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Sample records for acute neurotoxic effects

  1. Acute neurotoxic effects of mancozeb and maneb in mesencephalic neuronal cultures are associated with mitochondrial dysfunction.

    PubMed

    Domico, Lisa M; Zeevalk, Gail D; Bernard, Laura P; Cooper, Keith R

    2006-09-01

    Recent studies suggest that exposure to agrochemicals may contribute to the development of idiopathic Parkinson's disease. Maneb (MB), a widely used Mn-containing ethylene-bis-dithiocarbamate (EBDC) fungicide, has been implicated in selective dopaminergic neurotoxicity. In this study, we examine the potential neurotoxicity of mancozeb (MZ), a widely used EBDC fungicide that is structurally similar to MB, but contains both Zn and Mn. Primary mesencephalic cells isolated from Sprague-Dawley embryonic day 15 rat embryos were exposed in vitro to either MZ or MB to compare their cytotoxic potential. Exposure to 10-120 microM MZ or MB for 24h resulted in a dose-dependent toxicity in both the dopamine (DA) and GABA mesencephalic populations as assessed by a functional assay for high affinity transporter activity. Consistent with this, cell viability as well as tyrosine hydroxylase-positive neurons decreased with increasing doses of MZ or MB. Toxic potencies for MZ and MB were similar and no difference in sensitivity between the DA and GABA populations was observed with the fungicides. Exposure to ethylene thiourea, the major metabolite of either MZ or MB, was not toxic, implicating the parent compound in toxicity. Both the organic and Mn metal components of the fungicides were found to contribute to toxicity. Non-toxic exposures to the fungicides decreased ATP levels in a dose-dependent manner suggesting impairment of energy metabolism. In whole mitochondrial preparations isolated from adult rat brains, MZ and MB inhibited NADH-linked state 3 respiration. Mild to moderate mitochondrial uncoupling was also observed in response to the fungicides. In conclusion, our findings indicate that acute exposure to high doses of MZ and MB produce equipotent toxic effects in both DA and GABA neurons that may be associated with perturbations in mitochondrial respiration.

  2. Effects of blood purification therapy on a patient with ifosfamide-induced neurotoxicity and acute kidney injury.

    PubMed

    Nishimura, Hiroaki; Enokida, Hideki; Nagano, Satoshi; Yokouchi, Masahiro; Hayami, Hiroshi; Komiya, Setsuro; Nakagawa, Masayuki

    2014-03-01

    Ifosfamide combined with other antineoplastic agents has been effective in the treatment of osteosarcoma, although adverse effects are reported in the increasing use of ifosfamide. The most serious complications among the ifosfamide intoxications are neurotoxicity and nephrotoxicity. We report on a patient who suffered from ifosfamide-induced neurotoxicity and nephrotoxicity and rhabdomyolysis after chemotherapy, and was successfully treated with blood purification therapy. The patient had osteosarcoma with multiple lung metastases, wherein the chemotherapy included ifosfamide (3 g/m(2)) and VP-16 (60 mg/m(2)) per day for 3 days. The first day after chemotherapy, the patient experienced impaired consciousness and renal function. Based on the clinical course and laboratory data, the diagnosis was ifosfamide-induced neurotoxicity and the acute kidney injury caused by ifosfamide-induced nephrotoxicity and rhabdomyolysis. As a detoxification treatment, blood purification procedures were performed daily for 3 days. Thirty-six hours after the first hemodialysis session, the symptoms of neurotoxicity disappeared. In the lead-up to the 10th day following intoxication, the serum creatinine recovered to the baseline level. Serum ifosfamide concentration decreased from 41.9 to 12.1 ng/ml by the second session of blood purification. Despite the absence of an established detoxification method when complications present simultaneously, blood purification therapy should be considered for treating severe concurrent neurotoxicity and nephrotoxicity and rhabdomyolysis.

  3. Acute exposure to DE-71: effects on locomotor behavior and developmental neurotoxicity in zebrafish larvae.

    PubMed

    Chen, Lianguo; Huang, Changjiang; Hu, Chenyan; Yu, Ke; Yang, Lihua; Zhou, Bingsheng

