activity in nociception of a newly discovered 15-amino acid peptide, BPC 157, shown to have strong beneficial effect on intestinal and liver lesions. Therefore, from this viewpoint, we have studied the gastroprotective effect of the pentadecapeptide BPC 157, on gastric lesions produced in rats by 96% ethanol, restraint stress, and indomethacin. The possible involvement of sensory neurons in the salutary actions of BPC 157 (10 micrograms/kg, 10 ng/kg intraperitoneally) was studied with capsaicin, which has differential effects on sensory neurons: a high dose in adult (125 mg/kg subcutaneously, 3 months old) or administration (50 mg/kg subcutaneously) to neonatal animals (age of the 7 days) destroys sensory fibers, whereas a low dose (500 micrograms/kg intraperitoneally) activates neurotransmitter release and protective effects on the mucosa. In the absence of capsaicin, BPC 157 protected gastric mucosa against ethanol, restraint, and indomethacin application. In the presence of neurotoxic doses of capsaicin, the negative influence of capsaicin on restraint, ethanol, or indomethacin lesions consistently affected salutary activity of BPC 157. However, BPC 157 protection was still evident in the capsaicin-treated rats (either treated as adults or as newborns) in all of these assays. Interestingly, after neonatal capsaicin treatment, a complete abolition of BPC gastroprotection was noted if BPC 157 was applied as a single nanogram-regimen, but the mucosal protection was fully reversed when the same dose was used daily. In line with the excitatory dose of capsaicin the beneficial effectiveness of BPC 157 appears to be increased as well. Taken together, these data provide evidence for complex synergistic interaction between the beneficial effectiveness of BPC 157 and peptidergic sensory afferent neuron activity. PMID:8769287

  8. Studies on the potential neurotoxic and convulsant effects of increased blood levels of quinolinic acid in rats with altered blood-brain barrier permeability

    SciTech Connect

    Vezzani, A.; Stasi, M.A.; Wu, H.Q.; Castiglioni, M.; Weckermann, B.; Samanin, R. )

    1989-10-01

    Intravenous injection of 450 mg/kg quinolinic acid (Quin), an endogenous kynurenine metabolite with excitotoxic properties, induced only minor electroencephalographic (EEG) modifications and no neurotoxicity in rats with a mature blood-brain barrier (BBB). BBB permeability was altered in rats by focal unilateral irradiation of the cortex (7 mm in diameter and 5 mm in depth) with protons (60 Gy, 9 Gy/min). Three days after irradiation, Evans blue dye staining showed BBB breakdown in the dorsal hippocampus of the irradiated hemisphere. No neurotoxic or convulsant effects were observed as a consequence of the radiation itself. When BBB-lesioned rats were challenged with 225 mg/kg Quin iv, epileptiform activity was observed on EEG analysis. Tonic-clonic seizures were induced by 225-450 mg/kg Quin. Light microscopic analysis showed a dose-related excitotoxic type of lesion restricted to the hippocampus ipsilateral to the irradiated side. Neuro-degeneration was prevented by local injection of 120 nmol D(-)2-amino-7-phosphonoheptanoic acid, a selective N-methyl-D-aspartate receptor antagonist. No lesions or EEG or behavioral modifications occurred after 450 mg/kg nicotinic acid, an inactive analog of Quin. The potential neurotoxic and convulsant effects of increased blood levels of Quin under conditions of altered BBB permeability are discussed.

  9. The neurotrophic factor pleiotrophin modulates amphetamine-seeking behaviour and amphetamine-induced neurotoxic effects: evidence from pleiotrophin knockout mice.

    PubMed

    Gramage, Esther; Putelli, Alessia; Polanco, Maria J; González-Martín, Carmen; Ezquerra, Laura; Alguacil, Luis F; Pérez-Pinera, Pablo; Deuel, Thomas F; Herradón, Gonzalo

    2010-10-01

    Pleiotrophin (PTN), a neurotrophic factor with important roles in survival and differentiation of dopaminergic neurons, is up-regulated in the nucleus accumbens after amphetamine administration suggesting that PTN could modulate amphetamine-induced pharmacological or neuroadaptative effects. To test this hypothesis, we have studied the effects of amphetamine administration in PTN genetically deficient (PTN -/-) and wild type (WT, +/+) mice. In conditioning studies, we found that amphetamine induces conditioned place preference in both PTN -/- and WT (+/+) mice. When these mice were re-evaluated after a 5-day period without amphetamine administration, we found that WT (+/+) mice did not exhibit amphetamine-seeking behaviour, whereas, PTN -/- mice still showed a robust drug-seeking behaviour. In immunohystochemistry studies, we found that amphetamine (10 mg/kg, four times, every 2 hours) causes a significant increase of glial fibrillary acidic protein positive cells in the striatum of amphetamine-treated PTN -/- mice compared with WT mice 4 days after last administration of the drug, suggesting an enhanced amphetamine-induced astrocytosis in the absence of endogenous PTN. Interestingly, we found in concomitant in vitro studies that PTN (3 µM) limits amphetamine (1 mM)-induced loss of viability of PC12 cell cultures, effect that could be related to the ability of PTN to induce the phosphorylation of Akt and ERK1/2. To test this possibility, we used specific Akt and ERK1/2 inhibitors uncovering for the first time that PTN-induced protective effects against amphetamine-induced toxicity in PC12 cells are mediated by the ERK1/2 signalling pathway. The data suggest an important role of PTN to limit amphetamine-induced neurotoxic and rewarding effects. PMID:20192945

  10. Protective effects of Forsythia suspense extract with antioxidant and anti-inflammatory properties in a model of rotenone induced neurotoxicity.

    PubMed

    Zhang, Shuai; Shao, Si-Yuan; Song, Xiu-Yun; Xia, Cong-Yuan; Yang, Ya-Nan; Zhang, Pei-Cheng; Chen, Nai-Hong

    2016-01-01

    The present study investigated the neuroprotective effects of Forsythia suspense extract in a rotenone-induced neurotoxic model. FS8, one of the herbal extracts, markedly protected PC12 cells against rotenone toxicity and was selected for the in vivo study. Gavage administration of FS8 (50 and 200mg/kg, but not 10mg/kg) for 25 days significantly improved the behavior function, decreased the loss of dopaminergic neurons in substantia nigra (SN), and maintained the level of dopamine in striatum after unilateral infusion of rotenone in SN. Wherein, the protective effects of FS8 at the dose of 200mg/kg were better than selegiline. Further study indicated the excellent antioxidant activity of FS8 on the 5th and 21st days after intranigral injection of rotenone. Moreover, FS8 could inhibit microglia activity and accumulation in SN, and obviously decreased the expression of pro-inflammatory molecules (IL-6, TNF-α, iNOS and COX-2), which indicated the anti-inflammatory effects of FS8. In the PI3K/Akt/NF-κB and MAPK pathways, FS8 significantly down-regulated the protein expression of p-PI3K, p-Akt, p-IκB, p-P65, cleaved Caspase 8, p-p38 and p-JNK but not p-mTOR, cleaved Caspase 3 and p-ERK. Therefore, FS8 protected dopamine neurons against rotenone toxicity via antioxidant and anti-inflammatory effects, which suggested the promising application of FS8 in the prevention and treatment of Parkinson disease. PMID:26408940

  11. Clinical assessment of bilirubin-induced neurotoxicity in premature infants.

    PubMed

    Amin, Sanjiv B

    2004-10-01

    The clinical assessment of bilirubin-induced neurotoxicity in premature infants remains difficult in the absence of a gestational age-specific total or free (unbound) bilirubin level that predicts bilirubin-induced neurotoxicity. Because the total serum bilirubin concentration is an unreliable predictor of bilirubin-induced neurotoxicity in premature infants, alternative mean for predicting bilirubin-induced neurotoxicity in jaundiced preterm newborns is needed. Over the last few years, we have witnessed substantial gain in our knowledge involving usefulness of bilirubin-binding variables (total bilirubin, free bilirubin, bilirubin:albumin molar ratio) for clinical assessment of bilirubin-induced neurotoxicity in preterm infants. The knowledge gained has provided impetus for more clinical studies that are geared toward confirming the usefulness of free bilirubin as a predictor of bilirubin-induced neurotoxicity and identifying the gestational age-specific free bilirubin level that may increase the risk of bilirubin-induced neurotoxicity in premature infants. The paper has attempted to provide an overview of bilirubin-induced auditory toxicity along with the existing clinical evidence in favor of free bilirubin assay and usefulness of auditory brainstem evoked response for evaluation of bilirubin-induced neurotoxicity in premature infants. In addition, the author has described findings that suggest an association of apnea, a clinical manifestation, with acute bilirubin encephalopathy in premature infants. PMID:15686265

  12. Comparative protective effects of royal jelly and cod liver oil against neurotoxic impact of tartrazine on male rat pups brain.

    PubMed

    Mohamed, Amany Abdel-Rahman; Galal, Azza A A; Elewa, Yaser H A

    2015-09-01

    This study is aimed to evaluate the possible neurotoxic effect of tartrazine (T), an extensively used synthetic azo dye, as well as to determine the potential modulatory role of cod liver oil (CLO) or royal jelly (RJ) against such effects. For this purpose, thirty-six male rat pups were allocated into six groups. The 1st group received distilled water (control group), the 2nd group was given 300 mg RJ/kg bw (RJ group), the 3rd group was given 0.4 ml CLO/kg bw (CLO group), the 4th was given 500 mg T/kg bw (T group). The 5th group was given T concurrently with RJ (TRJ group) and the 6th group was given T concurrently with CLO (TCLO group), at the same doses as the former groups. All treatments were given orally for 30 consecutive days. The concentrations of different brain neurotransmitters, gamma amino butyric acid (GABA), dopamine (DA) and serotonin (5HT) as well as the antioxidant and oxidative stress biomarkers were measured in the brain homogenates. An immunohistochemical staining of the cerebral cortex was applied with the anti-ssDNA antibody (an apoptotic cell marker) to reveal the changes in brain structure. The T group revealed a significant decrease in the concentration of the brain neurotransmitters, a sharp shortage in the level of antioxidant biomarkers (super oxide dismutase, catalase and the reduced glutathione), a marked increase in malondialdehyde levels, and numerous apoptotic cells in the brain cortex compared with the other groups. Interestingly, all the previously mentioned parameters were almost retrieved in both the TRJ and TCLO groups compared to the T group. These results conclusively demonstrate that RJ and CLO administration provides sufficient protection against the ruinous effects of T on rat pups brain tissue function and structure. PMID:26190785

  13. Local Anesthetic-Induced Neurotoxicity

    PubMed Central

    Verlinde, Mark; Hollmann, Markus W.; Stevens, Markus F.; Hermanns, Henning; Werdehausen, Robert; Lirk, Philipp

    2016-01-01

    This review summarizes current knowledge concerning incidence, risk factors, and mechanisms of perioperative nerve injury, with focus on local anesthetic-induced neurotoxicity. Perioperative nerve injury is a complex phenomenon and can be caused by a number of clinical factors. Anesthetic risk factors for perioperative nerve injury include regional block technique, patient risk factors, and local anesthetic-induced neurotoxicity. Surgery can lead to nerve damage by use of tourniquets or by direct mechanical stress on nerves, such as traction, transection, compression, contusion, ischemia, and stretching. Current literature suggests that the majority of perioperative nerve injuries are unrelated to regional anesthesia. Besides the blockade of sodium channels which is responsible for the anesthetic effect, systemic local anesthetics can have a positive influence on the inflammatory response and the hemostatic system in the perioperative period. However, next to these beneficial effects, local anesthetics exhibit time and dose-dependent toxicity to a variety of tissues, including nerves. There is equivocal experimental evidence that the toxicity varies among local anesthetics. Even though the precise order of events during local anesthetic-induced neurotoxicity is not clear, possible cellular mechanisms have been identified. These include the intrinsic caspase-pathway, PI3K-pathway, and MAPK-pathways. Further research will need to determine whether these pathways are non-specifically activated by local anesthetics, or whether there is a single common precipitating factor. PMID:26959012

  14. Multiple mechanisms of PCB neurotoxicity

    SciTech Connect

    Carpenter, D.O.; Stoner, C.T.; Lawrence, D.A.

    1996-12-31

    Polychlorinated biphenyls (PCBs) have been implicated in cancer, but many of the symptoms in humans exposed to PCBs are related to the nervous system and behavior. We demonstrated three different direct mechanisms whereby PCBs are neurotoxic in rats. By using flow cytometry, we demonstrated that the orthosubstituted PCB congener 2,4,4{prime}, but neither TCDD nor the coplanar PCB congener 3,4,5,3{prime},4{prime}, causes rapid death of cerebellar granule cells. The ortho-substituted congener 2,4,4{prime} reduced long-term potentiation, an indicator of cognitive potential, in hippocampal brain slices, but a similar effect was observed for the coplanar congener 3,4,3{prime},4{prime}, indicating that this effect may be caused by both ortho- and coplanar congeners by mechanisms presumably not mediated via the Ah receptor. It was previously shown that some ortho-substituted PCB congeners cause a reduction in levels of the neurotransmitter dopamine, and we present in vitro and in vivo evidence that this is due to reduction of synthesis of dopamine via inhibition of the enzyme tyrosine hydroxylase. Thus, PCBs have a variety of mechanisms of primary neurotoxicity, and neurotoxicity is a characteristic of ortho-substituted, non-dioxin-like congeners as well as some coplanar congeners. The relative contribution of each of these mechanisms to the loss of cognitive function in humans exposed to PCBs remains to be determined. 42 refs., 3 figs., 1 tab.

  15. Local Anesthetic-Induced Neurotoxicity.

    PubMed

    Verlinde, Mark; Hollmann, Markus W; Stevens, Markus F; Hermanns, Henning; Werdehausen, Robert; Lirk, Philipp

    2016-01-01

    This review summarizes current knowledge concerning incidence, risk factors, and mechanisms of perioperative nerve injury, with focus on local anesthetic-induced neurotoxicity. Perioperative nerve injury is a complex phenomenon and can be caused by a number of clinical factors. Anesthetic risk factors for perioperative nerve injury include regional block technique, patient risk factors, and local anesthetic-induced neurotoxicity. Surgery can lead to nerve damage by use of tourniquets or by direct mechanical stress on nerves, such as traction, transection, compression, contusion, ischemia, and stretching. Current literature suggests that the majority of perioperative nerve injuries are unrelated to regional anesthesia. Besides the blockade of sodium channels which is responsible for the anesthetic effect, systemic local anesthetics can have a positive influence on the inflammatory response and the hemostatic system in the perioperative period. However, next to these beneficial effects, local anesthetics exhibit time and dose-dependent toxicity to a variety of tissues, including nerves. There is equivocal experimental evidence that the toxicity varies among local anesthetics. Even though the precise order of events during local anesthetic-induced neurotoxicity is not clear, possible cellular mechanisms have been identified. These include the intrinsic caspase-pathway, PI3K-pathway, and MAPK-pathways. Further research will need to determine whether these pathways are non-specifically activated by local anesthetics, or whether there is a single common precipitating factor. PMID:26959012

  16. EPA's neurotoxicity risk assessment guidelines.

    PubMed

    Boyes, W K; Dourson, M L; Patterson, J; Tilson, H A; Sette, W F; MacPhail, R C; Li, A A; O'Donoghue, J L

    1997-12-01

    The proposed Neurotoxicity Risk Assessment Guidelines (U.S. EPA, 1995c Fed. Reg. 60(192), 52032-52056) of the U.S. Environmental Protection Agency (EPA) were the subject of a workshop at the 1997 Meeting of the Society of Toxicology. The workshop considered the role of guidelines in the risk assessment process, the primary features, scientific basis, and implications of the guidelines for EPA program offices, as well as for industrial neurotoxicologists from the perspectives of both pesticides and toxic substances regulation. The U.S. National Academy of Sciences (NAS, 1983, Risk Assessment in the Federal Government: Managing the Process) established a framework for distinguishing risk management from risk assessment, the latter being the result of integrating hazard identification, hazard characterization, and exposure assessment data. The guidelines are intended to establish operating principles that will be used when examining data in a risk assessment context. The proposed neurotoxicity risk assessment guidelines provide a conceptual framework for deciding whether or not a chemically induced effect can be considered to be evidence of neurotoxicity. Topics in the proposed guidelines include structural and functional effects, dose-response and -duration considerations, and relationships between effects. Among the issues that must be considered are the multiplicity of chemical effects, the levels of biological organization in the nervous system, and the tests, measurements, and protocols used. Judgment of the adversity of an effect depends heavily on the amount and types of data available. The attribution of a chemically induced effect to an action on the nervous system depends on several factors such as the quality of the study, the nature of the outcome, dose-response and time-response relationships, and the possible involvement of nonneural factors. The guidelines will also serve as a reference for those conducting neurotoxicity testing, as well as establish a

  17. The neurotoxic effects of hydrogen peroxide and copper in Retzius nerve cells of the leech Haemopis sanguisuga.

    PubMed

    Jovanovic, Zorica D; Stanojevic, Marija B; Nedeljkov, Vladimir B

    2016-01-01

    Oxidative stress and the generation of reactive oxygen species (ROS) play an important role in cellular damage. Electrophysiological analyses have shown that membrane transport proteins are susceptible to ROS. In the present study, oxidative stress was induced in Retzius nerve cells of the leechHaemopis sanguisugaby bath application of 1 mM of hydrogen peroxide (H2O2) and 0.02 mM of copper (Cu) for 20 min. The H2O2/Cu(II) produced considerable changes in the electrical properties of the Retzius nerve cells. Intracellular recording of the resting membrane potential revealed that the neuronal membrane was depolarized in the presence of H2O2/Cu(II). We found that the amplitude of action potentials decreased, while the duration augmented in a progressive way along the drug exposure time. The combined application of H2O2and Cu(II) caused an initial excitation followed by depression of the spontaneous electrical activity. Voltage-clamp recordings revealed a second effect of the oxidant, a powerful inhibition of the outward potassium channels responsible for the repolarization of action potentials. The neurotoxic effect of H2O2/Cu(II) on the spontaneous spike electrogenesis and outward K(+)current of Retzius nerve cells was reduced in the presence of hydroxyl radical scavengers, dimethylthiourea and dimethyl sulfoxide, but not mannitol. This study provides evidence for the oxidative modification of outward potassium channels in Retzius nerve cells. The oxidative mechanism of the H2O2/Cu(II) system action on the electrical properties of Retzius neurons proposed in this study might have a wider significance, referring not only to leeches but also to mammalian neurons. PMID:26935393

  18. The neurotoxic effects of hydrogen peroxide and copper in Retzius nerve cells of the leech Haemopis sanguisuga

    PubMed Central

    Jovanovic, Zorica D.; Stanojevic, Marija B.; Nedeljkov, Vladimir B.

    2016-01-01

    ABSTRACT Oxidative stress and the generation of reactive oxygen species (ROS) play an important role in cellular damage. Electrophysiological analyses have shown that membrane transport proteins are susceptible to ROS. In the present study, oxidative stress was induced in Retzius nerve cells of the leech Haemopis sanguisuga by bath application of 1 mM of hydrogen peroxide (H2O2) and 0.02 mM of copper (Cu) for 20 min. The H2O2/Cu(II) produced considerable changes in the electrical properties of the Retzius nerve cells. Intracellular recording of the resting membrane potential revealed that the neuronal membrane was depolarized in the presence of H2O2/Cu(II). We found that the amplitude of action potentials decreased, while the duration augmented in a progressive way along the drug exposure time. The combined application of H2O2 and Cu(II) caused an initial excitation followed by depression of the spontaneous electrical activity. Voltage-clamp recordings revealed a second effect of the oxidant, a powerful inhibition of the outward potassium channels responsible for the repolarization of action potentials. The neurotoxic effect of H2O2/Cu(II) on the spontaneous spike electrogenesis and outward K+ current of Retzius nerve cells was reduced in the presence of hydroxyl radical scavengers, dimethylthiourea and dimethyl sulfoxide, but not mannitol. This study provides evidence for the oxidative modification of outward potassium channels in Retzius nerve cells. The oxidative mechanism of the H2O2/Cu(II) system action on the electrical properties of Retzius neurons proposed in this study might have a wider significance, referring not only to leeches but also to mammalian neurons. PMID:26935393

  19. Neuroprotective effect of (-)Delta9-tetrahydrocannabinol and cannabidiol in N-methyl-D-aspartate-induced retinal neurotoxicity: involvement of peroxynitrite.

    PubMed

    El-Remessy, Azza B; Khalil, Ibrahim E; Matragoon, Suraporn; Abou-Mohamed, Gamal; Tsai, Nai-Jer; Roon, Penny; Caldwell, Ruth B; Caldwell, Robert W; Green, Keith; Liou, Gregory I

    2003-11-01

    In glaucoma, the increased release of glutamate is the major cause of retinal ganglion cell death. Cannabinoids have been demonstrated to protect neuron cultures from glutamate-induced death. In this study, we test the hypothesis that glutamate causes apoptosis of retinal neurons via the excessive formation of peroxynitrite, and that the neuroprotective effect of the psychotropic Delta9-tetrahydroxycannabinol (THC) or nonpsychotropic cannabidiol (CBD) is via the attenuation of this formation. Excitotoxicity of the retina was induced by intravitreal injection of N-methyl-D-aspartate (NMDA) in rats, which also received 4-hydroxy-2,2,6,6-tetramethylpiperidine-n-oxyl (TEMPOL,a superoxide dismutase-mimetic), N-omega-nitro-L-arginine methyl ester (L-NAME, a nitric oxide synthase inhibitor), THC, or CBD. Retinal neuron loss was determined by TDT-mediated dUTP nick-end labeling assay, inner retinal thickness, and quantification of the mRNAs of ganglion cell markers. NMDA induced a dose- and time-dependent accumulation of nitrite/nitrate, lipid peroxidation, and nitrotyrosine (foot print of peroxynitrite), and a dose-dependent apoptosis and loss of inner retinal neurons. Treatment with L-NAME or TEMPOL protected retinal neurons and confirmed the involvement of peroxynitrite in retinal neurotoxicity. The neuroprotection by THC and CBD was because of attenuation of peroxynitrite. The effect of THC was in part mediated by the cannabinoid receptor CB1. These results suggest the potential use of CBD as a novel topical therapy for the treatment of glaucoma. PMID:14578199

  20. Antioxidant effect of Spirulina (Arthrospira) maxima in a neurotoxic model caused by 6-OHDA in the rat striatum.

    PubMed

    Tobón-Velasco, J C; Palafox-Sánchez, Victoria; Mendieta, Liliana; García, E; Santamaría, A; Chamorro-Cevallos, G; Limón, I Daniel

    2013-08-01

    There is evidence to support that an impaired energy metabolism and the excessive generation of reactive oxygen species (ROS) contribute to brain injury in neurodegenerative disorders such as Parkinson's disease (PD), whereas diets enriched in foods with an antioxidant action may modulate its progression. Several studies have proved that the antioxidant components produced by Spirulina, a microscopic blue-green alga, might prevent cell death by decreasing free radicals, inhibiting lipoperoxidation and upregulating the antioxidant enzyme systems. In our study, we investigated the protective effect of the Spirulina maxima (S. maxima) against the 6-OHDA-caused toxicity in the rat striatum. The S. maxima (700 mg/kg/day, vo) was administered for 40 days before and 20 days after a single injection of 6-OHDA (16 μg/2 μL) into the dorsal striatum. At 20-day postsurgery, the brain was removed and the striatum was obtained to evaluate the indicators of toxicity, such as nitric oxide levels, ROS formation, lipoperoxidation, and mitochondrial activity. These variables were found significantly stimulated in 6-OHDA-treated rats and were accompanied by declines in dopamine levels and motor activity. In contrast, the animals that received the chronic treatment with S. maxima had a restored locomotor activity, which is associated with the decreased levels of nitric oxide, ROS, and lipoperoxidation in the striatum, although mitochondrial functions and dopamine levels remained preserved. These findings suggest that supplementation with antioxidant phytochemicals (such as contained in S. maxima) represents an effective neuroprotective strategy against 6-OHDA-caused neurotoxicity vía free radical production to preserve striatal dopaminergic neurotransmission in vivo. PMID:23430275

  1. Protective effects of astragaloside IV against amyloid beta1-42 neurotoxicity by inhibiting the mitochondrial permeability transition pore opening.

    PubMed

    Sun, Qinru; Jia, Ning; Wang, Weixi; Jin, Hui; Xu, Jiehua; Hu, Haitao

    2014-01-01

    Mitochondrial dysfunction caused by amyloid β-peptide (Aβ) plays an important role in the pathogenesis of Alzheimer disease (AD). Substantial evidence has indicated that the mitochondrial permeability transition pore (mPTP) opening is involved in Aβ-induced neuronal death and reactive oxygen species (ROS) generation. Astragaloside IV (AS-IV), one of the major active constituents of Astragalus membranaceus, has been reported as an effective anti-oxidant for treating neurodegenerative diseases. However, the molecular mechanisms still need to be clarified. In this study, we investigated whether AS-IV could prevent Aβ1-42-induced neurotoxicity in SK-N-SH cells via inhibiting the mPTP opening. The results showed that pretreatment of AS-IV significantly increased the viability of neuronal cells, reduced apoptosis, decreased the generation of intracellular reactive oxygen species (ROS) and decreased mitochondrial superoxide in the presence of Aβ1-42. In addition, pretreatment of AS-IV inhibited the mPTP opening, rescued mitochondrial membrane potential (ΔΨm), enhanced ATP generation, improved the activity of cytochrome c oxidase and blocked cytochrome c release from mitochondria in Aβ1-42 rich milieu. Moreover, pretreatment of AS-IV reduced the expression of Bax and cleaved caspase-3 and increased the expression of Bcl-2 in an Aβ1-42 rich environment. These data indicate that AS-IV prevents Aβ1-42-induced SK-N-SH cell apoptosis via inhibiting the mPTP opening and ROS generation. These results provide novel insights of AS-IV for the prevention and treatment of neurodegenerative disorders such as AD. PMID:24905226

  2. INVESTIGATIONS OF AMITRAZ NEUROTOXICITY IN RATS. III. EFFECTS ON MOTOR ACTIVITY AND INHIBITION OF MONOAMINE OXIDASE

    EPA Science Inventory

    The formamidine pesticide amitraz (AMZ) produces many behavioral and physiological changes in rats. o explore possible neurochemical mechanisms for the behavioral effects of AMZ, we examined the dose effect and time course of AMZ on motor activity, monoamine oxidase (MAO) and ace...

  3. INVESTIGATIONS OF AMITRAZ NEUROTOXICITY IN RATS. 1. EFFECTS ON OPERANT PERFORMANCE (JOURNAL VERSION)

    EPA Science Inventory

    Amitraz (AMZ), a formamidine pesticide, displayed a unique spectrum of neurobehavioral effects which differed from that of the prototypic formamidine, chlordimeform (CDM). In male Long-Evans rats, general signs of intoxication included hypothermia, hyperreactivity, vasodilation, ...

  4. The tricyclic antidepressant desipramine inhibited the neurotoxic, kainate-induced [Ca(2+)]i increases in CA1 pyramidal cells in acute hippocampal slices.

    PubMed

    Koncz, István; Szász, Bernadett K; Szabó, Szilárd I; Kiss, János P; Mike, Arpád; Lendvai, Balázs; Sylvester Vizi, E; Zelles, Tibor

    2014-05-01

    Kainate (KA), used for modelling neurodegenerative diseases, evokes excitotoxicity. However, the precise mechanism of KA-evoked [Ca(2+)]i increase is unexplored, especially in acute brain slice preparations. We used [Ca(2+)]i imaging and patch clamp electrophysiology to decipher the mechanism of KA-evoked [Ca(2+)]i rise and its inhibition by the tricyclic antidepressant desipramine (DMI) in CA1 pyramidal cells in rat hippocampal slices and in cultured hippocampal cells. The effect of KA was dose-dependent and relied totally on extracellular Ca(2+). The lack of effect of dl-2-amino-5-phosphonopentanoic acid (AP-5) and abolishment of the response by 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) suggested the involvement of non-N-methyl-d-aspartate receptors (non-NMDARs). The predominant role of the Ca(2+)-impermeable α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate receptors (AMPARs) in the initiation of the Ca(2+) response was supported by the inhibitory effect of the selective AMPAR antagonist GYKI 53655 and the ineffectiveness of 1-naphthyl acetylspermine (NASPM), an inhibitor of the Ca(2+)-permeable AMPARs. The voltage-gated Ca(2+) channels (VGCC), blocked by ω-Conotoxin MVIIC+nifedipine+NiCl2, contributed to the [Ca(2+)]i rise. VGCCs were also involved, similarly to AMPAR current, in the KA-evoked depolarisation. Inhibition of voltage-gated Na(+) channels (VGSCs; tetrodotoxin, TTX) did not affect the depolarisation of pyramidal cells but blocked the depolarisation-evoked action potential bursts and reduced the Ca(2+) response. The tricyclic antidepressant DMI inhibited the KA-evoked [Ca(2+)]i rise in a dose-dependent manner. It directly attenuated the AMPA-/KAR current, but its more potent inhibition on the Ca(2+) response supports additional effect on VGCCs, VGSCs and Na(+)/Ca(2+) exchangers. The multitarget action on decisive players of excitotoxicity holds out more promise in clinical therapy of neurodegenerative diseases. PMID:24742525

  5. Endocrine, teratogenic and neurotoxic effects of cyanobacteria detected by cellular in vitro and zebrafish embryos assays.

    PubMed

    Jonas, Adam; Scholz, Stefan; Fetter, Eva; Sychrova, Eliska; Novakova, Katerina; Ortmann, Julia; Benisek, Martin; Adamovsky, Ondrej; Giesy, John P; Hilscherova, Klara

    2015-02-01

    Cyanobacteria contain various types of bioactive compounds, which could cause adverse effects on organisms. They are released into surface waters during cyanobacterial blooms, but there is little information on their potential relevance for effects in vivo. In this study presence of bioactive compounds was characterized in cyanobacteria Microcystis aeruginosa (Chroococcales), Planktothrix agardhii (Oscillatoriales) and Aphanizomenon gracile (Nostocales) with selected in vitro assays. The in vivo relevance of detected bioactivities was analysed using transgenic zebrafish embryos tg(cyp19a1b-GFP). Teratogenic potency was assessed by analysis of developmental disorders and effects on functions of the neuromuscular system by video tracking of locomotion. Estrogenicity in vitro corresponded to 0.95-54.6 ng estradiol equivalent(g dry weight (dw))(-1). In zebrafish embryos, estrogenic effects could not be detected potentially because they were masked by high toxicity. There was no detectable (anti)androgenic/glucocorticoid activity in any sample. Retinoid-like activity was determined at 1-1.3 μg all-trans-retinoic acid equivalent(g dw)(-1). Corresponding to the retinoid-like activity A. gracile extract also caused teratogenic effects in zebrafish embryos. Furthermore, exposure to biomass extracts at 0.3 gd wL(-1) caused increase of body length in embryos. There were minor effects on locomotion caused by 0.3 gd wL(-1)M. aeruginosa and P. agardhii extracts. The traditionally measured cyanotoxins microcystins did not seem to play significant role in observed effects. This indicates importance of other cyanobacterial compounds at least towards some species or their developmental phases. More attention should be paid to activity of retinoids, estrogens and other bioactive substances in phytoplankton using in vitro and in vivo bioassays. PMID:25170595

  6. Comparison the neuropreotective effect of Cortex Phellodendri chinensis and Cortex Phellodendri amurensis against beta-amyloid-induced neurotoxicity in PC12 cells.

    PubMed

    Xian, Yan-Fang; Lin, Zhi-Xiu; Ip, Siu-Po; Su, Zi-Ren; Chen, Jian-Nan; Lai, Xiao-Ping

    2013-01-15

    Cortex Phellodendron chinensis (CPC) and Cortex Phellodendron amurensis (CPA) derived from the dried bark of Phellodendron chinense Schneid. or Phellodendron amurense Rupr., respectively, are used interchangeably in clinical practice under the name "Huang Bai" for centuries in Chinese medicine for the treatment of various inflammatory conditions. Previous study in our laboratory demonstrated that CPC and CPA had different anti-diarrheal, anti-bacterial and anti-inflammatory effects. In this present study, we aimed to compare the protective effect of ethanol extract of Cortex Phellodendri chinensis (ECPC) and Cortex Phellodendri Amurensis (ECPA) against beta-amyloid (Aβ)-induced neurotoxicity in PC12 cells, a typical model of Alzheimer's disease. The results showed that ECPC and ECPA contain four common chemical markers such as berberine, but palmatine and jatrorrhizin were not found in CPC in contrast to the presence in CPA. In addition, both ECPC and ECPA can significantly increase the cell viability in Aβ-treated PC12 cells. Moreover, ECPC and ECPA can markedly elevate the ratio of the protein and mRNA levels of Bcl-2/Bax, while remarkably decrease the release of cytochrome c, and the protein and mRNA expression of caspase-3. Interestingly, ECPA has better protective effect than ECPC against Aβ-induced neurotoxicity in PC12 cells. These results indicate that both ECPC and ECPA have potential protective effect against Aβ-induced neurotoxicity in PC12 cells, and ECPA is more potential of the two species to be used in traditional medicine as a neuroprotective agent for the treatment of AD. The neuroprotective effect of the two species may be mediated, at least in part, via suppressing of the cellular apoptosis. PMID:23123224

  7. Autophagy and ethanol neurotoxicity

    PubMed Central

    Luo, Jia

    2015-01-01

    Excessive ethanol exposure is detrimental to the brain. The developing brain is particularly vulnerable to ethanol such that prenatal ethanol exposure causes fetal alcohol spectrum disorders (FASD). Neuronal loss in the brain is the most devastating consequence and is associated with mental retardation and other behavioral deficits observed in FASD. Since alcohol consumption during pregnancy has not declined, it is imperative to elucidate the underlying mechanisms and develop effective therapeutic strategies. One cellular mechanism that acts as a protective response for the central nervous system (CNS) is autophagy. Autophagy regulates lysosomal turnover of organelles and proteins within cells, and is involved in cell differentiation, survival, metabolism, and immunity. We have recently shown that ethanol activates autophagy in the developing brain. The autophagic preconditioning alleviates ethanol-induced neuron apoptosis, whereas inhibition of autophagy potentiates ethanol-stimulated reactive oxygen species (ROS) and exacerbates ethanol-induced neuroapoptosis. The expression of genes encoding proteins required for autophagy in the CNS is developmentally regulated; their levels are much lower during an ethanol-sensitive period than during an ethanol-resistant period. Ethanol may stimulate autophagy through multiple mechanisms; these include induction of oxidative stress and endoplasmic reticulum stress, modulation of MTOR and AMPK signaling, alterations in BCL2 family proteins, and disruption of intracellular calcium (Ca2+) homeostasis. This review discusses the most recent evidence regarding the involvement of autophagy in ethanol-mediated neurotoxicity as well as the potential therapeutic approach of targeting autophagic pathways. PMID:25484085

  8. Chemotherapy-induced neurotoxicity in pediatric solid non-CNS tumor patients: An update on current state of research and recommended future directions.

    PubMed

    Sleurs, Charlotte; Deprez, Sabine; Emsell, Louise; Lemiere, Jurgen; Uyttebroeck, Anne

    2016-07-01

    Neurocognitive sequelae are known to be induced by cranial radiotherapy and central-nervous-system-directed chemotherapy in childhood Acute Lymphoblastic Leukemia (ALL) and brain tumor patients. However, less evidence exists for solid non-CNS-tumor patients. To get a better understanding of the potential neurotoxic mechanisms of non-CNS-directed chemotherapy during childhood, we performed a comprehensive literature review of this topic. Here, we provide an overview of preclinical and clinical studies investigating neurotoxicity associated with chemotherapy in the treatment of pediatric solid non-CNS tumors. Research to date suggests that chemotherapy has deleterious biological and psychological effects, with animal studies demonstrating histological evidence for neurotoxic effects of specific agents and human studies demonstrating acute neurotoxicity. Although the existing literature suggests potential neurotoxicity throughout neurodevelopment, research into the long-term neurocognitive sequelae in survivors of non-CNS cancers remains limited. Therefore, we stress the critical need for neurodevelopmental focused research in children who are treated for solid non-CNS tumors, since they are at risk for potential neurocognitive impairment. PMID:27233118

  9. Microelectrode Array-evaluation of Neurotoxic Effects of Magnesium as an Implantable Biomaterial

    PubMed Central

    Huang, Ting; Wang, Zhonghai; Wei, Lina; Kindy, Mark; Zheng, Yufeng; Xi, Tingfei; Gao, Bruce Z.

    2016-01-01

    Magnesium (Mg)-based biomaterials have shown great potential in clinical applications. However, the cytotoxic effects of excessive Mg2+ and the corrosion products from Mg-based biomaterials, particularly their effects on neurons, have been little studied. Although viability tests are most commonly used, a functional evaluation is critically needed. Here, both methyl thiazolyl tetrazolium (MTT) and lactate dehydrogenase (LDH) assays were used to test the effect of Mg2+ and Mg-extract solution on neuronal viability. Microelectrode arrays (MEAs), which provide long-term, real-time recording of extracellular electrophysiological signals of in vitro neuronal networks, were used to test for toxic effects. The minimum effective concentrations (ECmin) of Mg2+ from the MTT and LDH assays were 3 mmol/L and 100 mmol/L, respectively, while the ECmin obtained from the MEA assay was 0.1 mmol/L. MEA data revealed significant loss of neuronal network activity when the culture was exposed to 25% Mg-extract solution, a concentration that did not affect neuronal viability. For evaluating the biocompatibility of Mg-based biomaterials with neurons, MEA electrophysiological testing is a more precise method than basic cell-viability testing. PMID:27110081

  10. A screening approach using zebrafish for the detection and characterization of developmental neurotoxicity.

    EPA Science Inventory

    Thousands of chemicals have little or no data to support developmental neurotoxicity risk assessments. Current developmental neurotoxicity guideline studies mandating mammalian model systems are expensive and time consuming. Therefore a rapid, cost-effective method to assess de...

  11. A cellular lipidomic study on the Aβ-induced neurotoxicity and neuroprotective effects of EGCG by using UPLC/MS-based glycerolipids profiling and multivariate analysis.

    PubMed

    Zhang, Hongyang; Wang, Jing-Rong; Yau, Lee Fong; Ho, Hing Man; Chan, Chi Leung; Hu, Ping; Liu, Liang; Jiang, Zhi-Hong

    2012-10-30

    The aim of this study was to investigate the cellular lipid metabolism associated with β-amyloid peptide (Aβ)-induced neurotoxicity as well as the neuroprotective effect of (-)-epigallocatechin gallate (EGCG), a major polyphenol in green tea. An ultra-performance liquid chromatography-quadrupole-time-of-flight mass spectrometry (UPLC-Q-TOF-MS)-based lipidomic approach was developed to screen and identify changes of the glycerolipids (GL) upon Aβ treatment with or without the presence of EGCG in PC12 cells. Principle component analysis (PCA) showed that the Aβ-treated group was well separated from the control group, whereas the EGCG group was closer to the control group. The GL levels were significantly elevated in Aβ-treated cells compared with the control group, but were restored near to normal levels after EGCG treatment. The elevated phosphatidylcholines (PCs) levels observed in the Aβ-treated PC12 cells were quite probably the integrated results of the reduced phospholipase A(2) (PLA(2)) activity and the enhanced activity of lysophospholipid acyltransferases. Moreover, an increased liberation of arachidonic acid (AA) from PCs was observed as another important response of PC12 cells to the Aβ aggregates, implying an active inflammatory process occurring in Aβ induced neurotoxicity. EGCG treatment can reverse the deregulated metabolism of PCs, which might be one of the biochemical mechanisms contributing to its neuroprotective effect. Collectively, results obtained from the current lipidomic analyses of PC12 cells provided important insight into the biochemical mechanisms underlying Aβ-induced neurotoxicity and neuro protective effects of EGCG. This is the first report of the lipidomic study on the neuroprotective effect of EGCG. PMID:23032920

  12. The neurotoxic effect of clindamycin - induced gut bacterial imbalance and orally administered propionic acid on DNA damage assessed by the comet assay: protective potency of carnosine and carnitine

    PubMed Central

    2013-01-01

    Background Comet assay is a quick method for assessing DNA damage in individual cells. It allows the detection of single and double DNA strand breaks, which represent the direct effect of some damaging agents. This study uses standard comet quantification models to compare the neurotoxic effect of orally administered propionic acid (PA) to that produced as a metabolite of bacterial overgrowth induced by clindamycin. Additionally, the protective effect of carnosine and carnitine as natural dietary supplements is assessed. Methods Single cell gel electrophoresis (comet assays) were performed on brain cortex and medulla samples after removal from nine groups of hamsters including: a control (untreated) group; PA-intoxicated group; clindamycin treated group; clindamycin-carnosine group and; clindamycin-carnitine group. Results There were significant double strand breaks recorded as tail length, tail moment and % DNA damage in PA and clindamycin-treated groups for the cortex and medulla compared to the control group. Neuroprotective effects of carnosine and carnitine were observed. Receiver Operating Characteristics curve (ROC) analysis showed satisfactory values of sensitivity and specificity of the comet assay parameters. Conclusion Percentage DNA damage, tail length, and tail moment are adequate biomarkers of PA neurotoxicity due to oral administration or as a metabolite of induced enteric bacterial overgrowth. Establishing biomarkers of these two exposures is important for protecting children’s health by documenting the role of the imbalance in gut microbiota in the etiology of autism through the gut-brain axis. These outcomes will help efforts directed at controlling the prevalence of autism, a disorder recently related to PA neurotoxicity. PMID:23587115

  13. Neurotoxicity in risk assessment

    SciTech Connect

    Weiss, B.

    1988-01-01

    Neurotoxicity is a property of many metals, even those deemed biologically essential. Manganese, one of the essential elements, can induce a syndrome displaying aspects of both Parkinsonism and dystonia, but accompanied, as well, by psychological abnormalities. At low exposure levels, however, neurotoxicity may be detectable with psychological tests. Mercury vapor exposure also induces neurological signs, psychological aberrations, and subtle evidence of dysfunction on psychological tests. Methylmercury and lead are particularly toxic to the developing brain. The most recent research indicates that psychological testing may uncover deficits even in children showing no evidence of impairment. Because of their special features, neurotoxic endpoints may have to be evaluated for risks by a process that diverges significantly from the standard program based on carcinogenicity.

  14. Protective effects of plant seed extracts against amyloid β-induced neurotoxicity in cultured hippocampal neurons

    PubMed Central

    Okada, Yoshinori; Okada, Mizue

    2013-01-01

    AIM: Alzheimer's disease (AD) is characterized by large deposits of amyloid β (Aβ) peptide. Aβ is known to increase reactive oxygen species (ROS) production in neurons, leading to cell death. In this study, we screened 15 plant seeds’ aqueous extracts (PSAE) for inhibitory effects on Aβ (25-35)-induced cell death using hippocampus neurons (HIPN). MATERIALS AND METHODS: Fifteen chosen plants were nine medical herbs (Japanese honeywort, luffa, rapeseed, Chinese colza, potherb mustard, Japanese radish, bitter melon, red shiso, corn, and kaiware radish) and six general commercial plants (common bean, komatsuna, Qing geng cai, bell pepper, kale, and lettuce). PSAE were measured for total phenolic content (TPC) with the Folin–Ciocalteu method, and the 2-diphenyl-1-picryl-hydrazyl (DPPH) radical scavenging effect of each seed extract was measured. To find a protectant against Aβ-induced oxidative stress, we screened 15 PSAE using a 2’, 7’-dichlorofluorescein diacetate assay. To further unravel the anti-inflammatory effects of PSAE on Aβ-induced inflammation, PSAE were added to HIPN. The neuroprotective effects of the PSAE were evaluated by Cell Counting Kit-8 assay, measuring the cell viability in Aβ-induced HIPN. RESULTS: TPC of 15 PSAE was in the range of 0.024-1.96 mg of chlorogenic acid equivalents/gram. The aqueous extracts showed antioxidant activities. Furthermore, intracellular ROS accumulation resulting from Aβ treatment was reduced when cells were treated with some PSAE. Kale, bitter melon, kaiware radish, red shiso, and corn inhibited tumor necrosis factor-alpha secretion by the Aβ-stimulated neurons and all samples except Japanese honeywort showed enhancement of cell survival. CONCLUSION: From these results, we suggest that some plant seed extracts offer protection against Aβ-mediated cell death. PMID:23833520

  15. Neuroprotective effects of purslane herb aquenous extracts against D-galactose induced neurotoxicity.

    PubMed

    Hongxing, Zhang; Nancai, Yu; Guofu, Huang; Jianbo, Shao; Yanxia, Wu; Hanju, Huang; Qian, Liu; Wei, Ma; Yandong, Yi; Hao, Huang

    2007-12-15

    In order to evaluate mechanisms of natural plant purslane herb aquenous extracts (PHAS) for neuroprotective, we assessed neuroprotective effects of PHAS at doses of 2.5, 5 and 10 mg/(kg day) on SD mice injected daily with D-gal (50 mg/(kg day)) by behavioral tests. PHAS-fed mice showed higher activity upon induction by new environmental stimuli, lower anxiety and higher novelty-seeking behavior in the open field tasks, and significantly improved learning and memory ability in step-through compared with D-gal-treated mice. We further examined the mechanisms involved in neuroprotective effects of PHAS on mouse brain. PHAS significantly increased superoxide dismutase (SOD) activity and decreased the malondialdehyde (MDA) level. Meanwhile, PHAS also could up-regulate telomere lengths and telomerase activity in PHAS-fed groups. Furthermore, we examined the expression of p21(waf1) and p53 mRNA and protein in mouse brain by western blot analysis and real-time RT-PCR. We found that p21(waf1)was down-regulated by PHAS without changing the expression of p53. The results of this study suggested that the PHAS might be a primary target of p21(waf1)and the neuroprotective effect of PHAS might be carried out through a p21(waf1)-dependent and p53-independent pathway. PMID:17764668

  16. Neurotoxic effects of ochratoxin A on the subventricular zone of adult mouse brain.

    PubMed

    Paradells, Sara; Rocamonde, Brenda; Llinares, Cristina; Herranz-Pérez, Vicente; Jimenez, Misericordia; Garcia-Verdugo, Jose Manuel; Zipancic, Ivan; Soria, Jose Miguel; Garcia-Esparza, Ma Angeles

    2015-07-01

    Ochratoxin A (OTA), a mycotoxin that was discovered as a secondary metabolite of the fungal species Aspergillus and Penicillium, is a common contaminant in food and animal feed. This mycotoxin has been described as teratogenic, carcinogenic, genotoxic, immunotoxic and has been proven a potent neurotoxin. Other authors have previously reported the effects of OTA in different structures of the central nervous system as well as in some neurogenic regions. However, the impact of OTA exposure in the subventricular zone (SVZ) has not been assessed yet. To elucidate whether OTA affects neural precursors of the mouse SVZ we investigated, in vitro and in vivo, the effects of OTA exposure on the SVZ and on the neural precursors obtained from this neurogenic niche. In this work, we prove the cumulative effect of OTA exposure on proliferation, differentiation and depletion of neural stem cells cultured from the SVZ. In addition, we corroborated these results in vivo by immunohistochemistry and electron microscopy. As a result, we found a significant alteration in the proliferation process, which was evidenced by a decrease in the number of 5-bromo-2-deoxyuridine-positive cells and glial cells, as well as, a significant decrease in the number of neuroblasts in the SVZ. To summarize, in this study we demonstrate how OTA could be a threat to the developing and the adult SVZ through its impact in cell viability, proliferation and differentiation in a dose-dependent manner. PMID:25256750

  17. Developmental Neurotoxic Effects of Percutaneous Drug Delivery: Behavior and Neurochemical Studies in C57BL/6 Mice.

    PubMed

    Wu, Huali; Feng, Junyi; Lv, Wenting; Huang, Qiaoling; Fu, Mengsi; Cai, Minxuan; He, Qiangqiang; Shang, Jing

    2016-01-01

    Dermatosis often as a chronic disease requires effective long-term treatment; a comprehensive evaluation of mental health of dermatology drug does not receive enough attention. An interaction between dermatology and psychiatry has been increasingly described. Substantial evidence has accumulated that psychological stress can be associated with pigmentation, endocrine and immune systems in skin to create the optimal responses against pathogens and other physicochemical stressors to maintain or restore internal homeostasis. Additionally, given the common ectodermal origin shared by the brain and skin, we are interested in assessing how disruption of skin systems (pigmentary, endocrine and immune systems) may play a key role in brain functions. Thus, we selected three drugs (hydroquinone, isotretinoin, tacrolimus) with percutaneous excessive delivery to respectively intervene in these systems and then evaluate the potential neurotoxic effects. Firstly, C57BL/6 mice were administrated a dermal dose of hydroquinone cream, isotretinoin gel or tacrolimus ointment (2%, 0.05%, 0.1%, respectively, 5 times of the clinical dose). Behavioral testing was performed and levels of proteins were measured in the hippocampus. It was found that mice treated with isotretinoin or tacrolimus, presented a lower activity in open-field test and obvious depressive-like behavior in tail suspension test. Besides, they damaged cytoarchitecture, reduced the level of 5-HT-5-HT1A/1B system and increased the expression of apoptosis-related proteins in the hippocampus. To enable sensitive monitoring the dose-response characteristics of the consecutive neurobehavioral disorders, mice received gradient concentrations of hydroquinone (2%, 4%, 6%). Subsequently, hydroquinone induced behavioral disorders and hippocampal dysfunction in a dose-dependent response. When doses were high as 6% which was 3 times higher than 2% dose, then 100% of mice exhibited depressive-like behavior. Certainly, 6% hydroquinone

  18. Effect of vitamin B/sub 6/ on the neurotoxicity and pharmacology of desmethylmisonidazole and misonidazole: clinical and laboratory studies

    SciTech Connect

    Coleman, C.N.; Hirst, V.K.; Brown, D.M.; Halsey, J.

    1984-08-01

    The clinical usefulness of misonidazole (MISO) and desmethylmisonidazole (DMM) is severely limited by neurotoxicity. Based on theoretical considerations and on laboratory data suggesting that pyridoxine (PN) decreased MISO toxicity in mice. The authors attempted to ameliorate the clinical neuropathy of DMM using oral PN. Pharmacokinetic analysis suggested interaction of PN and DMM but no protection against neuropathy was observed. Serial experiments with C3H and BALB/c mice were done using various forms of vitamin B/sub 6/ (PN, pyridoxal, pyridoxal phosphate) administered orally and i.p. No consistent protection was observed. Dexamethasone did not alter MISO toxicity in mice, contrary to the clinical findings. They conclude that vitamin B/sub 6/ is not useful in preventing clinical neurotoxicity of MISO or DMM.

  19. Neurotoxicity of Brominated Flame Retardants: (In)direct Effects of Parent and Hydroxylated Polybrominated Diphenyl Ethers on the (Developing) Nervous System

    PubMed Central

    van den Berg, Martin; Westerink, Remco H.S.

    2011-01-01

    Background/objective: Polybrominated diphenyl ethers (PBDEs) and their hydroxylated (OH-) or methoxylated forms have been detected in humans. Because this raises concern about adverse effects on the developing brain, we reviewed the scientific literature on these mechanisms. Data synthesis: Many rodent studies reported behavioral changes after developmental, neonatal, or adult exposure to PBDEs, and other studies documented subtle structural and functional alterations in brains of PBDE-exposed animals. Functional effects have been observed on synaptic plasticity and the glutamate–nitric oxide–cyclic guanosine monophosphate pathway. In the brain, changes have been observed in the expression of genes and proteins involved in synapse and axon formation, neuronal morphology, cell migration, synaptic plasticity, ion channels, and vesicular neurotransmitter release. Cellular and molecular mechanisms include effects on neuronal viability 
(via apoptosis and oxidative stress), neuronal differentiation and migration, neurotransmitter release/uptake, neurotransmitter receptors and ion channels, calcium (Ca2+) homeostasis, and intracellular signaling pathways. Discussion: Bioactivation of PBDEs by hydroxylation has been observed for several endocrine end points. This has also been observed for mechanisms related to neurodevelopment, including binding to thyroid hormone receptors and transport proteins, disruption of Ca2+ homeostasis, and modulation of GABA and nicotinic acetylcholine receptor function. Conclusions: The increased hazard for developmental neurotoxicity by hydroxylated (OH-)PBDEs compared with their parent congeners via direct neurotoxicity and thyroid disruption clearly warrants further investigation into a) the role of oxidative metabolism in producing active metabolites of PBDEs and their impact on brain development; b) concentrations of parent and OH-PBDEs in the brain; and c) interactions between different environmental contaminants during exposure to

  20. Neurotoxic effects of low-level methylmercury contamination in the Amazonian basin

    SciTech Connect

    Lebel, J.; Mergler, D.; Lucotte, M.; Larribe, F.; Dolbec, J.; Branches, F.; Amorim, M.

    1998-10-01

    Many studies have demonstrated mercury contamination in the Amazonian ecosystem, particularly in fish, a dietary mainstay of populations in this region. The present study focused on potential health effects of this low-level methylmercury exposure. The study was carried out in a village on the Tapajos River, a tributary of the Amazon, on 91 adults inhabitants whose hair mercury levels were inferior to 50 {micro}/g. Performance on a neurofunctional test battery and clinical manifestations of nervous system dysfunction were examined in relation to hair mercury concentrations. Near visual contrast sensitivity and manual dexterity, adjusted for age, decreased significantly with hair mercury levels (P < 0.05), while there was a tendency for muscular fatigue to increase and muscular strength to decrease in women. For the most part, clinical examinations were normal, however, hair mercury levels were significantly higher (P < 0.05) for persons who presented disorganized movements on an alternating movement task and for persons with restricted visual fields. These results suggest dose-dependent nervous system alterations at hair mercury levels below 50 {micro}g/g, previously considered a threshold for clinical effects. The profile of dysfunction in this adult population is consistent with the current knowledge on methylmercury poisoning. The long-term implications of these findings are unknown and need to be addressed.

  1. Protective effect of hispidulin on kainic acid-induced seizures and neurotoxicity in rats.

    PubMed

    Lin, Tzu Yu; Lu, Cheng Wei; Wang, Su Jane; Huang, Shu Kuei

    2015-05-15

    Hispidulin is a flavonoid compound which is an active ingredient in a number of traditional Chinese medicinal herbs, and it has been reported to inhibit glutamate release. The purpose of this study was to investigate whether hispidulin protects against seizures induced by kainic acid, a glutamate analog with excitotoxic properties. The results indicated that intraperitoneally administering hispidulin (10 or 50mg/kg) to rats 30 min before intraperitoneally injecting kainic acid (15 mg/kg) increased seizure latency and decreased seizure score. In addition, hispidulin substantially attenuated kainic acid-induced hippocampal neuronal cell death, and this protective effect was accompanied by the suppression of microglial activation and the production of proinflammatory cytokines such as interleukin-1β, interleukin-6, and tumor necrosis factor-α in the hippocampus. Moreover, hispidulin reduced kainic acid-induced c-Fos expression and the activation of mitogen-activated protein kinases in the hippocampus. These data suggest that hispidulin has considerable antiepileptic, neuroprotective, and antiinflammatory effects on kainic acid-induced seizures in rats. PMID:25746462

  2. Misonidazole in patients receiving radical radiotherapy: pharmacokinetic effects of phenytoin tumor response and neurotoxicity

    SciTech Connect

    Moore, J.L.; Biol, F.I.; Patterson, I.C.M.; Dawes, P.J.D.K.; Henk, J.M.

    1982-03-01

    In 1978, a pilot study began of 29 patients with advanced tumors of the head and neck. The study showed an initial peripheral neuropathy rate of 55%, despite a dose limitation of 12 g/m/sup 2/ of misonidazole. Tumor response at 9 months was most encouraging. We are now able to examine tumor response and persistence of neuropathy in these patients 2 1/2 years after radical radiotherapy. The results are comparable with those obtained with hyperbaric oxygen in a clinical trial at this center during the 1970's. Neuropathy was a serious side effect but the drug phenytoin has been shown to shorten the half-life of misonidazole. We have examined the effect of phenytoin on the pharmacokinetics of misonidazole in 13 patients who received radical radiotherapy for advanced head and neck tumors or oesophageal tumors. Misonidazole was given in multiple doses, i.e. daily or weekly as it would be used in conventional therapy. Phenytoin was given either daily throughout treatment, or it was withdrawn during treatment. There were dramatic changes in the half-life of misonidazole, but the concentration at the time of irradiation was little affected. The significant changes in the half-life of misonidazole and the increased concentration of the metabolite desmethylmisonidazole are discussed.

  3. Neurotoxic effects of fractions isolated from Tityus bahiensis scorpion venom (Perty, 1834).

    PubMed

    Lourenço, Geane Antiques; Lebrun, Ivo; Dorce, Valquiria A Coronado

    2002-02-01

    Tityus serrulatus and Tityus bahiensis are considered to be the most venomous scorpions in Brazil and are responsible for most of the accidents that occur in our country. The main toxic agents in scorpion venoms are small basic polypeptides that act as neurotoxins. They cause a derangement of ion channels that result in abnormal release of neurotransmitters. In the present study we fractionated the venom of Tityus bahiensis and studied the effects of fractions P2, P3, P4, P5, P6 and P7, on the mammalian central nervous system. Intravenous injection of P5, P6 and P7 in rats induced spontaneous convulsion, intrahippocampal injection caused behavioural seizures, and P5 and P6 induced electrographic seizures. P5 caused neuronal damage in the CA1 area and P6 in the CA1, CA3 areas and hilus of the dentate gyrus (DG) of the hippocampus. Injection of P3 in the hippocampus did not induce convulsions or lesions. However, when injected intravenously in mice, this fraction reduced behavioural activity in an open field test. Unilateral injection of P4 in the hippocampus caused neuronal damage in the contralateral CA3, but not in the ipsilateral hippocampus. These results suggest that scorpion toxins present in the venom are able to act directly on the central nervous system promoting behavioural and histopathological effects. PMID:11689236

  4. Voluntary exercise reduces the neurotoxic effects of 6-hydroxydopamine in maternally separated rats

    PubMed Central

    Mabandla, Musa Vuyisile; Russell, Vivienne Ann

    2010-01-01

    Maternal separation has been associated with development of anxiety-like behaviour and learning impairments in adult rats. This has been linked to changes in brain morphology observed after exposure to high levels of circulating glucocorticoids during the stress-hyporesponsive period (P4 to P14). In the present study, adult rats that had been subjected to maternal separation (180 min/day for 14 days) during the stress-hyporesponsive period, received unilateral infusions of a small dose of 6-hydroxydopamine (6-OHDA, 5 μg/4 μl saline) into the medial forebrain bundle. The results showed that voluntary exercise had a neuroprotective effect in both non-stressed and maternally separated rats in that there was a decrease in forelimb akinesia (step test) and limb use asymmetry (cylinder test). Maternal separation increased forelimb akinesia and forelimb use asymmetry and reduced the beneficial effect of exercise on forelimb akinesia. It also reduced exploratory behaviour, consistent with anxiety-like behaviour normally associated with maternal separation. Exercise appeared to reduce dopamine neuron destruction in the lesioned substantia nigra when expressed as a percentage of the non-lesioned hemisphere. However, this appeared to be due to a compensatory decrease in completely stained tyrosine hydroxylase positive neurons in the contralateral, non-lesioned substantia nigra. In agreement with reports that maternal separation increases the 6-OHDA-induced loss of dopamine terminals in the striatum, there was a small increase in dopamine neuron destruction when expressed as a percentage of the non-lesioned hemisphere but there was no difference in dopamine cell number, suggesting that exposure to maternal separation did not exacerbate dopamine cell loss. PMID:20206210

  5. Protective effect of recombinant soluble neprilysin against β-amyloid induced neurotoxicity.

    PubMed

    Oh, Jae Hoon; Choi, Sunghyun; Shin, Jeehae; Park, Jong-Sang

    2016-09-01

    A few decades ago, researchers found emerging evidence showing that a number of sequential events lead to the pathological cascade of Alzheimer's disease (AD) which is caused by the accumulation of amyloid beta (Aβ), a physiological peptide, in the brain. Therefore, regulation of Aβ represents a crucial treatment approach for AD. Neprilysin (NEP), a membrane metallo-endopeptidase, is a rate-limiting peptidase which is known to degrade the amyloid beta peptide. This study investigated soluble NEP (sNEP) produced by recombinant mammalian cells stably transfected with a non-viral NEP expression vector to demonstrate its protective effect against Aβ peptides in neuronal cells in vitro. Stably transfected HEK 293 cells were used to purify the soluble protein. sNEP and Aβ peptide co-treated hippocampal cells had a decreased level of Aβ peptides shown by an increase in cell viability and decrease in apoptosis measured by the CCK-8 and relative caspase-3 activity ratio assays, respectively. This study shows that stably transfected mammalian cells can produce soluble NEP proteins which could be used to protect against Aβ accumulation in AD and subsequently neuronal toxicity. Additionally, approaches using protein therapy for potential targets could change the pathological cascade of Alzheimer's disease. PMID:27395340

  6. Methamphetamine-, d-Amphetamine-, and p-Chloroamphetamine-Induced Neurotoxicity Differentially Effect Impulsive Responding on the Stop-Signal Task in Rats.

    PubMed

    Furlong, Teri M; Leavitt, Lee S; Keefe, Kristen A; Son, Jong-Hyun

    2016-05-01

    Abused amphetamines, such as d-amphetamine (AMPH) and methamphetamine (METH), are highly addictive and destructive to health and productive lifestyles. The abuse of these drugs is associated with impulsive behavior, which is likely to contribute to addiction. The amphetamines also differentially damage dopamine (DA) and serotonin (5-HT) systems, which regulate impulsive behavior; therefore, exposure to these drugs may differentially alter impulsive behavior to effect the progression of addiction. We examined the impact of neurotoxicity induced by three amphetamines on impulsive action using a stop-signal task in rats. Animals were rewarded with a food pellet after lever pressing (i.e., a go trial), unless an auditory cue was presented and withholding lever press gained reward (i.e., a stop trial). Animals were trained on the task and then exposed to a neurotoxic regimen of either AMPH, p-chloroamphetamine (PCA), or METH. These regimens preferentially reduced DA transporter levels in striatum, 5-HT transporter levels in prefrontal cortex, or both, respectively. Assessment of performance on the stop-signal task beginning 1 week after the treatment revealed that AMPH produced a deficit in go-trial performance, whereas PCA did not alter performance on either trial type. In contrast, METH produced a deficit in stop-trial performance (i.e., impulsive action) but not go-trial performance. These findings suggest that the different neurotoxic consequences of substituted amphetamines are associated with different effects on inhibitory control over behavior. Thus, the course of addiction and maladaptive behavior resulting from exposure to these substances is likely to differ. PMID:26846719

  7. Hypothesizing that designer drugs containing cathinones ("bath salts") have profound neuro-inflammatory effects and dangerous neurotoxic response following human consumption.

    PubMed

    Blum, Kenneth; Foster Olive, M; Wang, Kevin K W; Febo, Marcelo; Borsten, Joan; Giordano, John; Hauser, Mary; Gold, Mark S

    2013-09-01

    Consensus in the most recent literature indicates that psychoactive "bath salts" is a relatively new drug-combination that was added to Schedule I classification in October 2011. Common ingredients include the cathinone analogs: mephedrone and methylenedioxypyrovalerone (MDPV). The mechanism of action of these synthetic cathinone analogs has not yet been well studied. We propose an intensive systematic investigation to determine the potential for cathinones to produce neurotoxic effects in various brain regions. In spite of a lack of evidence, for neurotoxicity there are number of horrific cases now on record that suggest intensification of research is needed. For example, a suicide by hanging had high 3,4-MDPV concentration while a driver under the influence had the highest reported methylone (MEPH) concentration. More interestingly, there have been consistent case reports indicating delayed responses, including: severe agitation with possible psychosis, suicidal ideation, rhabdomyolysis, hypertension, tachycardia, and death. In animal studies, amphetamine (AMPH), methamphetamine (METH) and cocaine release dopamine (DA), similarly to the action of cathinone and particular cathinone analogues. Two components of bath salts, MEPH and MDPV produce opposite effects at human dopamine transporter (hDAT) comparable to METH and cocaine, respectively. Moreover, it has already been found by others that MEPH is almost as potent as METH; and MDPV is much more potent than cocaine with longer lasting effects. It has been conjectured correctly that bath salts containing MDPV and MEPH (or a similar drug) might be expected both, to initially release DA and subsequently prevent its reuptake via hDAT. The null hypothesis, that cathinones do not cause neurotoxicity to dopamine nerve endings of the striatum, seems parsimonious and requires intensive investigation. Our hypothesis is that when consumed by humans, cathinones may induce neurotoxic pathways involving the neuro

  8. 40 CFR 795.250 - Developmental neurotoxicity screen.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 40 Protection of Environment 32 2014-07-01 2014-07-01 false Developmental neurotoxicity screen. 795.250 Section 795.250 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) TOXIC SUBSTANCES CONTROL ACT (CONTINUED) PROVISIONAL TEST GUIDELINES Provisional Health Effects Guidelines § 795.250 Developmental neurotoxicity screen....

  9. 40 CFR 799.9620 - TSCA neurotoxicity screening battery.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 40 Protection of Environment 33 2012-07-01 2012-07-01 false TSCA neurotoxicity screening battery... REQUIREMENTS Health Effects Test Guidelines § 799.9620 TSCA neurotoxicity screening battery. (a) Scope. This... battery consists of a functional observational battery, motor activity, and neuropathology. The...

  10. 40 CFR 799.9620 - TSCA neurotoxicity screening battery.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 40 Protection of Environment 32 2011-07-01 2011-07-01 false TSCA neurotoxicity screening battery... REQUIREMENTS Health Effects Test Guidelines § 799.9620 TSCA neurotoxicity screening battery. (a) Scope. This... battery consists of a functional observational battery, motor activity, and neuropathology. The...

  11. 40 CFR 799.9620 - TSCA neurotoxicity screening battery.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 40 Protection of Environment 32 2014-07-01 2014-07-01 false TSCA neurotoxicity screening battery... REQUIREMENTS Health Effects Test Guidelines § 799.9620 TSCA neurotoxicity screening battery. (a) Scope. This... battery consists of a functional observational battery, motor activity, and neuropathology. The...

  12. Neurotoxicity and Behavior

    EPA Science Inventory

    Neurotoxicity is important to consider as a component of occupational and environmental safety and health programs. The failure to do so has contributed to a number of cases in which workers, consumers of manufactured products, and people exposed in the environment were irreparab...

  13. Neurotoxic and teratogenic effects of an organophosphorus insecticide (phenyl phosphonothioic acid-O-ethyl -O-[4-nitrophenyl] ester) on mallard development

    USGS Publications Warehouse

    Hoffman, D.J.; Sileo, L.

    1984-01-01

    Phenyl phosphonothioic acid-O-ethyl-O-[4-nitrophenyl] ester (EPN) is one of the 10 most frequently used organophosphorus insecticides and causes delayed neurotoxicity in adult chickens and mallards. Small amounts of organophosphorus insecticides placed on birds' eggs are embryotoxic and teratogenic. For this reason, the effects of topical egg application on EPN were examined on mallard (Anas platyrhynchos) embryo development. Mallard eggs were treated topically at 72 hr of incubation with 25 microliter of a nontoxic oil vehicle or with EPN in the vehicle at concentrations of approximately 12, 36, or 108 micrograms/g egg, equivalent to one, three, and nine times the agricultural level of application used to spray crops. Treatment with EPN resulted in 22 to 44% mortality over this dose range by 18 days of development compared with 4 and 5% for untreated and vehicle-treated controls. EPN impaired embryonic growth and was highly teratogenic: 37-42% of the surviving embryos at 18 days were abnormal with cervical and axial scoliosis as well as severe edema. Brain weights were significantly lower in EPN-treated groups at different stages of development including hatchlings. Brain neurotoxic esterase (NTE) activity was inhibited by as much as 91% at 11 days, 81% at 18 days, and 79% in hatchlings. Examination of brain NTE activity during the course of normal development revealed an increase of nearly sixfold from Day 11 through hatching. The most rapid increase occurred between Day 20 and hatching. Brain acetylcholinesterase (AChE) activity was inhibited by as much as 41% at 11 days, 47% at 18 days, and 20% in hatchlings. Plasma cholinesterase and alkaline phosphatase activities were inhibited and plasma aspartate aminotransferase activity was increased at one or more stages of development. Hatchlings from EPN-treated eggs were weaker and slower to right themselves. Histopathological examination did not reveal demyelination and axonopathy of the spinal cord that was

  14. NEUROTOXIC EFFECTS OF COLCHICINE

    EPA Science Inventory

    Neurotoxicants have found increasing use as tools to study the structure and function of the central nervous system. ne class of compounds which block mitosis and disrupt axoplasmic transport includes colchicine, a chemical which is highly toxic to certain neuronal populations. o...

  15. Neuroprotective effects of honokiol against beta-amyloid-induced neurotoxicity via GSK-3β and β-catenin signaling pathway in PC12 cells.

    PubMed

    Xian, Yan-Fang; Ip, Siu-Po; Mao, Qing-Qiu; Lin, Zhi-Xiu

    2016-07-01

    Beta-amyloid (Aβ) accumulation, one of the most important pathogenic traits of Alzheimer's disease (AD), has been reported to induce neurotoxicity in vitro as well as in vivo. Honokiol, isolated from the bark of Magnolia officinalis, has neuroprotective effects in different models of AD in vivo and in vitro. However, the exact mechanism for its neuroprotective effect is not well understood. The present study aimed to investigate the molecular mechanisms underlying the protective action of honokiol against Aβ1-42-induced neurotoxicity in cultured rat pheochromocytoma (PC12) cells. The results revealed that honokiol protected PC12 cells from Aβ1-42 induced cytotoxicity with increases in cell viability, GSH production and Bcl-2 expression, but decreases in the release of lactate dehydrogenase and cytochrome c, the amount of DNA fragmentation and MDA level, as well as Bax expression. Mechanistic study showed that honokiol could inhibit the activation of glycogen synthase kinase (GSK)-3β, attenuate the nuclear accumulation of β-catenin and suppress the phosphorylation of β-catenin (Ser33/Ser37/Thr41 site) in the Aβ1-42-treated PC12 cells. These results indicate that the anti-oxidative and anti-apoptotic effects of honokiol in Aβ1-42-treated PC12 cells may be mediated, at least in part, by regulation the GSK-3β and β-catenin signaling pathways. PMID:27131736

  16. Early Activation of STAT3 Regulates Reactive Astrogliosis Induced by Diverse Forms of Neurotoxicity

    PubMed Central

    O'Callaghan, James P.; Kelly, Kimberly A.; VanGilder, Reyna L.; Sofroniew, Michael V.; Miller, Diane B.

    2014-01-01

    Astrogliosis, a cellular response characterized by astrocytic hypertrophy and accumulation of GFAP, is a hallmark of all types of central nervous system (CNS) injuries. Potential signaling mechanisms driving the conversion of astrocytes into “reactive” phenotypes differ with respect to the injury models employed and can be complicated by factors such as disruption of the blood-brain barrier (BBB). As denervation tools, neurotoxicants have the advantage of selective targeting of brain regions and cell types, often with sparing of the BBB. Previously, we found that neuroinflammation and activation of the JAK2-STAT3 pathway in astrocytes precedes up regulation of GFAP in the MPTP mouse model of dopaminergic neurotoxicity. Here we show that multiple mechanistically distinct mouse models of neurotoxicity (MPTP, AMP, METH, MDA, MDMA, KA, TMT) engender the same neuroinflammatory and STAT3 activation responses in specific regions of the brain targeted by each neurotoxicant. The STAT3 effects seen for TMT in the mouse could be generalized to the rat, demonstrating cross-species validity for STAT3 activation. Pharmacological antagonists of the neurotoxic effects blocked neuroinflammatory responses, pSTAT3tyr705 and GFAP induction, indicating that damage to neuronal targets instigated astrogliosis. Selective deletion of STAT3 from astrocytes in STAT3 conditional knockout mice markedly attenuated MPTP-induced astrogliosis. Monitoring STAT3 translocation in GFAP-positive cells indicated that effects of MPTP, METH and KA on pSTAT3tyr705 were localized to astrocytes. These findings strongly implicate the STAT3 pathway in astrocytes as a broadly triggered signaling pathway for astrogliosis. We also observed, however, that the acute neuroinflammatory response to the known inflammogen, LPS, can activate STAT3 in CNS tissue without inducing classical signs of astrogliosis. Thus, acute phase neuroinflammatory responses and neurotoxicity-induced astrogliosis both signal through

  17. MANAGING EXPOSURES TO NEUROTOXIC AIR POLLUTANTS.

    EPA Science Inventory

    Researchers at EPA's National Health and Environmental Effects Research Laboratory are developing a biologically-based dose-response model to describe the neurotoxic effects of exposure to volatile organic compounds (VOCs). The model is being developed to improve risk assessment...

  18. Neuroprotective approaches in experimental models of beta-amyloid neurotoxicity: relevance to Alzheimer's disease.

    PubMed

    Harkany, T; Hortobágyi, T; Sasvári, M; Kónya, C; Penke, B; Luiten, P G; Nyakas, C

    1999-08-01

    1. beta-Amyloid peptides (A beta s) accumulate abundantly in the Alzheimer's disease (AD) brain in areas subserving information acquisition and processing, and memory formation. A beta fragments are produced in a process of abnormal proteolytic cleavage of their precursor, the amyloid precursor protein (APP). While conflicting data exist in the literature on the roles of A beta s in the brain, and particularly in AD, recent studies have provided firm experimental evidence for the direct neurotoxic properties of A beta. 2. Sequence analysis of A beta s revealed a high degree of evolutionary conservation and inter-species homology of the A beta amino acid sequence. In contrast, synthetic A beta fragments, even if modified fluorescent or isotope-labeled derivatives, are pharmacological candidates for in vitro and in vivo modeling of their cellular actions. During the past decade, acute injection, prolonged mini-osmotic brain perfusion approaches or A beta infusions into the blood circulation were developed in order to investigate the effects of synthetic A beta s, whereas transgenic models provided insight into the distinct molecular steps of pathological APP cleavage. 3. The hippocampus, caudate putamen, amygdala and neocortex all formed primary targets of acute neurotoxicity screening, but functional consequences of A beta infusions were primarily demonstrated following either intracerebroventricular or basal forebrain (medial septum or magnocellular basal nucleus (MBN)) infusions of A beta fragments. 4. In vivo investigations confirmed that, while the active core of A beta is located within the beta(25-35) sequence, the flanking peptide regions influence not only the folding properties of the A beta fragments, but also their in vivo neurotoxic potentials. 5. It has recently been established that A beta administration deranges neuron-glia signaling, affects the glial glutamate uptake and thereby induces noxious glutamatergic stimulation of nerve cells. In fact, a

  19. Neurotoxicity of Immunosuppressive Therapies in Organ Transplantation

    PubMed Central

    ANGHEL, Daniela; TANASESCU, Radu; CAMPEANU, Ana; LUPESCU, Ioana; PODDA, Giulio; BAJENARU, Ovidiu

    2013-01-01

    ABSTRACT Immunosuppressive agents have revolutionized clinical transplantation medicine, allowing the avoidance of immune system attack on the transplanted graft. Nevertheless, the use of medications such as cyclosporine, tacrolimus and others also brought the side effects of these drugs. Early identification of drug-induced neurotoxicity in transplanted patients and of its specific causes is important, not only because of patient's poor clinical status but because of concomitant systemic and metabolic disorders which may obscure symptoms. Treatment and prognosis are highly dependent on the type of complication and it's early recognition. This review focuses on the clinical entities of neurotoxicity caused by immunosuppressive drugs in transplanted patients. PMID:24371481

  20. Neurotoxic injury pathways in differentiated mouse motor neuron–neuroblastoma hybrid (NSC-34D) cells in vitro—Limited effect of riluzole on thapsigargin, but not staurosporine, hydrogen peroxide and homocysteine neurotoxicity

    SciTech Connect

    Hemendinger, Richelle A.; Brooks, Benjamin Rix

    2012-01-15

    The neuroblastoma–spinal motor neuron fusion cell line, NSC-34, in its differentiated form, NSC-34D, permits examining the effects of riluzole, a proven treatment for amyotrophic lateral sclerosis (ALS) on cell death induction by staurosporine (STS), thapsigargin (Thaps), hydrogen peroxide (H{sub 2}O{sub 2}) and homocysteine (HCy). These neurotoxins, applied exogenously, have mechanisms of action related to the various proposed molecular pathogenetic pathways in ALS and are differentiated from endogenous cell death that is associated with cytoplasmic aggregate formation in motor neurons. Nuclear morphology, caspase-3/7 activation and high content imaging were used to assess toxicity of these neurotoxins with and without co-treatment with riluzole, a benzothiazole compound with multiple pharmacological actions. STS was the most potent neurotoxin at killing NSC-34D cells with a toxic concentration at which 50% of maximal cell death is achieved (TC{sub 50} = 0.01 μM), followed by Thaps (TC{sub 50} = 0.9 μM) and H{sub 2}O{sub 2} (TC{sub 50} = 15 μM) with HCy requiring higher concentrations to kill at the same level (TC{sub 50} = 2200 μM). Riluzole provided neurorescue with a 20% absolute reduction (47.6% relative reduction) in apoptotic cell death against Thaps-induced NSC-34D cell (p ≤ 0.05), but had no effect on STS-, H{sub 2}O{sub 2}- and HCy-induced NSC-34D cell death. This effect of riluzole on Thaps induction of cell death was independent of caspase-3/7 activation. Riluzole mitigated a toxin that can cause intracellular calcium dysregulation associated with endoplasmic reticulum (ER) stress but not toxins associated with other cell death mechanisms. -- Highlights: ► Calcium-dependent neurotoxins are potent cell death inducers in NSC-34D cells. ► Riluzole provides neurorescue against Thaps-induced NSC-34D cell death. ► Riluzole had no effect on neurotoxicity by STS, H{sub 2}O{sub 2} and Hcy. ► Riluzole reduces NSC-34D cell death independent of

  1. C-Phycocyanin protects against acute tributyltin chloride neurotoxicity by modulating glial cell activity along with its anti-oxidant and anti-inflammatory property: A comparative efficacy evaluation with N-acetyl cysteine in adult rat brain.

    PubMed

    Mitra, Sumonto; Siddiqui, Waseem A; Khandelwal, Shashi

    2015-08-01

    Spirulina is a widely used health supplement and is a dietary source of C-Phycocyanin (CPC), a potent anti-oxidant. We have previously reported the neurotoxic potential of tributyltin chloride (TBTC), an environmental pollutant and potent biocide. In this study, we have evaluated the protective efficacy of CPC against TBTC induced neurotoxicity. To evaluate the extent of neuroprotection offered by CPC, its efficacy was compared with the degree of protection offered by N-acetylcysteine (NAC) (a well known neuroprotective drug, taken as a positive control). Male Wistar rats (28 day old) were administered with 20mg/kg TBTC (oral) and 50mg/kg CPC or 50mg/kg NAC (i.p.), alone or in combination, and various parameters were evaluated. These include blood-brain barrier (BBB) damage; redox parameters (ROS, GSH, redox pathway associated enzymes, oxidative stress markers); inflammatory, cellular, and stress markers; apoptotic proteins and in situ cell death assay (TUNEL). We observed increased CPC availability in cortical tissue following its administration. Although BBB associated proteins like claudin-5, p-glycoprotein and ZO-1 were restored, CPC/NAC failed to protect against TBTC induced overall BBB permeability (Evans blue extravasation). Both CPC and NAC remarkably reduced oxidative stress and inflammation. NAC effectively modulated redox pathway associated enzymes whereas CPC countered ROS levels efficiently. Interestingly, CPC and NAC were equivalently capable of reducing apoptotic markers, astroglial activation and cell death. This study illustrates the various pathways involved in CPC mediated neuroprotection against this environmental neurotoxicant and highlights its capability to modulate glial cell activity. PMID:26079211

  2. TRIPHENYL PHOSPHITE: IN VIVO AND IN VITRO INHIBITION OF RAT NEUROTOXIC ESTERASE (JOURNAL VERSION)

    EPA Science Inventory

    Organophosphorus compounds which, after acute administration, inhibit neurotoxic esterase (NTE) by > or = 65% and undergo a subsequent 'aging' reaction, produce a delayed neuropathy characterized by degeneration of large and long nerve fibers. The present studies examine in detai...

  3. Neuroprotective effects of a sesquiterpene lactone and flavanones from Paulownia tomentosa Steud. against glutamate-induced neurotoxicity in primary cultured rat cortical cells.

    PubMed

    Kim, Soo-Ki; Cho, Sang-Buem; Moon, Hyung-In

    2010-12-01

    The neuroprotective effects of Paulownia tomentosa against glutamate-induced neurotoxicity were studied in primary cultured rat cortical cells. It was found that the aqueous extract of this medicinal plant significantly attenuated glutamate-induced toxicity. In order to clarify the mechanism(s) underlying this neuroprotective effect, the active fractions and components were isolated and identified. Five compounds were isolated as the methanol extracts from air-dried flowers of P. tomentosa. Isoatriplicolide tiglate exhibited significant neuroprotective activity against glutamate-induced toxicity at concentrations ranging from 1 μM to 10 μM, and exhibited cell viability of approximately 43-78%. Therefore, the neuroprotective effect of P. tomentosa might be due to the inhibition of glutamate-induced toxicity by the sesquiterpene lactone derivative it contains. PMID:20683844

  4. NEUROTOXICITY OF TETRACHLOROETHYLENE (PERCHLOROETHYLENE): DISCUSSION PAPER

    EPA Science Inventory

    This paper is a background document for a meeting of neurotoxicity experts to discuss the central nervous system effects of exposure to perchloroethylene (perc). The document reviews the literature on neurological testing of people exposed to perc occupationally in dry cleanin...

  5. PRINCIPLES OF IDENTIFYING AND CHARACTERIZING NEUROTOXICITY

    EPA Science Inventory

    There is currently considerable interest in the neurotoxic effects of environmental pollutants. ome of this interest is due to epidemiological, clinical and laboratory studies showing that the nervous system is a target for many toxic substances. he interest is also due to a real...

  6. Acute Biphasic Effects of Ayahuasca

    PubMed Central

    Schenberg, Eduardo Ekman; Alexandre, João Felipe Morel; Filev, Renato; Cravo, Andre Mascioli; Sato, João Ricardo; Muthukumaraswamy, Suresh D.; Yonamine, Maurício; Waguespack, Marian; Lomnicka, Izabela; Barker, Steven A.; da Silveira, Dartiu Xavier

    2015-01-01

    Ritual use of ayahuasca, an amazonian Amerindian medicine turned sacrament in syncretic religions in Brazil, is rapidly growing around the world. Because of this internationalization, a comprehensive understanding of the pharmacological mechanisms of action of the brew and the neural correlates of the modified states of consciousness it induces is important. Employing a combination of electroencephalogram (EEG) recordings and quantification of ayahuasca's compounds and their metabolites in the systemic circulation we found ayahuasca to induce a biphasic effect in the brain. This effect was composed of reduced power in the alpha band (8–13 Hz) after 50 minutes from ingestion of the brew and increased slow- and fast-gamma power (30–50 and 50–100 Hz, respectively) between 75 and 125 minutes. Alpha power reductions were mostly located at left parieto-occipital cortex, slow-gamma power increase was observed at left centro-parieto-occipital, left fronto-temporal and right frontal cortices while fast-gamma increases were significant at left centro-parieto-occipital, left fronto-temporal, right frontal and right parieto-occipital cortices. These effects were significantly associated with circulating levels of ayahuasca’s chemical compounds, mostly N,N-dimethyltryptamine (DMT), harmine, harmaline and tetrahydroharmine and some of their metabolites. An interpretation based on a cognitive and emotional framework relevant to the ritual use of ayahuasca, as well as it's potential therapeutic effects is offered. PMID:26421727

  7. Acute Biphasic Effects of Ayahuasca.

    PubMed

    Schenberg, Eduardo Ekman; Alexandre, João Felipe Morel; Filev, Renato; Cravo, Andre Mascioli; Sato, João Ricardo; Muthukumaraswamy, Suresh D; Yonamine, Maurício; Waguespack, Marian; Lomnicka, Izabela; Barker, Steven A; da Silveira, Dartiu Xavier

    2015-01-01

    Ritual use of ayahuasca, an amazonian Amerindian medicine turned sacrament in syncretic religions in Brazil, is rapidly growing around the world. Because of this internationalization, a comprehensive understanding of the pharmacological mechanisms of action of the brew and the neural correlates of the modified states of consciousness it induces is important. Employing a combination of electroencephalogram (EEG) recordings and quantification of ayahuasca's compounds and their metabolites in the systemic circulation we found ayahuasca to induce a biphasic effect in the brain. This effect was composed of reduced power in the alpha band (8-13 Hz) after 50 minutes from ingestion of the brew and increased slow- and fast-gamma power (30-50 and 50-100 Hz, respectively) between 75 and 125 minutes. Alpha power reductions were mostly located at left parieto-occipital cortex, slow-gamma power increase was observed at left centro-parieto-occipital, left fronto-temporal and right frontal cortices while fast-gamma increases were significant at left centro-parieto-occipital, left fronto-temporal, right frontal and right parieto-occipital cortices. These effects were significantly associated with circulating levels of ayahuasca's chemical compounds, mostly N,N-dimethyltryptamine (DMT), harmine, harmaline and tetrahydroharmine and some of their metabolites. An interpretation based on a cognitive and emotional framework relevant to the ritual use of ayahuasca, as well as it's potential therapeutic effects is offered. PMID:26421727

  8. Dose-response analysis indicating time-dependent neurotoxicity caused by organic and inorganic mercury-Implications for toxic effects in the developing brain.

    PubMed

    Pletz, Julia; Sánchez-Bayo, Francisco; Tennekes, Henk A

    2016-03-10

    A latency period preceding neurotoxicity is a common characteristic in the dose-response relationship induced by organic mercury. Latency periods have typically been observed with genotoxicants in carcinogenesis, with cancer being manifested a long time after the initiating event. These observations indicate that even a very small dose may cause extensive adverse effects later in life, so the toxicity of the genotoxic compound is dose and time-dependent. In children, methylmercury exposure during pregnancy (in utero) has been associated with delays in reaching developmental milestones (e.g., age at first walking) and decreases in intelligence, increasing in severity with increasing exposure. Ethylmercury exposure from thimerosal in some vaccines has been associated, in some studies, with autism and other neurological disorders in children. In this paper, we have examined whether dose-response data from in vitro and in vivo organic mercury toxicity studies fit the Druckrey-Küpfmüller equation c·t(n)=constant (c=exposure concentration, t=latency period), first established for genotoxic carcinogens, and whether or not irreversible effects are enhanced by time of exposure (n≥1), or else toxic effects are dose-dependent while time has only minor influence on the adverse outcome (n<1). The mode of action underlying time-dependent toxicity is irreversible binding to critical receptors causing adverse and cumulative effects. The results indicate that the Druckrey-Küpfmüller equation describes well the dose-response characteristics of organic mercury induced neurotoxic effects. This amounts to a paradigm shift in chemical risk assessment of mercurial compounds and highlights that it is vital to perform toxicity testing geared to investigate time-dependent effects. PMID:26945727

  9. Effects of acute caffeine administration on adolescents.

    PubMed

    Temple, Jennifer L; Dewey, Amber M; Briatico, Laura N

    2010-12-01

    Acute caffeine administration has physiological, behavioral, and subjective effects. Despite its widespread use, few studies have described the impact of caffeine consumption in children and adolescents. The purpose of this study was to investigate the effects of acute caffeine administration in adolescents. We measured cardiovascular responses and snack food intake after acute administration of 0 mg, 50 mg, 100 mg, and 200 mg of caffeine. We also compared usual food intake and subjective effects of caffeine between high- and low-caffeine consumers. Finally, we conducted a detailed analysis of caffeine sources and consumption levels. We found main effects of caffeine dose on heart rate (HR) and diastolic blood pressure (DBP), with HR decreasing and DBP increasing with increasing caffeine dose. There were significant interactions among gender, caffeine use, and time on DBP. High caffeine consumers (>50 mg/day) reported using caffeine to stay awake and drinking coffee, tea, soda, and energy drinks more than low consumers (<50 mg/day). Boys were more likely than girls to report using getting a rush, more energy, or improved athletic performance from caffeine. Finally, when we examined energy and macronutrient intake, we found that caffeine consumption was positively associated with laboratory energy intake, specifically from high-sugar, low-fat foods and also positively associated with protein and fat consumption outside of the laboratory. When taken together, these data suggest that acute caffeine administration has a broad range of effects in adolescents and that the magnitude of these effects is moderated by gender and chronic caffeine consumption. PMID:21186925

  10. Neurotoxicity in Aquatic Systems: Evaluation of Anthropogenic Trace Substances

    EPA Science Inventory

    The U.S. Environmental Protection Agency is evaluating methods to screen and prioritize large numbers of chemicals for developmental toxicity, as well as acute and developmental neurotoxicity. In this endeavor, one of our focuses is on contaminants found in drinking water. To exp...

  11. Development of a pluripotent stem cell derived neuronal model to identify chemically induced pathway perturbations in relation to neurotoxicity: Effects of CREB pathway inhibition

    SciTech Connect

    Pistollato, Francesca; Louisse, Jochem; Scelfo, Bibiana; Mennecozzi, Milena; Accordi, Benedetta; Basso, Giuseppe; Gaspar, John Antonydas; Zagoura, Dimitra; Barilari, Manuela; Palosaari, Taina; Sachinidis, Agapios; Bremer-Hoffmann, Susanne

    2014-10-15

    According to the advocated paradigm shift in toxicology, acquisition of knowledge on the mechanisms underlying the toxicity of chemicals, such as perturbations of biological pathways, is of primary interest. Pluripotent stem cells (PSCs), such as human embryonic stem cells (hESCs) and human induced pluripotent stem cells (hiPSCs), offer a unique opportunity to derive physiologically relevant human cell types to measure molecular and cellular effects of such pathway modulations. Here we compared the neuronal differentiation propensity of hESCs and hiPSCs with the aim to develop novel hiPSC-based tools for measuring pathway perturbation in relation to molecular and cellular effects in vitro. Among other fundamental pathways, also, the cAMP responsive element binding protein (CREB) pathway was activated in our neuronal models and gave us the opportunity to study time-dependent effects elicited by chemical perturbations of the CREB pathway in relation to cellular effects. We show that the inhibition of the CREB pathway, using 2-naphthol-AS-E-phosphate (KG-501), induced an inhibition of neurite outgrowth and synaptogenesis, as well as a decrease of MAP2{sup +} neuronal cells. These data indicate that a CREB pathway inhibition can be related to molecular and cellular effects that may be relevant for neurotoxicity testing, and, thus, qualify the use of our hiPSC-derived neuronal model for studying chemical-induced neurotoxicity resulting from pathway perturbations. - Highlights: • HESCs derived neuronal cells serve as benchmark for iPSC based neuronal toxicity test development. • Comparisons between hESCs and hiPSCs demonstrated variability of the epigenetic state • CREB pathway modulation have been explored in relation to the neurotoxicant exposure KG-501 • hiPSC might be promising tools to translate theoretical AoPs into toxicological in vitro tests.

  12. Assessment of neurotoxic effects and brain region distribution in rat offspring prenatally co-exposed to low doses of BDE-99 and methylmercury.

    PubMed

    Zhao, Wenchang; Cheng, Jinping; Gu, Jinmin; Liu, Yuanyuan; Fujimura, Masatake; Wang, Wenhua

    2014-10-01

    Exposure to polybrominated diphenyl ether (PDBE) and methylmercury (MeHg) can occur simultaneously as both contaminants are found in the same food sources, especially fish, seafood, marine mammals and milk. The aim of this study was to assess the effects of exposure to low levels of MeHg (2.0 μg mL(-1) in drinking water) and BDE-99 (0.2 mg kg(-1) d(-1)) from gestational day 6 to postnatal day (PND) 21, alone and in combination, on neurobehavioral development and redox responses in offspring. The present study demonstrated an interaction due to co-exposure with low doses of MeHg and BDE-99 enhanced developmental neurotoxic effects. These effects were manifested as the delayed appearance of negative geotaxis reflexes, impaired motor coordination, and induction of oxidative stress in the cerebellum. In particular, the cerebellum may be a sensitive target for combined MeHg and BDE-99 toxicity. The neurotoxicity of low dose MeHg was exacerbated by the presence of low dose of BDE-99. It is concluded that prenatal co-exposure to MeHg and BDE-99 causes oxidative stress in the cerebellum of offspring by altering the activity of different antioxidant enzymes and producing free radicals. Hg retention was not affected by co-exposure to BDE-99. However, MeHg co-exposure seemed to increase BDE-99 concentrations in selected brain regions in pups compared to pups exposed to BDE-99 only. These results showed that the adverse effects following prenatal co-exposure to MeHg and BDE-99 were associated with tissue concentrations very close to the current human body burden of this persistent bioaccumulative compound. PMID:25048903

  13. Striatal dopamine release in vivo following neurotoxic doses of methamphetamine and effect of the neuroprotective drugs, chlormethiazole and dizocilpine.

    PubMed Central

    Baldwin, H. A.; Colado, M. I.; Murray, T. K.; De Souza, R. J.; Green, A. R.

    1993-01-01

    1. Administration to rats of methamphetamine (15 mg kg-1, i.p.) every 2 h to a total of 4 doses resulted in a neurotoxic loss of striatal dopamine of 36% and of 5-hydroxytryptamine (5-HT) in the cortex (43%) and hippocampus (47%) 3 days later. 2. Administration of chlormethiazole (50 mg kg-1, i.p.) 15 min before each dose of methamphetamine provided complete protection against the neurotoxic loss of monoamines while administration of dizocilpine (1 mg kg-1, i.p.) using the same dose schedule provided substantial protection. 3. Measurement of dopamine release in the striatum by in vivo microdialysis revealed that methamphetamine produced an approximate 7000% increase in dopamine release after the first injection. The enhanced release response was somewhat diminished after the third injection but still around 4000% above baseline. Dizocilpine (1 mg kg-1, i.p.) did not alter this response but chlormethiazole (50 mg kg-1, i.p.) attenuated the methamphetamine-induced release by approximately 40%. 4. Dizocilpine pretreatment did not influence the decrease in the dialysate concentration of the dopamine metabolites dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) produced by administration of methamphetamine while chlormethiazole pretreatment decreased the dialysate concentration of these metabolites still further. 5. The concentration of dopamine in the dialysate during basal conditions increased modestly during the course of the experiment. This increase did not occur in chlormethiazole-treated rats. HVA concentrations were unaltered by chlormethiazole administration. 6. Chlormethiazole (100-1000 microM) did not alter methamphetamine (100 microM) or K+ (35 mM)-evoked release of endogenous dopamine from striatal prisms in vitro.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:8467354

  14. Studies with neuronal cells: From basic studies of mechanisms of neurotoxicity to the prediction of chemical toxicity.

    PubMed

    Suñol, C; Babot, Z; Fonfría, E; Galofré, M; García, D; Herrera, N; Iraola, S; Vendrell, I

    2008-08-01

    Neurotoxicology considers that chemicals perturb neurological functions by interfering with the structure or function of neural pathways, circuits and systems. Using in vitro methods for neurotoxicity studies should include evaluation of specific targets for the functionalism of the nervous system and general cellular targets. In this review we present the neuronal characteristics of primary cultures of cortical neurons and of cerebellar granule cells and their use in neurotoxicity studies. Primary cultures of cortical neurons are constituted by around 40% of GABAergic neurons, whereas primary cultures of cerebellar granule cells are mainly constituted by glutamatergic neurons. Both cultures express functional GABAA and ionotropic glutamate receptors. We present neurotoxicity studies performed in these cell cultures, where specific neural targets related to GABA and glutamate neurotransmission are evaluated. The effects of convulsant polychlorocycloalkane pesticides on the GABAA, glycine and NMDA receptors points to the GABAA receptor as the neural target that accounts for their in vivo acute toxicity, whereas NMDA disturbance might be relevant for long-term toxicity. Several compounds from a list of reference compounds, whose severe human poisoning result in convulsions, inhibited the GABAA receptor. We also present cell proteomic studies showing that the neurotoxic contaminant methylmercury affect mitochondrial proteins. We conclude that the in vitro assays that have been developed can be useful for their inclusion in an in vitro test battery to predict human toxicity. PMID:18467072

  15. Effect of fraxetin on antioxidant defense and stress proteins in human neuroblastoma cell model of rotenone neurotoxicity. Comparative study with myricetin and N-acetylcysteine

    SciTech Connect

    Molina-Jimenez, Maria Francisca . E-mail: jbenedi@farm.ucm.es

    2005-12-15

    Mitochondrial complex I inhibitor rotenone induces apoptosis through enhancing mitochondrial reactive oxygen species production. Recently, it has been shown that fraxetin (coumarin) and myricetin (flavonoid) have significant neuroprotective effects against apoptosis induced by rotenone, increase the total glutathione levels in vitro, and inhibit lipid peroxidation. Thus, these considerations prompted us to investigate the way in which fraxetin and myricetin affect the endogenous antioxidant defense system, such as Mn and CuZn superoxide dismutase (MnSOD, CuZnSOD), catalase, glutathione reductase (GR), and glutathione peroxidase (GPx) on rotenone neurotoxicity in neuroblastoma cells. N-acetylcysteine (NAC), a potent antioxidant, was employed as a comparative agent. Also, the expression and protein levels of HSP70 by Northern and Western blot analysis were assayed in SH-SY5Y cells. After incubation for 16 h, rotenone significantly increased the expression and activity of MnSOD, GPx, and catalase. When cells were preincubated with fraxetin, there was a decrease in the protein levels and activity of both MnSOD and catalase, in comparison with the rotenone treatment. The myricetin effect was less pronounced. Activity and expression of GPx were increased by rotenone and pre-treatment with fraxetin did not modify significantly these levels. The significant enhancement in HSP70 expression at mRNA and protein levels induced by fraxetin was observed by pre-treatment of cells 0.5 h before rotenone insult. These data suggest that major features of rotenone-induced neurotoxicity are partially mediated by free radical formation and oxidative stress, and that fraxetin partially protects against rotenone toxicity affecting the main protection system of the cells against oxidative injury.

  16. Neuroprotective effects of the anti‐cancer drug sunitinib in models of HIV neurotoxicity suggests potential for the treatment of neurodegenerative disorders

    PubMed Central

    Wrasidlo, Wolf; Crews, Leslie A; Tsigelny, Igor F; Stocking, Emily; Kouznetsova, Valentina L; Price, Diana; Paulino, Amy; Gonzales, Tania; Overk, Cassia R; Patrick, Christina; Rockenstein, Edward; Masliah, Eliezer

    2014-01-01

    Background and Purpose Anti-retrovirals have improved and extended the life expectancy of patients with HIV. However, as this population ages, the prevalence of cognitive changes is increasing. Aberrant activation of kinases, such as receptor tyrosine kinases (RTKs) and cyclin-dependent kinase 5 (CDK5), play a role in the mechanisms of HIV neurotoxicity. Inhibitors of CDK5, such as roscovitine, have neuroprotective effects; however, CNS penetration is low. Interestingly, tyrosine kinase inhibitors (TKIs) display some CDK inhibitory activity and ability to cross the blood–brain barrier. Experimental Approach We screened a small group of known TKIs for a candidate with additional CDK5 inhibitory activity and tested the efficacy of the candidate in in vitro and in vivo models of HIV-gp120 neurotoxicity. Key Results Among 12 different compounds, sunitinib inhibited CDK5 with an IC50 of 4.2 μM. In silico analysis revealed that, similarly to roscovitine, sunitinib fitted 6 of 10 features of the CDK5 pharmacophore. In a cell-based model, sunitinib reduced CDK5 phosphorylation (pCDK5), calpain-dependent p35/p25 conversion and protected neuronal cells from the toxic effects of gp120. In glial fibrillary acidic protein-gp120 transgenic (tg) mice, sunitinib reduced levels of pCDK5, p35/p25 and phosphorylated tau protein, along with amelioration of the neurodegenerative pathology. Conclusions and Implications Compounds such as sunitinib with dual kinase inhibitory activity could ameliorate the cognitive impairment associated with chronic HIV infection of the CNS. Moreover, repositioning existing low MW compounds holds promise for the treatment of patients with neurodegenerative disorders. PMID:25117211

  17. TESTING FOR DEVELOPMENTAL NEUROTOXICITY: CURRENT APPROACHES AND FUTURE NEEDS.

    EPA Science Inventory

    There are many adverse effects on the nervous system following exposure to environmental chemicals during development. In a number of cases (e.g., lead, methyl mercury) the developing nervous system is a highly susceptible. Developmental Neurotoxicity Testing (DNT) guidelines...

  18. ONTOGENY OF PROTEINS FOR USE AS BIOMARKERS OF DEVELOPMENTAL NEUROTOXICITY.

    EPA Science Inventory

    The developing nervous system can be uniquely susceptible to adverse effects following exposure to environmental chemicals, and several advisory panels (e.g. ILSI, NRC, NAS) have highlighted the need for rapid and sensitive developmental neurotoxicity testing methods. Measurement...

  19. [Acute tonsillopharyngitis: the effectiveness of topical therapy].