    2012-10-01

    The aim of the present study was to investigate the acute developmental neurotoxicity of polybrominated diphenyl ethers (PBDEs) in zebrafish larvae. From 2 to 120 h postfertilization zebrafish embryos were exposed to DE-71 (0, 31.0, 68.7, and 227.6 µg/L). The authors studied the locomotor behavior of larvae, involvement of the cholinergic system, and selected gene and protein expressions in the central nervous system. The results showed that low DE-71 concentration caused hyperactivity, whereas higher concentrations decreased activity during the dark period. During the light period, larval activity was significantly reduced in a concentration-dependent manner. In the cholinergic system, acetylcholinesterase activity significantly increased (10.7 and 12.4%) in the 68.7 and 227.6 µg/L exposure groups, respectively, and acetylcholine concentration accordingly decreased (60.5%) in the 227.6 µg/L exposure group. The mRNA expressions of genes encoding myelin basic protein, neuron microtubule protein (α1-tubulin), and sonic hedgehog a were significantly downregulated. Western blotting assay demonstrated that the protein concentration of α1-tubulin was also decreased. Overall, the present study demonstrated that acute exposure to PBDEs can disrupt the neurobehavior of zebrafish larvae and affect cholinergic neurotransmission and neuron development.

  4. 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

    2015-06-02

    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

  5. 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.

  6. Cadmium and Its Neurotoxic Effects

    PubMed Central

    Wang, Bo; Du, Yanli

    2013-01-01

    Cadmium (Cd) is a heavy metal that has received considerable concern environmentally and occupationally. Cd has a long biological half-life mainly due to its low rate of excretion from the body. Thus, prolonged exposure to Cd will cause toxic effect due to its accumulation over time in a variety of tissues, including kidneys, liver, central nervous system (CNS), and peripheral neuronal systems. Cd can be uptaken from the nasal mucosa or olfactory pathways into the peripheral and central neurons; for the latter, Cd can increase the blood brain barrier (BBB) permeability. However, mechanisms underlying Cd neurotoxicity remain not completely understood. Effect of Cd neurotransmitter, oxidative damage, interaction with other metals such as cobalt and zinc, estrogen-like, effect and epigenetic modification may all be the underlying mechanisms. Here, we review the in vitro and in vivo evidence of neurotoxic effects of Cd. The available finding indicates the neurotoxic effects of Cd that was associated with both biochemical changes of the cell and functional changes of central nervous system, suggesting that neurotoxic effects may play a role in the systemic toxic effects of the exposure to Cd, particularly the long-term exposure. PMID:23997854

  7. 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.

  8. A comparison of the potency of newly developed oximes (K347, K628) and currently available oximes (obidoxime, HI-6) to counteract acute neurotoxic effects of Tabun in rats.

    PubMed

    Kassa, Jirí; Karasová, Jana Zdarová; Tesarová, Sandra; Musílek, Kamil; Kuca, Kamil

    2010-01-01

    The ability of newly developed oximes (K347, K628) to reduce tabun-induced acute neurotoxic signs and symptoms was compared with currently available oximes (obidoxime, HI-6) using a functional observational battery. The neuroprotective effects of the oximes studied (K347, K628, obidoxime, HI-6) combined with atropine on rats poisoned with tabun at a sublethal dose (220 microg/kg i.m.; 80% of LD50 value) were evaluated. Tabun-induced neurotoxicity was monitored by a functional observational battery and automatic measurement of motor activity at 24 hours following tabun challenge. The results indicate that all tested oximes combined with atropine enable tabun-poisoned rats to survive 24 hours following tabun challenge. Both newly developed oximes (K347, K628) combined with atropine are able to decrease tabun-induced neurotoxicity in the case of sublethal poisonings but they do not eliminate all tabun-induced acute neurotoxic signs and symptoms. Their ability to decrease the tabun-induced acute neurotoxicity is higher than that of the oxime HI-6 and it is slightly slower than the neuroprotective efficacy of obidoxime. As the neuroprotective potency of both newly developed oximes (K347, K628) is not as high as the potency of obidoxime, they are not a suitable replacement for obidoxime for the treatment of acute tabun poisonings.

  9. Neurotoxic effects of methamphetamine.

    PubMed

    Thrash, Bessy; Karuppagounder, Senthilkumar S; Uthayathas, Subramaniam; Suppiramaniam, Vishnu; Dhanasekaran, Muralikrishnan

    2010-01-01

    In Parkinson's disease, depletion of dopamine in the striatum leads to various symptoms such as tremor, rigidity and akinesia. Methamphetamine use has significantly increased in USA and around the world and there are several reports showing that its long-term use increases the risk for dopamine depletion. However, the toxic mechanisms of methamphetamine are not well understood. This study was undertaken to gain greater mechanistic understanding of the toxicity induced by methamphetamine. We evaluated the effect of methamphetamine on the generation of reactive oxygen species, mitochondrial monoamine oxidase, complex I & IV activities. Behavioral analysis evaluated the effect on catalepsy, akinesia and swim score. Neurotransmitter levels were evaluated using high pressure liquid chromatography (HPLC) electrochemical detection (ECD). Results showed that methamphetamine caused significant generation of reactive oxygen species and decreased complex I activity in the mitochondria leading to dopamine depletion in the striatum.