    PubMed

    Nosulya, E V; Kim, I A; Chernykh, N M; Karnoukhova, O A

    2015-01-01

    The objective of the present study was to evaluate the clinical effectiveness of a furasol sore throat gargle solution for the treatment of acute tonsillopharyngitis. Forty patients presenting with acute tonsillopharyngitis were allocated to two groups, 20 subjects in each, by means of independent sequential randomization. Prior to the onset of the treatment, all the patients were examined for determining the species composition of pharyngeal microflora with the use of an «AutoScan4 System» analyzer («Siemens», USA) and estimating the resistance to antibacterial preparations (by the disk diffusion method). All the participants of the study were prescribed antibacterial therapy. In the patients of group 1 (study group), the antibacterial treatment of acute tonsillopharyngitis was supplemented by a furasol sore throat gargle solution whereas those of group 2 (controls) were treated without topical therapy. The quantitative evaluation of the severity of manifestations of the disease before and after the treatment was based on a 5-point visual-analog scale. It was shown that systemic antibacterial therapy resulted in the consistent decrease of the frequency of occurrence of pathogenic and potentially pathogenic microflora in the patients comprising both groups. Treatment with a furasol sore throat gargle solution did not lead to the appearance of bacterial species alien to the oropharynx, nor was it accompanied by the impairment of resistance of its mucous membrane to the colonization by microorganisms. The results of the study give evidence of the well apparent regression of the subjective signs of tonsillopharyngitis and the inflammatory changes in the mucous membrane of the pharynx in the patients given the topical treatment in the form of a furasol sore throat gargle solution in addition to antibacterial therapy. It is concluded that a furasol sore throat gargle solution can be recommended for the introduction into the combined treatment of the patients

  20. Neurotoxic cyanobacterial toxins.

    PubMed

    Aráoz, Rómulo; Molgó, Jordi; Tandeau de Marsac, Nicole

    2010-10-01

    Worldwide development of cyanobacterial blooms has significantly increased in marine and continental waters in the last century due to water eutrophication. This phenomenon is favoured by the ability of planktonic cyanobacteria to synthesize gas vesicles that allow them to float in the water column. Besides, benthic cyanobacteria that proliferate at the bottom of lakes, rivers and costal waters form dense mats near the shore. Cyanobacterial massive proliferation is of public concern regarding the capacity of certain cyanobacterial strains to produce hepatotoxic and neurotoxic compounds that can affect public health, human activities and wild and stock animals. The cholinergic synapses and voltage-gated sodium channels constitute the targets of choice of cyanobacterial neurotoxins. Anatoxin-a and homoanatoxin-a are agonists of nicotinic acetylcholine receptors. Anatoxin-a(s) is an irreversible inhibitor of acetylcholinesterase. Saxitoxin, kalkitoxin and jamaicamide are blockers of voltage-gated sodium channels, whereas antillatoxin is an activator of such channels. Moreover the neurotoxic amino acid l-beta-N-methylamino-l-alanine was shown to be produced by diverse cyanobacterial taxa. Although controversial, increasing in vivo and in vitro evidence suggest a link between the ingestion of l-beta-N-methylamino-l-alanine and the development of amyotrophic lateral sclerosis/Parkinsonism-dementia complex, a neurodegenerative disease. This paper reviews the occurrence of cyanobacterial neurotoxins, their chemical properties, mode of action and biosynthetic pathways. PMID:19660486

  1. Corneal Neurotoxicity Due to Topical Benzalkonium Chloride

    PubMed Central

    Sarkar, Joy; Chaudhary, Shweta; Namavari, Abed; Ozturk, Okan; Chang, Jin-Hong; Yco, Lisette; Sonawane, Snehal; Khanolkar, Vishakha; Hallak, Joelle; Jain, Sandeep

    2012-01-01

    Purpose. The aim of this study was to determine and characterize the effect of topical application of benzalkonium chloride (BAK) on corneal nerves in vivo and in vitro. Methods. Thy1-YFP+ neurofluorescent mouse eyes were treated topically with vehicle or BAK (0.01% or 0.1%). Wide-field stereofluorescence microscopy was performed to sequentially image the treated corneas in vivo every week for 4 weeks, and changes in stromal nerve fiber density (NFD) and aqueous tear production were determined. Whole-mount immunofluorescence staining of corneas was performed with antibodies to axonopathy marker SMI-32. Western immunoblot analyses were performed on trigeminal ganglion and corneal lysates to determine abundance of proteins associated with neurotoxicity and regeneration. Compartmental culture of trigeminal ganglion neurons was performed in Campenot devices to determine whether BAK affects neurite outgrowth. Results. BAK-treated corneas exhibited significantly reduced NFD and aqueous tear production, and increased inflammatory cell infiltration and fluorescein staining at 1 week (P < 0.05). These changes were most significant after 0.1% BAK treatment. The extent of inflammatory cell infiltration in the cornea showed a significant negative correlation with NFD. Sequential in vivo imaging of corneas showed two forms of BAK-induced neurotoxicity: reversible neurotoxicity characterized by axonopathy and recovery, and irreversible neurotoxicity characterized by nerve degeneration and regeneration. Increased abundance of beta III tubulin in corneal lysates confirmed regeneration. A dose-related significant reduction in neurites occurred after BAK addition to compartmental cultures of dissociated trigeminal ganglion cells. Although both BAK doses (0.0001% and 0.001%) reduced nerve fiber length, the reduction was significantly more with the higher dose (P < 0.001). Conclusion. Topical application of BAK to the eye causes corneal neurotoxicity, inflammation, and reduced aqueous

  2. Mutual enhancement of central neurotoxicity induced by ketamine followed by methamphetamine

    SciTech Connect

    Ke, J.-J.; Chen, H.-I.; Jen, C.J.; Kuo, Y.-M.; Cherng, C.G.; Tsai, Y.-P.N.; Ho, M.-C.; Tsai, C.-W.; Lung Yu

    2008-03-01

    We hereby report that repeated administration of ketamine (350 mg/kg in total) and methamphetamine (30 mg/kg in total) causes specific glutamatergic and dopaminergic neuron deficits, respectively, in adult mouse brain. Acute ketamine did not affect basal body temperature or the later methamphetamine-induced hyperthermia. However, pretreatment with repeated doses of ketamine aggravated methamphetamine-induced dopaminergic terminal loss as evidenced by a drastic decrease in the levels of dopamine, 3,4-dihydroxyphenylacetic acid, and dopamine transporter density as well as poor gait balance performance. In contrast, methamphetamine-induced serotonergic depletion was not altered by ketamine pretreatment. Likewise, the subsequent treatment with methamphetamine exacerbated the ketamine-induced glutamatergic damage as indicated by reduced levels of the vesicular glutamate transporter in hippocampus and striatum and poor memory performance in the Morris water maze. Finally, since activation of the D1 and AMPA/kainate receptors has been known to be involved in the release of glutamate and dopamine, we examined the effects of co-administration of SCH23390, a D1 antagonist, and CNQX, an AMPA/kainate antagonist. Intraventricular CNQX infusion abolished ketamine's potentiation of methamphetamine-induced dopamine neurotoxicity, while systemic SCH23390 mitigated methamphetamine's potentiation of ketamine-induced glutamatergic toxicity. We conclude that repeated doses of ketamine potentiate methamphetamine-induced dopamine neurotoxicity via AMPA/kainate activation and that conjunctive use of methamphetamine aggravates ketamine-induced glutamatergic neurotoxicity possibly via D1 receptor activation.

  3. Receptor mechanisms and circuitry underlying NMDA antagonist neurotoxicity.

    PubMed

    Farber, N B; Kim, S H; Dikranian, K; Jiang, X P; Heinkel, C

    2002-01-01

    NMDA glutamate receptor antagonists are used in clinical anesthesia, and are being developed as therapeutic agents for preventing neurodegeneration in stroke, epilepsy, and brain trauma. However, the ability of these agents to produce neurotoxicity in adult rats and psychosis in adult humans compromises their clinical usefulness. In addition, an NMDA receptor hypofunction (NRHypo) state might play a role in neurodegenerative and psychotic disorders, like Alzheimer's disease and schizophrenia. Thus, understanding the mechanism underlying NRHypo-induced neurotoxicity and psychosis could have significant clinically relevant benefits. NRHypo neurotoxicity can be prevented by several classes of agents (e.g. antimuscarinics, non-NMDA glutamate antagonists, and alpha(2) adrenergic agonists) suggesting that the mechanism of neurotoxicity is complex. In the present study a series of experiments was undertaken to more definitively define the receptors and complex neural circuitry underlying NRHypo neurotoxicity. Injection of either the muscarinic antagonist scopolamine or the non-NMDA antagonist NBQX directly into the cortex prevented NRHypo neurotoxicity. Clonidine, an alpha(2) adrenergic agonist, protected against the neurotoxicity when injected into the basal forebrain. The combined injection of muscarinic and non-NMDA Glu agonists reproduced the neurotoxic reaction. Based on these and other results, we conclude that the mechanism is indirect, and involves a complex network disturbance, whereby blockade of NMDA receptors on inhibitory neurons in multiple subcortical brain regions, disinhibits glutamatergic and cholinergic projections to the cerebral cortex. Simultaneous excitotoxic stimulation of muscarinic (m(3)) and glutamate (AMPA/kainate) receptors on cerebrocortical neurons appears to be the proximal mechanism by which the neurotoxic and psychotomimetic effects of NRHypo are mediated. PMID:11803444

  4. Effects of exposure period and nutrition on the developmental neurotoxicity of anticonvulsants in rats: short and long-term effects.

    PubMed

    Vorhees, C V; Rindler, J M; Minck, D R

    1990-01-01

    The results of three experiments on the functional neuroteratogenicity of anticonvulsants in rats are presented. Two of the experiments have been reported previously and are reviewed here, while the third experiment is presented here for the first time. The first experiment examined prenatal phenytoin (200 mg/kg), trimethadione (250 mg/kg), and phenobarbital (80 mg/kg) for critical period effects by exposing separate groups of rats to the drugs or to vehicle on embryonic (E) days 7-10, 11-14, or 15-18. Phenytoin produced effects in the E11-14 offspring, but few effects in the E15-18 offspring, and almost no effects in the E7-10 offspring. Phenytoin's E11-14 effects in the offspring were increased pivoting, delayed swimming ontogeny, hyperactivity, impaired water maze learning, and impaired passive avoidance retention. The second experiment looked for phenytoin's long-term effects. Phenytoin-exposed offspring administered 200 mg/kg on E7-18 exhibited numerous postnatal dysfunctions, including water maze learning deficits that persisted to beyond 501 days of age. The learning deficits were neither increased nor decreased in severity at this age compared to those seen in littermates tested at 50 days of age. The third experiment assessed the role of manganese in counteracting phenytoin-induced postnatal dysfunction and the possible confounding effects of maternal undernutrition associated with the drug's administration. The typical pattern of phenytoin-induced behavioral effects was observed in rat offspring. The results demonstrated that undernutrition was not a confound, since pair-feeding and pair-watering controls did not diminish the phenytoin-induced dysfunction in the offspring. Also, administration of a manganese supplementation (200 ppm in the drinking water) during gestation did not significantly alter the pattern of phenytoin-induced postnatal effects. PMID:2234544

  5. Behavioral evaluation of the neurotoxicity produced by dichloroacetic acid in rats.

    PubMed

    Moser, V C; Phillips, P M; McDaniel, K L; MacPhail, R C

    1999-01-01

    Dichloroacetic acid (DCA) is commonly found in drinking water as a by-product of chlorination disinfection. It is a known neurotoxicant in rats, dogs, and humans. We have characterized DCA neurotoxicity in rats using a neurobehavioral screening battery under varying exposure durations (acute, subchronic, and chronic) and routes of administration (oral gavage and drinking water). Studies were conducted in both weanling and adult rats, and comparisons were made between Long-Evans and Fischer-344 rats. DCA produced neuromuscular toxicity comprised of limb weakness and deficits in gait and righting reflex; altered gait and decreased hindlimb grip strength were the earliest indicators of toxicity. Other effects included mild tremors, ocular abnormalities, and a unique chest-clasping response (seen in Fischer-344 rats only). Neurotoxicity was permanent (i.e., through 2 years) following a 6-month exposure to high dose levels, whereas the effects of intermediate dose levels with exposures of 3 months or less were slowly reversible. The severity, specificity, and recovery of neurological changes were route, duration, and strain dependent. Fischer-344 rats were more sensitive than Long-Evans rats, and weanling rats may be somewhat more sensitive than adults. Oral gavage produced significantly less toxicity compared to the same intake level received in drinking water. Neurotoxicity was progressive with continued exposure, and was observed at exposure levels as low as 16 mg/kg/day (lowest dose level tested) when administered via drinking water in subchronic studies. The data from these studies characterize the neurotoxicity produced by DCA, and show it to be more pronounced, persistent, and occurring at lower exposures than has been previously reported. Further research should take into account these marked route, age, and strain differences. PMID:10560779

  6. Tissue Plasminogen Activator Neurotoxicity is Neutralized by Recombinant ADAMTS 13

    PubMed Central

    Fan, Mengchen; Xu, Haochen; Wang, Lixiang; Luo, Haiyu; Zhu, Ximin; Cai, Ping; Wei, Lixiang; Lu, Lu; Cao, Yongliang; Ye, Rong; Fan, Wenying; Zhao, Bing-Qiao

    2016-01-01

    Tissue plasminogen activator (tPA) is an effective treatment for ischemic stroke, but its neurotoxicity is a significant problem. Here we tested the hypothesis that recombinant ADAMTS 13 (rADAMTS 13) would reduce tPA neurotoxicity in a mouse model of stroke. We show that treatment with rADAMTS 13 in combination with tPA significantly reduced infarct volume compared with mice treated with tPA alone 48 hours after stroke. The combination treatment significantly improved neurological deficits compared with mice treated with tPA or vehicle alone. These neuroprotective effects were associated with significant reductions in fibrin deposits in ischemic vessels and less severe cell death in ischemic brain. The effect of rADAMTS13 on tPA neurotoxicity was mimicked by the N-methyl-D-aspartate (NMDA) receptor antagonist M-801, and was abolished by injection of NMDA. Moreover, rADAMTS 13 prevents the neurotoxicity effect of tPA, by blocking its interaction with the NMDA receptor NR2B and the attendant phosphorylation of NR2B and activation of ERK1/2. Finally, the NR2B-specific NMDA receptor antagonist ifenprodil abolished tPA neurotoxicity and rADAMTS 13 treatment had no further beneficial effect. Our data suggest that the combination of rADAMTS 13 and tPA may provide a novel treatment of ischemic stroke by diminishing the neurotoxic effects of exogenous tPA. PMID:27181025

  7. Tissue Plasminogen Activator Neurotoxicity is Neutralized by Recombinant ADAMTS 13.

    PubMed

    Fan, Mengchen; Xu, Haochen; Wang, Lixiang; Luo, Haiyu; Zhu, Ximin; Cai, Ping; Wei, Lixiang; Lu, Lu; Cao, Yongliang; Ye, Rong; Fan, Wenying; Zhao, Bing-Qiao

    2016-01-01

    Tissue plasminogen activator (tPA) is an effective treatment for ischemic stroke, but its neurotoxicity is a significant problem. Here we tested the hypothesis that recombinant ADAMTS 13 (rADAMTS 13) would reduce tPA neurotoxicity in a mouse model of stroke. We show that treatment with rADAMTS 13 in combination with tPA significantly reduced infarct volume compared with mice treated with tPA alone 48 hours after stroke. The combination treatment significantly improved neurological deficits compared with mice treated with tPA or vehicle alone. These neuroprotective effects were associated with significant reductions in fibrin deposits in ischemic vessels and less severe cell death in ischemic brain. The effect of rADAMTS13 on tPA neurotoxicity was mimicked by the N-methyl-D-aspartate (NMDA) receptor antagonist M-801, and was abolished by injection of NMDA. Moreover, rADAMTS 13 prevents the neurotoxicity effect of tPA, by blocking its interaction with the NMDA receptor NR2B and the attendant phosphorylation of NR2B and activation of ERK1/2. Finally, the NR2B-specific NMDA receptor antagonist ifenprodil abolished tPA neurotoxicity and rADAMTS 13 treatment had no further beneficial effect. Our data suggest that the combination of rADAMTS 13 and tPA may provide a novel treatment of ischemic stroke by diminishing the neurotoxic effects of exogenous tPA. PMID:27181025

  8. Effects of acute dieldrin exposure on neurotransmitters and global gene transcription in largemouth bass (Micropterus salmoides) hypothalamus

    PubMed Central

    Martyniuk, Christopher J.; Feswick, April; Spade, Daniel J.; Kroll, Kevin J.; Barber, David S.; Denslow, Nancy D.

    2010-01-01

    Exposure to dieldrin induces neurotoxic effects in the vertebrate CNS and disrupts reproductive processes in teleost fish. Reproductive impairment observed in fish by dieldrin is likely the result of multiple effects along the hypothalamic-pituitary-gonadal axis but the molecular signaling cascades are not well characterized. To better elucidate the mode of action of dieldrin in the hypothalamus, this study measured neurotransmitter levels and examined the transcriptomic response in female largemouth bass (LMB) to an acute treatment of dieldrin. Male and female LMB were injected with either vehicle or 10 mg dieldrin/kg and sacrificed after seven days. There were no significant changes in dopamine or DOPAC concentrations in the neuroendocrine brain of males and females after treatment but GABA levels in females were moderately increased 20–30% in the hypothalamus and cerebellum. In the female hypothalamus, there were 227 transcripts (p<0.001) identified as being differentially regulated by dieldrin. Functional enrichment analysis revealed transcription, DNA repair, ubiquitin-proteasome pathway, and cell communication, as biological processes over-represented in the microarray analysis. Pathway analysis identified DNA damage, inflammation, regeneration, and Alzheimer’s disease as major cell processes and diseases affected by dieldrin. Using multiple bioinformatics approaches, this study demonstrates that the teleostean hypothalamus is a target for dieldrin-induced neurotoxicity and provides mechanistic evidence that dieldrin activates similar cell pathways and biological processes that are also associated with the etiology of human neurological disorders. PMID:20438755

  9. Antagonistic effects of Spirulina platensis against sub-acute deltamethrin toxicity in mice: Biochemical and histopathological studies.

    PubMed

    Abdel-Daim, Mohamed; El-Bialy, Badr E; Rahman, Haidy G Abdel; Radi, Abeer M; Hefny, Hany A; Hassan, Ahmed M

    2016-02-01

    Spirulina platensis (SP); a microalga with high antioxidant and anti-inflammatory activities, acts as a food supplement in human and as many animal species. Deltamethrin (DLM) is a synthetic pyrethroid with broad spectrum activities against acaricides and insects and widely used for veterinary and agricultural purposes. Exposure to DLM leads to hepatotoxic, nephrotoxic and neurotoxic side effects for human and many species, including birds and fish. The present study was undertaken to examine the potential hepatoprotective, nephroprotective, neuroprotective and antioxidant effects of SP against sub-acute DLM toxicity in male mice. DLM intoxicated animals revealed a significant increase in serum hepatic and renal injury biomarkers as well as TNF-α level and AChE activity. Moreover, liver, kidney and brain lipid peroxidation and oxidative stress markers were altered due to DLM toxicity. Spirulina normalized the altered serum levels of AST, ALT, APL, LDH, γ-GT, cholesterol, uric acid, urea, creatinine AChE and TNF-α. Furthermore, it reduced DLM-induced tissue lipid peroxidation, nitric oxide and oxidative stress in a dose-dependent manner. Collectively, that Spirulina supplementation could overcome DLM-induced hepatotoxicty, nephrotoxicity and neurotoxicity by abolishing oxidative tissue injuries. PMID:26796269

  10. The neurotoxicity of amphetamines during the adolescent period.

    PubMed

    Teixeira-Gomes, Armanda; Costa, Vera Marisa; Feio-Azevedo, Rita; Bastos, Maria de Lourdes; Carvalho, Félix; Capela, João Paulo

    2015-04-01

    Amphetamine-type psychostimulants (ATS), such as amphetamine (AMPH), 3,4-methylenedioxymethamphetamine (MDMA), and methamphetamine (METH) are psychoactive substances widely abused, due to their powerful central nervous system (CNS) stimulation ability. Young people particularly use ATS as recreational drugs. Moreover, AMPH is used clinically, particularly for attention deficit hyperactivity disorder, and has the ability to cause structural and functional brain alterations. ATS are known to interact with monoamine transporter sites and easily diffuse across cellular membranes, attaining high levels in several tissues, particularly the brain. Strong evidence suggests that ATS induce neurotoxic effects, raising concerns about the consequences of drug abuse. Considering that many teenagers and young adults commonly use ATS, our main aim was to review the neurotoxic effects of amphetamines, namely AMPH, MDMA, and METH, in the adolescence period of experimental animals. Reports agree that adolescent animals are less susceptible than adult animals to the neurotoxic effects of amphetamines. The susceptibility to the neurotoxic effects of ATS seems roughly located in the early adolescent period of animals. Many authors report that the age of exposure to ATS is crucial for the neurotoxic outcome, showing that the stage of brain maturity has a strong importance. Moreover, recent studies have been undertaken in young adults and/or consumers during adolescence that clearly indicate brain or behavioural damage, arguing for long-term neurotoxic effects in humans. There is an urgent need for more studies during the adolescence period, in order to unveil the mechanisms and the brain dysfunctions promoted by ATS. PMID:25482046

  11. Memory-enhancing effect of aspirin is mediated through opioid system modulation in an AlCl3-induced neurotoxicity mouse model

    PubMed Central

    RIZWAN, SAIMA; IDREES, AYESHA; ASHRAF, MUHAMMAD; AHMED, TOUQEER

    2016-01-01

    Neurodegenerative disorders such as Alzheimers disease (AD) are multifaceted and there are currently a limited number of therapeutic strategies available to treat them. Aspirin is known to act on multiple therapeutic targets and is a successful anti-inflammatory agent in various tissues. The present study aimed to ascertain the performance of aspirin when employed as a therapeutic agent to treat neurodegeneration on novel targets, including opioid system genes, in an AlCl3-induced neurotoxicity mouse model. The effects of two doses of aspirin (5 and 20 mg/kg aspirin for 12 days) were investigated in an AlCl3-induced neurotoxicity mouse model (150 mg/kg AlCl3 for 12 days). Neurological improvements were assessed through different behavioral tests and the effects of aspirin on opioid system gene expression levels were assessed by reverse transcription-polymerase chain reaction. Both doses resulted in improvements in cognitive behavior. A 5 mg/kg dose of aspirin was revealed to be effective for spatial memory improvement (7.14±0.84 sec), whilst a 20 mg/kg dose was superior for improving extinction learning (7.63±4.04%). Aspirin (5 mg/kg) also significantly improved contextual memory (48.05±10.6%) when compared with the AlCl3-treated group (1.49±0.62%; P<0.001). Aspirin was also observed to significantly decrease δ-opioid receptor expression in the cortex (1.09±0.08 and 1.27±0.08, respectively) at both doses (5 and 20 mg/kg) when compared with the AlCl3-treated group (3.69±1.43; P<0.05). Furthermore, aspirin at 5 mg/kg significantly reduced expression of prodynorphin in the cortex (0.57±0.20) when compared with the AlCl3-treated group (1.95±0.84; P<0.05). Notably, the effect of aspirin was significant in the cortex but not in the hippocampus. In summary, aspirin was effective in ameliorating the AD-like symptoms via the modulation of opioid systems. However, additional studies are required to determine the long term effects of aspirin on such conditions. PMID

  12. Paclitaxel- and/or cisplatin-induced ocular neurotoxicity: a case report and literature review

    PubMed Central

    Li, Ying; Li, Yanping; Li, Junyu; Pi, Guoliang; Tan, Wenyong

    2014-01-01

    Paclitaxel (PTX) and/or cisplatin (CDDP), as important cytotoxic anti-cancer agents, are widely used to treat various solid tumors. Both may cause moderate or severe neurotoxicity, but ocular neurotoxicity is also occasionally reported. A patient diagnosed with nasopharyngeal cancer suffering acute ocular neurotoxicity 10 days after paclitaxel and CDDP administration at the recommended dose is described in the present case report, and PTX- and/or CDDP-induced ocular neurotoxicity are summarized according to previous reports. Possible mechanisms and the potential diagnostic, therapeutic and predictive strategies of PTX- and/or CDDP-induced ocular neurotoxicity are reviewed, to help the oncologist to take the infrequent toxicity of cytotoxic drugs into account and improve patient safety during anti-cancer therapy. PMID:25114574

  13. Evaluation of drug-induced neurotoxicity based on metabolomics, proteomics and electrical activity measurements in complementary CNS in vitro models.

    PubMed

    Schultz, Luise; Zurich, Marie-Gabrielle; Culot, Maxime; da Costa, Anaelle; Landry, Christophe; Bellwon, Patricia; Kristl, Theresa; Hörmann, Katrin; Ruzek, Silke; Aiche, Stephan; Reinert, Knut; Bielow, Chris; Gosselet, Fabien; Cecchelli, Romeo; Huber, Christian G; Schroeder, Olaf H-U; Gramowski-Voss, Alexandra; Weiss, Dieter G; Bal-Price, Anna

    2015-12-25

    The present study was performed in an attempt to develop an in vitro integrated testing strategy (ITS) to evaluate drug-induced neurotoxicity. A number of endpoints were analyzed using two complementary brain cell culture models and an in vitro blood-brain barrier (BBB) model after single and repeated exposure treatments with selected drugs that covered the major biological, pharmacological and neuro-toxicological responses. Furthermore, four drugs (diazepam, cyclosporine A, chlorpromazine and amiodarone) were tested more in depth as representatives of different classes of neurotoxicants, inducing toxicity through different pathways of toxicity. The developed in vitro BBB model allowed detection of toxic effects at the level of BBB and evaluation of drug transport through the barrier for predicting free brain concentrations of the studied drugs. The measurement of neuronal electrical activity was found to be a sensitive tool to predict the neuroactivity and neurotoxicity of drugs after acute exposure. The histotypic 3D re-aggregating brain cell cultures, containing all brain cell types, were found to be well suited for OMICs analyses after both acute and long term treatment. The obtained data suggest that an in vitro ITS based on the information obtained from BBB studies and combined with metabolomics, proteomics and neuronal electrical activity measurements performed in stable in vitro neuronal cell culture systems, has high potential to improve current in vitro drug-induced neurotoxicity evaluation. PMID:26026931

  14. Yueju Pill Rapidly Induces Antidepressant-Like Effects and Acutely Enhances BDNF Expression in Mouse Brain

    PubMed Central

    Xue, Wenda; Zhou, Xin; Yi, Nan; Jiang, Lihua; Tao, Weiwei; Wu, Runjie; Wang, Dan; Jiang, Jingjing; Ge, Xiaoyin; Wang, Yuyue; Wu, Haoxin; Chen, Gang

    2013-01-01

    The traditional antidepressants have a major disadvantage in delayed onset of efficacy, and the emerging fast-acting antidepressant ketamine has adverse behavioral and neurotoxic effects. Yueju pill, an herb medicine formulated eight hundred years ago by Doctor Zhu Danxi, has been popularly prescribed in China for alleviation of depression-like symptoms. Although several clinical outcome studies reported the relative short onset of antidepressant effects of Yueju, this has not been scientifically investigated. We, therefore, examined the rapid antidepressant effect of Yueju in mice and tested the underlying molecular mechanisms. We found that acute administration of ethanol extract of Yueju rapidly attenuated depressive-like symptoms in learned helpless paradigm, and the antidepressant-like effects were sustained for at least 24 hours in tail suspension test in ICR mice. Additionally, Yueju, like ketamine, rapidly increased the expression of brain-derived neurotrophic factor (BDNF) in the hippocampus, whereas the BDNF mRNA expression remained unaltered. Yueju rapidly reduced the phosphorylation of eukaryotic elongation factor 2 (eEF2), leading to desuppression of BDNF synthesis. Unlike ketamine, both the BDNF expression and eEF2 phosphorylation were revered at 24 hours after Yueju administration. This study is the first to demonstrate the rapid antidepressant effects of an herb medicine, offering an opportunity to improve therapy of depression. PMID:23710213

  15. Methamphetamine and MDMA (ecstasy) neurotoxicity: 'of mice and men'.

    PubMed

    Itzhak, Yossef; Achat-Mendes, Cindy

    2004-05-01

    Methamphetamine (METH) and 3,4-meythylenedioxymethamphetamine (MDMA; 'ecstasy') are currently major drugs of abuse. One of the major concerns of amphetamines abuse is their potential neurotoxic effect on dopaminergic and serotonergic neurons. Although data from human studies are somewhat limited, compelling evidence suggests that these drugs cause neurotoxicity in rodents and primates. Recent studies in transgenic and knockout mice identified the role of dopamine transporters, nitric oxide, apoptotic proteins, and inflammatory cytokines in amphetamines neurotoxicity. Further research into the mechanisms underlying the dopaminergic and serotonergic neurotoxicity and the behavioral corollaries of these neuronal insults could facilitate our understanding of the consequences of human abuse of METH and MDMA on cognition, drug-seeking behavior, extinction and relapse. PMID:15370888

  16. In vitro techniques for the assessment of neurotoxicity.

    PubMed Central

    Harry, G J; Billingsley, M; Bruinink, A; Campbell, I L; Classen, W; Dorman, D C; Galli, C; Ray, D; Smith, R A; Tilson, H A

    1998-01-01

    Risk assessment is a process often divided into the following steps: a) hazard identification, b) dose-response assessment, c) exposure assessment, and d) risk characterization. Regulatory toxicity studies usually are aimed at providing data for the first two steps. Human case reports, environmental research, and in vitro studies may also be used to identify or to further characterize a toxic hazard. In this report the strengths and limitations of in vitro techniques are discussed in light of their usefulness to identify neurotoxic hazards, as well as for the subsequent dose-response assessment. Because of the complexity of the nervous system, multiple functions of individual cells, and our limited knowledge of biochemical processes involved in neurotoxicity, it is not known how well any in vitro system would recapitulate the in vivo system. Thus, it would be difficult to design an in vitro test battery to replace in vivo test systems. In vitro systems are well suited to the study of biological processes in a more isolated context and have been most successfully used to elucidate mechanisms of toxicity, identify target cells of neurotoxicity, and delineate the development and intricate cellular changes induced by neurotoxicants. Both biochemical and morphological end points can be used, but many of the end points used can be altered by pharmacological actions as well as toxicity. Therefore, for many of these end points it is difficult or impossible to set a criterion that allows one to differentiate between a pharmacological and a neurotoxic effect. For the process of risk assessment such a discrimination is central. Therefore, end points used to determine potential neurotoxicity of a compound have to be carefully selected and evaluated with respect to their potential to discriminate between an adverse neurotoxic effect and a pharmacologic effect. It is obvious that for in vitro neurotoxicity studies the primary end points that can be used are those affected

  17. INTRACELLULAR SIGNALING AND DEVELOPMENTAL NEUROTOXICITY.

    EPA Science Inventory

    A book chapter in ?Molecular Toxicology: Transcriptional Targets? reviewed the role of intracellular signaling in the developmental neurotoxicity of environmental chemicals. This chapter covered a number of aspects including the development of the nervous system, role of intrace...

  18. High concentrations of extracellular potassium enhance bacterial endotoxin lipopolysaccharide-induced neurotoxicity in glia-neuron mixed cultures.

    PubMed

    Chang, R C; Hudson, P M; Wilson, B C; Liu, B; Abel, H; Hong, J S

    2000-01-01

    A sudden increase in extracellular potassium ions (K(+)) often occurs in cerebral ischemia and after brain trauma. This increase of extracellular K(+) constitutes the basis for spreading depression across the cerebral cortex, resulting in the expansion of neuronal death after ischemic and traumatic brain injuries. Besides spreading depression, it has become clear that cerebral inflammation also is a key factor contributing to secondary brain injury in acute neurological disorders. Experiments to validate the relationship between elevated levels of extracellular K(+) and inflammation have not been studied. This study aims to elucidate the roles of high concentrations of extracellular K(+) in bacterial endotoxin lipopolysaccharide-induced production of inflammatory factors. Increased concentration of KCl in the medium (20mM) significantly enhanced neurotoxicity by lipopolysaccharide in glia-neuron mixed cultures. To delineate the underlying mechanisms of increased neurotoxicity, the effects of high extracellular K(+) were examined by using mixed glial cultures. KCl at 20mM significantly enhanced nitrite, an index for nitric oxide, production by about twofold, and was pronounced from 24 to 48h, depending on the concentration of KCl. Besides nitric oxide production of tumor necrosis factor-alpha was also enhanced. The augmentative effects of high KCl on the production of inflammatory factors were probably due to the further activation of microglia, since high KCl also enhanced the production of tumor necrosis factor-alpha in microglia-enriched cultures. The increased production of nitrite by high K(+) was eliminated through use of a K(+)-blocker. Taken together, the results show that increases of extracellular K(+) concentrations in spreading depression augment lipopolysaccharide-elicited neurotoxicity, because production of inflammatory factors such as nitric oxide and tumor necrosis factor-alpha are potentiated. Since spreading depression and cerebral inflammation

  19. Potential developmental neurotoxicity of pesticides used in Europe

    PubMed Central

    Bjørling-Poulsen, Marina; Andersen, Helle Raun; Grandjean, Philippe

    2008-01-01

    Pesticides used in agriculture are designed to protect crops against unwanted species, such as weeds, insects, and fungus. Many compounds target the nervous system of insect pests. Because of the similarity in brain biochemistry, such pesticides may also be neurotoxic to humans. Concerns have been raised that the developing brain may be particularly vulnerable to adverse effects of neurotoxic pesticides. Current requirements for safety testing do not include developmental neurotoxicity. We therefore undertook a systematic evaluation of published evidence on neurotoxicity of pesticides in current use, with specific emphasis on risks during early development. Epidemiologic studies show associations with neurodevelopmental deficits, but mainly deal with mixed exposures to pesticides. Laboratory experimental studies using model compounds suggest that many pesticides currently used in Europe – including organophosphates, carbamates, pyrethroids, ethylenebisdithiocarbamates, and chlorophenoxy herbicides – can cause neurodevelopmental toxicity. Adverse effects on brain development can be severe and irreversible. Prevention should therefore be a public health priority. The occurrence of residues in food and other types of human exposures should be prevented with regard to the pesticide groups that are known to be neurotoxic. For other substances, given their widespread use and the unique vulnerability of the developing brain, the general lack of data on developmental neurotoxicity calls for investment in targeted research. While awaiting more definite evidence, existing uncertainties should be considered in light of the need for precautionary action to protect brain development. PMID:18945337

  20. Conserved toxic responses across divergent phylogenetic lineages: a meta-analysis of the neurotoxic effects of RDX among multiple species using toxicogenomics.

    PubMed

    Garcia-Reyero, Natàlia; Habib, Tanwir; Pirooznia, Mehdi; Gust, Kurt A; Gong, Ping; Warner, Chris; Wilbanks, Mitchell; Perkins, Edward

    2011-05-01

    At military training sites, a variety of pollutants such as hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX), may contaminate the area originating from used munitions. Studies investigating the mechanism of toxicity of RDX have shown that it affects the central nervous system causing seizures in humans and animals. Environmental pollutants such as RDX have the potential to affect many different species, therefore it is important to establish how phylogenetically distant species may respond to these types of emerging pollutants. In this paper, we have used a transcriptional network approach to compare and contrast the neurotoxic effects of RDX among five phylogenetically disparate species: rat (Sprague-Dawley), Northern bobwhite quail (Colinus virginianus), fathead minnow (Pimephales promelas), earthworm (Eisenia fetida), and coral (Acropora formosa). Pathway enrichment analysis indicated a conservation of RDX impacts on pathways related to neuronal function in rat, Northern bobwhite quail, fathead minnows and earthworm, but not in coral. As evolutionary distance increased common responses decreased with impacts on energy and metabolism dominating effects in coral. A neurotransmission related transcriptional network based on whole rat brain responses to RDX exposure was used to identify functionally related modules of genes, components of which were conserved across species depending upon evolutionary distance. Overall, the meta-analysis using genomic data of the effects of RDX on several species suggested a common and conserved mode of action of the chemical throughout phylogenetically remote organisms. PMID:21516383

  1. Melatonin Attenuates Methamphetamine-Induced Neurotoxicity.

    PubMed

    Wongprayoon, Pawaris; Govitrapong, Piyarat

    2016-01-01

    Methamphetamine (METH), an illegal psycho-stimulant, is widely known as a recreational drug. In addition to its addictive effect, METH induces neurotoxicity via multiple mechanisms. The major contributors to METH-induced neurotoxicity are reactive oxygen species, which lead to cell death through apoptotic pathway and disturbances in mitochondria, the generation of neuroinflammation, and autophagy. Melatonin, a neurohormone secreted by the pineal gland, is a potent antioxidant compound that plays a beneficial role by protecting against the oxidative stress caused by METH. Melatonin also plays a role in maintaining mitochondrial homeostasis. Nanomolar concentrations of melatonin have been shown to protect against the inflammation caused by METH and to prevent the decrease in neurogenesis caused by METH in progenitor cells obtained from adult rat hippocampal tissue. The intent of this review is to describe the underlying mechanisms involving melatonin that protect against the neurodegeneration caused by METH. PMID:25248807

  2. Valacyclovir and Acyclovir Neurotoxicity With Status Epilepticus.

    PubMed

    Hoskote, Sumedh S; Annapureddy, Narender; Ramesh, Atul K; Rose, Keith; Jones, James P

    2016-01-01

    We present the case of a 52-year-old man with hypertension, diastolic congestive heart failure, end-stage renal disease on hemodialysis 3 times a week and a remote history of a hemorrhagic stroke who presented to the emergency department with a vesicular rash on his left arm. The rash was observed to be in a dermatomal distribution, and a diagnosis of herpes zoster was made. The patient was discharged home on valacyclovir 1 g 3 times a day for a duration of 7 days. The patient took 2 doses of valacyclovir before presenting to the hospital again with irritability and hallucinations. Over the next several days, the patient's neurologic status declined and he became disoriented and increasingly somnolent. Because of a concern for varicella zoster virus (VZV) or herpes simplex virus (HSV) meningoencephalitis, acyclovir was initiated intravenously at 600 mg (10 mg/kg) for every 12 hours. Computed tomography and magnetic resonance imaging of the brain failed to reveal an acute process. Electroencephalogram was interpreted as seizure activity versus metabolic encephalopathy. Lumbar puncture was not suggestive for meningitis, subarachnoid hemorrhage, or HSV/VZV infection. The patient subsequently had a witnessed seizure during dialysis and was felt to have status epilepticus due to acyclovir and valacyclovir neurotoxicity. The patient underwent daily hemodialysis for removal of the drug and eventually made a full neurologic recovery. Our case highlights that acyclovir neurotoxicity can result in status epilepticus, hallucinations, and altered consciousness. Differentiating acyclovir neurotoxicity from HSV or VZV meningoencephalitis is of crucial importance because the symptoms are similar but the management is vastly different. PMID:24368610

  3. Mitoprotective effect of Centella asiatica against aluminum-induced neurotoxicity in rats: possible relevance to its anti-oxidant and anti-apoptosis mechanism.

    PubMed

    Prakash, Atish; Kumar, Anil

    2013-08-01

    Role of mitochondrial dysfunction and oxidative stress has been well documented in various cognitive-related disorders such as Alzheimer's disease. Aluminum is a neurotoxic metal that may be involved in the progression of neurodegenerative processes. The antioxidant and memory enhancing effects of Centella asiatica (CA) are well known in the last few decades. Therefore, the present study has been designed to explore the neuroprotective effect of CA on chronic aluminum exposure induced mitochondrial enzyme alteration, oxidative stress, apoptosis and cognitive dysfunction in rat. Aluminum (100 mg/kg) and CA (150 and 300 mg/kg) were administered daily for a period of 6 weeks in male Wistar rats. Various behavioral, biochemical and cellular estimations and aluminum concentration were assessed. Chronic aluminum administration resulted in memory impairment and caused marked oxidative damage associated with mitochondria impairment. It also caused a significant increase in caspase-3 activity, acetylcholine esterase activity and aluminum concentration in hippocampus and cerebral cortex of rat brain. Chronic administration of CA significantly improved memory performance, oxidative defense decreased aluminum concentration, caspase-3, acetylcholinestrease activity and reversal of mitochondrial enzyme activity as compared to aluminum-treated animals. Results of the study demonstrate neuroprotective potential of CA against aluminum-induced cognitive dysfunction and mito- oxidative damage. PMID:23224641

  4. ACUTE BEHAVIORAL EFFECTS OF INHALED PERCHLOROETHYLENE IN RATS ARE DIRECTLY RELATED TO ITS CONCENTRATION IN THE BRAIN.

    EPA Science Inventory

    Perchloroethylene (PCE) is a volatile organic compound (VOC), frequently used in dry cleaning processes, that is currently being assessed by EPA for its risk to human health. Many VOCs are acutely neurotoxic and have been shown to affect attentional processes in humans and animal...

  5. Persistent Mobility Disability After Neurotoxic Chemotherapy

    PubMed Central

    Fitzgerald, G. Kelley; Studenski, Stephanie A.

    2010-01-01

    Background and Purpose The impact of cancer and its treatments on balance and functional mobility in older adults remains unknown but is increasingly important, given the evolution of cancer treatments. Subacute and more persistent side effects such as chemotherapy-induced peripheral neuropathy are on the rise, and the effects on mobility and balance, as well as the prognosis for resolution of any functional deficits, must be established before interventions can be trialed. The purpose of this case report is to describe the severity and long-term persistence of mobility decline in an older adult who received neurotoxic chemotherapy. To our knowledge, this is the first case report to describe an older adult with chemotherapy-induced peripheral neuropathy using results of standardized balance and mobility tests and to focus on prognosis by repeating these measures more than 2 years after chemotherapy. Case Description An 81-year-old woman received a neurotoxic agent (paclitaxel) after curative mastectomy for breast cancer. Baseline testing prior to taxane therapy revealed a socially active woman with no reported functional deficits or neuropathic symptoms, 1.2-m/s gait speed, and performance at the ceiling on balance and gait portions of a standardized mobility measure. Outcomes After 3 cycles, paclitaxel therapy was stopped by the oncologist because of neurotoxicity. Declines as large as 50% were seen in performance-based measures at 12 weeks and persisted at 2.5 years, and the patient reported recurrent falls, cane use, and mobility-related disability. Discussion This case highlights the extent to which function can decline in an older individual receiving neurotoxic chemotherapy, the potential for these deficits to persist years after treatment is stopped, and the need for physical therapy intervention and further research in this population. PMID:20813818

  6. Neurotoxic shellfish poisoning.

    PubMed

    Watkins, Sharon M; Reich, Andrew; Fleming, Lora E; Hammond, Roberta

    2008-01-01

    Neurotoxic shellfish poisoning (NSP) is caused by consumption of molluscan shellfish contaminated with brevetoxins primarily produced by the dinoflagellate, Karenia brevis. Blooms of K. brevis, called Florida red tide, occur frequently along the Gulf of Mexico. Many shellfish beds in the US (and other nations) are routinely monitored for presence of K. brevis and other brevetoxin-producing organisms. As a result, few NSP cases are reported annually from the US. However, infrequent larger outbreaks do occur. Cases are usually associated with recreationally-harvested shellfish collected during or post red tide blooms. Brevetoxins are neurotoxins which activate voltage-sensitive sodium channels causing sodium influx and nerve membrane depolarization. No fatalities have been reported, but hospitalizations occur. NSP involves a cluster of gastrointestinal and neurological symptoms: nausea and vomiting, paresthesias of the mouth, lips and tongue as well as distal paresthesias, ataxia, slurred speech and dizziness. Neurological symptoms can progress to partial paralysis; respiratory distress has been recorded. Recent research has implicated new species of harmful algal bloom organisms which produce brevetoxins, identified additional marine species which accumulate brevetoxins, and has provided additional information on the toxicity and analysis of brevetoxins. A review of the known epidemiology and recommendations for improved NSP prevention are presented. PMID:19005578

  7. Neurotoxic Shellfish Poisoning

    PubMed Central

    Watkins, Sharon M.; Reich, Andrew; Fleming, Lora E.; Hammond, Roberta

    2008-01-01

    Neurotoxic shellfish poisoning (NSP) is caused by consumption of molluscan shellfish contaminated with brevetoxins primarily produced by the dinoflagellate, Karenia brevis. Blooms of K. brevis, called Florida red tide, occur frequently along the Gulf of Mexico. Many shellfish beds in the US (and other nations) are routinely monitored for presence of K. brevis and other brevetoxin-producing organisms. As a result, few NSP cases are reported annually from the US. However, infrequent larger outbreaks do occur. Cases are usually associated with recreationally-harvested shellfish collected during or post red tide blooms. Brevetoxins are neurotoxins which activate voltage-sensitive sodium channels causing sodium influx and nerve membrane depolarization. No fatalities have been reported, but hospitalizations occur. NSP involves a cluster of gastrointestinal and neurological symptoms: nausea and vomiting, paresthesias of the mouth, lips and tongue as well as distal paresthesias, ataxia, slurred speech and dizziness. Neurological symptoms can progress to partial paralysis; respiratory distress has been recorded. Recent research has implicated new species of harmful algal bloom organisms which produce brevetoxins, identified additional marine species which accumulate brevetoxins, and has provided additional information on the toxicity and analysis of brevetoxins. A review of the known epidemiology and recommendations for improved NSP prevention are presented. PMID:19005578

  8. Lithium-mediated protection against ethanol neurotoxicity.

    PubMed

    Luo, Jia

    2010-01-01

    Lithium has long been used as a mood stabilizer in the treatment of manic-depressive (bipolar) disorder. Recent studies suggest that lithium has neuroprotective properties and may be useful in the treatment of acute brain injuries such as ischemia and chronic neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease and amyotrophic lateral sclerosis. One of the most important neuroprotective properties of lithium is its anti-apoptotic action. Ethanol is a neuroteratogen and fetal alcohol spectrum disorders (FASD) are caused by maternal ethanol exposure during pregnancy. FASD is the leading cause of mental retardation. Ethanol exposure causes neuroapoptosis in the developing brain. Ethanol-induced loss of neurons in the central nervous system underlies many of the behavioral deficits observed in FASD. Excessive alcohol consumption is also associated with Wernicke-Korsakoff syndrome and neurodegeneration in the adult brain. Recent in vivo and in vitro studies indicate that lithium is able to ameliorate ethanol-induced neuroapoptosis. Lithium is an inhibitor of glycogen synthase kinase 3 (GSK3) which has recently been identified as a mediator of ethanol neurotoxicity. Lithium's neuroprotection may be mediated by its inhibition of GSK3. In addition, lithium also affects many other signaling proteins and pathways that regulate neuronal survival and differentiation. This review discusses the recent evidence of lithium-mediated protection against ethanol neurotoxicity and potential underlying mechanisms. PMID:20661453

  9. Neurotoxic effects of berberine on long-term L-DOPA administration in 6-hydroxydopamine-lesioned rat model of Parkinson's disease.

    PubMed

    Shin, Keon Sung; Choi, Hyun Sook; Zhao, Ting Ting; Suh, Kwang Hoon; Kwon, Ik Hyun; Choi, Soon Ok; Lee, Myung Koo

    2013-06-01

    The effects of berberine on long-term administration of L-DOPA in 6-hydroxydopamine (6-OHDA)-lesioned rat model of Parkinson's disease (PD) were investigated. Rat models of PD were prepared by 6-OHDA lesions in the ipsilateral sides, and then were treated with berberine (5 and 15 mg/kg) and/or L-DOPA (10 mg/kg) once daily for 21 days. Treatments with either concentration of berberine (5 and 15 mg/kg) in 6-OHDA-lesioned groups decreased the numbers of tyrosine hydroxylase (TH)-immunopositive neurons in the substantia nigra and the levels of dopamine, norepinephrine, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in the striatum as compared to 6-OHDA-lesioned groups. In addition, dopaminergic neuronal cell death of the ipsilateral sides in 6-OHDA-lesioned groups was attenuated by L-DOPA administration. However, both concentrations of berberine in 6-OHDA-lesioned groups treated with L-DOPA aggravated the numbers of TH-immunopositive neurons in the substantia nigra and the levels of dopamine, norepinephrine, DOPAC and HVA in the striatum as compared to rats not treated with berberine. These results suggest that berberine leads to the degeneration of dopaminergic neuronal cells in the substantia nigra in the rat model of PD with chronic L-DOPA administration. Long-term L-DOPA therapy that may involve possibly neurotoxic isoquinoline agents including berberine should involve monitoring for adverse symptoms. PMID:23539311

  10. GSK3β in Ethanol Neurotoxicity

    PubMed Central

    2016-01-01

    Alcohol consumption during pregnancy is a significant public health problem and may result in a wide range of adverse outcomes for the child. The developing central nervous system (CNS) is particularly susceptible to ethanol toxicity. Children with fetal alcohol spectrum disorders (FASD) have a variety of cognitive, behavioral, and neurological impairments. FASD currently represents the leading cause of mental retardation in North America ahead of Down syndrome and cerebral palsy. Ethanol exposure during development causes multiple abnormalities in the brain such as permanent loss of neurons, ectopic neurons, and alterations in synaptogenesis and myelinogenesis. These alcohol-induced structural alterations in the developing brain underlie many of the behavioral deficits observed in FASD. The cellular and molecular mechanisms of ethanol neurotoxicity, however, remain unclear. Ethanol elicits cellular stresses, including oxidative stress and endoplasmic reticulum stress. Glycogen synthase kinase 3β (GSK3β), a multifunctional serine/ threonine kinase, responds to various cellular stresses. GSK3β is particularly abundant in the developing CNS, and regulates diverse developmental events in the immature brain, such as neurogenesis and neuronal differentiation, migration, and survival. Available evidence indicates that the activity of GSK3β in the CNS is affected by ethanol. GSK3β inhibition provides protection against ethanol neurotoxicity, whereas high GSK3β activity/expression sensitizes neuronal cells to ethanol-induced damages. It appears that GSK3β is a converging signaling point that mediates some of ethanol’s neurotoxic effects. PMID:19507062

  11. Acute and chronic glue sniffing effects and consequences of withdrawal on aggressive behavior.

    PubMed

    Bouchatta, Otmane; Ouhaz, Zakaria; Ba-Mhamed, Saadia; Kerekes, Nóra; Bennis, Mohamed

    2016-05-01

    Drug abuse act on brain mechanisms that cause a high-risk individual to engage in aggressive and violent behavior. While a drug-violence relationship exists, the nature of this relationship is often complex, with intoxication, neurotoxic, and withdrawal effects often being confused and/or confounded. Glue sniffing is often a springboard to the abuse of more addictive drugs. Despite its high prevalence and serious consequences, we know relatively little about the aggressive behavioral effects of volatile inhalants abuse, especially glue. The aim of the present study was to investigate the link between the duration of glue exposure, a common substance abuse problem in Morocco, and the level of aggressive behavior during withdrawal. For this we used the isolation-induced aggression model "residents" in three groups of mice. The first group served as control resident animals (n=10, without exposure); the second group as experimental resident mice (n=10) tested before and after acute (first day) and chronic exposure to the glue, and at 1 and 2weeks of withdrawal; and the third group of 10 intruder animals. The results showed that the number of attacks decreased (halved) and the latency of the first attack increased (doubled) following acute glue sniffing. However, the effects of chronic exposure and of 1week of withdrawal led to an increase in the intensity of agonistic encounters. After 2weeks of withdrawal, the intensity of aggressive behavior decreased again. These results indicated that chronic glue exposure and the first week of withdrawal are associated with increased aggression in mice. PMID:26969766

  12. Glial Reactivity in Resistance to Methamphetamine-Induced Neurotoxicity

    PubMed Central

    Friend, Danielle M.; Keefe, Kristen A.

    2013-01-01

    Neurotoxic regimens of methamphetamine (METH) result in reactive microglia and astrocytes in striatum. Prior data indicate that rats with partial dopamine (DA) loss resulting from prior exposure to METH are resistant to further decreases in striatal DA when re-exposed to METH 30 days later. Such resistant animals also do not show an activated microglia phenotype, suggesting a relation between microglial activation and METH-induced neurotoxicity. To date, the astrocyte response in such resistance has not been examined. Thus, this study examined glial-fibrillary acidic protein (GFAP) and CD11b protein expression in striata of animals administered saline or a neurotoxic regimen of METH on postnatal days 60 and/or 90 (Saline:Saline, Saline:METH, METH:Saline, METH:METH). Consistent with previous work, animals experiencing acute toxicity (Saline:METH) showed both activated microglia and astocytes, whereas those resistant to the acute toxicity (METH:METH) did not show activated microglia. Interestingly, GFAP expression remained elevated in rats exposed to METH at PND60 (METH:Saline), and was not elevated further in resistant rats treated for the second time with METH (METH:METH). These data suggest that astrocytes remain reactive up to 30 days post-METH exposure. Additionally, these data indicate that astrocyte reactivity does not reflect acute, METH-induced DA terminal toxicity, whereas microglial reactivity does. PMID:23414433

  13. Sustained Accumulation of Microtubule-Binding Chemotherapy Drugs in the Peripheral Nervous System: Correlations with Time Course and Neurotoxic Severity.

    PubMed

    Wozniak, Krystyna M; Vornov, James J; Wu, Ying; Nomoto, Kenichi; Littlefield, Bruce A; DesJardins, Christopher; Yu, Yanke; Lai, George; Reyderman, Larisa; Wong, Nancy; Slusher, Barbara S

    2016-06-01

    Chemotherapy-induced peripheral neuropathy is a dose-limiting side effect of many antineoplastic agents, but the mechanisms underlying the toxicities are unclear. At their MTDs, the microtubule-binding drugs paclitaxel and ixabepilone induce more severe neuropathy in mice relative to eribulin mesylate, paralleling their toxicity profiles in clinic. We hypothesized that the severity of their neurotoxic effects might be explained by the levels at which they accumulate in the peripheral nervous system. To test this hypothesis, we compared their pharmacokinetics and distribution in peripheral nerve tissue. After administration of a single intravenous dose, each drug was rapidly cleared from plasma but all persisted in the dorsal root ganglia (DRG) and sciatic nerve (SN) for up to 72 hours. Focusing on paclitaxel and eribulin, we performed a 2-week MTD-dosing regimen, followed by a determination of drug pharmacokinetics, tissue distribution, and multiple functional measures of peripheral nerve toxicity for 4 weeks. Consistent with the acute dosing study, both drugs persisted in peripheral nervous tissues for weeks, in contrast to their rapid clearance from plasma. Notably, although eribulin exhibited greater DRG and SN penetration than paclitaxel, the neurotoxicity observed functionally was consistently more severe with paclitaxel. Overall, our results argue that sustained exposure of microtubule-binding chemotherapeutic agents in peripheral nerve tissues cannot by itself account for their associated neurotoxicity. Cancer Res; 76(11); 3332-9. ©2016 AACR. PMID:27197173

  14. VARIATIONS IN THE NEUROTOXIC POTENCY OF TRIMETHYLTIN

    EPA Science Inventory

    Seven samples of trimethyltin obtained from three commercial sources were evaluated for neurotoxic potency in the rat. Hippocampus weight, histology and assays of the astrocyte protein, glial fibrillary acidic protein, were used as indices of neurotoxicity. A single administratio...

  15. Glutamic Acid Not Beneficial for the Prevention of Vincristine Neurotoxicity in Children with Cancer

    PubMed Central

    Bradfield, Scott M.; Sandler, Eric; Geller, Thomas; Tamura, Roy N.; Krischer, Jeffrey P.

    2014-01-01

    Background Vincristine causes known side effects of peripheral sensory, motor, autonomic and cranial neuropathies. No preventive interventions are known. Procedure We performed a randomized, placebo-controlled, double-blind trial of oral glutamic acid as a preventive agent in pediatric patients with cancer who would be receiving vincristine therapy for at least 9 consecutive weeks (Stratum 1= Wilms tumor and rhabdomyosarcoma) or 4 consecutive weeks in conjunction with steroids (Stratum 2=Acute lymphoblastic leukemia and Non-Hodgkin lymphoma). At designated time points, a scored neurologic exam using the Modified Balis Pediatric Scale of Peripheral Neuropathies was performed to document neurologic toxicity. Results Between 2007–12, 250 patients were enrolled (Stratum 1=50, Stratum 2=200). The glutamic acid treated group did not have a significantly lower percentage of neurotoxicity compared to placebo treated group either overall or within stratum or age subgroups. The only subgroup which was suggestive of treatment effect was for age. Patients 13 years or older showed a larger benefit in favor of glutamic acid (p=0.055) compared to patients less than 13 years (p=1.00). Constipation was the most frequently reported (14%) Grade II or higher neurotoxicity. Conclusion Vincristine-associated neurotoxicity in pediatric oncology remains a frequent complication of chemotherapy for multiple diagnoses with an approximate 30% of patients affected. Glutamic acid is not effective for prevention in pre-adolescents. There is a suggestion of benefit in patients 13 years or older, but the study was not designed to provide adequate power to test the treatment effect within this age group alone. PMID:25545757

  16. Cetuximab-induced hypomagnesaemia aggravates peripheral sensory neurotoxicity caused by oxaliplatin.

    PubMed

    Kono, Toru; Satomi, Machiko; Asama, Toshiyuki; Ebisawa, Yoshiaki; Chisato, Naoyuki; Suno, Manabu; Karasaki, Hidenori; Furukawa, Hiroyuki; Matsubara, Kazuo

    2010-12-01

    Calcium and magnesium replacement is effective in reducing oxaliplatin-induced neurotoxicity. However, cetuximab treatment has been associated with severe hypomagnesaemia. Therefore, we retrospectively investigated whether cetuximab-induced hypomagnesaemia exacerbated oxaliplatin-induced neurotoxicity. Six patients with metastatic colorectal cancer who were previously treated with oxaliplatin-fluorouracil combination therapy were administered cetuximab in combination with irinotecan alone or irinotecan and fluorouracil as a second-line treatment. All patients had normal magnesium levels before receiving cetuximab. The Common Terminology Criteria for Adverse Events version 3.0 was used to evaluate the grade of neurotoxicity, hypomagnesaemia, hypocalcaemia, and hypokalemia every week. All six patients had grade 1 or higher hypomagnesaemia after starting cetuximab therapy. The serum calcium and potassium levels were within the normal range at the onset of hypomagnesaemia. Oxaliplatin-induced neurotoxicity occurred in all patients at the beginning of cetuximab therapy, with grade 1 neurotoxicity in five patients and grade 2 in one patient. After cetuximab administration, the neurotoxicity worsened in all six patients, and three progressed to grade 3. Among the three patients with grade 3 neurotoxicity, two required a dose reduction and one had to discontinue cetuximab therapy. A discontinuation or dose reduction in cetuximab therapy was associated with exacerbated oxaliplatin-induced neurotoxicity due to cetuximab-induced hypomagnesaemia in half of patients who had previously received oxaliplatin. Therefore, when administering cetuximab after oxaliplatin therapy, we suggest serially evaluating serum magnesium levels and neurotoxicity. PMID:22811813

  17. Cetuximab-induced hypomagnesaemia aggravates peripheral sensory neurotoxicity caused by oxaliplatin

    PubMed Central

    Satomi, Machiko; Asama, Toshiyuki; Ebisawa, Yoshiaki; Chisato, Naoyuki; Suno, Manabu; Karasaki, Hidenori; Furukawa, Hiroyuki; Matsubara, Kazuo

    2010-01-01

    Calcium and magnesium replacement is effective in reducing oxaliplatin-induced neurotoxicity. However, cetuximab treatment has been associated with severe hypomagnesaemia. Therefore, we retrospectively investigated whether cetuximab-induced hypomagnesaemia exacerbated oxaliplatin-induced neurotoxicity. Six patients with metastatic colorectal cancer who were previously treated with oxaliplatin-fluorouracil combination therapy were administered cetuximab in combination with irinotecan alone or irinotecan and fluorouracil as a second-line treatment. All patients had normal magnesium levels before receiving cetuximab. The Common Terminology Criteria for Adverse Events version 3.0 was used to evaluate the grade of neurotoxicity, hypomagnesaemia, hypocalcaemia, and hypokalemia every week. All six patients had grade 1 or higher hypomagnesaemia after starting cetuximab therapy. The serum calcium and potassium levels were within the normal range at the onset of hypomagnesaemia. Oxaliplatin-induced neurotoxicity occurred in all patients at the beginning of cetuximab therapy, with grade 1 neurotoxicity in five patients and grade 2 in one patient. After cetuximab administration, the neurotoxicity worsened in all six patients, and three progressed to grade 3. Among the three patients with grade 3 neurotoxicity, two required a dose reduction and one had to discontinue cetuximab therapy. A discontinuation or dose reduction in cetuximab therapy was associated with exacerbated oxaliplatin-induced neurotoxicity due to cetuximab-induced hypomagnesaemia in half of patients who had previously received oxaliplatin. Therefore, when administering cetuximab after oxaliplatin therapy, we suggest serially evaluating serum magnesium levels and neurotoxicity. PMID:22811813

  18. Effects of (-)-sesamin on 6-hydroxydopamine-induced neurotoxicity in PC12 cells and dopaminergic neuronal cells of Parkinson's disease rat models.

    PubMed

    Park, Hyun Jin; Zhao, Ting Ting; Lee, Kyung Sook; Lee, Seung Ho; Shin, Keon Sung; Park, Keun Hong; Choi, Hyun Sook; Lee, Myung Koo

    2015-01-01

    The present study investigated the effects of (-)-sesamin on 6-hydroxydopamine (6-OHDA)-induced neurotoxicity using PC12 cells and dopaminergic neuronal cells of 6-OHDA-lesioned rat model of Parkinson's disease (PD). In PC12 cells, treatment with (-)-sesamin (25 µM) reduced 6-OHDA (100 µM)-induced cell death and induced transient extracellular signal-regulated kinase (ERK1/2) phosphorylation and Bad phosphorylation at Ser112 (BadSer112). In contrast, sustained ERK1/2 phosphorylation, p38 mitogen-activated protein kinase (p38MAPK) and c-Jun N-terminal kinase (JNK1/2) phosphorylation, and cleaved-caspase-3 activity, all of which were induced by 6-OHDA (100 µM), were inhibited by treatment with (-)-sesamin (25 µM). Furthermore, co-treatment with (-)-sesamin (30 mg/kg, p.o.) once a day for 28 days significantly increased the number of tyrosine hydroxylase-immunopositive neuronal cells and the levels of dopamine, norepinephrine, 3,4-dihydroxyphenylacetic acid, and homovanillic acid in the substantia nigra-striatum of 6-OHDA-lesioned rat model of PD with or without L-DOPA treatment. These results suggest that (-)-sesamin protects 6-OHDA-induced cytotoxicity via the activation of transient ERK1/2-BadSer112 system and the inhibition of sustained ERK-p38MAPK-JNK1/2-caspase-3 system in PC12 cells. (-)-Sesamin also shows protective effects on long-term L-DOPA therapy in dopaminergic neuronal cells of PD rat models. (-)-Sesamin may serve as adjuvant therapeutics in PD. PMID:25747493

  19. A human pluripotent carcinoma stem cell-based model for in vitro developmental neurotoxicity testing: effects of methylmercury, lead and aluminum evaluated by gene expression studies.

    PubMed

    Laurenza, Incoronata; Pallocca, Giorgia; Mennecozzi, Milena; Scelfo, Bibiana; Pamies, David; Bal-Price, Anna

    2013-11-01

    The major advantage of the neuronal cell culture models derived from human stem cells is their ability to replicate the crucial stages of neurodevelopment such as the commitment of human stem cells to the neuronal lineage and their subsequent stages of differentiation into neuronal and glial-like cell. In these studies we used mixed neuronal/glial culture derived from the NTERA-2 (NT-2) cell line, which has been established from human pluripotent testicular embryonal carcinoma cells. After characterization of the different stages of cell differentiation into neuronal- and glial-like phenotype toxicity studies were performed to evaluate whether this model would be suitable for developmental neurotoxicity studies. The cells were exposed during the differentiation process to non-cytotoxic concentrations of methylmercury chloride, lead chloride and aluminum nitrate for two weeks. The toxicity was then evaluated by measuring the mRNA levels of cell specific markers (neuronal and glial). The results obtained suggest that lead chloride and aluminum nitrate at low concentrations were toxic primarily to astrocytes and at the higher concentrations it also induced neurotoxicity. In contrast, MetHgCl was toxic for both cell types, neuronal and glial, as mRNA specific for astrocytes and neuronal markers were affected. The results obtained suggest that a neuronal mixed culture derived from human NT2 precursor cells is a suitable model for developmental neurotoxicity studies and gene expression could be used as a sensitive endpoint for initial screening of potential neurotoxic compounds. PMID:23501475

  20. Inhalation of diethylamine--acute nasal effects and subjective response

    SciTech Connect

    Lundqvist, G.R.; Yamagiwa, M.; Pedersen, O.F.; Nielsen, G.D. )

    1992-03-01

    Adult volunteers were exposed to 25 ppm (75 mg/m3) diethylamine in a climate chamber for 15 min in order to study the acute nasal reactions to an exposure equivalent to the present threshold limit value-short-term exposure limit. Changes in nasal volume and nasal resistance were measured by acoustic rhinometry and by rhinomanometry. Acute change in nasal volume, usually seen as acute nasal mucosa response to thermal stimuli, was not observed, nor was an acute change in nasal airway resistance. In a subsequent experiment, the aim was to measure acute sensory effects. Exposure to a concentration increasing from 0 to 12 ppm took place for 60 min, equal to an average concentration of 10 ppm (30 mg/m3). A moderate to strong olfactory response and distinct nasal and eye irritation were observed. In spite of considerable individual variation, the results were in agreement with sensory effect estimates obtained from animal studies.

  1. Ethoxyquin provides neuroprotection against cisplatin-induced neurotoxicity.

    PubMed

    Zhu, Jing; Carozzi, Valentina Alda; Reed, Nicole; Mi, Ruifa; Marmiroli, Paola; Cavaletti, Guido; Hoke, Ahmet

    2016-01-01

    Ethoxyquin was recently identified as a neuroprotective compound against toxic neuropathies and efficacy was demonstrated against paclitaxel-induced neurotoxicity in vivo. In this study we examined the efficacy of ethoxyquin in preventing neurotoxicity of cisplatin in rodent models of chemotherapy-induced peripheral neuropathy and explored its mechanism of action. Ethoxyquin prevented neurotoxicity of cisplatin in vitro in a sensory neuronal cell line and primary rat dorsal root ganglion neurons. In vivo, chronic co-administration of ethoxyquin partially abrogated cisplatin-induced behavioral, electrophysiological and morphological abnormalities. Furthermore, ethoxyquin did not interfere with cisplatin's ability to induce tumor cell death in ovarian cancer cell line in vitro and in vivo. Finally, ethoxyquin reduced the levels of two client proteins (SF3B2 and ataxin-2) of a chaperone protein, heat shock protein 90 (Hsp90) when co-administered with cisplatin in vitro. These results implied that the neuroprotective effect of ethoxyquin is mediated through these two client proteins of Hsp90. In fact, reducing levels of SF3B2 in tissue-cultured neurons was effective against neurotoxicity of cisplatin. These findings suggest that ethoxyquin or other compounds that inhibit chaperone activity of Hsp90 and reduce levels of its client protein, SF3B2 may be developed as an adjuvant therapy to prevent neurotoxicity in cisplatin-based chemotherapy protocols. PMID:27350330

  2. Ethoxyquin provides neuroprotection against cisplatin-induced neurotoxicity

    PubMed Central

    Zhu, Jing; Carozzi, Valentina Alda; Reed, Nicole; Mi, Ruifa; Marmiroli, Paola; Cavaletti, Guido; Hoke, Ahmet

    2016-01-01

    Ethoxyquin was recently identified as a neuroprotective compound against toxic neuropathies and efficacy was demonstrated against paclitaxel-induced neurotoxicity in vivo. In this study we examined the efficacy of ethoxyquin in preventing neurotoxicity of cisplatin in rodent models of chemotherapy-induced peripheral neuropathy and explored its mechanism of action. Ethoxyquin prevented neurotoxicity of cisplatin in vitro in a sensory neuronal cell line and primary rat dorsal root ganglion neurons. In vivo, chronic co-administration of ethoxyquin partially abrogated cisplatin-induced behavioral, electrophysiological and morphological abnormalities. Furthermore, ethoxyquin did not interfere with cisplatin’s ability to induce tumor cell death in ovarian cancer cell line in vitro and in vivo. Finally, ethoxyquin reduced the levels of two client proteins (SF3B2 and ataxin-2) of a chaperone protein, heat shock protein 90 (Hsp90) when co-administered with cisplatin in vitro. These results implied that the neuroprotective effect of ethoxyquin is mediated through these two client proteins of Hsp90. In fact, reducing levels of SF3B2 in tissue-cultured neurons was effective against neurotoxicity of cisplatin. These findings suggest that ethoxyquin or other compounds that inhibit chaperone activity of Hsp90 and reduce levels of its client protein, SF3B2 may be developed as an adjuvant therapy to prevent neurotoxicity in cisplatin-based chemotherapy protocols. PMID:27350330

  3. Persistent cerebellar dysfunction following acute lithium toxicity: A report of two cases

    PubMed Central

    Banwari, Girish; Chaudhary, Pradhyuman; Panchmatia, Ankit; Patel, Nisheet

    2016-01-01

    Neurological disturbances caused by lithium range from simple side effects such as benign tremor to acute reversible neurotoxicity. Rarely, lithium is reported to cause irreversible, permanent neurological sequelae most commonly manifested as cerebellar dysfunction, although other presentations have also been described. We report two cases of persistent cerebellar syndrome following acute lithium toxicity and discuss them in the light of existing literature on the subject. PMID:27298510

  4. 40 CFR 798.6560 - Subchronic delayed neuro-toxicity of organophosphorus substances.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 40 Protection of Environment 33 2013-07-01 2013-07-01 false Subchronic delayed neuro-toxicity of organophosphorus substances. 798.6560 Section 798.6560 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) TOXIC SUBSTANCES CONTROL ACT (CONTINUED) HEALTH EFFECTS TESTING GUIDELINES Neurotoxicity § 798.6560 Subchronic...

  5. 40 CFR 798.6560 - Subchronic delayed neuro-toxicity of organophosphorus substances.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 40 Protection of Environment 32 2014-07-01 2014-07-01 false Subchronic delayed neuro-toxicity of organophosphorus substances. 798.6560 Section 798.6560 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) TOXIC SUBSTANCES CONTROL ACT (CONTINUED) HEALTH EFFECTS TESTING GUIDELINES Neurotoxicity § 798.6560 Subchronic...

  6. Non-fibrillar amyloid-{beta} peptide reduces NMDA-induced neurotoxicity, but not AMPA-induced neurotoxicity

    SciTech Connect

    Niidome, Tetsuhiro; Goto, Yasuaki; Kato, Masaru; Wang, Pi-Lin; Goh, Saori; Tanaka, Naoki; Akaike, Akinori; Kihara, Takeshi; Sugimoto, Hachiro

    2009-09-04

    Amyloid-{beta} peptide (A{beta}) is thought to be linked to the pathogenesis of Alzheimer's disease. Recent studies suggest that A{beta} has important physiological roles in addition to its pathological roles. We recently demonstrated that A{beta}42 protects hippocampal neurons from glutamate-induced neurotoxicity, but the relationship between A{beta}42 assemblies and their neuroprotective effects remains largely unknown. In this study, we prepared non-fibrillar and fibrillar A{beta}42 based on the results of the thioflavin T assay, Western blot analysis, and atomic force microscopy, and examined the effects of non-fibrillar and fibrillar A{beta}42 on glutamate-induced neurotoxicity. Non-fibrillar A{beta}42, but not fibrillar A{beta}42, protected hippocampal neurons from glutamate-induced neurotoxicity. Furthermore, non-fibrillar A{beta}42 decreased both neurotoxicity and increases in the intracellular Ca{sup 2+} concentration induced by N-methyl-D-aspartate (NMDA), but not by {alpha}-amino-3-hydrozy-5-methyl-4-isoxazole propionic acid (AMPA). Our results suggest that non-fibrillar A{beta}42 protects hippocampal neurons from glutamate-induced neurotoxicity through regulation of the NMDA receptor.

  7. Minocycline Attenuates Iron Neurotoxicity in Cortical Cell Cultures

    PubMed Central

    Chen-Roetling, Jing; Chen, Lifen; Regan, Raymond F.

    2009-01-01

    Iron neurotoxicity may contribute to the pathogenesis of intracerebral hemorrhage (ICH). The tetracycline derivative minocycline is protective in ICH models, due putatively to inhibition of microglial activation. Although minocycline also chelates iron, its effect on iron neurotoxicity has not been reported, and was examined in this study. Cortical cultures treated with 10 μM ferrous sulfate for 24h sustained loss of most neurons and an increase in malondialdehyde. Minocycline prevented this injury, with near-complete protection at 30 μM. Two other inhibitors of microglial activation, doxycycline and macrophage/microglia inhibitory factor, were ineffective. Oxidation of isolated culture membranes by iron was also inhibited by minocycline. Consistent with prior observations, minocycline chelated iron in a siderophore colorometric assay; at concentrations less than 100 μM, its activity exceeded that of deferoxamine. These results suggest that attenuation of iron neurotoxicity may contribute to the beneficial effect of minocycline in hemorrhagic stroke and other CNS injury models. PMID:19523448

  8. IN VIVO NEUROTOXIC EFFECTS OF DIELDRIN ON GIANT NERVE FIBERS AND ESCAPE REFLEX FUNCTION IN THE EARTHWORM, 'EISENIA FOETIDA'

    EPA Science Inventory

    Neurotoxicological effects of dieldrin were assessed in adult earthworms, Eisenia foetida, using noninvasive electrophysiological recordings of escape reflex activity. After 48 hr body surface exposure to aqueous suspensions of dieldrin, dose-dependent reductions in medial and la...

  9. Unmasking silent neurotoxicity following developmental exposure to environmental toxicants.

    PubMed

    Kraft, Andrew D; Aschner, Michael; Cory-Slechta, Deborah A; Bilbo, Staci D; Caudle, W Michael; Makris, Susan L

    2016-01-01

    Silent neurotoxicity, a term introduced approximately 25years ago, is defined as a persistent change to the nervous system that does not manifest as overt evidence of toxicity (i.e. it remains clinically unapparent) unless unmasked by experimental or natural processes. Silent neurotoxicants can be challenging for risk assessors, as the multifactorial experiments needed to reveal their effects are seldom conducted, and they are not addressed by current study design guidelines. This topic was the focus of a symposium addressing the interpretation and use of silent neurotoxicity data in human health risk assessments of environmental toxicants at the annual meeting of the Developmental Neurotoxicology Society (previously the Neurobehavioral Teratology Society) on June 30th, 2014. Several factors important to the design and interpretation of studies assessing the potential for silent neurotoxicity were discussed by the panelists and audience members. Silent neurotoxicity was demonstrated to be highly specific to the characteristics of the animals being examined, the unmasking agent tested, and the behavioral endpoint(s) evaluated. Overall, the experimental examples presented highlighted a need to consider common adverse outcomes and common biological targets for chemical and non-chemical stressors, particularly when the exposure and stressors are known to co-occur. Risk assessors could improve the evaluation of silent neurotoxicants in assessments through specific steps from researchers, including experiments to reveal the molecular targets and mechanisms that may result in specific types of silent neurotoxicity, and experiments with complex challenges reminiscent of the human situation. PMID:27049787

  10. Protective effect of rosemary on acrylamide motor neurotoxicity in spinal cord of rat offspring: postnatal follow-up study

    PubMed Central

    Al-Gholam, Marwa A.; El-Mehi, Abeer E.; El-Barbary, Abd El-Moneum; Fokar, Ahmed Zo El

    2016-01-01

    The direct interactive effects of rosemary and acrylamide on the development of motor neurons in the spinal cord remains unknown. Our goal is to confirm the protective effects of rosemary against motor neuronal degeneration induced by acrylamide in the developing postnatal rat spinal cord using a postnatal rat model. We assigned the offspring of treated female rats into control, rosemary; acrylamide group; and recovery groups. This work depended on clinical, histopathological, morphometrically, immunohistochemical and genetic methods. In the acrylamide group, we observed oxidation, motor neuron degeneration, apoptosis, myelin degeneration, neurofilament reduction, reactive gliosis. Whoever, concomitant rosemary intake and withdrawal of acrylamide modulate these effects. These findings proof that dietary rosemary can directly protect motor neuron against acrylamide toxicity in the mammalian developing spinal cord. PMID:27051566

  11. Protective effect of rosemary on acrylamide motor neurotoxicity in spinal cord of rat offspring: postnatal follow-up study.

    PubMed

    Al-Gholam, Marwa A; Nooh, Hanaa Zakaria; El-Mehi, Abeer E; El-Barbary, Abd El-Moneum; Fokar, Ahmed Zo El

    2016-03-01

    The direct interactive effects of rosemary and acrylamide on the development of motor neurons in the spinal cord remains unknown. Our goal is to confirm the protective effects of rosemary against motor neuronal degeneration induced by acrylamide in the developing postnatal rat spinal cord using a postnatal rat model. We assigned the offspring of treated female rats into control, rosemary; acrylamide group; and recovery groups. This work depended on clinical, histopathological, morphometrically, immunohistochemical and genetic methods. In the acrylamide group, we observed oxidation, motor neuron degeneration, apoptosis, myelin degeneration, neurofilament reduction, reactive gliosis. Whoever, concomitant rosemary intake and withdrawal of acrylamide modulate these effects. These findings proof that dietary rosemary can directly protect motor neuron against acrylamide toxicity in the mammalian developing spinal cord. PMID:27051566

  12. The acute effect in rats of 3,4-methylenedioxyethamphetamine (MDEA, "eve") on body temperature and long term degeneration of 5-HT neurones in brain: a comparison with MDMA ("ecstasy").

    PubMed

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

    1999-06-01

    Administration of a single dose of the recreationally used drug 3,4-methylenedioxyethamphetamine (MDEA or "eve") to Dark Agouti rats resulted in an acute dose-dependent hyperthermic response. The peak effect and duration of hyperthermia of a dose of MDEA of 35 mg/kg intraperitoneally was similar to a dose of 3,4-methylenedioxymethamphetamine (MDMA or "ecstasy") of 15 mg/kg intraperitoneally. Seven days later this dose of MDMA produced a marked (approximately 50%) loss of 5-HT and its metabolite 5-HIAA in cortex, hippocampus and striatum and a similar loss of [3H]-paroxetine binding in cortex: these losses reflecting the MDMA-induced neurotoxic degeneration of 5-HT nerve endings. In contrast, administration of MDEA (15, 25 or 35 mg/kg), even at the highest dose, produced only a 20% loss in cortex and hippocampus and no decrease in striatum. The neurotoxic effect of MDEA was only weakly dose-dependent. Neither MDEA (35 mg/kg) nor MDMA (15 mg/kg) altered striatal dopamine content 7 days later. MDEA appeared to have about half the potency of MDMA in inducing acute hyperthermia and 25% of the potency in inducing degeneration of cerebral 5-HT neurones. However since higher doses of MDEA (compared to MDMA) are probably necessary to induce mood changing effects, these data do not support any contention that this compound is a "safer" recreational drug than MDMA in terms of either acute toxicity or long term neurodegeneration. PMID:10401727

  13. NEUROTOXIC EFFECTS OF CHRONIC EXPOSURE TO ARSENIC VIA DRINKING WATER IN INNER MONGOLIA: I. SYMPTOMS AND PINPRICK TESTING

    EPA Science Inventory


    This study was designed to assess the effects of exposure to arsenic in drinking water on neurosensory function. A symptom questionnaire and brief neurological exam consisting of pinprick testing of the arms and legs and knee-jerk test were administered to 321 residents of...

  14. Does diisocyanate exposure result in neurotoxicity?

    PubMed Central

    2014-01-01

    Context Diisocyanates have been associated with respiratory and dermal sensitization. Limited number of case reports, and a few case studies, media, and other references suggest potential neurotoxic effects from exposures to toluene diisocyanate (TDI), 1,6 hexamethylene diisocyanate (HDI), and methylene diisocyanate (MDI). However, a systematic review of the literature evaluating the causal association on humans does not exist to support this alleged association. Objective To perform systematic review examining the body of epidemiologic evidence and provide assessment of causal association based on principles of the Sir Austin Bradford Hill criteria or considerations for causal analysis. Methods A comprehensive search of public databases for published abstracts, case reports, cross-sectional surveys, and cohort studies using key search terms was conducted. Additional searches included regulatory reviews, EU IUCLID and EU Risk Assessment databases, and unpublished reports in the International Isocyanate Institute database. An expert panel consisting of physicians, toxicologists, and an epidemiologist critically reviewed accepted papers, providing examination of epidemiologic evidence of each report. Finally, the Hill criteria for causation were applied to the summative analysis of identified reports to estimate probability of causal association. Results Twelve papers reporting exposed populations with a variety of neurological symptoms or findings suitable for analysis were identified, including eleven case or case series reports, and one cross-sectional study. Three papers reported on the same population. Each of the papers was limited by paucity of diisocyanate exposure estimates, the presence of confounding exposures to known or suspected neurotoxicants, a lack of objective biological measures of exposure or neurotoxic effects, and lack of relative strength of association measures. Additionally, reported health symptoms and syndromes lacked consistency or

  15. Brain-derived neurotrophic factor as an indicator of chemical neurotoxicity: an animal-free CNS cell culture model.

    PubMed

    Woehrling, Elizabeth K; Hill, Eric J; Nagel, David; Coleman, Michael D

    2013-12-01

    Recent changes to the legislation on chemicals and cosmetics testing call for a change in the paradigm regarding the current 'whole animal' approach for identifying chemical hazards, including the assessment of potential neurotoxins. Accordingly, since 2004, we have worked on the development of the integrated co-culture of post-mitotic, human-derived neurons and astrocytes (NT2.N/A), for use as an in vitro functional central nervous system (CNS) model. We have used it successfully to investigate indicators of neurotoxicity. For this purpose, we used NT2.N/A cells to examine the effects of acute exposure to a range of test chemicals on the cellular release of brain-derived neurotrophic factor (BDNF). It was demonstrated that the release of this protective neurotrophin into the culture medium (above that of control levels) occurred consistently in response to sub-cytotoxic levels of known neurotoxic, but not non-neurotoxic, chemicals. These increases in BDNF release were quantifiable, statistically significant, and occurred at concentrations below those at which cell death was measureable, which potentially indicates specific neurotoxicity, as opposed to general cytotoxicity. The fact that the BDNF immunoassay is non-invasive, and that NT2.N/A cells retain their functionality for a period of months, may make this system useful for repeated-dose toxicity testing, which is of particular relevance to cosmetics testing without the use of laboratory animals. In addition, the production of NT2.N/A cells without the use of animal products, such as fetal bovine serum, is being explored, to produce a fully-humanised cellular model. PMID:24512234

  16. Mithramycin protects against dopaminergic neurotoxicity in the mouse brain after administration of methamphetamine.

    PubMed

    Hagiwara, Hiroko; Iyo, Masaomi; Hashimoto, Kenji

    2009-12-01

    The present study was undertaken to examine the effects of mithramycin, an inhibitor of transcription factor Specificity protein (Sp)-1, on the behavioral changes and dopaminergic neurotoxicity in the mouse striatum after administration of methamphetamine (METH). Pretreatment with mithramycin (75, 150 or 300 microg/kg) did not alter acute hyperlocomotion in mice after a single administration of METH (3 mg/kg). However, the development of behavioral sensitization in mice after repeated administration of METH (3 mg/kg/day, once daily for 5 days) was significantly blocked by pretreatment with mithramycin (300 microg/kg). Furthermore, pretreatment with mithramycin (300 microg/kg) significantly attenuated the hyperthermia in mice after repeated administration of METH (3 mg/kgx3, 3-h intervals). Moreover, the combination of pretreatment and subsequent administration of mithramycin (75, 150 or 300 microg/kg) significantly attenuated the reductions of dopamine (DA), its major metabolite 3,4-dihydroxyphenylacetic acid (DOPAC) and DA transporter (DAT) in the striatum after repeated administration of METH (3 mg/kgx3, 3-h intervals), and these attenuations were dose dependent. These findings suggest that mithramycin attenuates the development of behavioral sensitization and dopaminergic neurotoxicity in mice after repeated administration of METH. Therefore, mithramycin could have potential for the treatment of METH abusers, particularly since this drug has been approved by the Food and Drug Administration in the United States. In the future, however, another Sp1 inhibitors with fewer side effects might be more appropriate. PMID:19748494

  17. Tacrine and donepezil attenuate the neurotoxic effect of A beta(25-35) in rat PC12 cells.

    PubMed

    Svensson, A L; Nordberg, A

    1998-05-11

    The effect of the cholinesterase inhibitors tacrine and donepezil on A beta(25-35)-induced toxicity was investigated in rat pheochromocytoma PC12 cells by measuring the mitochondrial activity. Tacrine and donepezil was found in clinical relevant concentrations (10(-7)-10(-6) M) to attenuate A beta(25-35)-induced toxicity in PC12 cells. The neuroprotective effect of tacrine was blocked in the presence of the nicotinic antagonists mecamylamine (10(-5) M) and tubocurarine (10(-5) M), suggesting an interaction via nicotinic receptors. This study demonstrates that tacrine and donepezil can exert neuroprotective properties which might be of importance and contribute to the clinical efficacy of cholinesterase inhibitors in the treatment of Alzheimer's disease. PMID:9631459

  18. Fragment C Domain of Tetanus Toxin Mitigates Methamphetamine Neurotoxicity and Its Motor Consequences in Mice

    PubMed Central

    Mendieta, Liliana; Granado, Noelia; Aguilera, José; Tizabi, Yousef

    2016-01-01

    Background: The C-terminal domain of the heavy chain of tetanus toxin (Hc-TeTx) is a nontoxic peptide with demonstrated in vitro and in vivo neuroprotective effects against striatal dopaminergic damage induced by 1-methyl-4-phenylpyridinium and 6-hydoxydopamine, suggesting its possible therapeutic potential in Parkinson’s disease. Methamphetamine, a widely abused psychostimulant, has selective dopaminergic neurotoxicity in rodents, monkeys, and humans. This study was undertaken to determine whether Hc-TeTx might also protect against methamphetamine-induced dopaminergic neurotoxicity and the consequent motor impairment. Methods: For this purpose, we treated mice with a toxic regimen of methamphetamine (4mg/kg, 3 consecutive i.p. injections, 3 hours apart) followed by 3 injections of 40 ug/kg of Hc-TeTx into grastrocnemius muscle at 1, 24, and 48 hours post methamphetamine treatment. Results: We found that Hc-TeTx significantly reduced the loss of dopaminergic markers tyrosine hydroxylase and dopamine transporter and the increases in silver staining (a well stablished degeneration marker) induced by methamphetamine in the striatum. Moreover, Hc-TeTx prevented the increase of neuronal nitric oxide synthase but did not affect microglia activation induced by methamphetamine. Stereological neuronal count in the substantia nigra indicated loss of tyrosine hydroxylase-positive neurons after methamphetamine that was partially prevented by Hc-TeTx. Importantly, impairment in motor behaviors post methamphetamine treatment were significantly reduced by Hc-TeTx. Conclusions: Here we demonstrate that Hc-TeTx can provide significant protection against acute methamphetamine-induced neurotoxicity and motor impairment, suggesting its therapeutic potential in methamphetamine abusers. PMID:26945022

  19. The Potential for Plant Derivatives against Acrylamide Neurotoxicity.

    PubMed

    Adewale, O O; Brimson, J M; Odunola, O A; Gbadegesin, M A; Owumi, S E; Isidoro, C; Tencomnao, T

    2015-07-01

    Certain industrial chemicals and food contaminants have been demonstrated to possess neurotoxic activity and have been suspected to cause brain-related disorders in humans. Acrylamide (ACR), a confirmed neurotoxicant, can be found in trace amount in commonly consumed human aliments as a result of food processing or cooking. This discovery aroused a great concern in the public, and increasing efforts are continuously geared towards the resolution of this serious threat. The broad chemical diversity of plants may offer the resources for novel antidotes against neurotoxicants. With the goal of attenuating neurotoxicity of ACR, several plants extracts or derivatives have been employed. This review presents the plants and their derivatives that have been shown most active against ACR-induced neurotoxicity, with a focus on their origin, pharmacological activity, and antidote effects. PMID:25886076

  20. Effect of acute airway inflammation on the pulmonary antioxidant status.

    PubMed

    Deaton, Christopher M; Marlin, David J; Smith, Nicola C; Harris, Patricia A; Dagleish, Mark P; Schroter, Robert C; Kelly, Frank J

    2005-09-01

    Effects of acute airway inflammation induced by organic dust inhalation on pulmonary antioxidant status were investigated in healthy horses and horses affected by recurrent airway obstruction. Exposure to organic dust induced acute airway neutrophilia, which was associated with increases in elastase and decreases in ascorbic acid concentrations in bronchoalveolar lavage fluid. However, markers of oxidative stress were unaffected, as was hydrogen peroxide in breath condensate. Decreases in ascorbic acid correlated with increased respiratory resistance (P = .001) when both groups were combined. In conclusion, acute neutrophilic airway inflammation does not result in significant evidence of oxidative stress in horses affected by recurrent airway obstruction. PMID:16203621

  1. Beneficial effects of sodium butyrate in 6-OHDA induced neurotoxicity and behavioral abnormalities: Modulation of histone deacetylase activity.

    PubMed

    Sharma, Sorabh; Taliyan, Rajeev; Singh, Sumel

    2015-09-15

    Parkinson's disease (PD) is the second most common neurodegenerative disorder. Recent studies have investigated the involvement of epigenetic modifications in PD. Histone deacetylase (HDAC) inhibitors have been reported to be beneficial in cognitive and motor deficit states. The present study was designed to investigate the effect of sodium butyrate, a HDAC inhibitor in 6-hydroxydopamine (6-OHDA) - induced experimental PD like symptoms in rats. To produce motor deficit, 6-OHDA was administered unilaterally in the right medial forebrain bundle. Three weeks after 6-OHDA administration, the rats were challenged with apomorphine. Following this, the animals were treated with sodium butyrate (150 and 300 mg/kg i.p.) once daily for 14 days. Movement abnormalities were assessed by battery of behavioral tests. Biochemically, oxidative stress markers, neuroinflammation and dopamine were measured in striatal brain homogenate. Further, to explore the molecular mechanism(s), we measured the level of global H3 histone acetylation and brain derived neurotrophic factor (BDNF). 6-OHDA administration results in significant motor deficit along with reduction in striatal dopamine level. 6-OHDA treated rats showed elevated oxidative stress and neuroinflammatory markers. Treatment with sodium butyrate results in significant attenuation of motor deficits and increased striatal dopamine level. Moreover, sodium butyrate treatment attenuated the oxidative stress and neuroinflammatory markers. These effects occur concurrently with increased global H3 histone acetylation and BDNF levels. Thus, the observed results of the present study are indicative for the therapeutic potential of HDAC inhibitors in PD. PMID:26048426

  2. A single fraction from Uncaria sinensis exerts neuroprotective effects against glutamate-induced neurotoxicity in primary cultured cortical neurons.

    PubMed

    Kim, Ha Neui; Jang, Ji Yeon; Choi, Byung Tae

    2015-06-01

    We identified a neuroprotective single fraction among 62 ones of hexane extract from Uncaria sinensis (JGH43IA) and investigated its effects and mechanisms in primary cortical neurons. Pretreatment with JGH43IA showed a significantly increase cell viability in a dose-dependent manner with a decrease in the lactate dehydrogenase release. When we performed morphological assay and flow cytometry to determination of the type of cell death, pretreatment with JGH43IA showed a significant reduction of glutamate-induced apoptotic cell death. Then we explored the downstream signaling pathways of N-methyl-D-aspartate receptor (NMDAR) with calpain activation to elucidate possible pathways of neuroprotection by JGH43IA. Pretreatment with JGH43IA exhibited a significant attenuation of NMDAR GluN2B subunit activation and a decrease in active form of calpain 1 leading to subsequent cleavage of striatal-enriched protein tyrosine phosphatase (STEP). In addition, pretreatment with JGH43IA showed a marked increase of cAMP responsive element binding protein. These results suggest that JGH43IA may have neuroprotective effects through down-regulation of NMDAR GluN2B subunit and calpain 1 activation, and subsequent alleviation of STEP cleavage. This single fraction from U. sinensis might be a useful therapeutic agent for brain disorder associated with glutamate injury. PMID:26140220

  3. A single fraction from Uncaria sinensis exerts neuroprotective effects against glutamate-induced neurotoxicity in primary cultured cortical neurons

    PubMed Central

    Kim, Ha Neui; Jang, Ji Yeon

    2015-01-01

    We identified a neuroprotective single fraction among 62 ones of hexane extract from Uncaria sinensis (JGH43IA) and investigated its effects and mechanisms in primary cortical neurons. Pretreatment with JGH43IA showed a significantly increase cell viability in a dose-dependent manner with a decrease in the lactate dehydrogenase release. When we performed morphological assay and flow cytometry to determination of the type of cell death, pretreatment with JGH43IA showed a significant reduction of glutamate-induced apoptotic cell death. Then we explored the downstream signaling pathways of N-methyl-D-aspartate receptor (NMDAR) with calpain activation to elucidate possible pathways of neuroprotection by JGH43IA. Pretreatment with JGH43IA exhibited a significant attenuation of NMDAR GluN2B subunit activation and a decrease in active form of calpain 1 leading to subsequent cleavage of striatal-enriched protein tyrosine phosphatase (STEP). In addition, pretreatment with JGH43IA showed a marked increase of cAMP responsive element binding protein. These results suggest that JGH43IA may have neuroprotective effects through down-regulation of NMDAR GluN2B subunit and calpain 1 activation, and subsequent alleviation of STEP cleavage. This single fraction from U. sinensis might be a useful therapeutic agent for brain disorder associated with glutamate injury. PMID:26140220

  4. Cancer Treatment-Induced Neurotoxicity: A Focus on Newer Treatments

    PubMed Central

    Stone, Jacqueline B.; DeAngelis, Lisa M.

    2016-01-01

    Neurotoxicity from traditional chemotherapy and radiotherapy is widely recognized. The adverse effects of newer therapeutics such as biological and immunotherapeutic agents are less familiar and they are also associated with significant neurotoxicity in the central and peripheral nervous systems. This review addresses the main toxicities of cancer treatment by symptom with a focus on the newer therapeutics. Recognition of these patterns of toxicity is important as drug discontinuation or dose adjustment may prevent further neurologic injury. Also, knowledge of these toxicities helps to differentiate treatment-related symptoms from progression of cancer or its involvement of the nervous system. PMID:26391778

  5. Pomegranate seed oil: Effect on 3-nitropropionic acid-induced neurotoxicity in PC12 cells and elucidation of unsaturated fatty acids composition.

    PubMed

    Al-Sabahi, Bushra N; Fatope, Majek O; Essa, Musthafa Mohamed; Subash, Selvaraju; Al-Busafi, Saleh N; Al-Kusaibi, Fatma S N; Manivasagam, Thamilarasan

    2014-09-19

    Background Seed oils are used as cosmetics or topical treatment for wounds, allergy, dandruff, and other purposes. Natural antioxidants from plants were recently reported to delay the onset or progress of various neurodegenerative conditions. Over one thousand cultivars of Punica granatum (Punicaceae) are known and some are traditionally used to treat various ailments. Aim The effect of pomegranate oil on 3-nitropropionic acid- (3-NP) induced cytotoxicity in rat pheochromocytoma (PC12) neuronal cells was analyzed in this study. Furthermore, the analysis of unsaturated fatty acid composition of the seed oil of pomegranate by gas chromatography-electron impact mass spectrometry (GC-MS) was done. Results GC-MS study showed the presence of 6,9-octadecadiynoic acid (C18:2(6,9)) as a major component (60%) as 4,4-dimethyloxazoline derivative. The total extractable oil with light petroleum ether by Soxhlet from the dry seed of P. granatum was 4-6%. The oil analyzed for 48.90 ± 1.50 mg gallic acid equivalents/g of oil, and demonstrated radical-scavenging-linked antioxidant activities in various in vitro assays like the DPPH (2,2-diphenyl-l-picrylhydrazyl, % IP = 35.2 ± 0.9%), ABTS (2,2'-azino-bis-3-ethylene benzothiozoline-6-sulfonic acid, % IP 2.2 ± 0.1%), and β-carotene bleaching assay (% IP = 26 ± 3%), respectively, which could be due the possible role of one methylene interrupted diynoic acid system for its radical-scavenging/antioxidant properties of oil. The oil also reduced lipid peroxidation, suppressed reactive oxygen species, extracellular nitric oxide, lactate/pyruvate ratio, and lactase dehydrogenase generated by 3-NP- (100 mM) induced neurotoxicity in PC12 cells, and enhanced the levels of enzymatic and non-enzymatic antioxidants at 40 μg of gallic acid equivalents. Conclusion The protective effect of pomegranate seed oil might be due to the ability of an oil to neutralize ROS or enhance the expression of antioxidant gene. PMID:25238165

  6. Characterizing the Effect of Multivalent Conjugates Composed of Aβ-Specific Ligands and Metal Nanoparticles on Neurotoxic Fibrillar Aggregation.

    PubMed

    Streich, Carmen; Akkari, Laura; Decker, Christina; Bormann, Jenny; Rehbock, Christoph; Müller-Schiffmann, Andreas; Niemeyer, Felix Carlsson; Nagel-Steger, Luitgard; Willbold, Dieter; Sacca, Barbara; Korth, Carsten; Schrader, Thomas; Barcikowski, Stephan

    2016-08-23

    Therapeutically active small molecules represent promising nonimmunogenic alternatives to antibodies for specifically targeting disease-relevant receptors. However, a potential drawback compared to antibody-antigen interactions may be the lower affinity of small molecules toward receptors. Here, we overcome this low-affinity problem by coating the surface of nanoparticles (NPs) with multiple ligands. Specifically, we explored the use of gold and platinum nanoparticles to increase the binding affinity of Aβ-specific small molecules to inhibit Aβ peptide aggregation into fibrils in vitro. The interactions of bare NPs, free ligands, and NP-bound ligands with Aβ are comprehensively studied via physicochemical methods (spectroscopy, microscopy, immunologic tests) and cell assays. Reduction of thioflavin T fluorescence, as an indicator for β-sheet content, and inhibition of cellular Aβ excretion are even more effective with NP-bound ligands than with the free ligands. The results from this study may have implications in the development of therapeutics for treating Alzheimer's disease. PMID:27404114

  7. Protective Effects of Indole-3-Carbinol-Loaded Poly(lactic-co-glycolic acid) Nanoparticles Against Glutamate-Induced Neurotoxicity.

    PubMed

    Jeong, Ji Heun; Kim, Jwa-Jin; Bak, Dong Ho; Yu, Kwang Sik; Lee, Je Hun; Lee, Nam Seob; Jeong, Young Gil; Kim, Do Kyung; Kim, Dong-Kwan; Han, Seung-Yun

    2015-10-01

    Indole-3-carbinol (I3C) has anti-oxidant and anti-inflammatory properties. Nonetheless, the potential of I3C to treat neurodegenerative diseases remains unclear because of its poor ability to penetrate the blood-brain barrier (BBB). Because polymer-based drug delivery systems stabilized by surfactants have been intensively utilized as a strategy to cross the blood-brain barrier, we prepared I3C-loaded poly(D,L-lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) that were stabilized by Tween 80 (T80) (I3C-PLGA-T80-NPs) and examined their neuroprotective potential in vitro. We prepared I3C-PLGA-T80-NPs with an oil-in-water (o/w) emulsion solvent evaporation technique and confirmed their successful synthesis with both transmission electron microscopy and Fourier transform-infrared spectroscopy. I3C-PLGA-T80-NPs were then used to treat PC12 neuronal cells injured by glutamate excitotoxicity (GE) and examined the resulting survival rates compared with PC12 cells treated with I3C only. The 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) assay revealed higher survival rates in I3C-PLGA-T80-NPs-treated cells after GE injury compared with those treated with I3C only. Furthermore, I3C-PLGA-T80-NPs decreased the levels of reactive oxygen species (ROS) and apoptosis-related enzymes (Caspase-3 and -8) in GE-damaged neuronal cells. Taken together, I3C-PLGA-T80-NPs might possess neuroprotective effects against GE through ROS scavenging and subsequent apoptosis blockage. PMID:26726441

  8. Effects of glutamate and {alpha}2-noradrenergic receptor antagonists on the development of neurotoxicity produced by chronic rotenone in rats

    SciTech Connect

    Alam, Mesbah Danysz, Wojciech; Schmidt, Werner Juergen; Dekundy, Andrzej

    2009-10-15

    Systemic inhibition of complex I by rotenone in rats represents a model of Parkinson's disease (PD). The aim of this study was to elucidate whether neramexane (NMDA, nicotinic {alpha}9/{alpha}10 and 5-HT{sub 3} receptor antagonist), idazoxan ({alpha}{sub 2}-adrenoceptor antagonist) or 2-methyl-6-(phenyl-ethyl)-pyrimidine (MPEP, metabotropic glutamate receptor 5 antagonist) prevents rotenone-induced parkinsonian-like behaviours and neurochemical changes in rats. Rotenone (2.5 mg/kg i.p. daily) was administered over 60 days together with saline, neramexane (5 mg/kg i.p., b.i.d.), idazoxan (2.5 mg/kg i.p., b.i.d.) or MPEP (2.5 mg/kg i.p., b.i.d.). The same doses of neramexane, idazoxan and MPEP were administered to rats treated with vehicle instead of rotenone. Treatment-related effects on parkinsonian-like behaviours, such as hypokinesia/rigidity and locomotor activity, were evaluated. Moreover, concentrations of dopamine, serotonin and their metabolites were measured in rats from each experimental group. Over the 60-day treatment period, the rotenone + saline treated animals developed hypokinesia, expressed as an increase in the bar and grid descent latencies in the catalepsy test, and a decrease in locomotor activity. Neramexane and idazoxan partially prevented the development of catalepsy in rotenone-treated rats. Co-administration of MPEP with rotenone resulted only in a decrease in descent latency in the grid test on day 60. Chronic rotenone treatment reduced concentrations of dopamine and serotonin in the anterior striatum, which was blocked by co-treatment with neramexane or idazoxan but not with MPEP. Only neramexane treatment blocked the rotenone-induced decrease in dopamine levels in the substantia nigra pars compacta. In conclusion, neramexane and idazoxan counteracted to some extent the development of parkinsonian symptoms and neurochemical alterations in the rotenone model of Parkinson's disease.

  9. Neurotoxicity of Dietary Supplements from Annonaceae Species.

    PubMed

    Höllerhage, Matthias; Rösler, Thomas W; Berjas, Magda; Luo, Rensheng; Tran, Kevin; Richards, Kristy M; Sabaa-Srur, Armando U; Maia, José Guilherme S; Moraes, Maria Rosa de; Godoy, Helena T; Höglinger, Günter U; Smith, Robert E

    2015-01-01

    Dietary supplements containing plant materials of Annonaceae species (Annona muricata L., A. squamosa L., A. mucosa JACQ., A. squamosa × cherimola Mabb.) were extracted by hot, pressurized ethyl acetate and analyzed for their effect in vitro on Lund human mesencephalic neurons. Cell viability was measured by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, and cell death was determined by lactate dehydrogenase levels. Three supplements strongly decreased the cell viability at extract concentrations of 1 µg/mL, of which 1 decreased cell viability at 0.1 µg/µL. Also, strong neuronal toxicities of these supplements were found. Cell death was observed at concentrations of 10 µg/mL. The degree of toxicity was comparable to the ones found in Annonaceous fruit extracts. Two fruit pulps of Annonaceae (A. muricata and A. squamosa) showed a reduction in cell viability at lower concentrations. The fruit pulp extract of A. muricata revealed the strongest neurotoxic effect, with 67% cell death at a concentration of 1 µg/mL. A high reduction in cell viability coupled with pronounced cell death was found at 0.1 µg/mL for an Annonaceous seed extract. These results demonstrate that the intake of dietary supplements containing plant material from Annonaceae may be hazardous to health in terms of neurotoxicity. PMID:26405269

  10. Neurotoxicity and risk assessment of brominated and alternative flame retardants.

    PubMed

    Hendriks, Hester S; Westerink, Remco H S

    2015-01-01

    Brominated flame retardants (BFRs) are widely used chemicals that prevent or slow the onset and spreading of fire. Unfortunately, many of these compounds pose serious threats for human health and the environment, indicating an urgent need for safe(r) and less persistent alternative flame retardants (AFRs). As previous research identified the nervous system as a sensitive target organ, the neurotoxicity of past and present flame retardants is reviewed. First, an overview of the neurotoxicity of BFRs in humans and experimental animals is provided, and some common in vitro neurotoxic mechanisms of action are discussed. The combined epidemiological and toxicological studies clearly underline the need for replacing BFRs. Many potentially suitable AFRs are already in use, despite the absence of a full profile of their environmental behavior and toxicological properties. To prioritize the suitability of some selected halogenated and non-halogenated organophosphorous flame retardants and inorganic halogen-free flame retardants, the available neurotoxic data of these AFRs are discussed. The suitability of the AFRs is rank-ordered and combined with human exposure data (serum concentrations, breast milk concentrations and house dust concentrations) and physicochemical properties (useful to predict e.g. bioavailability and persistence in the environment) for a first semi-quantitative risk assessment of the AFRs. As can be concluded from the reviewed data, several BFRs and AFRs share some neurotoxic effects and modes of action. Moreover, the available neurotoxicity data indicate that some AFRs may be suitable substitutes for BFRs. However, proper risk assessment is hampered by an overall scarcity of data, particularly regarding environmental persistence, human exposure levels, and the formation of breakdown products and possible metabolites as well as their toxicity. Until these data gaps in environmental behavioral and toxicological profiles are filled, large scale use of

  11. A Threshold Neurotoxic Amphetamine Exposure Inhibits Parietal Cortex Expression of Synaptic Plasticity-Related Genes

    PubMed Central

    Bowyer, John F.; Pogge, Amy R.; Delongchamp, Robert R.; O'Callaghan, James P.; Patel, Kruti M.; Vrana, Kent E.; Freeman, Willard M.