  10. Acute neurotoxicity after trichloroethylene ingestion. Case report.

    PubMed

    Perticoni, G F; Bondi, L

    1988-04-01

    Trichloroethylene (TCE), a solvent widely used in the chemical industry, in dry cleaning because of its degreasing action and as a household grease remover, is known to have a toxic action, especially on the nervous system. Cases of intoxication, acute and chronic, due to inhalation, are reported. We report a case, certainly an unusual one, of acute oral intoxication.

  11. 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...

  12. Acute neurotoxicity after yohimbine ingestion by a body builder.

    PubMed

    Giampreti, Andrea; Lonati, Davide; Locatelli, Carlo; Rocchi, Loretta; Campailla, Maria Teresa

    2009-09-01

    Yohimbine is an alkaloid obtained from the Corynanthe yohimbe tree and other biological sources. Yohimbine is currently approved in the United States for erectile dysfunction and has undergone resurgence in street use as an aphrodisiac and mild hallucinogen. In recent years yohimbine use has become common in body-building communities for its presumed lipolytic and sympathomimetic effects. We describe a 37-year-old bodybuilder in which severe acute neurotoxic effects occurred in 2 h after yohimbine ingestion. The patient presented with malaise, vomiting, loss of consciousness, and repeated seizures after ingestion of 5 g of yohimbine during a body-building competition in a gymnasium. His Glasgow Coma Score was 3, requiring orotracheal intubation. Two hours after admission, vital signs were blood pressure 259/107 mmHg and heart rate 140 beats/min. Treatment with furosemide, labetalol, clonidine, and urapidil and gastrointestinal decontamination were performed. Twelve hours later the patient was extubated with normal hemodynamic parameters and neurological examination. The yohimbine blood levels at 3, 6, 14, and 22 h after ingestion were 5,240; 2,250; 1,530; and 865 ng/mL, respectively, with a mean half-life of 2 h. Few data are available about yohimbine toxicity and the related blood levels. This is a case of a large ingestion of yohimbine in which severe hemodynamic and neurological manifestations occurred and elevated blood levels of yohimbine were detected.

  13. Severe neurotoxicity following intrathecal methotrexate with nitrous oxide sedation in a child with acute lymphoblastic leukemia.

    PubMed

    Löbel, U; Trah, J; Escherich, G

    2015-03-01

    Systemic and intrathecal methotrexate is widely used in treatment protocols for childhood acute lymphoblastic leukemia. Its side effects vary in characteristics, intensity and time of onset, and depend on the administration route. Interactions with several drugs are known. Side effects of nitrous oxide sedation, often used for moderately painful procedures, typically occur after long time use and include neurological symptoms. We present a child who experienced a severe and long-lasting neurotoxicity after the third intrathecal application of methotrexate with short sedation by nitrous oxide during induction therapy for acute lymphoblastic leukemia. Symptoms completely resolved after 12 months.

  14. Effects of intralipid and caffeic acid phenethyl ester on neurotoxicity, oxidative stress, and acetylcholinesterase activity in acute chlorpyriphos intoxication

    PubMed Central

    Ozkan, Umit; Osun, Arif; Basarslan, Kagan; Senol, Serkan; Kaplan, Ibrahim; Alp, Harun