    2007-01-01

    Compulsive drug abuse has been conceptualized as a behavioral state where behavioral stimuli override normal decision making. Clinical studies of methamphetamine users have detailed decision making changes and imaging studies have found altered metabolism and activation in the parietal cortex. To examine the molecular effects of amphetamine on the parietal cortex, gene expression responses to amphetamine challenge (7.5mg/kg) were examined in the parietal cortex of rats pretreated for nine days with either saline, non-neurotoxic AMPH, or neurotoxic AMPH dosing regimens. The neurotoxic AMPH exposure [3 doses of 7.5 mg/kg/day AMPH (6 hr between doses), for nine days] produced histological signs of neurotoxicity in the parietal cortex while a non-neurotoxic dosing regimen (2.0 mg/kg/day × 3) did not. Neurotoxic AMPH pretreatment resulted in significantly diminished AMPH challenge-induced mRNA increases of activity-regulated cytoskeletal protein (ARC), nerve growth-factor inducible protein A (NGFI-A), and nerve growth-factor inducible protein B (NGFI-B) in the parietal cortex while neither saline pretreatment nor non-neurotoxic AMPH pretreatment did. This effect was specific to these genes as tissue plasminogen activator (t-PA), neuropeptide Y (NPY) and c-jun expression in response to AMPH challenge was unaltered or enhanced by amphetamine pretreatements. In the striatum, there were no differences between saline, neurotoxic AMPH, and non-neurotoxic AMPH pretreatments on ARC, NGFI-A or NGFI-B expression elicited by the AMPH challenge. These data indicate that the responsiveness of synaptic plasticity related genes are sensitive to disruption specifically in the parietal cortex by threshold neurotoxic AMPH exposures. PMID:17049170

  12. Occupational neurotoxic diseases in taiwan.

    PubMed

    Liu, Chi-Hung; Huang, Chu-Yun; Huang, Chin-Chang

    2012-12-01

    Occupational neurotoxic diseases have become increasingly common in Taiwan due to industrialization. Over the past 40 years, Taiwan has transformed from an agricultural society to an industrial society. The most common neurotoxic diseases also changed from organophosphate poisoning to heavy metal intoxication, and then to organic solvent and semiconductor agent poisoning. The nervous system is particularly vulnerable to toxic agents because of its high metabolic rate. Neurological manifestations may be transient or permanent, and may range from cognitive dysfunction, cerebellar ataxia, Parkinsonism, sensorimotor neuropathy and autonomic dysfunction to neuromuscular junction disorders. This study attempts to provide a review of the major outbreaks of occupational neurotoxins from 1968 to 2012. A total of 16 occupational neurotoxins, including organophosphates, toxic gases, heavy metals, organic solvents, and other toxic chemicals, were reviewed. Peer-reviewed articles related to the electrophysiology, neuroimaging, treatment and long-term follow up of these neurotoxic diseases were also obtained. The heavy metals involved consisted of lead, manganese, organic tin, mercury, arsenic, and thallium. The organic solvents included n-hexane, toluene, mixed solvents and carbon disulfide. Toxic gases such as carbon monoxide, and hydrogen sulfide were also included, along with toxic chemicals including polychlorinated biphenyls, tetramethylammonium hydroxide, organophosphates, and dimethylamine borane. In addition we attempted to correlate these events to the timeline of industrial development in Taiwan. By researching this topic, the hope is that it may help other developing countries to improve industrial hygiene and promote occupational safety and health care during the process of industrialization. PMID:23251841

  13. Role for the PI3K/Akt/Nrf2 signaling pathway in the protective effects of carnosic acid against methylglyoxal-induced neurotoxicity in SH-SY5Y neuroblastoma cells.

    PubMed

    de Oliveira, Marcos Roberto; Ferreira, Gustavo Costa; Schuck, Patrícia Fernanda; Dal Bosco, Simone Morelo

    2015-12-01

    Glycation, a process that occurs endogenously and generates advanced glycation end products (AGEs), presents an important role in cases of neurodegeneration, as for instance Alzheimer's disease (AD). Methylglyoxal (MG), a dicarbonyl compound, is the most potent inducer of AGEs, whose levels have been found increased in samples obtained from subjects suffering from AD. Moreover, MG induces protein cross-linking and redox impairment in vitro and in vivo. Carnosic acid (CA), a phenolic diterpene isolated from Rosmarinus officinalis, exerts protective effects in neuronal cells by increasing antioxidant defenses and detoxification systems. In the present work, we aimed to investigate whether there is a role for CA against MG-induced neurotoxicity. Data obtained here clearly demonstrate that CA pretreatment (1 μM for 12 h) caused cytoprotective effects and counteracted the damage elicited by MG in SH-SY5Y cells. CA inhibited loss of mitochondrial membrane polarity (MMP) and cytochrome c release from mitochondria, consequently blocking activation of pro-apoptotic caspase enzymes. Furthermore, CA alleviated MG-induced oxidative and nitrosative damage. CA prevented MG-dependent neurotoxicity by activating the PI3K/Akt/Nrf2 signaling pathway and the antioxidant enzymes modulated by Nrf2 transcription factor. Overall, the data presented here show the protective role of CA by its ability to counteract MG negative effects. PMID:26577515

  14. NEUROTOXICITY OF PARATHION-INDUCED ACETYLCHOLINESTERASE INHIBITION IN NEONATAL RATS

    EPA Science Inventory

    The biochemical and morphological neurotoxic effects of postnatal acetylcholinesterase (AChE) inhibition were examined in rat pups dosed with parathion, at time points critical to hippocampal neurogenesis and synaptogenesis (i.e., D5-20). ippocampal cytopathology as assessed by l...

  15. Valacyclovir-associated neurotoxicity in peritoneal dialysis patients.

    PubMed

    Chaudhari, Dhara; Ginn, David

    2014-01-01

    Valacyclovir is an oral antiviral agent being used more frequently than acyclovir because of the ease of administration and efficacy. Serious neuropsychiatric side effects have been demonstrated with the use of valacyclovir in renal failure patients. We report a case of valacyclovir neurotoxicity to emphasis the importance of dose adjustment in patients with chronic kidney disease and on dialysis. PMID:23528373

  16. The use of glial data in neurotoxicity risk assessment

    EPA Science Inventory

    Central nervous system (CNS) glia (i.e., astrocytes, microglia, and oligodendrocytes) are essential for normal brain function, and they orchestrate the CNS response to injury. While effects on glia are important to consider when evaluating the neurotoxicity risk of exposure to xe...

  17. Neurofunctional endpoints assessed in human neuroblastoma SH-SY5Y cells for estimation of acute systemic toxicity

    SciTech Connect

    Gustafsson, Helena; Runesson, Johan; Lundqvist, Jessica; Lindegren, Helene; Axelsson, Viktoria; Forsby, Anna

    2010-06-01

    The objective of the EU-funded integrated project ACuteTox is to develop a strategy in which general cytotoxicity, together with organ-specific toxicity and biokinetic features, are used for the estimation of human acute systemic toxicity. Our role in the project is to characterise the effect of reference chemicals with regard to neurotoxicity. We studied cell membrane potential (CMP), noradrenalin (NA) uptake, acetylcholine esterase (AChE) activity, acetylcholine receptor (AChR) signalling and voltage-operated calcium channel (VOCC) function in human neuroblastoma SH-SY5Y cells after exposure to 23 pharmaceuticals, pesticides or industrial chemicals. Neurotoxic alert chemicals were identified by comparing the obtained data with cytotoxicity data from the neutral red uptake assay in 3T3 mouse fibroblasts. Furthermore, neurotoxic concentrations were correlated with estimated human lethal blood concentrations (LC50). The CMP assay was the most sensitive assay, identifying eight chemicals as neurotoxic alerts and improving the LC50 correlation for nicotine, lindane, atropine and methadone. The NA uptake assay identified five neurotoxic alert chemicals and improved the LC50 correlation for atropine, diazepam, verapamil and methadone. The AChE, AChR and VOCC assays showed limited potential for detection of acute toxicity. The CMP assay was further evaluated by testing 36 additional reference chemicals. Five neurotoxic alert chemicals were generated and orphendrine and amitriptyline showed improved LC50 correlation. Due to the high sensitivity and the simplicity of the test protocol, the CMP assay constitutes a good candidate assay to be included in an in vitro test strategy for prediction of acute systemic toxicity.

  18. REDUCING UNCERTAINTY IN AIR TOXICS RISK ASSESSMENT: A MECHANISTIC EXPOSURE-DOSE-RESPONSE (EDR) MODEL FOR ASSESSING THE ACUTE NEUROTOXICITY OF VOLATILE ORGANIC COMPOUNDS (VOCS) BASED UPON A RECEPTOR-MEDIATED MODE OF ACTION

    EPA Science Inventory

    SUMMARY: The major accomplishment of NTD’s air toxics program is the development of an exposure-dose- response model for acute exposure to volatile organic compounds (VOCs), based on momentary brain concentration as the dose metric associated with acute neurological impairments...

  19. Neurotoxicity of Adjuvants used in Perineural Anesthesia and Analgesia in Comparison with Ropivacaine

    PubMed Central

    Williams, Brian A.; Hough, Karen A.; Tsui, Becky Y. K.; Ibinson, James W.; Gold, Michael S.; Gebhart, G.F.

    2011-01-01

    Background and Objectives Clonidine, buprenorphine, dexamethasone, and midazolam (C,B,D,M) have been used to prolong perineural local anesthesia in the absence of data on the influence of these adjuvants on local anesthetic (LA)-induced neurotoxicity. Therefore, the impact of these adjuvants on ropivacaine (R)-induced death of isolated sensory neurons was assessed. Methods The trypan blue exclusion assay was used to assess death of sensory neurons isolated from adult male Sprague-Dawley rats. Drugs were applied, alone or in combination, for 2 or 24 hrs at 37°C. Results Neuronal viability was halved by 24 hr exposure to R (2.5 mg/mL), far exceeding the neurotoxicity of C, B, D, or M (at 2–100 times estimated clinical concentrations). Plain M at twice the estimated clinical concentration produced a small but significant increase in neurotoxicity at 24 hr. After 2 hr exposure, high concentrations of B, C, and M increased the neurotoxicity of R; the combination of R+M killed over 90% of neurons. Estimated clinical concentrations of C+B (plus 66 µg/mL D) had no influence on (i) R-induced neurotoxicity, (ii) the increased neurotoxicity associated with the combination of R+M, or (iii) the neurotoxicity associated with estimated clinical concentrations of M. There was dose-response neurotoxicity with 133 µg/mL D combined with R+C+B Conclusions Results with R re-affirm the need to identify ways to mitigate LA-induced neurotoxicity. While having no protective effect on R-induced neurotoxicity in vitro, future research with adjuvants should address if the C+B+D combination can enable reducing R concentrations needed to achieve equi-analgesia (and/or provide equal or superior duration, in preclinical in vivo models). PMID:21519308

  20. Berberine Reduces Neurotoxicity Related to Nonalcoholic Steatohepatitis in Rats

    PubMed Central

    Ghareeb, Doaa A.; Khalil, Sofia; Hafez, Hani S.; Bajorath, Jürgen; Ahmed, Hany E. A.; Sarhan, Eman; Elwakeel, Eiman; El-Demellawy, Maha A.

    2015-01-01

    Berberine is a plant alkaloid that has several pharmacological effects such as antioxidant, antilipidemic, and anti-inflammatory effects. Nonalcoholic steatohepatitis (NASH) triggers different aspects of disorders such as impaired endogenous lipid metabolism, hypercholesterolemia, oxidative stress, and neurotoxicity. In this study, we examined the mechanism by which NASH induces neurotoxicity and the protective effect of berberine against both NASH and its associated neurotoxicity. NASH induced rats showed significant impairments in lipid metabolism with increased serum triglycerides, cholesterol, and low-density lipoprotein (LDL). The NASH induced group also demonstrated a significant oxidative stress which is characterized by increased TBARs level and decreased antioxidant capacity such as GSH and SOD levels. Moreover, the NASH induction was associated with inflammation which was demonstrated by increased TNFα and nitric oxide levels. Hyperglycemia and hyperinsulinemia were observed in the NASH induced group. Also, our results showed a significant increase in the expression of the acetylcholine esterase (AChE) and amyloid beta precursor protein (AβPP). These changes were significantly correlated with decreased insulin degrading enzyme (IDE) and beta-amyloid40 (Aβ40) and increased beta-amyloid42 (Aβ42) in the hippocampal region. Daily administration of berberine (50 mg/kg) for three weeks ameliorated oxidative stress, inflammation, hyperlipidemia, hyperglycemia, hyperinsulinemia, and the observed neurotoxicity. PMID:26576191

  1. Comparison of neurotoxic effects and potential risks from oral administration or ingestion of tricresyl phosphate and jet engine oil containing tricresyl phosphate.

    PubMed

    Mackerer, C R; Barth, M L; Krueger, A J; Chawla, B; Roy, T A

    1999-07-01

    Neurotoxicity of tricresyl phosphates (TCPs) and jet engine oil (JEO) containing TCPs were evaluated in studies conducted in both rat and hen. Results for currently produced samples ("conventional" and "low-toxicity") were compared with published findings on older samples to identify compositional changes and relate those changes to neurotoxic potential. Finally, a human risk assessment for exposure by oral ingestion of currently produced TCPs in JEO at 3% (JEO + 3%) was conducted. TCPs and certain other triaryl phosphates administered as single doses inhibited brain neuropathy target esterase (B-NTE; neurotoxic esterase) in the rat and the hen (hen 3.25 times as sensitive), and both species were deemed acceptable for initial screening purposes. Neither rat nor hen was sensitive enough to detect statistically significant inhibition of B-NTE after single doses of IEO + 3% "conventional" TCP. Subacute administration of 2 g/kg/d of JEO + 3% "conventional" TCP to the hen produced B-NTE inhibition (32%), which did not result in organophosphorus-induced delayed neurotoxicity (OPIDN). Subchronic administration of JEO + 3% TCP but not JEO + 1% TCP at 2 g/kg/d produced OPIDN. Thus, the threshold for OPIDN was between 20 and 60 mg "conventional" TCP/kg/d in JEO for 10 wk. The current "conventional" TCPs used in JEO and new "low-toxicity" TCPs now used in some JEO are synthesized from phenolic mixtures having reduced levels of ortho-cresol and ortho-xylenols resulting in TCPs of very high content of meta- and para-substituted phenyl moieties; this change in composition results in lower toxicity. The "conventional" TCPs still retain enough inhibitory activity to produce OPIDN, largely because of the presence of ortho-xylyl moieties; the "low-toxicity" TCPs are largely devoid of ortho substituents and have extremely low potential to cause OPIDN. The TCPs produced in the 1940s and 1950s were more than 400 times as toxic as the "low-toxicity" TCPs produced today. Analysis of the

  2. IN VIVO INHIBITION OF CHICKEN BRAIN ACETYLCHOLINESTERASE AND NEUROTOXIC ESTERASE IN RELATION TO THE DELAYED NEUROTOXICITY OF LEPTOPHOS AND CYANOFENPHOS

    EPA Science Inventory

    An equimolal single dose (1 mmole/kg) of leptophos or cyanofenphos was given orally to chickens to assay the clinical and biochemical neurotoxic effects of these two organophosphorus insecticides. Parathion and TOCP at 2 and 1000 mg/kg of chicken body weight were tested in the sa...

  3. Bilirubin-Induced Neurotoxicity in the Preterm Neonate.

    PubMed

    Watchko, Jon F

    2016-06-01

    Bilirubin-induced neurotoxicity in preterm neonates remains a clinical concern. Multiple cellular and molecular cascades likely underlie bilirubin-induced neuronal injury, including plasma membrane perturbations, excitotoxicity, neuroinflammation, oxidative stress, and cell cycle arrest. Preterm newborns are particularly vulnerable secondary to central nervous system immaturity and concurrent adverse clinical conditions that may potentiate bilirubin toxicity. Acute bilirubin encephalopathy in preterm neonates may be subtle and manifest primarily as recurrent symptomatic apneic events. Low-bilirubin kernicterus continues to be reported in preterm neonates, and although multifactorial in nature, is often associated with marked hypoalbuminemia. PMID:27235209

  4. Nanoparticles and Neurotoxicity

    PubMed Central

    Win-Shwe, Tin-Tin; Fujimaki, Hidekazu

    2011-01-01

    Humans are exposed to nanoparticles (NPs; diameter < 100 nm) from ambient air and certain workplaces. There are two main types of NPs; combustion-derived NPs (e.g., particulate matters, diesel exhaust particles, welding fumes) and manufactured or engineered NPs (e.g., titanium dioxide, carbon black, carbon nanotubes, silver, zinc oxide, copper oxide). Recently, there have been increasing reports indicating that inhaled NPs can reach the brain and may be associated with neurodegeneration. It is necessary to evaluate the potential toxic effects of NPs on brain because most of the neurobehavioral disorders may be of environmental origin. This review highlights studies on both combustion-derived NP- and manufactured or engineered NP-induced neuroinflammation, oxidative stress, and gene expression, as well as the possible mechanism of these effects in animal models and in humans. PMID:22016657

  5. Nanoparticles and neurotoxicity.

    PubMed

    Win-Shwe, Tin-Tin; Fujimaki, Hidekazu

    2011-01-01

    Humans are exposed to nanoparticles (NPs; diameter < 100 nm) from ambient air and certain workplaces. There are two main types of NPs; combustion-derived NPs (e.g., particulate matters, diesel exhaust particles, welding fumes) and manufactured or engineered NPs (e.g., titanium dioxide, carbon black, carbon nanotubes, silver, zinc oxide, copper oxide). Recently, there have been increasing reports indicating that inhaled NPs can reach the brain and may be associated with neurodegeneration. It is necessary to evaluate the potential toxic effects of NPs on brain because most of the neurobehavioral disorders may be of environmental origin. This review highlights studies on both combustion-derived NP- and manufactured or engineered NP-induced neuroinflammation, oxidative stress, and gene expression, as well as the possible mechanism of these effects in animal models and in humans. PMID:22016657

  6. A critical review of neonicotinoid insecticides for developmental neurotoxicity

    PubMed Central

    Sheets, Larry P.; Li, Abby A.; Minnema, Daniel J.; Collier, Richard H.; Creek, Moire R.; Peffer, Richard C.

    2016-01-01

    Abstract A comprehensive review of published and previously unpublished studies was performed to evaluate the neonicotinoid insecticides for evidence of developmental neurotoxicity (DNT). These insecticides have favorable safety profiles, due to their preferential affinity for nicotinic receptor (nAChR) subtypes in insects, poor penetration of the mammalian blood–brain barrier, and low application rates. Nevertheless, examination of this issue is warranted, due to their insecticidal mode of action and potential exposure with agricultural and residential uses. This review identified in vitro, in vivo, and epidemiology studies in the literature and studies performed in rats in accordance with GLP standards and EPA guidelines with imidacloprid, acetamiprid, thiacloprid, clothianidin, thiamethoxam, and dinotefuran, which are all the neonicotinoids currently registered in major markets. For the guideline-based studies, treatment was administered via the diet or gavage to primiparous female rats at three dose levels, plus a vehicle control (≥20/dose level), from gestation day 0 or 6 to lactation day 21. F1 males and females were evaluated using measures of motor activity, acoustic startle response, cognition, brain morphometry, and neuropathology. The principal effects in F1 animals were associated with decreased body weight (delayed sexual maturation, decreased brain weight, and morphometric measurements) and acute toxicity (decreased activity during exposure) at high doses, without neuropathology or impaired cognition. No common effects were identified among the neonicotinoids that were consistent with DNT or the neurodevelopmental effects associated with nicotine. Findings at high doses were associated with evidence of systemic toxicity, which indicates that these insecticides do not selectively affect the developing nervous system. PMID:26513508

  7. A critical review of neonicotinoid insecticides for developmental neurotoxicity.

    PubMed

    Sheets, Larry P; Li, Abby A; Minnema, Daniel J; Collier, Richard H; Creek, Moire R; Peffer, Richard C

    2016-02-01

    A comprehensive review of published and previously unpublished studies was performed to evaluate the neonicotinoid insecticides for evidence of developmental neurotoxicity (DNT). These insecticides have favorable safety profiles, due to their preferential affinity for nicotinic receptor (nAChR) subtypes in insects, poor penetration of the mammalian blood-brain barrier, and low application rates. Nevertheless, examination of this issue is warranted, due to their insecticidal mode of action and potential exposure with agricultural and residential uses. This review identified in vitro, in vivo, and epidemiology studies in the literature and studies performed in rats in accordance with GLP standards and EPA guidelines with imidacloprid, acetamiprid, thiacloprid, clothianidin, thiamethoxam, and dinotefuran, which are all the neonicotinoids currently registered in major markets. For the guideline-based studies, treatment was administered via the diet or gavage to primiparous female rats at three dose levels, plus a vehicle control (≥20/dose level), from gestation day 0 or 6 to lactation day 21. F1 males and females were evaluated using measures of motor activity, acoustic startle response, cognition, brain morphometry, and neuropathology. The principal effects in F1 animals were associated with decreased body weight (delayed sexual maturation, decreased brain weight, and morphometric measurements) and acute toxicity (decreased activity during exposure) at high doses, without neuropathology or impaired cognition. No common effects were identified among the neonicotinoids that were consistent with DNT or the neurodevelopmental effects associated with nicotine. Findings at high doses were associated with evidence of systemic toxicity, which indicates that these insecticides do not selectively affect the developing nervous system. PMID:26513508

  8. Effect of acute doses of controlled-release carbamazepine on clinical, psychomotor, electrophysiological, and cognitive parameters of brain function.

    PubMed

    van der Meyden, C H; Bartel, P R; Sommers, D K; Blom, M; Becker, P; Erasmus, S; Griesel, D

    1992-01-01

    The neurotoxic effect of acute doses of carbamazepine controlled-release (CBZ-CR) divitabs (800, 1,200, and 1,600 mg) was assessed on clinical, psychomotor, electrophysiological, and cognitive parameters of brain function in 10 healthy volunteers in a double-blind, randomised, placebo-controlled, phase I study. Significant changes compared to placebo were demonstrated for the clinical scales, ataxia (AT), convergence of the near-point (CNP), peak saccadic velocity (PSV), critical flicker fusion (CFF), spectral analysis of the EEG, and brainstem auditory evoked potential (BAEP) tests. Digit repetition, digit symbol substitution, Sternberg memory scanning time, Sternberg choice reaction time, saccadic latency, and saccadic accuracy showed important negative findings. Significant clinical tolerance to side effects developed within 20 to 33 h after CBZ-CR dosage during a period in which the mean CBZ blood levels remained virtually unchanged. CBZ-CR, 800, 1,200, and 1,600 mg yielded low, medium, and high therapeutic blood levels, respectively, for +10 to +33 h after dosage without the development of severe clinical side effects. PMID:1547763

  9. Mental retardation and developmental disabilities influenced by environmental neurotoxic insults.

    PubMed Central

    Schroeder, S R

    2000-01-01

    This paper sets a framework for the discussion of neurotoxicity as a potentially major contributor to the etiology of many types of mental retardation and developmental disabilities. In the past the literatures on developmental neurotoxicology and on mental retardation have evolved independently, yet we know that the developing brain is a target for neurotoxicity in the developing central nervous system through many stages of pregnancy as well as during infancy and early childhood. Our definitions and theories of mental retardation and developmental disabilities affect the models of neurotoxicity we espouse. For instance, models of developmental risk in neurotoxicology have guided environmental regulation to reduce the likelihood of neurotoxic effects. On the other hand, models of developmental risk for mental retardation aim not only at primary prevention,but also at secondary and tertiary prevention through early intervention. In the future, dynamic models of neuroplasticity based on the study of gene-brain-behavior relationships are likely to guide our views of developmental neurotoxicology and prevention of mental retardation and other disabilities. PMID:10852834

  10. Neurotoxicity of Synthetic Cannabinoids JWH-081 and JWH-210

    PubMed Central

    Cha, Hye Jin; Seong, Yeon-Hee; Song, Min-Ji; Jeong, Ho-Sang; Shin, Jisoon; Yun, Jaesuk; Han, Kyoungmoon; Kim, Young-Hoon; Kang, Hoil; Kim, Hyoung Soo

    2015-01-01

    Synthetic cannabinoids JWH-018 and JWH-250 in ‘herbal incense’ also called ‘spice’ were first introduced in many countries. Numerous synthetic cannabinoids with similar chemical structures emerged simultaneously and suddenly. Currently there are not sufficient data on their adverse effects including neurotoxicity. There are only anecdotal reports that suggest their toxicity. In the present study, we evaluated the neurotoxicity of two synthetic cannabinoids (JWH-081 and JWH-210) through observation of various behavioral changes and analysis of histopathological changes using experimental mice with various doses (0.1, 1, 5 mg/kg). In functional observation battery (FOB) test, animals treated with 5 mg/kg of JWH-081 or JWH-210 showed traction and tremor. Their locomotor activities and rotarod retention time were significantly (p<0.05) decreased. However, no significant change was observed in learning or memory function. In histopathological analysis, neural cells of the animals treated with the high dose (5 mg/kg) of JWH-081 or JWH-210 showed distorted nuclei and nucleus membranes in the core shell of nucleus accumbens, suggesting neurotoxicity. Our results suggest that JWH-081 and JWH-210 may be neurotoxic substances through changing neuronal cell damages, especially in the core shell part of nucleus accumbens. To confirm our findings, further studies are needed in the future. PMID:26535086

  11. Studies on aluminum neurotoxicity

    SciTech Connect

    Cho, S.

    1988-01-01

    This work reports the inhibitory effects of aluminum on glucose-6-phosphate dehydrogenase (G6PD) from yeast and brains. The aluminum contents and several enzyme activities in aluminum-fed rat brain homogenates were compared with those in age-matched control groups. The concentration of aluminum in the homogenates of the aluminum-fed groups were twice of that of the controls. Acetylcholinesterase activities were the same as in both groups but hexokinase and G6PD activities in the aluminum-fed group were about 73% and 70% of the control, respectively. Further studies on the inhibitory effects of aluminum on G6PD were performed with the enzymes purified from human and pig brains. Two forms of G6PD isozymes were purified from human and pig brain by ammonium sulfate fractionation, hydroxylapatite chromatography, affinity chromatography with NADP-agarose and Blue-Sepharose CL-6B, and gel filtration with Sephadex S-300. The two forms of isozymes (isozyme I and II), purified to be homogeneous, had a molecular weight of 220,000, and composed of 4 subunits of molecular weight of 57,000. HPLC peptide maps of tryptic digests and amino acid analyses of the isozymes showed extensive homologies between the isozymes. Interestingly, only the isozyme II in human and pig brain were active with 6-phosphogluconate as a substrate. No such an activity was found in isozyme I. Aluminum inactivated G6PD activity of the human and pig brain isozyme I and isozyme II without affecting the 6-phosphogluconate dehydrogenase activity of the isozyme II. Circular dichroism studies showed that the binding of aluminum to G6PD induced a decrease in {alpha}-helix and {beta}-sheet and a increase in random coil. Therefore it is suggested that inactivation of G6PD by aluminum is due to the conformational change induced by aluminum binding.

  12. Current Challenges in Neurotoxicity Risk Assessment

    EPA Science Inventory

    Neurotoxicity risk assessment must continue to evolve in parallel with advances in basic research. Along with this evolution is an expansion in the scope of neurotoxicity assessments of environmental health risks. Examples of this expansion include an increasing emphasis on compl...

  13. RISK CHARACTERIZATION OF PERSISTENT NEUROTOXIC CONTAMINANTS

    EPA Science Inventory

    Neurotoxicity is an adverse change in structure or function of the central and/or peripheral nervous system following exposure to a chemical, physical, or biological agent. Thousands of chemicals have been estimated to have neurotoxic potential. Many persistent and bioaccumulat...

  14. DEVELOPMENT OF AN 'IN VITRO' NEUROTOXICITY ASSAY

    EPA Science Inventory

    The aim of this research project was to investigate the possibility of developing the neurotoxic esterase (NTE) assay into a totally in vitro system to enable neurotoxicity assessment to be carried out rapidly on large numbers of compounds. The purified enzyme was to be immobiliz...

  15. Effects of Acute Exercise on Long-Term Memory

    ERIC Educational Resources Information Center

    Labban, Jeffrey D.; Etnier, Jennifer L.

    2011-01-01

    In this study, we tested the effect of acute exercise on long-term memory, specifically the timing of exercise relative to the memory challenge. We assessed memory via paragraph recall, in which participants listened to two paragraphs (exposure) and recounted them following a 35-min delay. Participants (n = 48) were randomly assigned to one of…

  16. Acute Stressor Effects on Goal-Directed Action in Rats

    ERIC Educational Resources Information Center

    Braun, Stephanie; Hauber, Wolfgang

    2013-01-01

    Here we examined effects of acute stressors that involve either systemic coadministration of corticosterone/yohimbine (3 mg/kg each) to increase glucocorticoid/noradrenaline activity (denoted as "pharmacological" stressor) or one or several distinct restraint stressors (denoted as "single" vs. "multiple" stressor) on…

  17. Evaluating Neurotoxicity of a Mixture of Five OP Pesticides Using a Composite Score

    EPA Science Inventory

    The evaluation of the cumulative effects of neurotoxic pesticides often involves the analysis of both neurochemical and behavioral endpoints. Multiple statistical tests on many endpoints can greatly inflate Type I error rates. Multiple comparison adjustments are often overly con...

  18. The Potential Contribution of Advanced Imaging Techniques to Developmental Neurotoxicity Risk Assessment

    EPA Science Inventory

    Neuropathologic assessment provides critical data essential to developmental neurotoxicity risk assessment. There are a number of objectives in conducting a neuropathologic assessment to effectively support risk assessment. These include a comprehensive assessment of the adult an...

  19. ALTERED THALAMOCORTICAL AXON MORPHOLOGY FOLLOWING NEONATAL PERIPHERAL NERVE DAMAGE: IMPLICATIONS FOR THE STUDY OF DEVELOPMENTAL NEUROTOXICITY

    EPA Science Inventory

    Toxicant effects on central connectivity have not been extensively characterized. Studies of developmental neurotoxicity have typically described malformations arising from damage to neuronal precursors. Toxicants may also affect later stages of neural development. In particular,...

  20. In vitro oxidation of MPTP by primate neural tissue: A potential model of MPTP neurotoxicity.

    PubMed

    Johannessen, J N; Kelner, L; Hanselman, D; Shih, M C; Markey, S P

    1985-01-01

    The compound 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) produces a parkinsonian syndrome in humans and primates. We have previously found that metabolism of MPTP to a quaternary species is necessary for the expression of its neurotoxic effects. We now report that the metabolism of MPTP occurs in primate brain tissue in vitro , and present a model of MPTP neurotoxicity which incorporates our findings to date. Since the toxicity of MPTP is metabolism dependent, we propose that the in vitro metabolism of MPTP by brain tissue should provide a useful model for studying selected aspects of MPTP neurotoxicity. PMID:20492913

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

    PubMed Central

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

    2009-01-01

    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 α-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. PMID:18088364

  2. Manganese Neurotoxicity: Lessons Learned from Longitudinal Studies in Nonhuman Primates

    PubMed Central

    Burton, Neal C.; Guilarte, Tomás R.

    2009-01-01

    Background Exposure to excess levels of the essential trace element manganese produces cognitive, psychiatric, and motor abnormalities. The understanding of Mn neurotoxicology is heavily governed by pathologic and neurochemical observations derived from rodent studies that often employ acute Mn exposures. The comparatively sparse studies incorporating in vivo neuroimaging in nonhuman primates provide invaluable insights on the effects of Mn on brain chemistry. Objectives The purpose of this review is to discuss important aspects of Mn neurotoxicology and to synthesize recent findings from one of the largest cohorts of nonhuman primates used to study the neurologic effects of chronic Mn exposure. Discussion We reviewed our recent in vivo and ex vivo studies that have significantly advanced the understanding of Mn-induced neurotoxicity. In those studies, we administered weekly doses of 3.3–5.0 (n = 4), 5.0–6.7 (n = 5), or 8.3–10.0 mg Mn/kg (n = 3) for 7–59 weeks to cynomolgus macaque monkeys. Animals expressed subtle deficits in cognition and motor function and decreases in the N-acetylaspartate-to-creatine ratio in the parietal cortex measured by magnetic resonance spectroscopy reflective of neuronal dysfunction. Impaired striatal dopamine release measured by positron emission tomography was observed in the absence of changes in markers of dopamine neuron degeneration. Neuropathology indicated decreased glutamine synthetase expression in the globus pallidus with otherwise normal markers of glutamatergic and GABAergic neurotransmission. Increased amyloid beta (A4) precursor-like protein 1 gene expression with multiple markers of neurodegeneration and glial cell activation was observed in the frontal cortex. Conclusions These findings provide new information on mechanisms by which Mn affects behavior, neurotransmitter function, and neuropathology in nonhuman primates. PMID:19337503

  3. Definition of a molecular pathway mediating α-synuclein neurotoxicity.

    PubMed

    Burré, Jacqueline; Sharma, Manu; Südhof, Thomas C

    2015-04-01

    α-Synuclein physiologically chaperones SNARE-complex assembly at the synapse but pathologically misfolds into neurotoxic aggregates that are characteristic for neurodegenerative disorders, such as Parkinson's disease, and that may spread from one neuron to the next throughout the brain during Parkinson's disease pathogenesis. In normal nerve terminals, α-synuclein is present in an equilibrium between a cytosolic form that is natively unfolded and monomeric and a membrane-bound form that is composed of an α-helical multimeric species that chaperones SNARE-complex assembly. Although the neurotoxicity of α-synuclein is well established, the relationship between the native conformations of α-synuclein and its pathological aggregation remain incompletely understood; most importantly, it is unclear whether α-synuclein aggregation originates from its monomeric cytosolic or oligomeric membrane-bound form. Here, we address this question by introducing into α-synuclein point mutations that block membrane binding and by then assessing the effect of blocking membrane binding on α-synuclein aggregation and neurotoxicity. We show that membrane binding inhibits α-synuclein aggregation; conversely, blocking membrane binding enhances α-synuclein aggregation. Stereotactic viral expression of wild-type and mutant α-synuclein in the substantia nigra of mice demonstrated that blocking α-synuclein membrane binding significantly enhanced its neurotoxicity in vivo. Our data delineate a folding pathway for α-synuclein that ranges from a physiological multimeric, α-helical, and membrane-bound species that acts as a SNARE-complex chaperone over a monomeric, natively unfolded form to an amyloid-like aggregate that is neurotoxic in vivo. PMID:25834048

  4. A novel nicotinic mechanism underlies β-amyloid-induced neurotoxicity.

    PubMed

    Liu, Qiang; Xie, Xitao; Emadi, Sharareh; Sierks, Michael R; Wu, Jie

    2015-10-01

    Loss of basal forebrain cholinergic neurons (BFCN) correlates with cognitive deficits in Alzheimer disease (AD). Our recent evidence suggests that chronic exposure to Aβ up-regulated neuronal α7-nAChRs and increased neuronal excitability in cultured hippocampal neurons. However, the impact of the up-regulated α7-nAChRs on Aβ-induced neurotoxicity remains unclear. In this study, we investigated the role of α7-nAChRs in the mediation of Aβ-induced neurotoxicity. The effects of Aβ exposure on α7-nAChRs and cytotoxicity were examined using whole-cell patch clamp recordings, atomic force microscope (AFM) imaging, immunoprecipitation, and lactate dehydrogenase (LDH) release assay in primary cultured hippocampal neurons as well as differentiated human neuroblastoma (SH-SY5Y) cells with cholinergic characteristics. We found that α7-nAChRs are necessary for Aβ-induced neurotoxicity in hippocampal neurons because chronic Aβ significantly increased LDH level in hippocampal cultures, which was prevented by either α7-nAChR antagonist methyllycaconitine (MLA) or by α7 subunit gene deletion (cultures prepared from nAChR α7 subunit KO mice), whereas β2-containing nAChR antagonist (dihydro-β-erythroidine, DhβE) or the genetic deletion of nAChR β2 subunit (cultures prepared from β2 KO mice) failed to prevent Aβ-induced toxicity. In SH-SY5Y cells, larger aggregates of Aβ preferentially up-regulated α7-nAChR expression and function accompanied by a significant decrease in cell viability. Co-treatment MLA, but not mecamylamine (MEC), prevented Aβ exposure-induced neurotoxicity. Our results suggest a detrimental role of upregulated α7-nAChRs in the mediation of Aβ-induced neurotoxicity. PMID:25959067

  5. Acute effects of tea consumption on attention and mood.

    PubMed

    Einöther, Suzanne J; Martens, Vanessa E

    2013-12-01

    Tea has historically been associated with mood and performance benefits, such as relaxation and concentration. This review summarizes the research on the acute effects of tea, and its ingredients theanine and caffeine, on attention and mood. Consistent with abundant research on the benefits of caffeine, the performance benefits of tea were identified in a number of studies, with particularly consistent evidence for improved attention. Tea consumption also consistently improved self-reported alertness and arousal, whereas effects on pleasure or relaxation were less consistent. In addition to the research on caffeine in real-life performance, 2 recent studies have provided a broader perspective on tea's effects on psychological function in that they showed beneficial effects in related areas such as work performance and creativity. These studies showed the validity of laboratory findings by supporting the idea that tea consumption has acute benefits on both mood and performance in real-life situations. PMID:24172303

  6. The effects of citicoline on acute ischemic stroke: a review.

    PubMed

    Overgaard, Karsten

    2014-08-01

    Early reopening of the occluded artery is, thus, important in ischemic stroke, and it has been calculated that 2 million neurons die every minute in an ischemic stroke if no effective therapy is given; therefore, "Time is Brain." In massive hemispheric infarction and edema, surgical decompression lowers the risk of death or severe disability defined as a modified Rankin Scale score greater than 4 in selected patients. The majority, around 80%-85% of all ischemic stroke victims, does not fulfill the criteria for revascularization therapy, and also for these patients, there is no effective acute therapy. Also there is no established effective acute treatment of spontaneous intracerebral bleeding. Therefore, an effective therapy applicable to all stroke victims is needed. The neuroprotective drug citicoline has been extensively studied in clinical trials with volunteers and more than 11,000 patients with various neurologic disorders, including acute ischemic stroke (AIS). The conclusion is that citicoline is safe to use and may have a beneficial effect in AIS patients and most beneficial in less severe stroke in older patients not treated with recombinant tissue plasminogen activator. No other neuroprotective agent had any beneficial effect in confirmative clinical trials or had any positive effect in the subgroup analysis. Citicoline is the only drug that in a number of different clinical stroke trials continuously had some neuroprotective benefit. PMID:24739589

  7. Neurotoxicity

    MedlinePlus

    ... organ transplants, as well as exposure to heavy metals such as lead and mercury, certain foods and food additives, pesticides, industrial and/or cleaning solvents, cosmetics, and some naturally occurring substances. Symptoms may appear immediately after exposure or be ...

  8. Endoplasmic Reticulum Stress and Ethanol Neurotoxicity.

    PubMed

    Yang, Fanmuyi; Luo, Jia

    2015-01-01

    Ethanol abuse affects virtually all organ systems and the central nervous system (CNS) is particularly vulnerable to excessive ethanol exposure. Ethanol exposure causes profound damages to both the adult and developing brain. Prenatal ethanol exposure induces fetal alcohol spectrum disorders (FASD) which is associated with mental retardation and other behavioral deficits. A number of potential mechanisms have been proposed for ethanol-induced brain damage; these include the promotion of neuroinflammation, interference with signaling by neurotrophic factors, induction of oxidative stress, modulation of retinoid acid signaling, and thiamine deficiency. The endoplasmic reticulum (ER) regulates posttranslational protein processing and transport. The accumulation of unfolded or misfolded proteins in the ER lumen triggers ER stress and induces unfolded protein response (UPR) which are mediated by three transmembrane ER signaling proteins: pancreatic endoplasmic reticulum kinase (PERK), inositol-requiring enzyme 1 (IRE1), and activating transcription factor 6 (ATF6). UPR is initiated to protect cells from overwhelming ER protein loading. However, sustained ER stress may result in cell death. ER stress has been implied in various CNS injuries, including brain ischemia, traumatic brain injury, and aging-associated neurodegeneration, such as Alzheimer's disease (AD), Huntington's disease (HD), Amyotrophic lateral sclerosis (ALS), and Parkinson's disease (PD). However, effects of ethanol on ER stress in the CNS receive less attention. In this review, we discuss recent progress in the study of ER stress in ethanol-induced neurotoxicity. We also examine the potential mechanisms underlying ethanol-mediated ER stress and the interaction among ER stress, oxidative stress and autophagy in the context of ethanol neurotoxicity. PMID:26473940

  9. Does escitalopram reduce neurotoxicity in major depression?

    PubMed

    Halaris, Angelos; Myint, Aye-Mu; Savant, Vidushi; Meresh, Edwin; Lim, Edwin; Guillemin, Gilles; Hoppensteadt, Debra; Fareed, Jawed; Sinacore, James

    2015-01-01

    A pro-inflammatory state and a dysregulation in the tryptophan/kynurenine pathway have been documented in depression. This study examined whether treatment with the SSRI, escitalopram (ESC), could suppress inflammation and favorably shift metabolites of the kynurenine pathway in patients with major depressive disorder (MDD) within the utilized treatment period. Twenty seven healthy control subjects were included for comparison. Thirty patients were enrolled after completing baseline assessments. They received a 12-week ESC monotherapy. Twenty subjects were completers. Clinical assessments were carried out at each visit using the HAM-D, HAM-A, CGI and BDI rating scales. Blood samples were collected at each assessment and stored until analyzed. Cytokines were analyzed with Randox multiplex assay and tryptophan and kynurenine metabolites were analyzed using HPLC/GCMS. Baseline plasma concentrations of hsCRP, TNFα, IL6 and MCP-1 were significantly higher in patients compared to healthy controls. IL10 trended toward an increase. Baseline plasma IL1β correlated significantly with IL1α, and IL4. Patients showed significant improvement in all outcome measures with a high remission rate. Significant correlations were obtained between specific symptoms and certain biomarkers at baseline but these correlations must be viewed as very preliminary. During ESC treatment concentrations of inflammatory biomarkers did not change except for TNFα that trended lower. Metabolites and ratios of the tryptophan/kynurenine pathway showed reductions of the neurotoxic metabolites, 3-hydroxykynurenine and quinolinic acid, 3-hydroxykynurenine/kynurenine, quinolinic acid/tryptophan, kynurenic acid/quinolinic acid and quinolinic acid/3-hydroxykynurenine. The results indicate that ESC may exert its antidepressant effect in part through inhibition of synthesis of certain neurotoxic kynurenine metabolites and possibly also through reduction of the inflammatory response, although there was no

  10. The effects of acute and chronic stress on diabetes control.

    PubMed

    Marcovecchio, M Loredana; Chiarelli, Francesco

    2012-10-23

    Stress is an important contributor to pathological conditions in humans. Hormonal changes that occur during acute and chronic stress situations can affect glucose homeostasis in both healthy people and in those with diabetes. Several studies have reported a negative effect of acute stress on maintenance of blood glucose concentrations in patients with type 1 and type 2 diabetes. The effect of stress on glycemic control in people with diabetes may be related to a direct effect of stress hormones on blood glucose levels and an indirect effect of stress on patient behaviors related to diabetes treatment and monitoring and meal and exercise plans. In contrast, there is no clear evidence that stressful life events promote the development of diabetes in children or in adults. Stress hyperglycemia, the development of hyperglycemia during acute illness, represents another interesting connection between the stress system and glucose homeostasis. A large body of evidence supports an association between stress hyperglycemia and increased morbidity and mortality in critically ill patients. Interestingly, there is some evidence supporting a beneficial effect of insulin in reducing morbidity and mortality in patients admitted to intensive care units. Finally, stress can influence the development of type 2 diabetes indirectly by promoting obesity and metabolic syndrome. PMID:23092890

  11. Acute effects of aflatoxins on guinea pig isolated ileum.

    PubMed

    Luzi, A; Cometa, M F; Palmery, M

    2002-10-01

    Previous studies on the aflatoxins have focused mainly on their chronic toxic effects. In this study we investigated the acute gastrointestinal effects of four common aflatoxins on isolated guinea pig ileum. AFB(1) (EC(50) 4.6+/-0.4 microM) and AFB(2) (EC(50)17+/-4.4 microM) contracted isolated guinea pig ileum in a dose-dependent manner, whereas AFG(1) and AFG(2) evoked no contractions. Atropine (5.9 nM 11.8 and 23.6 nM) antagonized AFB(1)-induced contractions in a dose-dependent manner. Pretreatment with the nicotinic ganglionic blocker, hexamethonium (up to 55 microM), left AFB(1)-induced contractions unchanged. In contrast, tetrodotoxin (0.3 microM), blocked AFB(1) contractile activity. The two inhibitors of ACh release, morphine (0.3 microM) and clonidine (0.4 microM), antagonized EC(50) AFB(1)-induced contractions, and apamin, a drug that increases neuronal excitability, facilitated the EC(50) AFB(1)-induced contractile effect. The choline uptake blocker, hemicholinium (17.4 microM) markedly reduced AFB(1)-induced contractions. These results suggest that aflatoxins induce their contractile effect indirectly through the cholinergic system by stimulating acetylcholine release from the postganglionic parasympathetic nerve endings. The acute actions of aflatoxins on isolated guinea pig ileum could explain their acute gastrointestinal effects in humans and animals. PMID:12206819

  12. Acute effects of cannabis on breath-holding duration.

    PubMed

    Farris, Samantha G; Metrik, Jane

    2016-08-01

    Distress intolerance (an individual's perceived or actual inability to tolerate distressing psychological or physiological states) is associated with cannabis use. It is unknown whether a biobehavioral index of distress intolerance, breath-holding duration, is acutely influenced (increased or decreased) by cannabis. Such information may further inform understanding of the expression of psychological or physiological distress postcannabis use. This within-subjects study examined whether smoked marijuana with 2.7%-3.0% delta-9-tetrahydrocannabinol (THC), relative to placebo, acutely changed duration of breath holding. Participants (n = 88; 65.9% male) were nontreatment-seeking frequent cannabis users who smoked placebo or active THC cigarette on two separate study days and completed a breath-holding task postsmoking. Controlling for baseline breath-holding duration and participant sex, THC produced significantly shorter breath-holding durations relative to placebo. There was a significant interaction of drug administration × frequency of cannabis use, such that THC decreased breath-holding time among less frequent but not among more frequent users. Findings indicate that cannabis may exacerbate distress intolerance (via shorter breath-holding durations). As compared to less frequent cannabis users, frequent users display tolerance to cannabis' acute effects including increased ability to tolerate respiratory distress when holding breath. Objective measures of distress intolerance are sensitive to contextual factors such as acute drug intoxication, and may inform the link between cannabis use and the expression of psychological distress. (PsycINFO Database Record PMID:27454678

  13. Norepinephrine and impulsivity: Effects of acute yohimbine

    PubMed Central

    Swann, Alan C.; Lijffijt, Marijn; Lane, Scott D.; Cox, Blake; Steinberg, Joel L.; Moeller, F. Gerard

    2013-01-01

    Rationale Rapid-response impulsivity, characterized by inability to withhold response to a stimulus until it is adequately appraised, is associated with risky behavior and may be increased in a state-dependent manner by norepinephrine. Objective We assessed effects of yohimbine, which increases norepinephrine release by blocking alpha-2 noradrenergic receptors, on plasma catecholamine metabolites, blood pressure, subjective symptoms, and laboratory-measured rapid-response impulsivity. Methods Subjects were twenty-three healthy controls recruited from the community, with normal physical examination and ECG, and negative history for hypertension, cardiovascular illness, and Axis I or II disorder. Blood pressure, pulse, and behavioral measures were obtained before and periodically after 0.4 mg/kg oral yohimbine or placebo in a randomized, counterbalanced design. Metabolites of norepinephrine (3-methoxy-4-hydroxyphenylglycol, MHPG; vanillylmandelic acid, VMA) and dopamine (homovanillic acid, HVA) were measured by high pressure liquid chromatography with electrochemical detection. Rapid-response impulsivity was measured by commission errors and reaction times on the Immediate Memory Task (IMT), a continuous performance test designed to measure impulsivity and attention. Results Yohimbine increased plasma MHPG and VMA but not HVA. Yohimbine increased systolic and diastolic blood pressure and pulse rate. On the IMT, yohimbine increased impulsive errors and impulsive response bias and accelerated reaction times. Yohimbine-associated increase in plasma MHPG correlated with increased impulsive response rates. Time courses varied; effects on blood pressure generally preceded those on metabolites and test performance. Conclusions These effects are consistent with increased rapid-response impulsivity after pharmacological noradrenergic stimulation in healthy controls. Labile noradrenergic responses, or increased sensitivity to norepinephrine, may increase risk for impulsive

  14. Immunosuppressant-associated neurotoxicity responding to olanzapine.

    PubMed

    Bourgeois, James A; Hategan, Ana

    2014-01-01

    Immunosuppressants, particularly tacrolimus, can induce neurotoxicity in solid organ transplantation cases. A lower clinical threshold to switch from tacrolimus to another immunosuppressant agent has been a common approach to reverse this neurotoxicity. However, immunosuppressant switch may place the graft at risk, and, in some cases, continuation of the same treatment protocol may be necessary. We report a case of immunosuppressant-associated neurotoxicity with prominent neuropsychiatric manifestation and describe psychiatric intervention with olanzapine that led to clinical improvement while continuing tacrolimus maintenance. PMID:25114826

  15. Acute effects of aerobic exercise promote learning.

    PubMed

    Perini, Renza; Bortoletto, Marta; Capogrosso, Michela; Fertonani, Anna; Miniussi, Carlo

    2016-01-01

    The benefits that physical exercise confers on cardiovascular health are well known, whereas the notion that physical exercise can also improve cognitive performance has only recently begun to be explored and has thus far yielded only controversial results. In the present study, we used a sample of young male subjects to test the effects that a single bout of aerobic exercise has on learning. Two tasks were run: the first was an orientation discrimination task involving the primary visual cortex, and the second was a simple thumb abduction motor task that relies on the primary motor cortex. Forty-four and forty volunteers participated in the first and second experiments, respectively. We found that a single bout of aerobic exercise can significantly facilitate learning mechanisms within visual and motor domains and that these positive effects can persist for at least 30 minutes following exercise. This finding suggests that physical activity, at least of moderate intensity, might promote brain plasticity. By combining physical activity-induced plasticity with specific cognitive training-induced plasticity, we favour a gradual up-regulation of a functional network due to a steady increase in synaptic strength, promoting associative Hebbian-like plasticity. PMID:27146330

  16. Formaldehyde exposure and acute health effects study

    SciTech Connect

    Quackenboss, J.J.; Lebowitz, M.D.; Michaud, J.P.; Bronnimann, D. )

    1989-01-01

    To assess the effects of formaldehyde exposures on health, exposure groups were defined using baseline exposure and health questionnaires. Formaldehyde concentrations were poorly correlated with these exposure classifications, perhaps due to the time delay between classification and monitoring. The 151 households reported here had a mean HCHO concentration of 35 (S.E. 1.5 and median 30) {mu}g/m{sup 3}. Passive samplers prepared in our lab were calibrated in a chamber to derive an estimated sampling rate of 0.311 {mu}g/(mg {center dot} m{sup {minus}3} {center dot} hr). They were also compared to commercially available samplers inside of the homes, with a correlation coefficient of 0.896 and mean difference of 2.6 {mu}g/m{sup 3}. In this report of initial findings from an ongoing study, daily symptoms and peak expiratory flow measurements were compared with an HCHO exposure classification based on the median measured concentrations. None of the symptoms groups were related to HCHO exposure when controlling for age and sex. There was a significant relationship between HCHO exposure and variability in peak expiratory flows that was dependent on age group. It may be especially important to assess the variability in reactive individuals and children to determine the short-term effects of HCHO exposures and possible long-term consequences.

  17. Acute effects of aerobic exercise promote learning

    PubMed Central

    Perini, Renza; Bortoletto, Marta; Capogrosso, Michela; Fertonani, Anna; Miniussi, Carlo

    2016-01-01

    The benefits that physical exercise confers on cardiovascular health are well known, whereas the notion that physical exercise can also improve cognitive performance has only recently begun to be explored and has thus far yielded only controversial results. In the present study, we used a sample of young male subjects to test the effects that a single bout of aerobic exercise has on learning. Two tasks were run: the first was an orientation discrimination task involving the primary visual cortex, and the second was a simple thumb abduction motor task that relies on the primary motor cortex. Forty-four and forty volunteers participated in the first and second experiments, respectively. We found that a single bout of aerobic exercise can significantly facilitate learning mechanisms within visual and motor domains and that these positive effects can persist for at least 30 minutes following exercise. This finding suggests that physical activity, at least of moderate intensity, might promote brain plasticity. By combining physical activity–induced plasticity with specific cognitive training–induced plasticity, we favour a gradual up-regulation of a functional network due to a steady increase in synaptic strength, promoting associative Hebbian-like plasticity. PMID:27146330

  18. Bioconcentration, metabolism and neurotoxicity of the organophorous flame retardant 1,3-dichloro 2-propyl phosphate (TDCPP) to zebrafish.

    PubMed

    Wang, Qiangwei; Lam, James Chung-Wah; Man, Yin-Chung; Lai, Nelson Lok-Shun; Kwok, Karen Ying; Guo, Yong yong; Lam, Paul Kwan-Sing; Zhou, Bingsheng

    2015-01-01

    Organophosphate flame retardants are ubiquitous environmental contaminants; however, knowledge is limited regarding their environmental health risks and toxicity. Here, we investigated the effects of acute and long-term exposure to tris(1,3-dichloro-2-propyl) phosphate (TDCPP) to the nervous system of zebrafish. Zebrafish embryos (2 h post-fertilization) were exposed to TDCPP (0-100 μg/L) for 6 months up until sexual maturation. Concentrations of TDCPP and its metabolic product (bis(1,3-dichloro-2-propyl) phosphate, BDCPP) were measured in the tissues of 5 day post-fertilization (dpf) larvae. There was no effect on locomotion, acetylcholinesterase activity, levels of the neurotransmitters dopamine and serotonin, and expression of mRNAs and proteins related to central nervous system development (e.g., myelin basic protein, α1-tubulin) in any exposure group. However, in adult fish, reductions of dopamine and serotonin levels were detected in the brains of females but not males. Downregulation of nervous system development genes was observed in both the male and female brain tissues. TDCPP concentrations were measured in adult fish tissues including the brain, and greater levels were detected in females. Our results showed that females are more sensitive to TDCPP stress than males in terms of TDCPP-induced neurotoxicity. We demonstrate that long-term exposure to lower concentrations of TDCPP in fish can lead to neurotoxicity. PMID:25461749

  19. The Protective Effects of Buzui on Acute Alcoholism in Mice

    PubMed Central

    Wen, Da-Chao; Gao, Shu-di; Hu, Xiao-yu; Yi, Cheng

    2016-01-01

    This study was designed to investigate the role of a traditional buzui recipe in anti-inebriation treatment. Buzui consists of Fructus Schisandrae Chinensis, Fructus Chebulae, Fructus Mume, Fructus Crataegi, Endothelium Corneum Gigeriae Galli, and Excrementum Bombycis. The buzui mixture was delivered by gavage, and ethanol was delivered subsequent to the final treatment. The effects of buzui on the righting reflex, inebriation rates, and the survival curve are depicted. Blood alcohol concentrations, alanine aminotransferase (ALT) levels, aspartate aminotransferase (AST) levels, and alkaline phosphatase (ALP) levels were recorded. The activities of alcohol dehydrogenase (ADH), aldehyde dehydrogenase (ALDH), and superoxide dismutase (SOD), as well as malonaldehyde (MDA) levels, were also measured. Our results demonstrated that a traditional buzui recipe showed significant effects on promoting wakefulness and the prevention of acute alcohol intoxication, accelerating the metabolism of alcohol in the liver and reducing the oxidative damage caused by acute alcoholism. PMID:26884793

  20. Cholinergic and behavioral neurotoxicity of carbaryl and cadmium to larval rainbow trout (Oncorhynchus mykiss).

    PubMed

    Beauvais, S L; Jones, S B; Parris, J T; Brewer, S K; Little, E E

    2001-05-01

    Pesticides and heavy metals are common environmental contaminants that can cause neurotoxicity to aquatic organisms, impairing reproduction and survival. Neurotoxic effects of cadmium and carbaryl exposures were estimated in larval rainbow trout (RBT; Oncorhynchus mykiss) using changes in physiological endpoints and correlations with behavioral responses. Following exposures, RBT were videotaped to assess swimming speed. Brain tissue was used to measure cholinesterase (ChE) activity, muscarinic cholinergic receptor (MChR) number, and MChR affinity. ChE activity decreased with increasing concentrations of carbaryl but not of cadmium. MChR were not affected by exposure to either carbaryl or cadmium. Swimming speed correlated with ChE activity in carbaryl-exposed RBT, but no correlation occurred in cadmium-exposed fish. Thus, carbaryl exposure resulted in neurotoxicity reflected by changes in physiological and behavioral parameters measured, while cadmium exposure did not. Correlations between behavior and physiology provide a useful assessment of neurotoxicity. PMID:11386719

  1. Cholinergic and behavioral neurotoxicity of carbaryl and cadmium to larval rainbow trout (oncorhynchus mykiss)

    USGS Publications Warehouse

    Beauvais, S.L.; Jones, S.B.; Parris, J.T.; Brewer, S.K.; Little, E.E.

    2001-01-01

    Pesticides and heavy metals are common environmental contaminants that can cause neurotoxicity to aquatic organisms, impairing reproduction and survival. Neurotoxic effects of cadmium and carbaryl exposures were estimated in larval rainbow trout (RBT; Oncorhynchus mykiss) using changes in physiological endpoints and correlations with behavioral responses. Following exposures, RBT were videotaped to assess swimming speed. Brain tissue was used to measure cholinesterase (ChE) activity, muscarinic cholinergic receptor (MChR) number, and MChR affinity. ChE activity decreased with increasing concentrations of carbaryl but not of cadmium. MChR were not affected by exposure to either carbaryl or cadmium. Swimming speed correlated with ChE activity in carbaryl-exposed RBT, but no correlation occurred in cadmium-exposed fish. Thus, carbaryl exposure resulted in neurotoxicity reflected by changes in physiological and behavioral parameters measured, while cadmium exposure did not. Correlations between behavior and physiology provide a useful assessment of neurotoxicity. ?? 2001 Academic Press.

  2. Spaceflight Sensorimotor Analogs: Simulating Acute and Adaptive Effects

    NASA Technical Reports Server (NTRS)

    Taylor, Laura C.; Harm, Deborah L.; Kozlovskaya, Inessa; Reschke, Millard F.; Wood, Scott J.

    2009-01-01

    Adaptive changes in sensorimotor function during spaceflight are reflected by spatial disorientation, motion sickness, gaze destabilization and decrements in balance, locomotion and eye-hand coordination that occur during and following transitions between different gravitational states. The purpose of this study was to conduct a meta-synthesis of data from spaceflight analogs to evaluate their effectiveness in simulating adaptive changes in sensorimotor function. METHODS. The analogs under review were categorized as either acute analogs used to simulate performance decrements accompanied with transient changes, or adaptive analogs used to drive sensorimotor learning to altered sensory feedback. The effectiveness of each analog was evaluated in terms of mechanisms of action, magnitude and time course of observed deficits compared to spaceflight data, and the effects of amplitude and exposure duration. RESULTS. Parabolic flight has been used extensively to examine effects of acute variation in gravitational loads, ranging from hypergravity to microgravity. More recently, galvanic vestibular stimulation has been used to elicit acute postural, locomotor and gaze dysfunction by disrupting vestibular afferents. Patient populations, e.g., with bilateral vestibular loss or cerebellar dysfunction, have been proposed to model acute sensorimotor dysfunction. Early research sponsored by NASA involved living onboard rotating rooms, which appeared to approximate the time course of adaptation and post-exposure recovery observed in astronauts following spaceflight. Exposure to different bed-rest paradigms (6 deg head down, dry immersion) result in similar motor deficits to that observed following spaceflight. Shorter adaptive analogs have incorporated virtual reality environments, visual distortion paradigms, exposure to conflicting tilt-translation cues, and exposure to 3Gx centrifugation. As with spaceflight, there is considerable variability in responses to most of the analogs

  3. Relative Neurotoxicity of Ivermectin and Moxidectin in Mdr1ab (−/−) Mice and Effects on Mammalian GABA(A) Channel Activity

    PubMed Central

    Ménez, Cécile; Sutra, Jean-François; Prichard, Roger; Lespine, Anne

    2012-01-01

    The anthelmintics ivermectin (IVM) and moxidectin (MOX) display differences in toxicity in several host species. Entrance into the brain is restricted by the P-glycoprotein (P-gp) efflux transporter, while toxicity is mediated through the brain GABA(A) receptors. This study compared the toxicity of IVM and MOX in vivo and their interaction with GABA(A) receptors in vitro. Drug toxicity was assessed in Mdr1ab(−/−) mice P-gp-deficient after subcutaneous administration of increasing doses (0.11–2.0 and 0.23–12.9 µmol/kg for IVM and MOX in P-gp-deficient mice and half lethal doses (LD50) in wild-type mice). Survival was evaluated over 14-days. In Mdr1ab(−/−) mice, LD50 was 0.46 and 2.3 µmol/kg for IVM and MOX, respectively, demonstrating that MOX was less toxic than IVM. In P-gp-deficient mice, MOX had a lower brain-to-plasma concentration ratio and entered into the brain more slowly than IVM. The brain sublethal drug concentrations determined after administration of doses close to LD50 were, in Mdr1ab(−/−) and wild-type mice, respectively, 270 and 210 pmol/g for IVM and 830 and 740–1380 pmol/g for MOX, indicating that higher brain concentrations are required for MOX toxicity than IVM. In rat α1β2γ2 GABA channels expressed in Xenopus oocytes, IVM and MOX were both allosteric activators of the GABA-induced response. The Hill coefficient was 1.52±0.45 for IVM and 0.34±0.56 for MOX (p<0.001), while the maximum potentiation caused by IVM and MOX relative to GABA alone was 413.7±66.1 and 257.4±40.6%, respectively (p<0.05), showing that IVM causes a greater potentiation of GABA action on this receptor. Differences in the accumulation of IVM and MOX in the brain and in the interaction of IVM and MOX with GABA(A) receptors account for differences in neurotoxicity seen in intact and Mdr1-deficient animals. These differences in neurotoxicity of IVM and MOX are important in considering their use in humans. PMID:23133688

  4. Acute hemodialysis effects on doppler echocardiographic indices.

    PubMed

    Abid, Leila; Rekik, Hajer; Jarraya, Fayçal; Kharrat, Ilyes; Hachicha, Jamil; Kammoun, Samir

    2014-07-01

    Conventional echocardiographic (ECHO) parameters of systolic and diastolic function of the left ventricular (LV) have been shown to be load dependent. However, the impact of pre-load reduction on tissue Doppler (TD) parameters of LV function is incompletely understood. To evaluate the effect of a single hemodialysis (HD) session on LV systolic and diastolic function using pulsed Doppler echocardiography and pulsed tissue Doppler imaging (TDI), we studied 81 chronic HD patients (40 males; mean age 52.4 ± 16.4 years) with these tools. ECHO parameters were obtained 30 min before and 30 min after HD. Fluid volume removed by HD was 1640 ± 730 cm³. HD led to reduction in LV end-diastolic volume (P <0.001), end-systolic volume (P <0.001), left atrium area (P <0.001), peak early (E-wave) trans-mitral flow velocity (P <0.001), the ratio of early to late Doppler velocities of diastolic mitral inflow (P <0.001) and aortic time velocity integral (P <0.001). No significant change in peak S velocity of pulmonary vein flow after HD was noted. Early and late diastolic (E') TDI velocities and the ratio of early to late TDI diastolic velocities (E'/A') on the lateral side of the mitral annulus decreased significantly after HD (P = 0.013; P = 0.007 and P = 0.008, respectively). Velocity of flow progression (Vp) during diastole was not affected by pre-load reduction. Pulmonary artery systolic pressure and the diameter of the inferior vena cava decreased significantly (P <0.001 and P <0.001, respectively) after HD. We conclude that most of the Doppler-derived indices of diastolic function are pre-load-dependent and velocity of flow progression was minimally affected by pre-load reduction in HD patients. PMID:24969184

  5. Resveratrol attenuates hypoxia-induced neurotoxicity through inhibiting microglial activation.

    PubMed

    Zhang, Qun; Yuan, Lin; Zhang, Qingrui; Gao, Yan; Liu, Guangheng; Xiu, Meng; Wei, Xiang; Wang, Zhen; Liu, Dexiang

    2015-09-01

    Resveratrol is a natural polyphenol enriched in Polygonum cuspidatum and has been found to afford neuroprotective effects against neuroinflammation in the brain. Activated microglia can secrete various pro-inflammatory cytokines and neurotoxic mediators, which may contribute to hypoxic brain injuries. The aim of this study is to investigate the potential role of resveratrol in attenuating hypoxia-induced neurotoxicity via its anti-inflammatory actions through in vitro models of the BV-2 microglial cell line and primary microglia. We found that resveratrol significantly inhibited hypoxia-induced microglial activation and reduced subsequent release of pro-inflammatory factors. In addition, resveratrol inhibited the hypoxia-induced degradation of IκB-alpha and phosphorylation of p65 NF-κB protein. Hypoxia-induced ERK1/2 and JNK phosphorylation was also strongly inhibited by resveratrol, whereas resveratrol had no effect on hypoxia-stimulated p38 MAPK phosphorylation. Importantly, treating primary cortical neurons with conditioned medium (CM) from hypoxia-stimulated microglia induced neuronal apoptosis, which was reversed by CM co-treated with resveratrol. Taken together, resveratrol exerts neuroprotection against hypoxia-induced neurotoxicity through its anti-inflammatory effects in microglia. These effects were mediated, at least in part, by suppressing the activation of NF-ĸB, ERK and JNK MAPK signaling pathways. PMID:26225925

  6. Synergistic neurotoxicity induced by methylmercury and quercetin in mice

    PubMed Central

    Martins, Roberta de P.; Braga, Hugo de C.; da Silva, Aline P.; Dalmarco, Juliana B.; de Bem, Andreza F.; dos Santos, Adair Roberto S.; Dafre, Alcir L.; Pizzolatti, Moacir G.; Latini, Alexandra; Aschner, Michael; Farina, Marcelo

    2010-01-01

    Methylmercury (MeHg) is a highly neurotoxic pollutant, whose mechanisms of toxicity are related to its pro-oxidative properties. A previous report showed under in vivo conditions the neuroprotective effects of plants of the genus Polygala against MeHg-induced neurotoxicity. Moreover, the flavonoid quercetin, isolated from Polygala sabulosa, displayed beneficial effects against MeHg-induced oxidative damage under in vitro conditions. In this study, we sought for potential beneficial effects of quercetin against the neurotoxicity induced by MeHg in Swiss female mice. Animals were divided into six experimental groups: control, quercetin low dose (5 mg/Kg), quercetin high dose (50 mg/Kg), MeHg (40 mg/L, in tap water), MeHg + quercetin low dose, and MeHg + quercetin high dose. After the treatment (21 days), a significant motor deficit was observed in MeHg + quercetin groups. Biochemical parameters related to oxidative stress showed that the simultaneous treatment with quercetin and MeHg caused a higher cerebellar oxidative damage when compared to the individual exposures. MeHg plus quercetin elicited a higher cerebellar lipid peroxidation than MeHg or quercetin alone. The present results indicate that under in vivo conditions quercetin and MeHg cause additive pro-oxidative effects toward the mice cerebellum and that such phenomenon is associated with the observed motor deficit. PMID:19141311

  7. Neurotoxicity and Mode of Action of N, N-Diethyl-Meta-Toluamide (DEET)

    PubMed Central

    Swale, Daniel R.; Sun, Baonan; Tong, Fan; Bloomquist, Jeffrey R.

    2014-01-01

    Recent studies suggest that N, N-diethyl-meta-toluamide (DEET) is an acetylcholinesterase inhibitor and that this action may result in neurotoxicity and pose a risk to humans from its use as an insect repellent. We investigated the mode of action of DEET neurotoxicity in order to define the specific neuronal targets related to its acute toxicity in insects and mammals. Although toxic to mosquitoes (LD50 ca. 1.5 µg/mg), DEET was a poor acetylcholinesterase inhibitor (<10% inhibition), even at a concentration of 10 mM. IC50 values for DEET against Drosophila melanogaster, Musca domestica, and human acetylcholinesterases were 6–12 mM. Neurophysiological recordings showed that DEET had excitatory effects on the housefly larval central nervous system (EC50: 120 µM), but was over 300-fold less potent than propoxur, a standard anticholinesterase insecticide. Phentolamine, an octopamine receptor antagonist, completely blocked the central neuroexcitation by DEET and octopamine, but was essentially ineffective against hyperexcitation by propoxur and 4-aminopyridine, a potassium channel blocker. DEET was found to illuminate the firefly light organ, a tissue utilizing octopamine as the principal neurotransmitter. Additionally, DEET was shown to increase internal free calcium via the octopamine receptors of Sf21 cells, an effect blocked by phentolamine. DEET also blocked Na+ and K+ channels in patch clamped rat cortical neurons, with IC50 values in the micromolar range. These findings suggest DEET is likely targeting octopaminergic synapses to induce neuroexcitation and toxicity in insects, while acetylcholinesterase in both insects and mammals has low (mM) sensitivity to DEET. The ion channel blocking action of DEET in neurons may contribute to the numbness experienced after inadvertent application to the lips or mouth of humans. PMID:25101788

  8. Bilirubin Neurotoxicity in Preterm Infants: Risk and Prevention

    PubMed Central

    Bhutani, Vinod K.; Wong, Ronald J.

    2013-01-01

    Hemolytic conditions in preterm neonates, including Rhesus (Rh) disease, can lead to mortality and long-term impairments due to bilirubin neurotoxicity. Universal access to Rh immunoprophylaxis, coordinated perinatal-neonatal care, and effective phototherapy has virtually eliminated the risk of kernicterus in many countries. In the absence of jaundice due to isoimmunization and without access to phototherapy or exchange transfusion (in 1955), kernicterus was reported at 10.1%, 5.5%, and 1.2% in babies <30, 31-32, and 33-34 wks gestational age, respectively. Phototherapy initiated at 24±12 hr effectively prevented hyperbilirubinemia in infants <2,000 g even in the presence of hemolysis. This approach (in 1985) reduced exchange transfusions from 23.9% to 4.8%. Now with 3 decades of experience in implementing effective phototherapy, the need for exchange transfusions has virtually been eliminated. However, bilirubin neurotoxicity continues to be associated with prematurity alone. The ability to better predict this risk, other than birthweight and gestation, has been elusive. Objective tests such as total bilirubin, unbound or free bilirubin, albumin levels, and albumin-bilirubin binding, together with observations of concurrent hemolysis, sepsis, and rapid rate of bilirubin rise have been considered, but their individual or combined predictive utility has yet to be refined. The disruptive effects of immaturity, concurrent neonatal disease, cholestasis, use of total parenteral nutrition or drugs that alter bilirubin-binding abilities augment the clinical risk of neurotoxicity. Current management options rely on the “fine-tuning” of each infant's exposure to beneficial antioxidants and avoidance of silent neurotoxic properties of bilirubin navigated within the safe spectrum of operational thresholds demarcated by experts. PMID:24049745

  9. REINFORCEMENT ENHANCING EFFECTS OF ACUTE NICOTINE VIA ELECTRONIC CIGARETTES

    PubMed Central

    Perkins, Kenneth A.; Karelitz, Joshua L.; Michael, Valerie C.

    2015-01-01

    Background Recent human studies confirm animal research showing that nicotine enhances reinforcement from rewards unrelated to nicotine. These effects of acute nicotine via tobacco smoking may also occur when consumed from non-tobacco products. Methods We assessed acute effects of nicotine via electronic cigarettes (“e-cigarettes”) on responding reinforced by music, video, or monetary rewards, or for no reward (control). In a fully within-subjects design, adult dependent smokers (N=28) participated in three similar experimental sessions, each following overnight abstinence (verified by CO≤10 ppm). Varying only in e-cigarette condition, sessions involved controlled exposure to a nicotine (labeled “36 mg/ml”) or placebo (“0”) e-cigarette, or no e-cigarette use. A fourth session involved smoking one’s own tobacco cigarette brand after no abstinence, specifically to compare responses under typical nicotine satiation with these acute e-cigarette conditions after abstinence. Results Reinforced responding for video reward, but not the other rewards, was greater due to use of the nicotine versus placebo e-cigarette (i.e., nicotine per se), while no differences were found between the placebo e-cigarette and no e-cigarette conditions (i.e., e-cigarette use per se). For nicotine via tobacco smoking, responding compared to the nicotine e-cigarette was similar for video but greater for music, while both video and music reward were enhanced relative to the non-nicotine conditions (placebo and no e-cigarette). Conclusions Acute nicotine from a non-tobacco product has some reinforcement enhancing effects in humans, in a manner partly consistent with nicotine via tobacco smoking and perhaps contributing to the rising popularity of nicotine e-cigarette use. PMID:26070455

  10. Evaluation of Cisplatin Neurotoxicity in Cultured Rat Dorsal Root Ganglia via Cytosolic Calcium Accumulation

    PubMed Central

    Erol, Kevser; Yiğitaslan, Semra; Ünel, Çiğdem; Kaygısız, Bilgin; Yıldırım, Engin

    2016-01-01

    Background: Calcium homeostasis is considered to be important in antineoplastic as well as in neurotoxic adverse effects of cisplatin. Aims: This study aimed to investigate the role of Ca2+ in cisplatin neurotoxicity in cultured rat dorsal root ganglia (DRG) cells. Study Design: Cell culture study. Methods: DRG cells prepared from 1-day old Sprague-Dawley rats were used to determine the role of Ca2+ in the cisplatin (10–600 μM) neurotoxicity. The cells were incubated with cisplatin plus nimodipine (1–3 μM), dizocilpine (MK-801) (1–3 μM) or thapsigargin (100–300 nM). Toxicity of cisplatinon DRG cells was determined by the MTT assay. Results: The neurotoxicity of cisplatin was significant when used in high concentrations (100–600 μM). Nimodipine (1 μM) but not MK-801 or thapsigargin prevented the neurotoxic effects of 200 μM of cisplatin. Conclusion: Voltage-dependent calcium channels may play a role in cisplatin neurotoxicity. PMID:27403382

  11. Neurotoxic Effect of Benzo[a]pyrene and Its Possible Association with 6-Hydroxydopamine Induced Neurobehavioral Changes during Early Adolescence Period in Rats

    PubMed Central

    Das, Saroj Kumar; Patel, Bhupesh

    2016-01-01

    Exposure to persistent genotoxicants like benzo[a]pyrene (B[a]P) during postnatal days causes neurobehavioral changes in animal models. However, neurotoxic potential of B[a]P and its association with 6-hydroxydopamine (6-OHDA) induced neurobehavioral changes are yet to be explored. The growth of rat brain peaks at the first week of birth and continues up to one month with the attainment of adolescence. Hence, the present study was conducted on male Wistar rats at postnatal day 5 (PND 5) following single intracisternal administration of B[a]P to compare with neurobehavioral and neurotransmitter changes induced by 6-OHDA at PND 30. Spontaneous motor activity was significantly increased by 6-OHDA showing similar trend following B[a]P administration. Total distance travelled in novel open field arena and elevated plus maze was significantly increased following B[a]P and 6-OHDA administration. Neurotransmitter estimation showed significant alleviation of dopamine in striatum following B[a]P and 6-OHDA administration. Histopathological studies of striatum by hematoxylin and eosin (H&E) staining revealed the neurodegenerative potential of B[a]P and 6-OHDA. Our results indicate that B[a]P-induced spontaneous motor hyperactivity in rats showed symptomatic similarities with 6-OHDA. In conclusion, early postnatal exposure to B[a]P in rats causing neurobehavioral changes may lead to serious neurodegenerative consequences during adolescence. PMID:27034665

  12. Alternatively Spliced Methionine Synthase in SH-SY5Y Neuroblastoma Cells: Cobalamin and GSH Dependence and Inhibitory Effects of Neurotoxic Metals and Thimerosal.

    PubMed

    Waly, Mostafa; Power-Charnitsky, Verna-Ann; Hodgson, Nathaniel; Sharma, Alok; Audhya, Tapan; Zhang, Yiting; Deth, Richard

    2016-01-01

    The folate and cobalamin (Cbl-) dependent enzyme methionine synthase (MS) is highly sensitive to oxidation and its activity affects all methylation reactions. Recent studies have revealed alternative splicing of MS mRNA in human brain and patient-derived fibroblasts. Here we show that MS mRNA in SH-SY5Y human neuroblastoma cells is alternatively spliced, resulting in three primary protein species, thus providing a useful model to examine cofactor dependence of these variant enzymes. MS activity was dependent upon methylcobalamin (MeCbl) or the combination of hydroxocobalamin (OHCbl) and S-adenosylmethionine (SAM). OHCbl-based activity was eliminated by depletion of the antioxidant glutathione (GSH) but could be rescued by provision of either glutathionylcobalamin (GSCbl) or MeCbl. Pretreatment of cells with lead, arsenic, aluminum, mercury, or the ethylmercury-containing preservative thimerosal lowered GSH levels and inhibited MS activity in association with decreased uptake of cysteine, which is rate-limiting for GSH synthesis. Thimerosal treatment decreased cellular levels of GSCbl and MeCbl. These findings indicate that the alternatively spliced form of MS expressed in SH-SY5Y human neuronal cells is sensitive to inhibition by thimerosal and neurotoxic metals, and lower GSH levels contribute to their inhibitory action. PMID:26989453

  13. Alternatively Spliced Methionine Synthase in SH-SY5Y Neuroblastoma Cells: Cobalamin and GSH Dependence and Inhibitory Effects of Neurotoxic Metals and Thimerosal

    PubMed Central

    Power-Charnitsky, Verna-Ann; Sharma, Alok; Audhya, Tapan; Zhang, Yiting

    2016-01-01

    The folate and cobalamin (Cbl-) dependent enzyme methionine synthase (MS) is highly sensitive to oxidation and its activity affects all methylation reactions. Recent studies have revealed alternative splicing of MS mRNA in human brain and patient-derived fibroblasts. Here we show that MS mRNA in SH-SY5Y human neuroblastoma cells is alternatively spliced, resulting in three primary protein species, thus providing a useful model to examine cofactor dependence of these variant enzymes. MS activity was dependent upon methylcobalamin (MeCbl) or the combination of hydroxocobalamin (OHCbl) and S-adenosylmethionine (SAM). OHCbl-based activity was eliminated by depletion of the antioxidant glutathione (GSH) but could be rescued by provision of either glutathionylcobalamin (GSCbl) or MeCbl. Pretreatment of cells with lead, arsenic, aluminum, mercury, or the ethylmercury-containing preservative thimerosal lowered GSH levels and inhibited MS activity in association with decreased uptake of cysteine, which is rate-limiting for GSH synthesis. Thimerosal treatment decreased cellular levels of GSCbl and MeCbl. These findings indicate that the alternatively spliced form of MS expressed in SH-SY5Y human neuronal cells is sensitive to inhibition by thimerosal and neurotoxic metals, and lower GSH levels contribute to their inhibitory action. PMID:26989453

  14. Peripheral Ammonia as a Mediator of Methamphetamine Neurotoxicity

    PubMed Central

    Halpin, Laura E.; Yamamoto, Bryan K.

    2012-01-01

    Ammonia is metabolized by the liver and has established neurological effects. The current study examined the possibility that ammonia contributes to the neurotoxic effects of methamphetamine (METH). The results show that a binge dosing regimen of METH to the rat increased plasma and brain ammonia concentrations that were paralleled by evidence of hepatotoxicity. The role of peripheral ammonia in the neurotoxic effects of METH was further substantiated by the demonstration that the enhancement of peripheral ammonia excretion blocked the increases in brain and plasma ammonia and attenuated the long term depletions of dopamine and serotonin typically produced by METH. Conversely, the localized perfusion of ammonia in combination with METH, but not METH alone or ammonia alone, into the striatum recapitulated the neuronal damage produced by the systemic administration of METH. Furthermore, this damage produced by the local administration of ammonia and METH was blocked by the GYKI 52466, an AMPA receptor antagonist. These findings highlight the importance of ammonia derived from the periphery as a small molecule mediator of METH neurotoxicity and more broadly emphasize the importance of peripheral organ damage as a possible mechanism that mediates the neuropathology produced by drugs of abuse and other neuroactive molecules. PMID:22993432

  15. Specific effects of acute moderate exercise on cognitive control.

    PubMed

    Davranche, Karen; McMorris, Terry

    2009-04-01

    The main issue of this study was to determine whether cognitive control is affected by acute moderate exercise. Twelve participants [4 females (VO(2 max)=42 ml/kg/min) and 8 males (VO(2 max) = 48 ml/kg/min)] performed a Simon task while cycling at a carefully controlled workload intensity corresponding to their individual ventilatory threshold. The distribution-analytical technique and the delta plot analysis [Ridderinkhof, K. R. (2002). Activation and suppression in conflict tasks: Empirical clarification through distributional analyses. In W. Prinz & B. Hommel (Eds.), Common mechanisms in perception and action. Attention and performance (Vol. 19, pp. 494-519). Oxford: Oxford University Press.] were used to assess the role of selective response inhibition in resolving response conflict. Results showed that cognitive processes appeared to be differently affected by acute moderate exercise. Reaction time results confirmed that performance is better (faster without change in accuracy) when the cognitive task is performed simultaneously with exercise. Between-trial adjustments (post-conflict and post-error) highlighted that cognitive control adjustments are also fully efficient during exercise. However, the effect of congruency (Simon effect) appeared to be more pronounced during exercise compared to rest which suggests that the response inhibition is deteriorated during exercise. The present findings suggest that acute moderate exercise differently affects some specific aspects of cognitive functions. PMID:19138814

  16. The double-edged sword: Neurotoxicity of chemotherapy.

    PubMed

    Magge, Rajiv S; DeAngelis, Lisa M

    2015-03-01

    The number of available therapies for hematologic malignancies continues to grow at a rapid pace. Unfortunately, many of these treatments carry both central and peripheral nervous system toxicities, potentially limiting a patient's ability to tolerate a full course of treatment. Neurotoxicity with chemotherapy is common and second only to myelosuppression as a reason to limit dosing. This review addresses the neurotoxicity of newly available therapeutic agents including brentuximab vedotin and blinatumomab as well as classic ones such as methotrexate, vinca alkaloids and platinums. Although peripheral neuropathy is common with many drugs, other complications such as seizures and encephalopathy may require more immediate attention. Rapid recognition of adverse neurologic effects may lead to earlier treatment and appropriate adjustment of dosing regimens. In addition, knowledge of common toxicities may help differentiate chemotherapy-related symptoms from actual progression of cancer into the CNS. PMID:25445718

  17. Effect and Safety of Rosuvastatin in Acute Ischemic Stroke

    PubMed Central

    Heo, Ji Hoe; Song, Dongbeom; Nam, Hyo Suk; Kim, Eung Yeop; Kim, Young Dae; Lee, Kyung-Yul; Lee, Ki-Jeong; Yoo, Joonsang; Kim, Youn Nam; Lee, Byung Chul; Yoon, Byung-Woo; Kim, Jong S.

    2016-01-01

    Background and Purpose The benefit of statins in acute stroke remains uncertain. Statins may prevent stroke recurrence during the acute stage of stroke via pleiotropic effects. However, statins may increase the risk of intracerebral hemorrhage. We investigated the effect and safety of rosuvastatin in acute stroke patients. Methods This randomized, double-blind, multi-center trial compared rosuvastatin 20 mg and placebo in statin-naïve stroke patients who underwent diffusion-weighted imaging (DWI) within 48 hours after symptom onset. The primary outcome was occurrence of new ischemic lesions on DWI at 5 or 14 days. Results This trial was stopped early after randomization of 316 patients due to slow enrollment. Among 289 patients with at least one follow-up imaging, the frequency of new ischemic lesions on DWI was not different between groups (rosuvastatin: 27/137, 19.7% vs. placebo: 36/152, 23.6%) (relative risk 0.83, 95% confidence interval 0.53–1.30). Infarct volume growth at 5 days (log-transformed volume change, rosuvastatin: 0.2±1.0 mm3 vs. placebo: 0.3±1.3 mm3; P=0.784) was not different, either. However, hemorrhagic infarction or parenchymal/subarachnoid hemorrhage on gradient-recalled echo magnetic resonance imaging occurred less frequently in the rosuvastatin group (6/137, 4.4%) than the placebo group (22/152, 14.5%, P=0.007). Among 314 patients with at least one dose of study medication, progression or clinical recurrence of stroke tended to occur less frequently in the rosuvastatin group (1/155, 0.6% vs. 7/159, 4.4%, P=0.067). Adverse events did not differ between groups. Conclusions The efficacy of rosuvastatin in reducing recurrence in acute stroke was inconclusive. However, statin use was safe and reduced hemorrhagic transformation. PMID:26846760

  18. Effects of acute oligohydramnios on respiratory system of fetal sheep.

    PubMed

    Savich, R D; Guerra, F A; Lee, C C; Padbury, J F; Kitterman, J A

    1992-08-01

    Prolonged oligohydramnios, or a lack of amniotic fluid, is associated with pulmonary hypoplasia and subsequent perinatal morbidity, but it is unclear whether short-term or acute oligohydramnios has any effect on the fetal respiratory system. To investigate the acute effects of removal of amniotic fluid, we studied nine chronically catheterized fetal sheep at 122-127 days gestation. During a control period, we measured the volume of fluid in the fetal potential airways and air spaces (VL), production rate of that fluid, incidence and amplitude of fetal breathing movements, tracheal pressures, and fetal plasma concentrations of cortisol, epinephrine, and norepinephrine. We then drained the amniotic fluid for a short period of time [24-48 h, 30.0 +/- 4.0 (SE) h] and repeated the above measurements. The volume of fluid drained for the initial studies was 1,004 +/- 236 ml. Acute oligohydramnios decreased VL from 35.4 +/- 2.9 ml/kg during control to 22.0 +/- 1.6 after oligohydramnios (P less than 0.004). Acute oligohydramnios did not affect the fetal lung fluid production rate, fetal breathing movements, or any of the other measured variables. Seven repeat studies were performed in six of the fetuses after reaccumulation of the amniotic fluid at 130-138 days, and in four of these studies the lung volume also decreased, although the overall mean for the repeat studies was not significantly different (27.0 +/- 5.2 ml/kg for control vs. 25.5 +/- 5.5 ml/kg for oligohydramnios). Again, none of the other measured variables were altered by oligohydramnios in the repeat studies.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:1399988

  19. Translating neurobehavioural endpoints of developmental neurotoxicity tests into in vitro assays and readouts

    PubMed Central

    van Thriel, Christoph; Westerink, Remco; Beste, Christian; Bale, Ambuja S.; Lein, Pamela J.; Leist, Marcel

    2011-01-01

    The developing nervous system is particularly vulnerable to chemical insults. Exposure to chemicals can results in neurobehavioural alterations, and these have been be used as sensitive readouts to assess neurotoxicity in animals and man. Deconstructing neurobehaviour into relevant cellular and molecular components may allow for detection of specific neurotoxic effects in cell-based systems, which in turn may allow an easier examination of neurotoxic pathways and modes of actions and eventually inform the regulatory assessment of chemicals with potential developmental neurotoxicity. Here, current developments towards these goals are reviewed. Imaging genetics (CB) provides new insights into the neurobiological correlates of cognitive function that are being used to delineate neurotoxic mechanisms. The gaps between in vivo neurobehaviour and real-time in vitro measurements of neuronal function are being bridged by ex vivo measurements of synaptic plasticity (RW). An example of solvent neurotoxicity demonstrates how an in vivo neurological defect can be linked via the N-methyl-D-aspartate (NMDA)-glutamate receptor as a common target to in vitro readouts (AB). Axonal and dendritic morphology in vitro proved to be good correlates of neuronal connectivity and neurobehaviour in animals exposed to polychlorinated biphenyls and organophosphorus pesticides (PJL). Similarly, chemically-induced changes in neuronal morphology affected the formation of neuronal networks on structured surfaces. Such network formation may become an important readout for developmental neurotoxicity in vitro (CvT), especially when combined with human neurons derived from embryonic stem cells (ML). We envision that future in vitro test systems for developmental neurotoxicity will combine the above approaches with exposure information, and we suggest a strategy for test system development and cell-based risk assessment. PMID:22008243

  20. Functional Rehabilitation of Cadmium-Induced Neurotoxicity Despite Persistent Peripheral Pathophysiology in the Olfactory System

    PubMed Central

    Czarnecki, Lindsey A.; Moberly, Andrew H.; Turkel, Daniel J.; Rubinstein, Tom; Pottackal, Joseph; Rosenthal, Michelle C.; McCandlish, Elizabeth F. K.; Buckley, Brian; McGann, John P.

    2012-01-01

    Intranasal exposure to the heavy metal cadmium has been linked to olfactory dysfunction and neurotoxicity. Here, we combine optical imaging of in vivo neurophysiology, genetically defined anatomical tract tracing, mass spectrometry, and behavioral psychophysical methods to evaluate the persistent harmful effects of acute intranasal exposure to cadmium in a mouse model and to investigate the functional consequences of sensory rehabilitation training. We find that an acute intranasal instillation of cadmium chloride leads to an accumulation of cadmium in the brain's olfactory bulb that persists for at least 4 weeks. This is accompanied by persistent severe pathophysiology of the olfactory nerve, a gradual reduction in axonal projections from the olfactory epithelium, and complete impairment on an olfactory detection task. Remarkably, 2 weeks of odorant-guided operant conditioning training proved sufficient to restore olfactory detection performance to control levels in cadmium-exposed mice. Optical imaging from rehabilitated mice showed that this training did not cause any detectable restoration of olfactory nerve function, suggesting that the recovery of function was mediated by central neuroplasticity in which the brain learned to interpret the degraded sensory input. These data demonstrate that sensory learning can mask even severe damage from neurotoxicants and suggest that explicit sensory training may be useful in rehabilitation of olfactory dysfunction. PMID:22287023

  1. Acute effect of ascorbic acid on fibrinolytic activity.

    PubMed

    Bordia, A; Paliwal, D K; Jain, K; Kothari, L K

    1978-08-01

    The acute effect of 1 g oral ascorbic acid on serum fibrinolytic activity was studied in 40 adult males. In Group I (healthy adults) administration of ascorbic acid raised the serum level by about 71%, while the fibrinolytic activity increased to a peak of 137% at 6 h. In patients with CAD (Group II) an essentially similar increase in FA was observed. In Group III, simultaneous administration of ascorbic acid with 100 g fat effectively prevented a fall in fibrinolytic activity and actually raised it by 64% above the fasting level. PMID:568476

  2. Homocysteine excess: delineating the possible mechanism of neurotoxicity and depression.

    PubMed

    Bhatia, Pankaj; Singh, Nirmal

    2015-12-01

    Homocysteine (Hcy) is a nonproteogenic sulfur containing amino acid derived from dietary methionine through demethylation. Homocysteine can be re-methylated to methionine [precursor of S-adenosylmethionine (SAM)] via the re-methylation or 5-methyltetrahydrofolate pathway or undergoes transsulfuration to form cysteine by the action of metabolic enzymes and cofactors. Impaired metabolism due to genetic alteration in metabolic enzymes (methionine synthase, methyltetrahydrofolate reductase (MTHFR), cystathionine β-synthase (CβS), and cystathionine-γ-lyase (CγL) or deficiency in cofactors (vitamin B6 , B12 , folate) may lead to acquired metabolic anomaly known as hyperhomocysteinemia. Hcy excess decreases the S-adenosylmethionine (SAM)-dependent synthesis of catecholamines, viz. dopamine, norepinephrine, epinephrine, and noncatecholamine, viz. serotonin (5-HT), due to genetic alteration in key enzyme MTHFR in the homocysteine metabolism pathway that leads to depression. Thus, hyperhomocysteinemia (HHcy)-induced SAM level is influenced by the single nucleotide polymorphism (SNP) MTHFR C677T. Furthermore, HHcy leads to production of precarious neurotoxic product homocysteic acid (HCA) and cysteine sulfinic acid (CSA) which acts as an N-methyl-D-aspartate (NMDA) receptor agonist and has neurotoxic effects on dopaminergic neurons. In the current review, an attempt has been made to discuss the neurotoxic effects of HHcy in the pathogenesis of depression. PMID:26376956

  3. Neurotoxic catecholamine metabolite in nociceptors contributes to painful peripheral neuropathy.

    PubMed

    Dina, Olayinka A; Khasar, Sachia G; Alessandri-Haber, Nicole; Bogen, Oliver; Chen, Xiaojie; Green, Paul G; Reichling, David B; Messing, Robert O; Levine, Jon D

    2008-09-01

    The neurotoxic effects of catecholamine metabolites have been implicated in neurodegenerative diseases. As some sensory neurons express tyrosine hydroxylase and monoamine oxidase (MAO), we investigated the potential contribution of catecholamine metabolites to neuropathic pain in a model of alcoholic neuropathy. The presence of catecholamines in sensory neurons is supported by capsaicin-stimulated epinephrine release, an effect enhanced in ethanol-fed rats. mRNA for enzymes in dorsal root ganglia involved in catecholamine uptake and metabolism, dopamine beta-hydroxylase and MAO-A, were decreased by neonatal administration of capsaicin. Ethanol-induced hyperalgesia was attenuated by systemic and local peripheral administration of inhibitors of MAO-A, reduction of norepinephrine transporter (NET) in sensory neurons and a NET inhibitor. Finally, intradermal injection of 3,4-dihydroxyphenylglycolaldehyde (DOPEGAL), a neurotoxic MAO-A catecholamine metabolite, produced robust mechanical hyperalgesia. These observations suggest that catecholamines in nociceptors are metabolized to neurotoxic products by MAO-A, which can cause neuronal dysfunction underlying neuropathic pain. PMID:18783367

  4. Phytochemicals Mediated Remediation of Neurotoxicity Induced by Heavy Metals

    PubMed Central

    Gupta, Vivek Kumar; Singh, Shweta; Agrawal, Anju; Siddiqi, Nikhat Jamal; Sharma, Bechan

    2015-01-01

    Almost all the environmental components including both the abiotic and biotic factors have been consistently threatened by excessive contamination of heavy metals continuously released from various sources. Different heavy metals have been reported to generate adverse effects in many ways. Heavy metals induced neurotoxicity and impairment in signalling cascade leading to cell death (apoptosis) has been indicated by several workers. On one hand, these metals are required by the cellular systems to regulate various biological functions of normal cells, while on the other their biomagnification in the cellular systems produces adverse effects. The mechanism by which the heavy metals induce neurotoxicity follows free radicals production pathway(s) specially the generation of reactive oxygen species and reactive nitrogen species. These free radicals produced in excess have been shown to create an imbalance between the oxidative and antioxidative systems leading to emergence of oxidative stress, which may cause necrosis, DNA damage, and many neurodegenerative disorders. This mini review summarizes the current knowledge available on the protective role of varied natural products isolated from different herbs/plants in imparting protection against heavy metals (cadmium, lead, arsenic, and mercury) mediated neurotoxicity. PMID:26618004

  5. Phytochemicals Mediated Remediation of Neurotoxicity Induced by Heavy Metals.

    PubMed

    Gupta, Vivek Kumar; Singh, Shweta; Agrawal, Anju; Siddiqi, Nikhat Jamal; Sharma, Bechan

    2015-01-01

    Almost all the environmental components including both the abiotic and biotic factors have been consistently threatened by excessive contamination of heavy metals continuously released from various sources. Different heavy metals have been reported to generate adverse effects in many ways. Heavy metals induced neurotoxicity and impairment in signalling cascade leading to cell death (apoptosis) has been indicated by several workers. On one hand, these metals are required by the cellular systems to regulate various biological functions of normal cells, while on the other their biomagnification in the cellular systems produces adverse effects. The mechanism by which the heavy metals induce neurotoxicity follows free radicals production pathway(s) specially the generation of reactive oxygen species and reactive nitrogen species. These free radicals produced in excess have been shown to create an imbalance between the oxidative and antioxidative systems leading to emergence of oxidative stress, which may cause necrosis, DNA damage, and many neurodegenerative disorders. This mini review summarizes the current knowledge available on the protective role of varied natural products isolated from different herbs/plants in imparting protection against heavy metals (cadmium, lead, arsenic, and mercury) mediated neurotoxicity. PMID:26618004

  6. Drug-induced neurotoxicity in addiction medicine: From prevention to harm reduction.

    PubMed

    Mohammad Ahmadi Soleimani, S; Ekhtiari, Hamed; Cadet, Jean Lud

    2016-01-01

    Neurotoxicity is considered as a major cause of neurodegenerative disorders. Most drugs of abuse have nonnegligible neurotoxic effects many of which are primarily mediated by several dopaminergic and glutamatergic neurotransmitter systems. Although many researchers have investigated the medical and cognitive consequences of drug abuse, the neurotoxicity induced by these drugs still requires comprehensive attention. The science of neurotoxicity promises to improve preventive and therapeutic strategies for brain disorders such as Alzheimer disease and Parkinson's disease. However, its clinical applications for addiction medicine remain to be defined adequately. This chapter reviews the most commonly discussed mechanisms underlying neurotoxicity induced by common drugs of abuse including amphetamines, cocaine, opiates, and alcohol. In addition, the known factors that trigger and/or predispose to drug-induced neurotoxicity are discussed. These factors include drug-related, individual-related, and environmental insults. Moreover, we introduce some of the potential pharmacological antineurotoxic interventions deduced from experimental animal studies. These interventions involve various targets such as dopaminergic system, mitochondria, cell death signaling, and NMDA receptors, among others. We conclude the chapter with a discussion of addicted patients who might benefit from such interventions. PMID:26806769

  7. Evaluation of the antidepressant-like effects of acute and sub-acute administration of crocin and crocetin in mice

    PubMed Central

    Amin, Bahareh; Nakhsaz, Alireza; Hosseinzadeh, Hossein

    2015-01-01

    Objective: The present study was designed to investigate the putative antidepressant effects of crocin and crocetin, two major active ingredients of Crocus sativus L. (saffron) using mice in two different regimens of acute and sub-acute administration. Material and Methods: In acute treatment, antidepressant-like activities of crocin and crocetin (10, 20 and 40 mg/kg, i.p.) were evaluated using forced swim test (FST). In sub-acute study (21 times with 24-h intervals), antidepressant-like effects of oral administration of drugs were examined using FST and tail suspension test (TST). Locomotor activity and motor coordination were studied using open field and rotarod tests, respectively. Results: Acute treatment with crocin (40 mg/kg) and crocetin (20 and 40 mg/kg) produced antidepressant-like effect in FST without affecting the baseline locomotion in mice. Sub-acute oral administration of crocin significantly decreased immobility time only at the highest dose (100 mg/kg). Crocetin (12.5, 25 and 50 mg/kg) was able to decrease immobility time in FST and TST. Locomotor activity and coordination of mice were not affected by crocin or crocetin. Conclusion: Since higher doses of crocin was required to show antidepressant effects, more efficacy of crocetin may be concluded. This observation provides further support for metabolism of crocin to crocetin following oral administration. PMID:26468466

  8. The Portland Neurotoxicity Scale: validation of a brief self-report measure of antiepileptic-drug-related neurotoxicity.

    PubMed

    Salinsky, Martin C; Storzbach, Daniel

    2005-03-01

    The Portland Neurotoxicity Scale (PNS) is a brief patient-based survey of neurotoxicity complaints commonly encountered with the use of antiepileptic drugs (AEDs). The authors present data on the validity of this scale, particularly when used in longitudinal studies. Participants included 55 healthy controls, 23 epilepsy patient controls, and 86 healthy volunteers who took various AEDs or placebos for 12 weeks as part of randomized, double-blind studies of AED effects on cognitive abilities. Test-retest reliability in the control groups averaged .80 (total score). Test-retest changes in the PNS were sensitive to AED usage in general (p < .001) and to each of the five AEDs tested but not to placebo. Test-retest changes in the PNS were strongly correlated with several scales of the Profile of Mood States but only weakly correlated with objective cognitive test measures. The PNS has satisfactory psychometric properties and is sensitive to AED usage in test-retest studies. PMID:15695749

  9. ASSAY OF CHICKEN BRAIN NEUROTOXIC ESTERASE ACTIVITY USING LEPTOPHOSOXON AS THE SELECTIVE NEUROTOXIC INHIBITOR

    EPA Science Inventory

    Hen brain microsomal preparation has phenyl valeratehydrolyzing activity associated with neurotoxic esterase activity. Part of that activity is due to paraoxon-insensitive esterases and a sub-part of this is sensitive to neurotoxic organophosphates, i.e., mipafox and leptophosoxo...

  10. Toxicological dose assessment and acute health effect criteria

    SciTech Connect

    Stalker, A.C.; White, B.

    1992-01-01

    The use of hazardous materials requires the means of assessing doses from postulated accidental exposures to the hazardous materials. Hazardous materials include radiological and toxicological substances. Health effects are often divided into either acute (short term exposure) or chronic (long-term-exposure)-categories. Dose assessments and health effects are used in Hazard Classification, Safety Analysis Reports and Unreviewed Safety Question Determinations. The use of hazardous substances requires a means of assessing the potential health effects from exposure. Two types of toxicological data exist. The first is measured effects from human exposure, either accidentally or studies. The second consists of data from toxicity and lethality studies on mammals, often mice or rats. Because the data for human exposure is severely limited, an approach is needed that uses basic toxicity and lethality data from animal studies to estimate acute health effects in humans. The approach chosen is the one suggested jointly by the EPA, FEMA, and DOT in their Technical Guidance for Hazards Analysis'', December 1987.

  11. Toxicological dose assessment and acute health effect criteria

    SciTech Connect

    Stalker, A.C.; White, B.

    1992-09-01

    The use of hazardous materials requires the means of assessing doses from postulated accidental exposures to the hazardous materials. Hazardous materials include radiological and toxicological substances. Health effects are often divided into either acute (short term exposure) or chronic (long-term-exposure)-categories. Dose assessments and health effects are used in Hazard Classification, Safety Analysis Reports and Unreviewed Safety Question Determinations. The use of hazardous substances requires a means of assessing the potential health effects from exposure. Two types of toxicological data exist. The first is measured effects from human exposure, either accidentally or studies. The second consists of data from toxicity and lethality studies on mammals, often mice or rats. Because the data for human exposure is severely limited, an approach is needed that uses basic toxicity and lethality data from animal studies to estimate acute health effects in humans. The approach chosen is the one suggested jointly by the EPA, FEMA, and DOT in their ``Technical Guidance for Hazards Analysis``, December 1987.

  12. Biomarkers of neurotoxic shellfish poisoning.

    PubMed

    Abraham, Ann; Plakas, Steven M; Flewelling, Leanne J; El Said, Kathleen R; Jester, Edward L E; Granade, Hudson R; White, Kevin D; Dickey, Robert W

    2008-08-01

    Urine specimens from patients diagnosed with neurotoxic shellfish poisoning (NSP) were examined for biomarkers of brevetoxin intoxication. Brevetoxins were concentrated from urine by using solid-phase extraction (SPE), and analyzed by enzyme-linked immunosorbent assay (ELISA) and liquid chromatography-tandem mass spectrometry (LC-MS/MS). Urine extracts were fractionated by LC, and fractions analyzed for brevetoxins by ELISA. In subsequent LC-MS/MS analyses, several brevetoxin metabolites of B-type backbone were identified, with elution profiles consistent with those of ELISA. The more abundant brevetoxin metabolites in urine were characterized structurally by LC-MS/MS. With the exception of BTX-3, brevetoxin metabolites in urine differed from those found in shellfish and in shellfish meal remnants. Proposed structures of these major urinary metabolites are methylsulfoxy BTX-3, 27-epoxy BTX-3, and reduced BTX-B5. BTX-3 was found in all specimens examined. BTX-3 concentrations in urine, as determined by LC-MS/MS, correlated well with composite toxin measurements by ELISA (r(2)=0.96). BTX-3 is a useful biomarker for confirmation of clinical diagnosis of NSP. PMID:18582487

  13. Lithium Protects Against Anaesthesia Neurotoxicity In The Infant Primate Brain

    PubMed Central

    Noguchi, Kevin K.; Johnson, Stephen A.; Kristich, Lauren E.; Martin, Lauren D.; Dissen, Gregory A.; Olsen, Emily A.; Olney, John W.; Brambrink, Ansgar M.

    2016-01-01

    Exposure of infant animals, including non-human primates (NHPs), to anaesthetic drugs causes apoptotic death of neurons and oligodendrocytes (oligos) and results in long-term neurodevelopmental impairment (NDI). Moreover, retrospective clinical studies document an association between anaesthesia exposure of human infants and significant increase in NDI. These findings pose a potentially serious dilemma because millions of human infants are exposed to anaesthetic drugs every year as part of routine medical care. Lithium (Li) at clinically established doses is neuroprotective in various cerebral injury models. We therefore investigated whether Li also protects against anaesthesia neurotoxicity in infant NHPs. On postnatal day 6 NHPs were anaesthetized with the widely used anaesthetic isoflurane (ISO) for 5 h employing the same standards as in a human pediatric surgery setting. Co-administration of Li completely prevented the acute ISO-induced neuroapoptosis and significantly reduced ISO-induced apoptosis of oligodendroglia. Our findings are highly encouraging as they suggest that a relatively simple pharmacological manipulation might protect the developing primate brain against the neurotoxic action of anaesthetic drugs while not interfering with the beneficial actions of these drugs. Further research is needed to determine Li’s potential to prevent long-term NDI resulting from ISO anaesthesia, and to establish its safety in human infants. PMID:26951756

  14. Lithium Protects Against Anaesthesia Neurotoxicity In The Infant Primate Brain.

    PubMed

    Noguchi, Kevin K; Johnson, Stephen A; Kristich, Lauren E; Martin, Lauren D; Dissen, Gregory A; Olsen, Emily A; Olney, John W; Brambrink, Ansgar M

    2016-01-01

    Exposure of infant animals, including non-human primates (NHPs), to anaesthetic drugs causes apoptotic death of neurons and oligodendrocytes (oligos) and results in long-term neurodevelopmental impairment (NDI). Moreover, retrospective clinical studies document an association between anaesthesia exposure of human infants and significant increase in NDI. These findings pose a potentially serious dilemma because millions of human infants are exposed to anaesthetic drugs every year as part of routine medical care. Lithium (Li) at clinically established doses is neuroprotective in various cerebral injury models. We therefore investigated whether Li also protects against anaesthesia neurotoxicity in infant NHPs. On postnatal day 6 NHPs were anaesthetized with the widely used anaesthetic isoflurane (ISO) for 5 h employing the same standards as in a human pediatric surgery setting. Co-administration of Li completely prevented the acute ISO-induced neuroapoptosis and significantly reduced ISO-induced apoptosis of oligodendroglia. Our findings are highly encouraging as they suggest that a relatively simple pharmacological manipulation might protect the developing primate brain against the neurotoxic action of anaesthetic drugs while not interfering with the beneficial actions of these drugs. Further research is needed to determine Li's potential to prevent long-term NDI resulting from ISO anaesthesia, and to establish its safety in human infants. PMID:26951756

  15. A neurotoxic alcohol exposure paradigm does not induce hepatic encephalopathy.

    PubMed

    Hashimoto, Joel G; Wiren, Kristine M; Wilhelm, Clare J

    2016-01-01

    Alcohol abuse is associated with neurological dysfunction, brain morphological deficits and frank neurotoxicity. Although these disruptions may be a secondary effect due to hepatic encephalopathy, no clear evidence of causality is available. This study examined whether a 72h period of alcohol intoxication known to induce physical dependence, followed by a single withdrawal, was sufficient to induce signs of hepatic encephalopathy in male and female mice. Animals were continuously intoxicated via alcohol vapor inhalation, a procedure previously shown to induce significant neurotoxicity in female mice. At peak synchronized withdrawal (8h following the end of alcohol exposure), blood samples were taken and levels of several liver-regulated markers and brain swelling were characterized. Glutathione levels were also determined in the medial frontal cortex (mFC) and hippocampus. Results revealed elevated levels of cholesterol, albumin, alkaline phosphatase (ALP), alanine aminotransferase (ALT) and decreased levels of blood urea nitrogen and total bilirubin in alcohol-exposed male and female groups compared to controls. Brain water weight was not affected by alcohol exposure, though males tended to have slightly more water weight overall. Alcohol exposure led to reductions in tissue levels of glutathione in both the hippocampus and mFC which may indicate increased oxidative stress. Combined, these results suggest that hepatic encephalopathy does not appear to play a significant role in the neurotoxicity observed following alcohol exposure in this model. PMID:27268733

  16. The targets of acetone cyanohydrin neurotoxicity in the rat are not the ones expected in an animal model of konzo.

    PubMed

    Soler-Martín, Carla; Riera, Judith; Seoane, Ana; Cutillas, Blanca; Ambrosio, Santiago; Boadas-Vaello, Pere; Llorens, Jordi

    2010-01-01

    Konzo is a neurotoxic motor disease caused by excess consumption of insufficiently processed cassava. Cassava contains the cyanogenic glucoside linamarin, but konzo does not present the known pathological effects of cyanide. We hypothesized that the aglycone of linamarin, acetone cyanohydrin, may be the cause of konzo. This nitrile rapidly decomposes into cyanide and acetone, but the particular exposure and nutrition conditions involved in the emergence of konzo may favor its stabilization and subsequent acute neurotoxicity. A number of preliminary observations were used to design an experiment to test this hypothesis. In the experiment, young female Long-Evans rats were given 10mM acetone cyanohydrin in drinking water for 2 weeks, and then 20mM for 6 weeks. Nutrition deficits associated with konzo were modeled by providing tapioca (cassava starch) as food for the last 3 of these weeks. After this period, rats were fasted for 24h in order to increase endogenous acetone synthesis, and then exposed to 0 (control group) or 50 micromol/kg-h of acetone cyanohydrin for 24h (treated group) through subcutaneous osmotic minipump infusion (n=6/group). Motor activity and gait were evaluated before exposure (pre-test), and 1 and 6 days after exposure. Brains (n=4) were stained for neuronal degeneration by fluoro-jade B. Rats exposed to 50 micromol/kg-h of acetone cyanohydrin showed acute signs of toxicity, but no persistent motor deficits. Two animals showed fluoro-jade staining in discrete thalamic nuclei, including the paraventricular and the ventral reuniens nuclei; one also exhibited labeling of the dorsal endopiriform nucleus. Similar effects were not elicited by equimolar KCN exposure. Therefore, acetone cyanohydrin may cause selective neuronal degeneration in the rat, but the affected areas are not those expected in an animal model of konzo. PMID:19932169

  17. Acute effects of cigarette smoking on microcirculation of the thumb.

    PubMed

    van Adrichem, L N; Hovius, S E; van Strik, R; van der Meulen, J C

    1992-01-01

    The acute effect of smoking on the microcirculation of the skin of the thumb was investigated in healthy volunteers. Twenty-two were smokers and 10 were non-smokers. The flow was assessed by means of laser Doppler flowmetry. The smokers inhaled 2 cigarettes. During smoking of their first and second cigarette respectively, a mean decrease in laser Doppler flow of 23.8% and 29.0% was seen (p = 0.03; p = 0.01). Ten minutes after smoking this decrease was recovered by half. This experiment confirms that one should prohibit smoking of cigarettes pre- and postoperatively for optimal wound healing conditions. PMID:1737221

  18. Acute interactive motoric effects of permethrin and xylene

    SciTech Connect

    Durnam, M.R.

    1992-01-01

    The potential interactive motoric effects of permethrin (a type I pyrethroid pesticide) and xylene (an aromatic hydrocarbon solvent) were assessed in male CD-I mice following acute exposure. The hypothesis was that these two compounds would interact (the effects would be more than additive) to disrupt motor performance on inverted screen tent performance and/or locomotor activity. The data obtained from this experiment do not support this hypothesis. The results failed to show a significant interaction between the permethrin and xylene on either task, however, the combination of these compounds altered the time course of motoric effects. The peak effect on the inverted screen test occurred earlier for xylene and permethrin than for permethrin alone. The xylene probably increased the rate of absorption of xylene. On locomotor activity, permethrin and xylene when given separately increased activity, however, the highest dose combination of permethrin and xylene produced a strong decrease in activity at all time points.

  19. Acute effects of bright light exposure on cortisol levels.

    PubMed

    Jung, Christopher M; Khalsa, Sat Bir S; Scheer, Frank A J L; Cajochen, Christian; Lockley, Steven W; Czeisler, Charles A; Wright, Kenneth P

    2010-06-01

    Multisynaptic neural and endocrine pathways from the suprachiasmatic nucleus of the hypothalamus have been hypothesized to communicate circadian and photic information to the adrenal glands. In humans, light exposure has been reported to have no effect, increase, or decrease cortisol levels. These inconsistent findings in humans may be related to differences among studies including the intensity (approximately 500 to 5500 lux), duration (15 min to 4 h), and circadian phase of light exposure. The authors assessed the influence of exposure to bright light on cortisol levels in humans during the rising and descending phases of the circadian rhythm of cortisol, that is, when cortisol levels are high. Twenty healthy men and women were studied using a within-subject research design. Subjects were studied in an environment free of time cues for 9 to 10 days. Subjects received a 6.7-h exposure of bright light (approximately 10,000 lux; equivalent to ambient light intensity just after sunrise or just before sunset) or dim light (approximately 3 lux; equivalent to candle light) during the biological night and morning. Bright light exposure significantly reduced plasma cortisol levels at both circadian phases studied, whereas dim light exposure had little effect on cortisol levels. The finding of an acute suppressive effect of bright light exposure on cortisol levels supports the existence of a mechanism by which photic information can acutely influence the human adrenal glands. PMID:20484692

  20. A Case Report of Metronidazole Induced Neurotoxicity in Liver Abscess Patient and the Usefulness of MRI for its Diagnosis

    PubMed Central

    Agarwal, Arjit; Shukla, Arvind; Joon, Pawan

    2016-01-01

    Metronidazole is a very widely used drug for the treatment of multiple ailments caused by anaerobic bacteria as well as some protozoan parasites. Though its usual side effects are not very serious, yet sometimes it may cause profound adverse effects like neurotoxicity. We present here a case of liver abscess. The patient was treated for a long time with metronidazole and developed sudden onset neurotoxicity which was diagnosed by MRI. The present case also highlights the need of vigilant monitoring of patients on metronidazole for symptoms of neurotoxicity and the usefulness of MRI for diagnosis of the same. PMID:26894145

  1. The effects of acute nicotine on contextual safety discrimination.

    PubMed

    Kutlu, Munir G; Oliver, Chicora; Gould, Thomas J

    2014-11-01

    Anxiety disorders, such as post-traumatic stress disorder (PTSD), may be related to an inability to distinguish safe versus threatening environments and to extinguish fear memories. Given the high rate of cigarette smoking in patients with PTSD, as well as the recent finding that an acute dose of nicotine impairs extinction of contextual fear memory, we conducted a series of experiments to investigate the effect of acute nicotine in an animal model of contextual safety discrimination. Following saline or nicotine (at 0.0275, 0.045, 0.09 and 0.18 mg/kg) administration, C57BL/6J mice were trained in a contextual discrimination paradigm, in which the subjects received presentations of conditioned stimuli (CS) that co-terminated with a foot-shock in one context (context A (CXA)) and only CS presentations without foot-shock in a different context (context B (CXB)). Therefore, CXA was designated as the 'dangerous context', whereas CXB was designated as the 'safe context'. Our results suggested that saline-treated animals showed a strong discrimination between dangerous and safe contexts, while acute nicotine dose-dependently impaired contextual safety discrimination (Experiment 1). Furthermore, our results demonstrate that nicotine-induced impairment of contextual safety discrimination learning was not a result of increased generalized freezing (Experiment 2) or contingent on the common CS presentations in both contexts (Experiment 3). Finally, our results show that increasing the temporal gap between CXA and CXB during training abolished the impairing effects of nicotine (Experiment 4). The findings of this study may help link nicotine exposure to the safety learning deficits seen in anxiety disorder and PTSD patients. PMID:25271215

  2. Modulation of benzo[a]pyrene induced neurotoxicity in female mice actively immunized with a B[a]P–diphtheria toxoid conjugate

    SciTech Connect

    Schellenberger, Mario T.; Grova, Nathalie; Farinelle, Sophie; Willième, Stéphanie; Muller, Claude P.

    2013-09-01

    Benzo[a]pyrene (B[a]P) is a small molecular weight carcinogen and the prototype of polycyclic aromatic hydrocarbons (PAHs). While these compounds are primarily known for their carcinogenicity, B[a]P and its metabolites are also neurotoxic for mammalian species. To develop a prophylactic immune strategy against detrimental effects of B[a]P, female Balb/c mice immunized with a B[a]P–diphtheria toxoid (B[a]P–DT) conjugate vaccine were sub-acutely exposed to 2 mg/kg B[a]P and behavioral performances were monitored in tests related to learning and memory, anxiety and motor coordination. mRNA expression of the NMDA receptor (NR1, 2A and 2B subunits) involved in the above behavioral functions was measured in 5 brain regions. B[a]P induced NMDA1 expression in three (hippocampus, amygdala and cerebellum) of five brain regions investigated, and modulated NMDA2 in two of the five brain regions (frontal cortex and cerebellum). Each one of these B[a]P-effects was reversed in mice that were immunized against this PAH, with measurable consequences on behavior such as anxiety, short term learning and memory. Thus active immunization against B[a]P with a B[a]P–DT conjugate vaccine had a protective effect and attenuated the pharmacological and neurotoxic effects even of high concentrations of B[a]P. - Highlights: • B[a]P-antibodies attenuated B[a]P induced NMDA expression in several brain regions. • B[a]P had measurable consequences on anxiety, short term learning and memory. • B[a]P immunization attenuated the pharmacological and neurotoxic effects of B[a]P. • Vaccination may also provide some protection against chemical carcinogenesis.

  3. Special Issue: Environmental Chemicals and Neurotoxicity Oxidative stress in MeHg-induced neurotoxicity

    PubMed Central

    Farina, Marcelo; Aschner, Michael; Rocha, João B. T.

    2011-01-01

    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 been 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

  4. Acute effects of carbon monoxide on cardiac electrical stability

    SciTech Connect

    Verrier, R.L.; Mills, A.K.; Skornik, W.A. )

    1990-10-01

    The objective of this project was to determine the effects of acute carbon monoxide exposure on cardiac electrical stability. To obtain a comprehensive assessment, diverse biological models were employed. These involved cardiac electrical testing in the normal and ischemic heart in anesthetized and conscious dogs. The experimental plan was designed both to examine the direct effects of carbon monoxide exposure on the myocardium and to evaluate possible indirect influences through alterations in platelet aggregability or changes in central nervous system activity in the conscious animal. Our results indicate that exposure to relatively high levels of carbon monoxide, leading to carboxyhemoglobin concentrations of up to 20 percent, is without significant effect on ventricular electrical stability. This appears to be the case in the acutely ischemic heart as well as in the normal heart. It is important to note that the total exposure period was in the range of 90 to 124 minutes. The possibility that longer periods of exposure or exacerbation from nicotine in cigarette smoke could have a deleterious effect cannot be excluded. We also examined whether or not alterations in platelet aggregability due to carbon monoxide exposure could be a predisposing factor for cardiac arrhythmias. A model involving partial coronary artery stenosis was used to simulate the conditions under which platelet plugs could lead to myocardial ischemia and life-threatening arrhythmias. We found no changes either in the cycle frequency of coronary blood flow oscillations or in platelet aggregability during carbon monoxide exposure. Thus, carbon monoxide exposure does not appear to alter platelet aggregability or its effect on coronary blood flow during stenosis. In the final series of experiments, we examined the effects of carbon monoxide exposure in the conscious state.

  5. Neurobehavioral effects of acute styrene exposure in fiberglass boatbuilders

    SciTech Connect

    Letz, R.; Mahoney, F.C.; Hershman, D.L.; Woskie, S.; Smith, T.J. )

    1990-11-01

    A field investigation of the effects of acute exposure to styrene among fiberglass boatbuilders was performed. Personal samples of styrene in breathing zone air and postshift urinary mandelic acid were collected for 105 workers exposed and not exposed to styrene in 6 fiberglass boatbuilding companies in New England. Three tests from the computerized Neurobehavioral Evaluation System (NES) were performed by the subjects in the morning before exposure to styrene, near midday, and at the end of the work day. Duration of exposure averaged 2.9 years (SD = 4.6), 8-hour TWA styrene exposure averaged 29.9 ppm (SD = 36.2), and urinary mandelic acid averaged 347 mg/g creatinine (SD = 465). Regression analyses indicated a statistically significant relationship between postshift performance on the Symbol-Digit test and both acute styrene exposure and mandelic acid. Other analyses comparing workers exposed to less than 50 ppm and greater than 50 ppm styrene also showed a significant effect on Symbol-Digit performance. All three NES tests showed test-retest correlation coefficients above .80, and ease of use for collection of neurobehavioral data under field conditions was demonstrated.

  6. Effects of age on hemorheological responses to acute endurance exercise.

    PubMed

    Ahmadizad, Sajad; Moradi, Akram; Nikookheslat, Saeed; Ebrahimi, Hadi; Rahbaran, Adel; Connes, Philippe

    2011-01-01

    The purpose of this investigation was to examine the effects of age on the acute responses of hemorheological variables and biochemical parameters to a single bout of sub-maximal endurance exercise. Fifteen young (20-30 years), 15 middle-aged (40-50 years) and 12 old (60-70 years) male subjects participated in the study. All subjects performed one single bout of endurance exercise encompassed 30-min cycling at 70-75% of maximal heart rate which was followed by 30-min recovery. Three blood samples were taken before, immediately after exercise and after 30-min recovery. Resting levels of hematocrit, red blood cells count, plasma albumin and fibrinogen concentrations, plasma viscosity and whole blood viscosity were significantly different among the three groups (P < 0.01). Thirty minutes of cycling resulted in significant increases (P < 0.05) in all parameters; while these changes were temporary and returned to pre-exercise level at the end of recovery. Responses of all parameters to exercise and recovery were not significantly different among the three groups (P > 0.05). Fibrinogen changes during exercise and recovery were corrected for exercise- and recovery-induced changes in plasma volume. Data analysis showed effects of exercise and recovery only for raw data (P > 0.05). In addition, raw and corrected fibrinogen data in response to exercise and recovery were not age-related. Our results demonstrate that age does not affect the hemorheological responses to an acute endurance exercise in healthy men. PMID:22214687

  7. Effectiveness of chelation therapy with time after acute uranium intoxication

    SciTech Connect

    Domingo, J.L.; Ortega, A.; Llobet, J.M.; Corbella, J. )

    1990-01-01

    The effect of increasing the time interval between acute uranium exposure and chelation therapy was studied in male Swiss mice. Gallic acid, 4,5-dihydroxy-1,3- benzenedisulfonic acid (Tiron), diethylenetriaminepentaacetic acid (DTPA), and 5-aminosalicylic acid (5-AS) were administered ip at 0, 0.25, 1, 4, and 24 hr after sc injection of 10 mg/kg of uranyl acetate dihydrate. Chelating agents were given at doses equal to one-fourth of their respective LD50 values. Daily elimination of uranium into urine and feces was determined for 4 days after which time the mice were killed, and the concentration of uranium was measured in kidney, spleen, and bone. The excretion of uranium was especially rapid in the first 24 hr. Treatment with Tiron or gallic acid at 0, 0.25, or 1 hr after uranium exposure significantly increased the total excretion of the metal. In kidney and bone, only administration of Tiron at 0, 0.25, or 1 hr after uranium injection, or gallic acid at 1 hr after uranium exposure significantly reduced tissue uranium concentrations. Treatment at later times (4 to 24 hr) did not increase the total excretion of the metal and did not decrease the tissue uranium concentrations 4 days after uranyl acetate administration. The results show that the length of time before initiating chelation therapy for acute uranium intoxication greatly influences the effectiveness of this therapy.

  8. Can Zebrafish be used to Identify Developmentally Neurotoxic Chemicals

    EPA Science Inventory

    Can Zebrafish be Used to Identify Developmentally Neurotoxic Chemicals? The U.S. Environmental Protection Agency is evaluating methods to screen and prioritize large numbers of chemicals for developmental neurotoxicity. We are exploring behavioral methods using zebrafish by desig...

  9. MPA-capped CdTe quantum dots exposure causes neurotoxic effects in nematode Caenorhabditis elegans by affecting the transporters and receptors of glutamate, serotonin and dopamine at the genetic level, or by increasing ROS, or both

    NASA Astrophysics Data System (ADS)

    Wu, Tianshu; He, Keyu; Zhan, Qinglin; Ang, Shengjun; Ying, Jiali; Zhang, Shihan; Zhang, Ting; Xue, Yuying; Tang, Meng

    2015-12-01

    As quantum dots (QDs) are widely used in biomedical applications, the number of studies focusing on their biological properties is increasing. While several studies have attempted to evaluate the toxicity of QDs towards neural cells, the in vivo toxic effects on the nervous system and the molecular mechanisms are unclear. The aim of the present study was to investigate the neurotoxic effects and the underlying mechanisms of water-soluble cadmium telluride (CdTe) QDs capped with 3-mercaptopropionic acid (MPA) in Caenorhabditis elegans (C. elegans). Our results showed that exposure to MPA-capped CdTe QDs induced behavioral defects, including alterations to body bending, head thrashing, pharyngeal pumping and defecation intervals, as well as impaired learning and memory behavior plasticity, based on chemotaxis or thermotaxis, in a dose-, time- and size-dependent manner. Further investigations suggested that MPA-capped CdTe QDs exposure inhibited the transporters and receptors of glutamate, serotonin and dopamine in C. elegans at the genetic level within 24 h, while opposite results were observed after 72 h. Additionally, excessive reactive oxygen species (ROS) generation was observed in the CdTe QD-treated worms, which confirmed the common nanotoxicity mechanism of oxidative stress damage, and might overcome the increased gene expression of neurotransmitter transporters and receptors in C. elegans induced by long-term QD exposure, resulting in more severe behavioral impairments.

  10. Side effects of using nitrates to treat heart failure and the acute coronary syndromes, unstable angina and acute myocardial infarction.

    PubMed

    Thadani, Udho; Ripley, Toni L

    2007-07-01

    Nitrates are potent venous dilators and anti-ischemic agents. They are widely used for the relief of chest pain and pulmonary congestion in patients with acute coronary syndromes and heart failure. Nitrates, however, do not reduce mortality in patients with acute coronary syndromes. Combination of nitrates and hydralazine when given in addition to beta-blockers and angiotensin-converting enzyme (ACE) inhibitors reduce mortality and heart failure hospitalizations in patients with heart failure due to left ventricular systolic dysfunction who are of African-American origin. Side effects during nitrate therapy are common but are less well described in the literature compared with the reported side effects in patients with stable angina pectoris. The reported incidence of side effects varies highly among different studies and among various disease states. Headache is the most commonly reported side effect with an incidence of 12% in acute heart failure, 41-73% in chronic heart failure, 3-19% in unstable angina and 2-26% in acute myocardial infarction. The reported incidence of hypotension also differs: 5-10% in acute heart failure, 20% in chronic heart failure, 9% in unstable angina and < 1-48% in acute myocardial infarction, with the incidence being much higher with concomitant nitrate therapy plus angiotensin-converting enzyme inhibitors. Reported incidence of dizziness is as low as 1% in patients with acute myocardial infarction to as high as 29% in patients with heart failure. Severe headaches and/or symptomatic hypotension may necessitate discontinuation of nitrate therapy. Severe life threatening hypotension or even death may occur when nitrates are used in patients with acute inferior myocardial infarction associated with right ventricular dysfunction or infarction, or with concomitant use of phosphodiesterase-5 inhibitors or N-acetylcysteine. Despite the disturbing observational reports in the literature that continuous and prolonged use of nitrates may lead to

  11. Polymorphisms of the vincristine pathway and response to treatment in children with childhood acute lymphoblastic leukemia

    PubMed Central

    Ceppi, Francesco; Langlois-Pelletier, Chloé; Gagné, Vincent; Rousseau, Julie; Ciolino, Claire; Lorenzo, Samanta De; Kevin, Kojok M; Cijov, Diana; Sallan, Stephen E; Silverman, Lewis B; Neuberg, Donna; Kutok, Jeffery L; Sinnett, Daniel; Laverdière, Caroline; Krajinovic, Maja

    2015-01-01

    Background Vincristine (VCR) is a standard component in the treatment of childhood acute lymphoblastic leukemia (ALL). VCR cytotoxicity is primarily due to its ability to disrupt the formation of microtubules of the mitotic spindle. Patients & methods A total of 17 polymorphisms in regulatory and coding regions of genes controlling VCR targets (TUBB1, MAP4, ACTG1 and CAPG) or potentially influencing VCR levels (ABCB1 and CYP3A5) were investigated for an association with peripheral neuropathy and outcome in childhood ALL patients. Results High-grade neurotoxicity was more frequent in carriers of the A allele of synonymous (Ala310) G to A (rs1135989) variation in the ACTG1 gene. Substitution (rs4728709) in the promoter of the ABCB1 gene had a protective effect against lower grade neurotoxicity and C to A variation (rs3770102) located 17 nucleotides upstream from the transcription start site had a protective effect against high-grade neurotoxicity. Patients with the ABCB1 3435TT genotype had lower event-free survival; the association with event-free survival was not supported by the analysis in the replication patient set. Conclusion The polymorphisms in the ACTG1, CAPG and ABCB1 genes may modulate VCR-related neurotoxicity, whereas the risk of relapse seems not to be affected by the genes of the VCR pathway. PMID:25084203

  12. Nucleus Accumbens Invulnerability to Methamphetamine Neurotoxicity

    PubMed Central

    Kuhn, Donald M.; Angoa-Pérez, Mariana; Thomas, David M.

    2016-01-01

    Methamphetamine (Meth) is a neurotoxic drug of abuse that damages neurons and nerve endings throughout the central nervous system. Emerging studies of human Meth addicts using both postmortem analyses of brain tissue and noninvasive imaging studies of intact brains have confirmed that Meth causes persistent structural abnormalities. Animal and human studies have also defined a number of significant functional problems and comorbid psychiatric disorders associated with long-term Meth abuse. This review summarizes the salient features of Meth-induced neurotoxicity with a focus on the dopamine (DA) neuronal system. DA nerve endings in the caudate-putamen (CPu) are damaged by Meth in a highly delimited manner. Even within the CPu, damage is remarkably heterogeneous, with ventral and lateral aspects showing the greatest deficits. The nucleus accumbens (NAc) is largely spared the damage that accompanies binge Meth intoxication, but relatively subtle changes in the disposition of DA in its nerve endings can lead to dramatic increases in Meth-induced toxicity in the CPu and overcome the normal resistance of the NAc to damage. In contrast to the CPu, where DA neuronal deficiencies are persistent, alterations in the NAc show a partial recovery. Animal models have been indispensable in studies of the causes and consequences of Meth neurotoxicity and in the development of new therapies. This research has shown that increases in cytoplasmic DA dramatically broaden the neurotoxic profile of Meth to include brain structures not normally targeted for damage. The resistance of the NAc to Meth-induced neurotoxicity and its ability to recover reveal a fundamentally different neuroplasticity by comparison to the CPu. Recruitment of the NAc as a target of Meth neurotoxicity by alterations in DA homeostasis is significant in light of the numerous important roles played by this brain structure. PMID:23382149

  13. Acute off-target effects of neural circuit manipulations.

    PubMed

    Otchy, Timothy M; Wolff, Steffen B E; Rhee, Juliana Y; Pehlevan, Cengiz; Kawai, Risa; Kempf, Alexandre; Gobes, Sharon M H; Ölveczky, Bence P

    2015-12-17

    Rapid and reversible manipulations of neural activity in behaving animals are transforming our understanding of brain function. An important assumption underlying much of this work is that evoked behavioural changes reflect the function of the manipulated circuits. We show that this assumption is problematic because it disregards indirect effects on the independent functions of downstream circuits. Transient inactivations of motor cortex in rats and nucleus interface (Nif) in songbirds severely degraded task-specific movement patterns and courtship songs, respectively, which are learned skills that recover spontaneously after permanent lesions of the same areas. We resolve this discrepancy in songbirds, showing that Nif silencing acutely affects the function of HVC, a downstream song control nucleus. Paralleling song recovery, the off-target effects resolved within days of Nif lesions, a recovery consistent with homeostatic regulation of neural activity in HVC. These results have implications for interpreting transient circuit manipulations and for understanding recovery after brain lesions. PMID:26649821

  14. Modulation of benzo[a]pyrene induced neurotoxicity in female mice actively immunized with a B[a]P-diphtheria toxoid conjugate.

    PubMed

    Schellenberger, Mario T; Grova, Nathalie; Farinelle, Sophie; Willième, Stéphanie; Schroeder, Henri; Muller, Claude P

    2013-09-01

    Benzo[a]pyrene (B[a]P) is a small molecular weight carcinogen and the prototype of polycyclic aromatic hydrocarbons (PAHs). While these compounds are primarily known for their carcinogenicity, B[a]P and its metabolites are also neurotoxic for mammalian species. To develop a prophylactic immune strategy against detrimental effects of B[a]P, female Balb/c mice immunized with a B[a]P-diphtheria toxoid (B[a]P-DT) conjugate vaccine were sub-acutely exposed to 2mg/kg B[a]P and behavioral performances were monitored in tests related to learning and memory, anxiety and motor coordination. mRNA expression of the NMDA receptor (NR1, 2A and 2B subunits) involved in the above behavioral functions was measured in 5 brain regions. B[a]P induced NMDA1 expression in three (hippocampus, amygdala and cerebellum) of five brain regions investigated, and modulated NMDA2 in two of the five brain regions (frontal cortex and cerebellum). Each one of these B[a]P-effects was reversed in mice that were immunized against this PAH, with measurable consequences on behavior such as anxiety, short term learning and memory. Thus active immunization against B[a]P with a B[a]P-DT conjugate vaccine had a protective effect and attenuated the pharmacological and neurotoxic effects even of high concentrations of B[a]P. PMID:23684556

  15. RAGE and amyloid-beta peptide neurotoxicity in Alzheimer's disease.

    PubMed

    Yan, S D; Chen, X; Fu, J; Chen, M; Zhu, H; Roher, A; Slattery, T; Zhao, L; Nagashima, M; Morser, J; Migheli, A; Nawroth, P; Stern, D; Schmidt, A M

    1996-08-22

    Amyloid-beta peptide is central to the pathology of Alzheimer's disease, because it is neurotoxic--directly by inducing oxidant stress, and indirectly by activating microglia. A specific cell-surface acceptor site that could focus its effects on target cells has been postulated but not identified. Here we present evidence that the 'receptor for advanced glycation end products' (RAGE) is such a receptor, and that it mediates effects of the peptide on neurons and microglia. Increased expressing of RAGE in Alzheimer's disease brain indicates that it is relevant to the pathogenesis of neuronal dysfunction and death. PMID:8751438

  16. Enhancement of endocannabinoid signaling protects against cocaine-induced neurotoxicity

    SciTech Connect

    Vilela, Luciano R.; Gobira, Pedro H.; Viana, Thercia G.; Medeiros, Daniel C.; Ferreira-Vieira, Talita H.; Doria, Juliana G.; Rodrigues, Flávia; Aguiar, Daniele C.; Pereira, Grace S.; Massessini, André R.; Ribeiro, Fabíola M.; Oliveira, Antonio Carlos P. de; Moraes, Marcio F.D.; Moreira, Fabricio A.

    2015-08-01

    Cocaine is an addictive substance with a potential to cause deleterious effects in the brain. The strategies for treating its neurotoxicity, however, are limited. Evidence suggests that the endocannabinoid system exerts neuroprotective functions against various stimuli. Thus, we hypothesized that inhibition of fatty acid amide hydrolase (FAAH), the main enzyme responsible for terminating the actions of the endocannabinoid anandamide, reduces seizures and cell death in the hippocampus in a model of cocaine intoxication. Male Swiss mice received injections of endocannabinoid-related compounds followed by the lowest dose of cocaine that induces seizures, electroencephalographic activity and cell death in the hippocampus. The molecular mechanisms were studied in primary cell culture of this structure. The FAAH inhibitor, URB597, reduced cocaine-induced seizures and epileptiform electroencephalographic activity. The cannabinoid CB{sub 1} receptor selective agonist, ACEA, mimicked these effects, whereas the antagonist, AM251, prevented them. URB597 also inhibited cocaine-induced activation and death of hippocampal neurons, both in animals and in primary cell culture. Finally, we investigated if the PI3K/Akt/ERK intracellular pathway, a cell surviving mechanism coupled to CB{sub 1} receptor, mediated these neuroprotective effects. Accordingly, URB597 injection increased ERK and Akt phosphorylation in the hippocampus. Moreover, the neuroprotective effect of this compound was reversed by the PI3K inhibitor, LY294002. In conclusion, the pharmacological facilitation of the anandamide/CB1/PI3K signaling protects the brain against cocaine intoxication in experimental models. This strategy may be further explored in the development of treatments for drug-induced neurotoxicity. - Highlights: • Cocaine toxicity is characterized by seizures and hippocampal cell death. • The endocannabinoid anandamide acts as a brain protective mechanism. • Inhibition of anandamide hydrolysis

  17. Evidence for Dose-Additive Effects of Pyrethroids on Motor Activity in Rats

    EPA Science Inventory

    BACKGROUND: Pyrethroids are neurotoxic insecticides used in a variety of indoor and outdoor applications. Previous research characterized the acute dose-effect functions for 11 pyrethroids administered orally in corn oil (1 mL/kg) based on assessment of motor activity. OBJECTIVES...

  18. Diurnal Spectral Sensitivity of the Acute Alerting Effects of Light

    PubMed Central

    Rahman, Shadab A.; Flynn-Evans, Erin E.; Aeschbach, Daniel; Brainard, George C.; Czeisler, Charles A.; Lockley, Steven W.

    2014-01-01

    Study Objectives: Previous studies have demonstrated short-wavelength sensitivity for the acute alerting response to nocturnal light exposure. We assessed daytime spectral sensitivity in alertness, performance, and waking electroencephalogram (EEG). Design: Between-subjects (n = 8 per group). Setting: Inpatient intensive physiologic monitoring unit. Participants: Sixteen healthy young adults (mean age ± standard deviation = 23.8 ± 2.7 y). Interventions: Equal photon density exposure (2.8 × 1013 photons/cm2/s) to monochromatic 460 nm (blue) or 555 nm (green) light for 6.5 h centered in the middle of the 16-h episode of wakefulness during the biological day. Results were compared retrospectively to 16 individuals who were administered the same light exposure during the night. Measurements and Results: Daytime and nighttime 460-nm light exposure significantly improved auditory reaction time (P < 0.01 and P < 0.05, respectively) and reduced attentional lapses (P < 0.05), and improved EEG correlates of alertness compared to 555-nm exposure. Whereas subjective sleepiness ratings did not differ between the two spectral conditions during the daytime (P > 0.05), 460-nm light exposure at night significantly reduced subjective sleepiness compared to 555-nm light exposure at night (P < 0.05). Moreover, nighttime 460-nm exposure improved alertness to near-daytime levels. Conclusions: The alerting effects of short-wavelength 460-nm light are mediated by counteracting both the circadian drive for sleepiness and homeostatic sleep pressure at night, but only via reducing the effects of homeostatic sleep pressure during the day. Citation: Rahman SA; Flynn-Evans EE; Aeschbach D; Brainard GC; Czeisler CA; Lockley SW. Diurnal spectral sensitivity of the acute alerting effects of light. SLEEP 2014;37(2):271-281. PMID:24501435

  19. Acute Physiological and Behavioral Effects of Intranasal Methamphetamine in Humans

    PubMed Central

    Hart, Carl L; Gunderson, Erik W; Perez, Audrey; Kirkpatrick, Matthew G; Thurmond, Andrew; Comer, Sandra D; Foltin, Richard W

    2016-01-01

    Intranasal methamphetamine abuse has increased dramatically in the past decade, yet only one published study has investigated its acute effects under controlled laboratory conditions. Thus, the current study examined the effects of single-dose intranasal methamphetamine administration on a broad range of behavioral and physiological measures. Eleven nontreatment-seeking methamphetamine abusers (two females, nine males) completed this four-session, in-patient, within-participant, double-blind study. During each session, one of four intranasal methamphetamine doses (0, 12, 25, and 50 mg/70 kg) was administered and methamphetamine plasma concentrations, cardiovascular, subjective, and psychomotor/cognitive performance effects were assessed before drug administration and repeatedly thereafter. Following drug administration, methamphetamine plasma concentrations systematically increased for 4 h postdrug administration then declined. Methamphetamine dose dependently increased cardiovascular measures and ‘positive’ subjective effects, with peaks occurring approximately 5–15 min after drug administration, when plasma levels were still ascending. In addition, cognitive performance on less complicated tasks was improved by all active methamphetamine doses, whereas performance on more complicated tasks was improved only by the intermediate doses (12 and 25 mg). These results show that intranasal methamphetamine produced predictable effects on multiple behavioral and physiological measures before peak plasma levels were observed. Of interest is the dissociation between methamphetamine plasma concentrations with cardiovascular measures and positive subjective effects, which might have important implications for potential toxicity after repeated doses. PMID:17851535

  20. Neurotoxicity may be an overlooked consequence of benzo[a]pyrene exposure that is relevant to human health risk assessment.

    PubMed

    Chepelev, Nikolai L; Moffat, Ivy D; Bowers, Wayne J; Yauk, Carole L

    2015-01-01

    Benzo[a]pyrene (BaP) is a well-studied environmental compound that requires metabolic activation to have a carcinogenic effect. The neurotoxicity of BaP has received considerably less attention than its carcinogenicity. Environmental exposure to BaP correlates with impaired learning and memory in adults, and poor neurodevelopment in children. We carried out a comprehensive literature review to examine the neurotoxicity of BaP. The data were used to identify potential point of departure (POD) values for cancer and neurotoxicity endpoints using benchmark dose (BMD) modelling to compare the utility of both endpoints in the risk assessment of BaP. The POD for neurotoxicity in rodents, based on a standard behavioural test (Morris water maze), was 0.025 mg BaP/kg-bw-day compared to 0.54 mg BaP/kg-bw-day for rodent forestomach carcinogenicity, suggesting that neurotoxic endpoints are more sensitive than cancer endpoints for health risks associated with BaP exposure. Using the limited number of published studies on this topic, we propose a preliminary mode of action (MOA) to explain BaP-induced neurotoxicity in rodents. The MOA includes: (1) BaP binding to the aryl hydrocarbon receptor (AHR); (2) AHR-dependent modulation of the transcription of N-methyl-d-aspartate glutamate receptor (NMDAR) subunits; (3) NMDAR-mediated loss of neuronal activity and decreased long-term potentiation; and (4) compromised learning and memory. More data are needed to explore the proposed neurotoxic MOA. In addition, we consider alternative MOAs, including the hypothesis that BaP-mediated DNA damage may lead to either carcinogenicity or neurotoxicity, depending on the tissue. Our proposed MOA is intended to serve as a basis for hypothesis testing in future studies. We emphasise that further studies are needed to validate the proposed MOA, to evaluate its human relevance, and to explore other potential mechanisms of BaP neurotoxicity. PMID:26041267

  1. Investigation of acute stroke: what is the most effective strategy?

    PubMed Central

    Dunbabin, D. W.; Sandercock, P. A.

    1991-01-01

    Techniques of investigation of acute stroke syndromes have progressed rapidly in recent years, outpacing developments in effective stroke treatment. The clinician is thus faced with a variety of tests, each with different cost implications and each altering management to a greater or lesser extent. This review will concentrate on the basic tests which should be performed for all strokes (full blood count, ESR, biochemical screen, blood glucose, cholesterol, syphilis serology, chest X-ray and electrocardiogram). Additional tests may be required in selected cases: CT scan to diagnose 'non-stroke' lesions, to exclude cerebral haemorrhage if anti-haemostatic therapy is planned, and to detect strokes which may require emergency intervention (such as cerebellar stroke with hydrocephalus); echocardiography to detect cardiac sources of emboli; and in a few cases lumbar puncture and specialized haematological tests. Other tests, which are currently research tools, may be suitable for widespread use in the future including NMR, SPECT and PET scanning. PMID:2062773

  2. The effects of an acute psychosocial stressor on episodic memory

    PubMed Central

    Stawski, Robert S.; Sliwinski, Martin J.; Smyth, Joshua M.

    2009-01-01

    Although stressors are believed to impair memory, experimental studies with humans have provided inconsistent support for this conclusion. The current study was designed to examine the effect of an acute psychosocial stressor, and subsequent reactivity, on episodic memory. One hundred participants completed a list-recall task before and after random assignment into a stressor or nonstressor condition. Participants assigned to the stressor condition exhibited both impaired delayed and immediate recall, and also exhibited increasesin the commission of intrusions and perseverations. The experience of off-task thoughts and intentional suppression of such thoughts, were associated with greater impairment of immediate recall. Changes in state anxiety, negative mood, and heart rate were unrelated to changes in memory. These data indicate that exposure to a stressor impaired the recall of previously learned information, and compromised the recall of newly acquired information. Furthermore, cognitive interference is an important factor regarding stress-related impairments of episodic memory. memory. PMID:19727439

  3. Acute Effects of Marijuana Smoking on Negative and Positive Affect

    PubMed Central

    Metrik, Jane; Kahler, Christopher W.; McGeary, John E.; Monti, Peter M.; Rohsenow, Damaris J.

    2013-01-01

    Human studies and animal experiments present a complex and often contradictory picture of the acute impact of marijuana on emotions. The few human studies specifically examining changes in negative affect find either increases or reductions following delta-9-tetrahydrocannabinol (THC) administration. In a 2 × 2, instructional set (told THC vs. told no THC) by drug administration (smoked marijuana with 2.8% THC vs. placebo) between-subjects design, we examined the pharmacologic effect of marijuana on physiological and subjective stimulation, subjective intoxication, and self-reported negative and positive affect with 114 weekly marijuana smokers. Individuals were first tested under a baseline/no smoking condition and again under experimental condition. Relative to placebo, THC significantly increased arousal and confusion/bewilderment. However, the direction of effect on anxiety varied depending on instructional set: Anxiety increased after THC for those told placebo but decreased among other participants. Furthermore, marijuana users who expected more impairment from marijuana displayed more anxiety after smoking active marijuana, whereas those who did not expect the impairment became less anxious after marijuana. Both pharmacologic and stimulus expectancy main effects significantly increased positive affect. Frequent marijuana users were less anxious after smoking as compared to less frequent smokers. These findings show that expectancy instructions and pharmacology play independent roles in effects of marijuana on negative affect. Further studies examining how other individual difference factors impact marijuana's effects on mood are needed. PMID:24319318

  4. Acute Effects of Carbohydrate Supplementation on Intermittent Sports Performance.

    PubMed

    Baker, Lindsay B; Rollo, Ian; Stein, Kimberly W; Jeukendrup, Asker E

    2015-07-01

    Intermittent sports (e.g., team sports) are diverse in their rules and regulations but similar in the pattern of play; that is, intermittent high-intensity movements and the execution of sport-specific skills over a prolonged period of time (~1-2 h). Performance during intermittent sports is dependent upon a combination of anaerobic and aerobic energy systems, both of which rely on muscle glycogen and/or blood glucose as an important substrate for energy production. The aims of this paper are to review: (1) potential biological mechanisms by which carbohydrate may impact intermittent sport performance; (2) the acute effects of carbohydrate ingestion on intermittent sport performance, including intermittent high-intensity exercise capacity, sprinting, jumping, skill, change of direction speed, and cognition; and (3) what recommendations can be derived for carbohydrate intake before/during exercise in intermittent sports based on the available evidence. The most researched intermittent sport is soccer but some sport-specific studies have also been conducted in other sports (e.g., rugby, field hockey, basketball, American football, and racquet sports). Carbohydrate ingestion before/during exercise has been shown in most studies to enhance intermittent high-intensity exercise capacity. However, studies have shown mixed results with regards to the acute effects of carbohydrate intake on sprinting, jumping, skill, change of direction speed, and cognition. In most of these studies the amount of carbohydrate consumed was ~30-60 g/h in the form of a 6%-7% carbohydrate solution comprised of sucrose, glucose, and/or maltodextrin. The magnitude of the impact that carbohydrate ingestion has on intermittent sport performance is likely dependent on the carbohydrate status of the individual; that is, carbohydrate ingestion has the greatest impact on performance under circumstances eliciting fatigue and/or hypoglycemia. Accordingly, carbohydrate ingestion before and during a game

  5. Acute Effects of Carbohydrate Supplementation on Intermittent Sports Performance

    PubMed Central

    Baker, Lindsay B.; Rollo, Ian; Stein, Kimberly W.; Jeukendrup, Asker E.

    2015-01-01

    Intermittent sports (e.g., team sports) are diverse in their rules and regulations but similar in the pattern of play; that is, intermittent high-intensity movements and the execution of sport-specific skills over a prolonged period of time (~1–2 h). Performance during intermittent sports is dependent upon a combination of anaerobic and aerobic energy systems, both of which rely on muscle glycogen and/or blood glucose as an important substrate for energy production. The aims of this paper are to review: (1) potential biological mechanisms by which carbohydrate may impact intermittent sport performance; (2) the acute effects of carbohydrate ingestion on intermittent sport performance, including intermittent high-intensity exercise capacity, sprinting, jumping, skill, change of direction speed, and cognition; and (3) what recommendations can be derived for carbohydrate intake before/during exercise in intermittent sports based on the available evidence. The most researched intermittent sport is soccer but some sport-specific studies have also been conducted in other sports (e.g., rugby, field hockey, basketball, American football, and racquet sports). Carbohydrate ingestion before/during exercise has been shown in most studies to enhance intermittent high-intensity exercise capacity. However, studies have shown mixed results with regards to the acute effects of carbohydrate intake on sprinting, jumping, skill, change of direction speed, and cognition. In most of these studies the amount of carbohydrate consumed was ~30–60 g/h in the form of a 6%–7% carbohydrate solution comprised of sucrose, glucose, and/or maltodextrin. The magnitude of the impact that carbohydrate ingestion has on intermittent sport performance is likely dependent on the carbohydrate status of the individual; that is, carbohydrate ingestion has the greatest impact on performance under circumstances eliciting fatigue and/or hypoglycemia. Accordingly, carbohydrate ingestion before and during a

  6. Manganese Neurotoxicity: A Focus on the Neonate

    PubMed Central

    Erikson, Keith M.; Thompson, Khristy; Aschner, Judy; Aschner, Michael

    2007-01-01

    Manganese (Mn) is an essential trace metal found in all tissues, and it is required for normal amino acid, lipid, protein, and carbohydrate metabolism. While Mn deficiency is extremely rare in humans, toxicity due to overexposure of Mn is more prevalent. The brain appears to be especially vulnerable. Mn neurotoxicity is most commonly associated with occupational exposure to aerosols or dusts that contain extremely high levels (> 1-5 mg Mn/m3) of Mn, consumption of contaminated well water, or parenteral nutrition therapy in patients with liver disease or immature hepatic functioning such as the neonate. This review will focus primarily on the neurotoxicity of Mn in the neonate. We will discuss putative transporters of the metal in the neonatal brain and then focus on the implications of high Mn exposure to the neonate focusing on typical exposure modes (e.g., dietary and parenteral). Although Mn exposure via parenteral nutrition is uncommon in adults, in premature infants, it is more prevalent, so this mode of exposure becomes salient in this population. We will briefly review some of the mechanisms of Mn neurotoxicity and conclude with a discussion of ripe areas for research in this underreported area of neurotoxicity. PMID:17084903

  7. USE OF CELL CULTURE FOR EVALUATING NEUROTOXICITY

    EPA Science Inventory

    This chapter familiarizes the reader with the need to develop, validate and utilize in vitro models to test chemicals for neurotoxic potential. he major advantages and disadvantages of using cell and tissue culture, factors which have stimulated and hampered the promulgation of i...

  8. Chemotherapy-induced peripheral neurotoxicity (CIPN): what we need and what we know.

    PubMed

    Cavaletti, Guido

    2014-06-01

    Chemotherapy-induced peripheral neurotoxicity (CIPN) is one of the most frequent and severe long-term side effects of cancer chemotherapy. Preclinical and clinical studies have extensively investigated CIPN searching for effective strategies to limit its severity or to treat CIPN-related impairment, but the results have been disappointing. Among the reasons for this failure are methodological flaws in both preclinical and clinical investigations. Their successful resolution might provide a brighter perspective for future studies. Among the several neurotoxic chemotherapy drugs, oxaliplatin may offer a clear example of a methodological approach eventually leading to successful clinical trials. However, the same considerations apply to the other neurotoxic agents and, although frequently neglected, also to the new "targeted" agents. PMID:24976572

  9. Pathophysiology of Manganese-Associated Neurotoxicity

    PubMed Central

    Racette, Brad A.; Aschner, Michael; Guilarte, Tomas R.; Dydak, Ulrike; Criswell, Susan R.; Zheng, Wei

    2012-01-01

    Conference Summary Manganese (Mn) is a well established neurotoxin associated with specific damage to the basal ganglia in humans. The phenotype associated with Mn neurotoxicity was first described in two workers with occupational exposure to Mn oxide.(Couper, 1837) Although the description did not use modern clinical terminology, a parkinsonian illness characterized by slowness of movement (bradykinesia), masked facies, and gait impairment (postural instability) appears to have predominated. Nearly 100 years later an outbreak of an atypical parkinsonian illness in a Chilean Mn mine provided a phenotypic description of a fulminant neurologic disorder with parkinsonism, dystonia, and neuropsychiatric symptoms.(Rodier J, 1955) Exposures associated with this syndrome were massive and an order of magnitude greater than modern exposures.(Rodier J, 1955; Hobson et al., 2011) The clinical syndrome associated with Mn neurotoxicity has been called manganism. Modern exposures to Mn occur primarily through occupations in the steel industry and welding. These exposures are often chronic and varied, occurring over decades in the healthy workforce. Although the severe neurologic disorder described by Rodier and Couper are no longer seen, several reports have suggested a possible increased risk of neurotoxicity in these workers.(Racette et al., 2005b; Bowler et al., 2007; Harris et al., 2011) Based upon limited prior imaging and pathologic investigations into the pathophysiology of neurotoxicity in Mn exposed workers,(Huang et al., 2003) many investigators have concluded that the syndrome spares the dopamine system distinguishing manganism from Parkinson disease (PD), the most common cause of parkinsonism in the general population, and a disease with characteristic degenerative changes in the dopaminergic system.(Jankovic, 2005) The purpose of this symposium was to highlight recent advances in the understanding of the pathophysiology of Mn associated neurotoxicity from C. elegans

  10. INTERRELATIONSHIPS OF UNDERNUTRITION AND NEUROTOXICITY: FOOD FOR THOUGHT AND RESEARCH ATTENTION

    PubMed Central

    Spencer, Peter S.; Palmer, Valerie S.

    2012-01-01

    The neurotoxic actions of chemical agents on humans and animals are usually studied with little consideration of the subject’s nutritional status. States of protein-calorie, vitamin and mineral undernutrition are associated with a range of neurodevelopmental, neurological and psychiatric disorders, commonly with involvement of both the central and peripheral nervous system. Undernutrition can modify risk for certain chemical-induced neurologic diseases, and in some cases undernutrition may be a prerequisite for neurotoxicity to surface. In addition, neurologic disease associated with undernutrition or neurotoxicity may show similarities in clinical and neuropathological expression, especially in the peripheral nervous system. The combined effects of undernutrition and chemical neurotoxicity are most relevant to people of low-income who experience chronic hunger, parasitism and infectious disease, monotonous diets of plants with neurotoxic potential (notably cassava), environmental pollution from rapid industrial development, chronic alcohol abuse, and prolonged treatment with certain therapeutic drugs. Undernutrition alone or in combination with chemical exposure is also important in high-income societies in the setting of drug and alcohol abuse, old age, food faddism, post-bariatric surgery, and drug treatment for certain medical conditions, including cancer and tuberculosis. The nutritional demands of pregnancy and lactation increases the risk of fetal and infant undernutrition and chemical interactions therewith. PMID:22394483

  11. Federal regulatory response to the problem of neurotoxicity

    SciTech Connect

    Courteau, J.B.; Young, J.S.

    1988-12-01

    The purpose of the chapter is to examine the Federal regulatory response to the control of neurotoxicants. The first section presents an overview of legislation and regulations designed to protect the public from toxic substances and of the specific ways in which the statutes and regulations apply to controlling neurotoxic chemicals. Subsequent sections present the regulatory process in greater detail, describing how information on toxic effects is gathered and evaluated, and outlining some new initiatives in regulating neurotoxins. The chapter concludes with a discussion of the consistency and adequacy of the Federal regulatory framework.

  12. Acute side effects of homologous interleukin-3 in rhesus monkeys.

    PubMed Central

    van Gils, F. C.; Mulder, A. H.; van den Bos, C.; Burger, H.; van Leen, R. W.; Wagemaker, G.

    1993-01-01

    Interleukin-3 treatment of juvenile rhesus monkeys elicits a dose- and time-dependent syndrome that includes urticaria, palpable lymph nodes, splenomegaly, thrombocytopenia, anemia, vomiting, diarrhea, intestinal bleeding, edema, and arthritis, apart from a strong stimulation of hemopoiesis. Arthritis was found to occur significantly more often in animals expressing the major histocompatibility complex alleles B9 and Dr5. Histological analysis revealed an abundance of mast cells in urticaria and, to a lesser extent, in lungs and synovia of arthritic joints. Active osteoclasts were abundant in ribs and arthritic joints. Extramedullary hemopoiesis was encountered in liver, spleen, and kidneys. The spleen showed deposits of hemosiderin, and in the liver, Kupffer cells were loaded with iron, indicating enhanced turnover of hemoglobin. Lymph nodes and bone marrow showed macrophages involved in hemophagocytosis, which probably contributed to the development of anemia and thrombopenia. Biochemical parameters in sera were indicative of parenchymal liver damage, with cholestasis and increased erythrocyte destruction. The side effects were strongly reduced in monkeys subjected to total body irradiation just before interleukin-3 treatment. Histamine antagonists were not significantly effective in preventing side effects, which is explained by the perpetual stimulation of basophilic granulocytes by exogenous interleukin-3. The nature of the side effects indicates that interleukin-3 may be involved in the pathogenesis of acute type hypersensitivity reactions and arthritis. Images Figure 1 Figure 2 Figure 3 PMID:8256852

  13. Acute and Chronic Effects of Cocaine on the Spontaneous Behavior of Pigeons

    ERIC Educational Resources Information Center

    Pinkston, Jonathan W.; Branch, Marc N.

    2010-01-01

    The present experiment examined the effects of acute and daily cocaine on spontaneous behavior patterns of pigeons. After determining the acute effects of a range of doses, 9 pigeons were divided into three groups that received one of three doses of cocaine daily, either 1.0, 3.0, or 10.0 mg/kg cocaine. Measures were taken of spontaneous…

  14. 21 CFR 320.28 - Correlation of bioavailability with an acute pharmacological effect or clinical evidence.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 5 2011-04-01 2011-04-01 false Correlation of bioavailability with an acute pharmacological effect or clinical evidence. 320.28 Section 320.28 Food and Drugs FOOD AND DRUG ADMINISTRATION... Correlation of bioavailability with an acute pharmacological effect or clinical evidence. Correlation of...

  15. 21 CFR 320.28 - Correlation of bioavailability with an acute pharmacological effect or clinical evidence.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 5 2010-04-01 2010-04-01 false Correlation of bioavailability with an acute pharmacological effect or clinical evidence. 320.28 Section 320.28 Food and Drugs FOOD AND DRUG ADMINISTRATION... Correlation of bioavailability with an acute pharmacological effect or clinical evidence. Correlation of...

  16. DEVELOPMENTAL NEUROTOXICITY OF POLYBROMINATED DIPHENYL ETHER (PBDE) FLAME RETARDANTS

    PubMed Central

    Costa, Lucio G.; Giordano, Gennaro

    2007-01-01

    Polybrominated diphenyl ethers (PBDEs) are a class of flame retardants used in a variety of consumer products. In the past 25 years, PBDEs have become ubiquitous environmental contaminants. They have been detected in soil, air, sediments, birds, marine species, fish, house dust, and human tissues, blood and breast milk. Diet and house dust appear to be the major sources of PBDE exposure in the general population, though occupational exposure can also occur. Levels of PBDEs in human tissues are particularly high in North America, compared to Asian and European countries, and have been increasing in the past 30 years. Concentrations of PBDEs are particularly high in breast milk, resulting in high exposure of infants. In addition, for toddlers, dust has been estimated to account for a large percentage of exposure. PBDEs can also cross the placenta, as they have been detected in fetal blood and liver. Tetra-, penta- and hexa BDEs are most commonly present in human tissues. The current greatest concern for potential adverse effects of PBDEs relates to their developmental neurotoxicity. Pre- or postnatal exposure of mice or rats to various PBDEs has been shown to cause long-lasting changes in spontaneous motor activity, mostly characterized as hyperactivity or decreased habituation, and to disrupt performance in learning and memory tests. While a reduction in circulating thyroid hormone (T4) may contribute to the developmental neurotoxicity of PBDEs, direct effects on the developing brain have also been reported. Among these, PBDEs have been shown to affect signal transduction pathways and to cause oxidative stress. Levels of PBDEs causing developmental neurotoxicity in animals are not much dissimilar from levels found in highly exposed infants and toddlers. PMID:17904639

  17. [The prevention of neurotoxic reactions during the treatment of pulmonary tuberculosis in middle-aged and elderly patients].

    PubMed

    Markova, E F

    1990-10-01

    To prevent and control neurotoxic reactions in the treatment of pulmonary tuberculosis in elderly and old patients the author used dipromonium (derivative of pangamic acid). Use of this agent at the beginning of the treatment course reduced the incidence of side-effects of neurotoxic character. In case of development of reactions of the central and peripheral nervous system dipromonium treatment resulted in their weakening or liquidation. PMID:2080583

  18. Effects of acute cooling on fish electroretinogram: a comparative study.

    PubMed

    Gačić, Zoran; Milošević, Milena; Mićković, Branislav; Nikčević, Miroslav; Damjanović, Ilija

    2015-06-01

    Temperature dependence of electroretinogram (ERG) was investigated in 3 fish species occupying different habitats--dogfish shark (Scyliorhinus canicula), Prussian carp (Carassius gibelio) and European eel (Anguilla anguilla). Acute cooling of the shark isolated eyecup from 23°C down to 6°C induced suppression of the electroretinographic b-wave--a complete degradation of this component was observed at 6°C. On the other hand, photoreceptor component of the ERG, the negative late receptor potential was not affected by cooling. The fact that the suppression of the dogfish shark b-wave at low temperatures was as a rule irreversible testifies about breakdown of neural retinal function at cold temperature extremes. Although in vivo experiments on immobilized Prussian carps have never resulted in complete deterioration of the b-wave at low temperatures, significant suppression of this ERG component by cooling was detected. Suppressing the effect of low temperatures on Prussian carp ERG might be due to the fact that C. gibelio, as well as other cyprinids, can be characterized as a warmwater species preferring temperatures well above cold extremes. The ERG of the eel, the third examined species, exhibited the strongest resistance to extremely low temperatures. During acute cooling of in situ eyecup preparations of migrating silver eels from 30°C down to 2°C the form of ERG became wider, but the amplitude of the b-wave only slightly decreased. High tolerance of eel b-wave to cold extremes shown in our study complies with ecological data confirming eurythermia in migrating silver eels remarkably adapted to cold-water environment as well. PMID:25759261

  19. Workshop on the qualitative and quantitative comparability of human and animal developmental neurotoxicity, Work Group I report: comparability of measures of developmental neurotoxicity in humans and laboratory animals.

    PubMed

    Stanton, M E; Spear, L P

    1990-01-01

    Assessment measures used in developmental neurotoxicology are reviewed for their comparability in humans and laboratory animals, and their ability to detect comparable adverse effects across species. Compounds used for these comparisons include: substances of abuse, anticonvulsant drugs, ethanol, methylmercury, lead, PCBs, and ionizing radiation. At the level of functional category (sensory, motivational, cognitive and motor function, and social behavior), close agreement was found across species for all neurotoxic agents reviewed, particularly at high exposure levels. This was true even though the specific end points used to assess these functions often varied substantially across species. In addition, it was found that: 1) the U.S. EPA Developmental Neurotoxicology Test Battery presented at the Workshop would have identified the hazard to humans of exposure to the above compounds, although it may have underestimated human risk in some cases; 2) assessment of developmental neurotoxicity should involve evaluation of all categories of function; 3) for most compounds reviewed, the neurotoxic effects of prenatal exposure cannot be attributed to maternal toxicity, and exposure at or just below the threshold for such toxicity is an appropriate upper level for developmental neurotoxicity testing; 4) maternal exposure during the postnatal period poses a number of serious methodological problems; and 5) animal studies would better parallel human studies if more emphasis was placed on evaluation during development. PMID:2115099

  20. Effects of acute restraint stress on set-shifting and reversal learning in male rats

    PubMed Central

    Thai, Chester A.; Zhang, Ying

    2015-01-01

    Exposure to acute stress alters cognition; however, few studies have examined the effects of acute stress on executive functions such as behavioral flexibility. The goal of the present experiments was to determine the effects of acute periods of stress on two distinct forms of behavioral flexibility: set-shifting and reversal learning. Male Sprague-Dawley rats were trained and tested in an operant-chamber-based task. Some of the rats were exposed to acute restraint stress (30 min) immediately before either the set-shifting test day or the reversal learning test day. Acute stress had no effect on set-shifting, but it significantly facilitated reversal learning, as assessed by both trials to criterion and total errors. In a second experiment, the roles of glucocorticoid (GR) and mineralocorticoid receptors (MR) in the acute-stress-induced facilitation of reversal learning were examined. Systemic administration of the GR-selective antagonist RU38486 (10 mg/kg) or the MR-selective antagonist spironolactone (50 mg/kg) 30 min prior to acute stress failed to block the facilitation on reversal learning. The present results demonstrate a dissociable effect of acute stress on set-shifting and reversal learning and suggest that the facilitation of reversal learning by acute stress may be mediated by factors other than corticosterone. PMID:23055093

  1. Mechanisms of mycotoxin-induced neurotoxicity through oxidative stress-associated pathways.

    PubMed

    Doi, Kunio; Uetsuka, Koji

    2011-01-01

    Among many mycotoxins, T-2 toxin, macrocyclic trichothecenes, fumonisin B(1) (FB(1)) and ochratochin A (OTA) are known to have the potential to induce neurotoxicity in rodent models. T-2 toxin induces neuronal cell apoptosis in the fetal and adult brain. Macrocyclic trichothecenes bring about neuronal cell apoptosis and inflammation in the olfactory epithelium and olfactory bulb. FB(1) induces neuronal degeneration in the cerebral cortex, concurrent with disruption of de novo ceramide synthesis. OTA causes acute depletion of striatal dopamine and its metabolites, accompanying evidence of neuronal cell apoptosis in the substantia nigra, striatum and hippocampus. This paper reviews the mechanisms of neurotoxicity induced by these mycotoxins especially from the viewpoint of oxidative stress-associated pathways. PMID:21954354

  2. A case of delayed oxaliplatin-induced pseudo-obstruction: an atypical presentation of oxaliplatin neurotoxicity.

    PubMed

    Vandamme, M; Pauwels, W; Bleecker, J De

    2015-06-01

    Chemotherapy-induced neurotoxicity is a serious complication of cancer treatment. Oxaliplatin, a third-generation platinum drug, has become one of the first-line therapies used in the treatment of metastatic colorectal cancer. Peripheral neuropathy is a common complication of platinum-based chemotherapy. Most commonly a sensory neuropathy occurs with cold-triggered symptoms in the acute phase and numbness and painful paresthesias as a late presentation. Autonomic neurotoxicity and late presentation, months after cessation of the therapy, has rarely been described. We report a patient who clinically presented with a pseudo-obstruction months after treatment with oxaliplatin for metastatic colorectal cancer. Intestinal adhesions and relapsing malignancy were carefully excluded. By exclusion the pseudo-obstruction was attributed to a toxic oxaliplatin-induced autonomic neuropathy which slowly improved during months of follow-up. PMID:25523317

  3. A case with reversible neurotoxicity after 2 years of dementia secondary to maintenance lithium treatment.

    PubMed

    Soriano-Barceló, Juan; Alonso, María Tajes; Traba, María Begoña Portela; Vilar, Alberte Araúxo; Kahn, David A

    2015-03-01

    Chronic neurotoxicity caused by lithium salts can be reversible or irreversible and may appear after years of treatment, even at serum levels considered within the usual therapeutic range. The authors present the case of a patient with bipolar disorder who developed dementia at the age of 54 after being treated with lithium carbonate at therapeutic levels for 4 years. Nevertheless, lithium treatment was continued. At age 56, the patient presented with an acute encephalopathy caused by toxic lithium levels, which resolved only after lithium carbonate was discontinued. Full recovery from the dementia, which had started 2 years earlier, occurred only after cessation of lithium. The authors conclude that when patients treated with lithium develop subacute cognitive impairment, the possibility of lithium toxicity should be considered, even if the serum levels are considered within the therapeutic range. A long duration of neurotoxicity associated with lithium treatment does not necessarily indicate an irreversible prognosis. PMID:25782766

  4. Antitumoral effect of Ocoxin on acute myeloid leukemia

    PubMed Central

    Díaz-Rodríguez, Elena; Hernández-García, Susana; Sanz, Eduardo; Pandiella, Atanasio

    2016-01-01

    Acute myeloid leukemia (AML) is a heterogeneous hematological malignancy whose incidence is growing in developed countries. In the relapse setting, very limited therapeutic options are available and in most cases only palliative care can be offered to patients. The effect of a composite formulation that contains several antioxidants, Ocoxin Oral solution (OOS), was tested in this condition. When analyzed in vitro, OOS exhibited anti-AML action that was both time and dose dependent. In vivo OOS induced a ralentization of tumor growth that was due to a decrease in cell proliferation. Such effect could, at least partially, be due to an increase in the cell cycle inhibitor p27, although other cell cycle proteins seemed to be altered. Besides, OOS induced an immunomodulatory effect through the induction of IL6. When tested in combination with other therapeutic agents normally used in the treatment of AML patients, OOS demonstrated a higher antiproliferative action, suggesting that it may be used in combination with those standard of care treatments to potentiate their antiproliferative action in the AML clinic. PMID:26756220

  5. The investigation of correlation between Iminoral concentration and neurotoxic levels after kidney transplantation

    PubMed Central

    Tolou-Ghamari, Zahra; Mortazavi, Mojgan; Palizban, Abbas-Ali; Najafi, Mohammad-Reza

    2015-01-01

    Background: Neurotoxicity side effects related to cyclosporine kinetics could lead to dysfunction of kidney graft and patient outcome after transplantation. The aim of this study was evidence-based pharmacotherapy of kidney transplant recipients and to investigate neurotoxic levels of Iminoral. Materials and Methods: The results of 2239 cyclosporine trough levels obtained from 743 patients were studied. Seventy-five adult kidney recipients who received Iminoral were studied for neurotoxicity symptoms. Demographic, clinical, hematology and biochemical data were recorded in d-base and analyzed using SPSS application for windows. Results: The mean value related to cyclosporine C0 was 246.3 μg/l. In the 48% the signs of neurotoxicity such as tremor and headache were noted, but only in 9% the levels of cyclosporine C0 were >400 μg/l. Further studies on 75 patients showed that the incidence of neurotoxic side effects were as follows: Tremor in 35, headache in 24 and anxiety in 34 recipients of kidney. The prescribed drug regimens from the day of transplant in most patients were based on mycophenolic acid or cellcept, pulse therapy using methylprednisolone (daily from kidney transplant up to 3 days after transplant), cyclosporine or Iminoral plus other drugs related to each individual. Administrations of ganciclovir, thymoglobulin, clotrimazol and prednisolone were also distinguished with immunosuppressant-based therapy simultaneously. Conclusion: Evidence-based study related to pharmacotherapy of Iminoral showed that clinical presentation related to neurotoxic side effects such as tremor, headache and anxiety might be due to many factors such as polypharmacy. Planning immunosuppression to individual patients based on programmed therapeutic Iminoral monitoring, avoiding polypharmacy in terms of removal or drug minimization and focusing on first week after transplant seem to be a realistic option. PMID:25802828

  6. Inhibition of hen brain acetylcholinesterase and neurotoxic esterase by chlorpyrifos in vivo and kinetics of inhibition by chlorpyrifos oxon in vitro: application to assessment of neuropathic risk.

    PubMed

    Richardson, R J; Moore, T B; Kayyali, U S; Fowke, J H; Randall, J C

    1993-04-01

    Chlorpyrifos (CPS; O,O-diethyl 3,5,6-trichloro-2-pyridyl phosphorothionate; Dursban) is a widely used broad-spectrum organophosphorus (OP) insecticide. Because some OP compounds can cause a sensory-motor distal axonopathy called OP compound-induced delayed neurotoxicity (OPIDN), CPS has been evaluated for this paralytic effect. Early studies of the neurotoxicity of CPS in young and adult hens reported reversible leg weakness but failed to detect OPIDN. More recently, a human case of mild OPIDN was reported to result from ingestion of a massive dose (about 300 mg/kg) in a suicide attempt. Subsequent experiments in adult hens (the currently accepted animal model of choice for studies of OPIDN) showed that doses of CPS in excess of the LD50 in atropine-treated animals inhibited brain neurotoxic esterase (NTE) and produced mild to moderate ataxia. Considering the extensive use of CPS and its demonstrated potential for causing OPIDN at supralethal doses, additional data are needed to enable quantitative estimates to be made of the neuropathic risk of this compound. Previous work has shown that the ability of OP insecticides to cause acute cholinergic toxicity versus OPIDN can be predicted from their relative tendency to inhibit the intended target, acetylcholinesterase (AChE), versus the putative neuropathic target, NTE, in brain tissue. The present study was designed to clarify the magnitude of neuropathic risk associated with CPS exposures by measuring hen brain AChE and NTE inhibition following dosing in vivo and determining the bimolecular rate constant of inhibition (ki) for each enzyme by the active metabolite, CPS oxon (CPO), in vitro.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:7684990

  7. [Acute Toxic Effects of Bromate on Aquatic Organisms].

    PubMed

    Wang, Zhi-wei; Liu, Dong-mei; Zhang, Wen-juan; Cui, Fu-yi

    2016-02-15

    Acute toxic effects of potassium bromate, sodium bromate and potassium bromide on luminescent bacteria, water flea, green alga and zebrafish were studied using standard toxic testing methods. The results showed that the pollutants had no effect on the luminous intensity of luminescent bacteria. The 96 h EC5. of potassium bromate on Scenedesmus obliquus was 738.18 mg x L(-1), 48 h EC50 on Daphnia magna and Moina was 154.01 mg x L(-1) was 161.80 mg x L(-1), while 48 h LC50 was 198 52 mg x L(-1), 175.68 mg x L(-1), and 96 h LC50 on zebrafish was 931.4 mg x L(-1). The 96 h EC50 of sodium bromate on Scenedesmus obliquus was 540.26 mg x L(-1), 48 h EC50 Daphnia magna and Moina was 127.90 mg x L(-1), 111.07 mg x L(-1), while 48 h LC50 was 161.80 mg x L(-1), 123.47 mg x L(-1), and 96 h LC50 on zebrafish was 1065.6 mg x L(-1). But the effects of potassium bromide on the above several kinds of aquatic organisms were far smaller than those of potassium bromate and sodium bromate. The toxic effects on test organisms were due to the impacts of bromate after the comparison of different pollutants, and the effects were more obvious with the increase of exposure time. The order of sensitivity to the toxic effects of bromate was Daphnia magna, Moina > Scenedesmus obliquus > zebrafish > Chlorella vulgaris, luminescent bacteria. PMID:27363170

  8. Oxidative damage and neurodegeneration in manganese-induced neurotoxicity

    SciTech Connect

    Milatovic, Dejan; Yu, Yingchun

    2009-10-15

    Exposure to excessive manganese (Mn) levels results in neurotoxicity to the extrapyramidal system and the development of Parkinson's disease (PD)-like movement disorder, referred to as manganism. Although the mechanisms by which Mn induces neuronal damage are not well defined, its neurotoxicity appears to be regulated by a number of factors, including oxidative injury, mitochondrial dysfunction and neuroinflammation. To investigate the mechanisms underlying Mn neurotoxicity, we studied the effects of Mn on reactive oxygen species (ROS) formation, changes in high-energy phosphates (HEP), neuroinflammation mediators and associated neuronal dysfunctions both in vitro and in vivo. Primary cortical neuronal cultures showed concentration-dependent alterations in biomarkers of oxidative damage, F{sub 2}-isoprostanes (F{sub 2}-IsoPs) and mitochondrial dysfunction (ATP), as early as 2 h following Mn exposure. Treatment of neurons with 500 {mu}M Mn also resulted in time-dependent increases in the levels of the inflammatory biomarker, prostaglandin E{sub 2} (PGE{sub 2}). In vivo analyses corroborated these findings, establishing that either a single or three (100 mg/kg, s.c.) Mn injections (days 1, 4 and 7) induced significant increases in F{sub 2}-IsoPs and PGE{sub 2} in adult mouse brain 24 h following the last injection. Quantitative morphometric analyses of Golgi-impregnated striatal sections from mice exposed to single or three Mn injections revealed progressive spine degeneration and dendritic damage of medium spiny neurons (MSNs). These findings suggest that oxidative stress, mitochondrial dysfunction and neuroinflammation are underlying mechanisms in Mn-induced neurodegeneration.

  9. Sensory and Cognitive Effects of Acute Exposure to Hydrogen Sulfide

    PubMed Central

    Fiedler, Nancy; Kipen, Howard; Ohman-Strickland, Pamela; Zhang, Junfeng; Weisel, Clifford; Laumbach, Robert; Kelly-McNeil, Kathie; Olejeme, Kelechi; Lioy, Paul

    2008-01-01

    Background Some epidemiologic studies have reported compromised cognitive and sensory performance among individuals exposed to low concentrations of hydrogen sulfide (H2S). Objectives We hypothesized a dose–response increase in symptom severity and reduction in sensory and cognitive performance in response to controlled H2S exposures. Methods In separate exposure sessions administered in random order over three consecutive weeks, 74 healthy subjects [35 females, 39 males; mean age (± SD) = 24.7 ± 4.2; mean years of education = 16.5 ± 2.4], were exposed to 0.05, 0.5, and 5 ppm H2S. During each exposure session, subjects completed ratings and tests before H2S exposure (baseline) and during the final hour of the 2-hr exposure period. Results Dose–response reduction in air quality and increases in ratings of odor intensity, irritation, and unpleasantness were observed. Total symptom severity was not significantly elevated across any exposure condition, but anxiety symptoms were significantly greater in the 5-ppm than in the 0.05-ppm condition. No dose–response effect was observed for sensory or cognitive measures. Verbal learning was compromised during each exposure condition. Conclusions Although some symptoms increased with exposure, the magnitude of these changes was relatively minor. Increased anxiety was significantly related to ratings of irritation due to odor. Whether the effect on verbal learning represents a threshold effect of H2S or an effect due to fatigue across exposure requires further investigation. These acute effects in a healthy sample cannot be directly generalized to communities where individuals have other health conditions and concomitant exposures. PMID:18197303

  10. A mechanistic view of polybrominated diphenyl ether (PBDE) developmental neurotoxicity

    PubMed Central

    Costa, Lucio G.; de Laat, Rian; Tagliaferri, Sara; Pellacani, Claudia

    2013-01-01

    Polybrominated diphenyl ethers (PBDEs), extensively used in the past few decades as flame retardants in a variety of consumer products, have become world-wide persistent environmental pollutants. Levels in North America are usually higher than those in Europe and Asia, and body burden is 3 to 9-fold higher in infants and toddlers than in adults. The latter has raised concern for potential developmental toxicity and neurotoxicity of PBDEs. Experimental studies in animals and epidemiological observations in humans suggest that PBDEs may be developmental neurotoxicants. Pre- and/or post-natal exposure to PBDEs may cause long-lasting behavioral abnormalities, particularly in the domains of motor activity and cognition. The mechanisms underlying the developmental neurotoxic effects of PBDEs are not known, though several hypotheses have been put forward. One general mode of action relates to the ability of PBDEs to impair thyroid hormone homeostasis, thus indirectly affecting the developing brain. An alternative or additional mode of action involves a direct effect of PBDEs on nervous system cells; PBDEs can cause oxidative stress-related damage (DNA damage, mitochondrial dysfunction, apoptosis), and interfere with signal transduction (particularly calcium signaling), and with neurotransmitter systems. Important issues such as bioavailability and metabolism of PBDEs, extrapolation of results to low level of exposures, and the potential effects of interactions among PBDE congeners and between PBDEs and other contaminants also need to be taken into account. PMID:24270005

  11. A mechanistic view of polybrominated diphenyl ether (PBDE) developmental neurotoxicity.

    PubMed

    Costa, Lucio G; de Laat, Rian; Tagliaferri, Sara; Pellacani, Claudia

    2014-10-15

    Polybrominated diphenyl ethers (PBDEs), extensively used in the past few decades as flame retardants in a variety of consumer products, have become world-wide persistent environmental pollutants. Levels in North America are usually higher than those in Europe and Asia, and body burden is 3-to-9-fold higher in infants and toddlers than in adults. The latter has raised concern for potential developmental toxicity and neurotoxicity of PBDEs. Experimental studies in animals and epidemiological observations in humans suggest that PBDEs may be developmental neurotoxicants. Pre- and/or post-natal exposure to PBDEs may cause long-lasting behavioral abnormalities, particularly in the domains of motor activity and cognition. The mechanisms underlying the developmental neurotoxic effects of PBDEs are not known, though several hypotheses have been put forward. One general mode of action relates to the ability of PBDEs to impair thyroid hormone homeostasis, thus indirectly affecting the developing brain. An alternative or additional mode of action involves a direct effect of PBDEs on nervous system cells; PBDEs can cause oxidative stress-related damage (DNA damage, mitochondrial dysfunction, apoptosis), and interfere with signal transduction (particularly calcium signaling), and with neurotransmitter systems. Important issues such as bioavailability and metabolism of PBDEs, extrapolation of results to low level of exposures, and the potential effects of interactions among PBDE congeners and between PBDEs and other contaminants also need to be taken into account. PMID:24270005

  12. Effects of melatonin implants in pony mares. 1. Acute effects.

    PubMed

    Peltier, M R; Robinson, G; Sharp, D C

    1998-04-15

    The effects of melatonin implant treatment over a four week period on LH, estradiol (E2) and progesterone (P4) secretion during the breeding season were studied in ovary-intact and ovariectomized pony mares. Mares with melatonin implants had significantly higher daytime melatonin concentrations than mares with sharm implants (P = 0.0065). In ovariectomized mares, LH secretion did not differ between mares with melatonin and sham implants. In ovary-intact mares, melatonin implants altered the pattern of LH secretion (P = 0.0023) in such a way that an increase in LH secretion was observed during the periovulatory period. Estradiol and P4 secretion were unaffected by melatonin implants. These results suggest that constant administration of melatonin may enhance the secretion of LH during the periovulatory surge but does not adversely affect E2, P4 or basal LH secretion in mares during the breeding season. PMID:10732050

  13. EFFECTS OF SUBSCUTE EXPOSURE TO NANOMOLAR CONCENTRATIONS OF METHYLMERCURY ON VOLTAGE-GATES SODIUM AND CALCIUM CURRENTS IN PC12 CELLS.

    EPA Science Inventory

    Methylmercury (CH3Hg+) alters the function of voltage-gated Na+ and Ca2+ channels in neuronal preparations following acute, in vitro, exposure. Because the developing nervous system is particularly sensitive to CH3Hg+ neurotoxicity, effects on voltage-gated Na+ (INa) and Ca2+ (IC...

  14. Acute Effect of Hookah Smoking on the Human Coronary Microcirculation.

    PubMed

    Nelson, Michael D; Rezk-Hanna, Mary; Rader, Florian; Mason, O'Neil R; Tang, Xiu; Shidban, Sarah; Rosenberry, Ryan; Benowitz, Neal L; Tashkin, Donald P; Elashoff, Robert M; Lindner, Jonathan R; Victor, Ronald G

    2016-06-01

    Hookah (water pipe) smoking is a major new understudied epidemic affecting youth. Because burning charcoal is used to heat the tobacco product, hookah smoke delivers not only nicotine but also large amounts of charcoal combustion products, including carbon-rich nanoparticles that constitute putative coronary vasoconstrictor stimuli and carbon monoxide, a known coronary vasodilator. We used myocardial contrast echocardiography perfusion imaging with intravenous lipid shelled microbubbles in young adult hookah smokers to determine the net effect of smoking hookah on myocardial blood flow. In 9 hookah smokers (age 27 ± 5 years, mean ± SD), we measured myocardial blood flow velocity (β), myocardial blood volume (A), myocardial blood flow (A × β) as well as myocardial oxygen consumption (MVO2) before and immediately after 30 minutes of ad lib hookah smoking. Myocardial blood flow did not decrease with hookah smoking but rather increased acutely (88 ± 10 to 120 ± 19 a.u./s, mean ± SE, p = 0.02), matching a mild increase in MVO2 (6.5 ± 0.3 to 7.6 ± 0.4 ml·minute(-1), p <0.001). This was manifested primarily by increased myocardial blood flow velocity (0.7 ± 0.1 to 0.9 ± 0.1 second(-1), p = 0.01) with unchanged myocardial blood volume (133 ± 7 to 137 ± 7 a.u., p = ns), the same pattern of coronary microvascular response seen with a low-dose β-adrenergic agonist. Indeed, with hookah, the increased MVO2 was accompanied by decreased heart rate variability, an indirect index of adrenergic overactivity, and eliminated by β-adrenergic blockade (i.v. propranolol). In conclusion, nanoparticle-enriched hookah smoke either is not an acute coronary vasoconstrictor stimulus or its vasoconstrictor effect is too weak to overcome the physiologic dilation of coronary microvessels matching mild cardiac β-adrenergic stimulation. PMID:27067622

  15. Are antibiotics a safe and effective treatment for acute uncomplicated appendicitis?

    PubMed

    Moraga, Felipe; Ahumada, Vanessa; Crovari, Fernando

    2016-01-01

    Acute appendicitis is a common cause of acute abdominal pain and the most frequent cause of emergency abdominal surgery. In the last two decades, growing evidence has been published about the use of antibiotics as the exclusive treatment for acute appendicitis. Searching in Epistemonikos database, which is maintained by screening 30 databases, we identified only one systematic review including one pertinent randomized trial. We generated a summary of findings following the GRADE approach. We concluded the use of antibiotics to treat acute uncomplicated appendicitis may be less effective than appendectomy and probably increases major complications compared with appendectomy. PMID:26817927

  16. Acute effects of acrolein in human volunteers during controlled exposure

    PubMed Central

    Dwivedi, Aishwarya M.; Johanson, Gunnar; Lorentzen, Johnny C.; Palmberg, Lena; Sjögren, Bengt; Ernstgård, Lena

    2015-01-01

    Abstract Context: Acrolein is a reactive aldehyde mainly formed by combustion. The critical effect is considered to be irritation of the eyes and airways; however, the scarce data available make it difficult to assess effect levels. Objective: The aim of the study was to determine thresholds for acute irritation for acrolein. Methods: Nine healthy volunteers of each sex were exposed at six occasions for 2 h at rest to: clean air, 15 ppm ethyl acetate (EA), and 0.05 ppm and 0.1 ppm acrolein with and without EA (15 ppm) to mask the potential influence of odor. Symptoms related to irritation and central nervous system effects were rated on 100-mm Visual Analogue Scales. Results: The ratings of eye irritation were slightly but significantly increased during exposure to acrolein in a dose-dependent manner (p < 0.001, Friedman test) with a median rating of 8 mm (corresponding to “hardly at all”) at the 0.1 ppm condition and with no influence from EA. No significant exposure-related effects were found for pulmonary function, or nasal swelling, nor for markers of inflammation and coagulation in blood (IL-6, C-reactive protein, serum amyloid A, fibrinogen, factor VIII, von Willebrand factor, and Clara cell protein) or induced sputum (cell count, differential cell count, IL-6 and IL-8). Blink frequency recorded by electromyography was increased during exposure to 0.1 ppm acrolein alone but not during any of the other five exposure conditions. Conclusion: Based on subjective ratings, the present study showed minor eye irritation by exposure to 0.1 ppm acrolein. PMID:26635308

  17. Targeting neurotrophic factors and their receptors, but not cholinesterase or neurotransmitter, in the neurotoxicity of TDCPP in Chinese rare minnow adults (Gobiocypris rarus).

    PubMed

    Yuan, Lilai; Li, Jiasu; Zha, Jinmiao; Wang, Zijian

    2016-01-01

    Organophosphate flame retardants (OPFRs) have been detected at high concentrations in various environmental and biotic samples, but little is known about their toxicity. In this study, the potential neurotoxicity of three OPFRs (TCEP, TDCPP, and TPP) and Chlorpyrifos (CPF, an organophosphate pesticide) were compared in Chinese rare minnow using an acute toxicity test and a 21-day fish assay. The acute test demonstrated significant inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) by CPF. Although significant AChE inhibition at high concentration of TPP was also observed, none of the OPFRs had effects similar to CPF on these enzymes, indicating that their acute toxicities to Chinese rare minnow may be unrelated to cholinesterase inhibition. In addition, the 21-day fish assay with TDCPP demonstrated no significant effects on cholinesterase activities or neurotransmitter levels. Nonetheless, this OPFR exhibited widespread effects on the neurotrophic factors and their receptors (e.g., ntf3, ntrk1, ntrk2, ngfr, and fgf2, fgf11, fgf22, fgfr4), indicating that TDCPP or other OPFRs may elicit neurological effects by targeting neurotrophic factors and their receptors in Chinese rare minnow. PMID:26552522

  18. Evidence for neurotoxicity associated with amoxicillin in juvenile rats.

    PubMed

    Atli, O; Demir-Ozkay, U; Ilgin, S; Aydin, T H; Akbulut, E N; Sener, E

    2016-08-01

    Amoxicillin (AMX) is one of the most commonly prescribed antibiotics for children, and childhood is the period to have the highest risk for toxicity cases including drug-induced adverse reactions. Some neurological adverse effects (anxiety, hyperactivity, confusion, convulsions, and behavioral changes) have been reported related to AMX treatment. In the present study, we aimed to determine the neurotoxic effects of AMX administration at clinically relevant doses in female juvenile rats. AMX was administered in single oral daily doses of 25 and 50 mg/kg for 14 days. According to our results, while AMX administration caused a significant increase in the immobility time of animals, swimming time of these animals significantly decreased. AMX administration significantly reduced the onset of pentylenetetrazole-induced convulsions. The serotonin levels of brain tissues in the AMX-administered groups were decreased significantly, which is thought to be related to depression. The glutamate levels in brain tissues increased significantly in AMX-administered groups, which is thought to be related to convulsion. Otherwise, superoxide dismutase and catalase activities were significantly decreased in brain tissues of AMX-administered groups. In conclusion, AMX administration triggered depression and shortened the time of the appearance of first seizure in juvenile rats. Also, altered brain neurotransmitter levels and increased oxidative stress observed in our study were thought to be the possible underlying mechanisms of AMX-induced neurotoxicity. PMID:26429924

  19. Molecular Mechanisms of Pyrethroid Insecticide Neurotoxicity: Recent Advances

    PubMed Central

    Soderlund, David M.

    2011-01-01

    Synthetic pyrethroid insecticides were introduced into widespread use for the control of insect pests and disease vectors more than three decades ago. In addition to their value in controlling agricultural pests, pyrethroids are at the forefront of efforts to combat malaria and other mosquito-borne diseases and are also common ingredients of household insecticide and companion animal ectoparasite control products. The abundance and variety of pyrethroid uses contribute to the risk of exposure and adverse effects in the general population. The insecticidal actions of pyrethroids depend on their ability to bind to and disrupt voltage-gated sodium channels of insect nerves. Sodium channels are also important targets for the neurotoxic effects of pyrethroids in mammals but other targets, particularly voltage-gated calcium and chloride channels, have been implicated as alternative or secondary sites of action for a subset of pyrethroids. This review summarizes information published during the past decade on the action of pyrethroids on voltage-gated sodium channels as well as on voltage-gated calcium and chloride channels and provides a critical re-evaluation of the role of these three targets in pyrethroid neurotoxicity based on this information. PMID:21710279

  20. Developmental Neurotoxicity: Some Old and New Issues

    PubMed Central

    Giordano, Gennaro; Costa, Lucio G.

    2012-01-01

    The developing central nervous system is often more vulnerable to injury than the adult one. Of the almost 200 chemicals known to be neurotoxic, many are developmental neurotoxicants. Exposure to these compounds in utero or during childhood can contribute to a variety of neurodevelopmental and neurological disorders. Two established developmental neurotoxicants, methylmercury and lead, and two classes of chemicals, the polybrominated diphenyl ether flame retardants and the organophosphorus insecticides, which are emerging as potential developmental neurotoxicants, are discussed in this paper. Developmental neurotoxicants may also cause silent damage, which would manifest itself only as the individual ages, and may contribute to neurodegenerative diseases such as Parkinson's or Alzheimer's diseases. Guidelines for developmental neurotoxicity testing have been implemented, but there is still room for their improvement and for searching and validating alternative testing approaches. PMID:23724296

  1. Environmental neurotoxicity of chemicals and radiation

    SciTech Connect

    Verity, M.A. )

    1993-06-01

    Epidemiologic and societal concerns continue to stimulate studies in the field of environmental neurotoxicology. Although the role of heavy metals, aluminum, and iron are unclear in the etiology of human neurodegenerative disorders, these toxins have provided fertile ground for in vivo and in vitro experimental studies to elucidate their role in neurotoxic injury. Experimental models of clinical syndromes are discussed with special relevance to developmental neurotoxicology. Cycloleucine, tellurium, and 1,3-dinitrobenzene provide models of subacute combined degeneration, primary peripheral nerve demyelination, and thiamine deficiency-like lesions, respectively. Increasing attention is being given to irradiation neurotoxicity, especially in the developing or young central nervous system. A fuller understanding of the pathogenesis of low-dose irradiation injury allows for a clearer understanding of its neurobiology and also provides a more rational approach to understanding an interventional therapy associated with brain irradiation for childhood neoplasia. 43 refs.

  2. Glutamate neurotoxicity, oxidative stress and mitochondria.

    PubMed

    Atlante, A; Calissano, P; Bobba, A; Giannattasio, S; Marra, E; Passarella, S

    2001-05-18

    The excitatory neurotransmitter glutamate plays a major role in determining certain neurological disorders. This situation, referred to as 'glutamate neurotoxicity' (GNT), is characterized by an increasing damage of cell components, including mitochondria, leading to cell death. In the death process, reactive oxygen species (ROS) are generated. The present study describes the state of art in the field of GNT with a special emphasis on the oxidative stress and mitochondria. In particular, we report how ROS are generated and how they affect mitochondrial function in GNT. The relationship between ROS generation and cytochrome c release is described in detail, with the released cytochrome c playing a role in the cell defense mechanism against neurotoxicity. PMID:11376653

  3. Neurotoxicity of Ecstasy metabolites in rat cortical neurons, and influence of hyperthermia.

    PubMed

    Capela, João Paulo; Meisel, Andreas; Abreu, Artur Reis; Branco, Paula Sério; Ferreira, Luísa Maria; Lobo, Ana Maria; Remião, Fernando; Bastos, Maria Lurdes; Carvalho, Félix

    2006-01-01

    3,4-Methylenedioxymethamphetamine (MDMA or "Ecstasy") is a widely abused, psychoactive recreational drug. There is growing evidence that the MDMA neurotoxic profile may be highly dependent on both its hepatic metabolism and body temperature. Metabolism of MDMA involves N-demethylation to 3,4-methylenedioxyamphetamine (MDA), which is also a drug of abuse. MDMA and MDA are O-demethylenated to N-methyl-alpha-methyldopamine (N-Me-alpha-MeDA) and alpha-methyldopamine (alpha-MeDA), respectively, both of which are catechols that can undergo oxidation to the corresponding ortho-quinones. In the presence of glutathione (GSH), ortho-quinones may be conjugated with GSH to form glutathionyl adducts. In this study, we evaluated the neurotoxicity of MDMA and three of its metabolites obtained by synthesis, N-Me-alpha-MeDA, alpha-MeDA, and 5-(GSH)-alpha-MeDA [5-(glutathion-S-yl)-alpha-methyldopamine] in rat cortical neuronal serum-free cultures under normal (36.5 degrees C) and hyperthermic (40 degrees C) conditions. Cell viability was assessed, and the mechanism of cell death was also evaluated. Our study shows that these metabolites are more neurotoxic [5-(GSH)-alpha-MeDA being the most toxic] than the parent compound MDMA. The neurotoxicity of MDMA metabolites was partially prevented by the antioxidants N-acetylcystein and also, in a minor extent, by alpha-phenyl-N-tert-butyl nitrone. All the tested compounds induced apoptotic cell death in cortical neurons, and their neurotoxic effect was potentiated under hyperthermic conditions. These data suggest that MDMA metabolites, especially under hyperthermic conditions, contribute to MDMA-induced neurotoxicity. PMID:16183702

  4. Effect of Acute and Chronic Calcium Administration on Plasma Renin

    PubMed Central

    Kotchen, Theodore A.; Mauli, Kimball I.; Luke, Robert; Rees, Douglas; Flamenbaum, Walter

    1974-01-01

    To evaluate the effect of Ca++ on renin release, plasma renin activity (PRA) was measured after acute and chronic Ca++ administration. 1% CaCl2 was infused into one renal artery of 10 anesthetized dogs (0.3 mg/kg/min). The excreted fraction of filtered calcium (EFca++) and EFNa+ from the infused kidney were elevated (P < 0.04) during three successive 15-min infusion periods. Serum calcium concentration was significantly elevated (P < 0.001). Creatinine clearance, systemic arterial pressure, and renal blood flow did not change (P > 0.10). Compared to control (45 ng/ml/h±5.2 SE), renal venous PRA was suppressed (P < 0.0001) after infusion of Ca++ for 15, 30, and 45 min (20 ng/ml/h±4.6, 16 ng/ml/h±4.0, and 13 ng/ml/h±2.7, respectively). 15 and 30-min after infusion, PRA did not differ from control (P > 0.20). Chronic Ca++ loading was achieved in Sprague-Dawley rats by replacing drinking water with 1% CaCl2 for 17 days. At sacrifice, serum Ca++, Na+, and K+ of controls (n = 12) did not differ (P > 0.60) from Ca++-loaded rats (n = 12). Ca++ excretion (467 μeq/24 h±51) was elevated (P < 0.001) compared to controls (85 μeq/24 h±12). PRA (8.6 ng/ml/h±1.4) and renal renin content of Ca++-loaded rats did not differ from controls (P > 0.80). However, after 8 days of sodium deprivation, both PRA and renal renin content of calcium-loaded animals were significantly lower than the respective values in pair-fed controls (P < 0.005). During the period of sodium deprivation, calcium-drinking animals were in greater negative sodium balance than controls (P < 0.005). The data are consistent with the hypothesis that acute and chronic calcium administration inhibit renin secretion. PMID:4436432

  5. Protective Effects of Hydrogen Gas on Experimental Acute Pancreatitis

    PubMed Central

    Zhou, Hao-xin; Han, Bing; Hou, Li-Min; An, Ting-Ting; Jia, Guang; Cheng, Zhuo-Xin; Ma, Yong; Zhou, Yi-Nan; Kong, Rui; Wang, Shuang-Jia; Wang, Yong-Wei; Sun, Xue-Jun; Pan, Shang-Ha; Sun, Bei

    2016-01-01

    Acute pancreatitis (AP) is an inflammatory disease mediated by damage to acinar cells and pancreatic inflammation. In patients with AP, subsequent systemic inflammatory responses and multiple organs dysfunction commonly occur. Interactions between cytokines and oxidative stress greatly contribute to the amplification of uncontrolled inflammatory responses. Molecular hydrogen (H2) is a potent free radical scavenger that not only ameliorates oxidative stress but also lowers cytokine levels. The aim of the present study was to investigate the protective effects of H2 gas on AP both in vitro and in vivo. For the in vitro assessment, AR42J cells were treated with cerulein and then incubated in H2-rich or normal medium for 24 h, and for the in vivo experiment, AP was induced through a retrograde infusion of 5% sodium taurocholate into the pancreatobiliary duct (0.1 mL/100 g body weight). Wistar rats were treated with inhaled air or 2% H2 gas and sacrificed 12 h following the induction of pancreatitis. Specimens were collected and processed to measure the amylase and lipase activity levels; the myeloperoxidase activity and production levels; the cytokine mRNA expression levels; the 8-hydroxydeoxyguanosine, malondialdehyde, and glutathione levels; and the cell survival rate. Histological examinations and immunohistochemical analyses were then conducted. The results revealed significant reductions in inflammation and oxidative stress both in vitro and in vivo. Furthermore, the beneficial effects of H2 gas were associated with reductions in AR42J cell and pancreatic tissue damage. In conclusion, our results suggest that H2 gas is capable of ameliorating damage to the pancreas and AR42J cells and that H2 exerts protective effects both in vitro and in vivo on subjects with AP. Thus, the results obtained indicate that this gas may represent a novel therapy agent in the management of AP. PMID:27115738

  6. The effects of acute hyperinsulinemia on bone metabolism

    PubMed Central

    Ivaska, Kaisa K; Heliövaara, Maikki K; Ebeling, Pertti; Bucci, Marco; Huovinen, Ville; Väänänen, H Kalervo; Nuutila, Pirjo; Koistinen, Heikki A

    2015-01-01

    Insulin signaling in bone-forming osteoblasts stimulates bone formation and promotes the release of osteocalcin (OC) in mice. Only a few studies have assessed the direct effect of insulin on bone metabolism in humans. Here, we studied markers of bone metabolism in response to acute hyperinsulinemia in men and women. Thirty-three subjects from three separate cohorts (n=8, n=12 and n=13) participated in a euglycaemic hyperinsulinemic clamp study. Blood samples were collected before and at the end of infusions to determine the markers of bone formation (PINP, total OC, uncarboxylated form of OC (ucOC)) and resorption (CTX, TRAcP5b). During 4 h insulin infusion (40 mU/m2 per min, low insulin), CTX level decreased by 11% (P<0.05). High insulin infusion rate (72 mU/m2 per min) for 4 h resulted in more pronounced decrease (−32%, P<0.01) whereas shorter insulin exposure (40 mU/m2 per min for 2 h) had no effect (P=0.61). Markers of osteoblast activity remained unchanged during 4 h insulin, but the ratio of uncarboxylated-to-total OC decreased in response to insulin (P<0.05 and P<0.01 for low and high insulin for 4 h respectively). During 2 h low insulin infusion, both total OC and ucOC decreased significantly (P<0.01 for both). In conclusion, insulin decreases bone resorption and circulating levels of total OC and ucOC. Insulin has direct effects on bone metabolism in humans and changes in the circulating levels of bone markers can be seen within a few hours after administration of insulin. PMID:26047829

  7. Acute effect of ephedrine on 24-h energy balance

    NASA Technical Reports Server (NTRS)

    Shannon, J. R.; Gottesdiener, K.; Jordan, J.; Chen, K.; Flattery, S.; Larson, P. J.; Candelore, M. R.; Gertz, B.; Robertson, D.; Sun, M.

    1999-01-01

    Ephedrine is used to help achieve weight control. Data on its true efficacy and mechanisms in altering energy balance in human subjects are limited. We aimed to determine the acute effect of ephedrine on 24-h energy expenditure, mechanical work and urinary catecholamines in a double-blind, randomized, placebo-controlled, two-period crossover study. Ten healthy volunteers were given ephedrine (50 mg) or placebo thrice daily during each of two 24-h periods (ephedrine and placebo) in a whole-room indirect calorimeter, which accurately measures minute-by-minute energy expenditure and mechanical work. Measurements were taken of 24-h energy expenditure, mechanical work, urinary catecholamines and binding of (+/-)ephedrine in vitro to human beta1-, beta2- and beta3-adrenoreceptors. Twenty-four-hour energy expenditure was 3.6% greater (8965+/-1301 versus 8648+/-1347 kJ, P<0.05) with ephedrine than with placebo, but mechanical work was not different between the ephedrine and placebo periods. Noradrenaline excretion was lower with ephedrine (0.032+/-0.011 microg/mg creatinine) compared with placebo (0.044+/-0.012 microg/mg creatinine) (P<0.05). (+/-)Ephedrine is a relatively weak partial agonist of human beta1- and beta2-adrenoreceptors, and had no detectable activity at human beta3-adrenoreceptors. Ephedrine (50 mg thrice daily) modestly increases energy expenditure in normal human subjects. A lack of binding of ephedrine to beta3-adrenoreceptors and the observed decrease in urinary noradrenaline during ephedrine treatment suggest that the thermogenic effect of ephedrine results from direct beta1-/beta2-adrenoreceptor agonism. An indirect beta3-adrenergic effect through the release of noradrenaline seems unlikely as urinary noradrenaline decreased significantly with ephedrine.

  8. Mechanisms of interleukin-22's beneficial effects in acute pancreatitis.

    PubMed

    Huan, Chongmin; Kim, Daniel; Ou, Peiqi; Alfonso, Antonio; Stanek, Albert

    2016-02-15

    Acute pancreatitis (AP) is a disorder characterized by parenchymal injury of the pancreas controlled by immune cell-mediated inflammation. AP remains a significant challenge in the clinic due to a lack of specific and effective treatment. Knowledge of the complex mechanisms that regulate the inflammatory response in AP is needed for the development of new approaches to treatment, since immune cell-derived inflammatory cytokines have been recognized to play critical roles in the pathogenesis of the disease. Recent studies have shown that interleukin (IL)-22, a cytokine secreted by leukocytes, when applied in the severe animal models of AP, protects against the inflammation-mediated acinar injury. In contrast, in a mild AP model, endogenous IL-22 has been found to be a predominantly anti-inflammatory mediator that inhibits inflammatory cell infiltration via the induction of Reg3 proteins in acinar cells, but does not protect against acinar injury in the early stage of AP. However, constitutively over-expressed IL-22 can prevent the initial acinar injury caused by excessive autophagy through the induction of the anti-autophagic proteins Bcl-2 and Bcl-XL. Thus IL-22 plays different roles in AP depending on the severity of the AP model. This review focuses on these recently reported findings for the purpose of better understanding IL-22's regulatory roles in AP which could help to develop a novel therapeutic strategy. PMID:26909233

  9. Effects of acute spinalization on neurons of postural networks

    PubMed Central

    Zelenin, Pavel V.; Lyalka, Vladimir F.; Hsu, Li-Ju; Orlovsky, Grigori N.; Deliagina, Tatiana G.

    2016-01-01

    Postural limb reflexes (PLRs) represent a substantial component of postural corrections. Spinalization results in loss of postural functions, including disappearance of PLRs. The aim of the present study was to characterize the effects of acute spinalization on two populations of spinal neurons (F and E) mediating PLRs, which we characterized previously. For this purpose, in decerebrate rabbits spinalized at T12, responses of interneurons from L5 to stimulation causing PLRs before spinalization, were recorded. The results were compared to control data obtained in our previous study. We found that spinalization affected the distribution of F- and E-neurons across the spinal grey matter, caused a significant decrease in their activity, as well as disturbances in processing of posture-related sensory inputs. A two-fold dec