    2014-01-01

    Chlorpyriphos is one of the most widely used organophosphate (OP) insecticide in agriculture with potential toxicity. Current post-exposure treatments consist of anti-cholinergic drugs and oxime compounds. We studied the effects of intralipid and caffeic acid phenethyl ester (CAPE) on chlorpyriphos toxicity to compose an alternative or supportive treatment for OP poisoning. Methods: Forty-nine rats were randomly divided into seven groups. Chlorpyriphos was administered for toxicity. Intralipid (IL) and CAPE administered immediately after chlorpyriphos. Serum acetylcholinesterase (AChE) level, total oxidant status (TOS), total antioxidant response (TAR), and histologic examination of cerebellum and brain tissue with Hematoxylin-Eosin and immunohistochemical dyes were examined. Results: Serum enzym levels showed that chlorpyriphos and CAPE inhibited AChE while IL alone had no effect, chlorpyriphos and CAPE intensifies the inhibition effect. Significant difference at AChE levels between the chlorpyriphos+IL and chlorpyriphos+CAPE verified that IL has a protective effect on AChE inhibition. TAR levels were significantly increased in all groups except chlorpyriphos group, TOS levels revealed that CAPE and IL decrease the amount of oxidative stress. Histologic examination revealed that neuronal degeneration was slightly decreased at chlorpyriphos+IL group, but CAPE had a significant effect on protection of neuronal degeneration. Conclusion: The results of this study gave us three key points. 1) AChE activity is important for diagnosis of OP intoxication but it has no value for determining the neuro-degeneration. 2) CAPE inhibits AChE activity and may increase the muscarinic-nicotinic hyperactivation. Therefore it should not be used for treatment of OP intoxication. 3) IL decreases the severity of neurodegeneration and symptoms of OP intoxication and it can be used as a supportive agent. PMID:24955152

  15. 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...

  16. 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.

  17. 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

  18. Comparing cognitive and screening tests for neurotoxicity. Effects of acute chlorpyrifos on visual signal detection and a neurobehavioral test battery in rats.

    PubMed

    Bushnell, P J; Moser, V C; Samsam, T E

    2001-01-01

    It is often assumed that cognitive function is more sensitive to neurotoxic chemicals than are the unconditioned behaviors employed in neurobehavioral screens; however, direct comparisons of the sensitivity of these test methods are lacking. The present studies were conducted to compare the effects of the widely used cholinesterase-inhibiting insecticide, chlorpyrifos (O,O'-diethyl O-3,5,6-trichloro-2-pyridyl phosphorothionate, CPF), on a visual signal detection task (SDT) with its effects on a neurobehavioral test battery. Adult male Long-Evans rats were trained to perform the SDT, dosed with CPF, and then assessed with both test instruments. Oral CPF (50 mg/kg) impaired signal detection for 8 days, and subcutaneous CPF (250 mg/kg) did so for 4 weeks. CPF (30 and 50 mg/kg po and 250 mg/kg sc) also lowered activity in the test battery for up to 18 days. Thus, CPF impaired attention and altered behavior in the test battery in the same dose ranges under two very different dosing scenarios.

  19. 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.

  20. A comparison of the potency of a novel bispyridinium oxime K203 and currently available oximes (obidoxime, HI-6) to counteract the acute neurotoxicity of sarin in rats.

    PubMed

    Kassa, Jiri; Misik, Jan; Karasova, Jana Zdarova

    2012-11-01

    The neuroprotective effects of a newly developed oxime K203 and currently available oximes (obidoxime, HI-6) in combination with atropine in rats poisoned with sarin were studied. The sarin-induced neurotoxicity was monitored using a functional observatory battery at 2 hr after sarin challenge. The results indicate that the potency of a novel bispyridinium oxime K203 to counteract sarin-induced neurotoxicity is relatively low and roughly corresponds to the neuroprotective efficacy of obidoxime. Among tested oximes, the oxime HI-6 seems to be significanlty more efficacious to counteract acute neurotoxicity of sarin than commonly used obidoxime and a newly developed oxime K203. Thus, the oxime K203 does not provide any beneficial effect for the antidotal treatment of acute poisoning with sarin in comparison with the oxime HI-6 that should be considered to be the best oxime for antidotal treatment of acute sarin poisonings.

  1. 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...

  2. 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…

  3. AGE-DEPENDENT HEAPATIC AND PLASMA METABOLISM OF DELTAMETHRIN IN VITRO: ROLE IN ACUTE NEUROTOXICITY.

    EPA Science Inventory

    Deltamethrin (DLM) is a relatively potent and a widely used pyrethroid insecticide. Inefficient metabolism is proposed to be the reason for the greater sensitivity of immature rats to DLM acute neurotoxicity. The aim of this study was to test this hypothesis by characterizing the...

  4. Developmental neurotoxic effects of two pesticides: Behavior and biomolecular studies on chlorpyrifos and carbaryl.

    PubMed

    Lee, Iwa; Eriksson, Per; Fredriksson, Anders; Buratovic, Sonja; Viberg, Henrik

    2015-11-01

    In recent times, an increased occurrence of neurodevelopmental disorders, such as neurodevelopmental delays and cognitive abnormalities has been recognized. Exposure to pesticides has been suspected to be a possible cause of these disorders, as these compounds target the nervous system of pests. Due to the similarities of brain development and composition, these pesticides may also be neurotoxic to humans. We studied two different pesticides, chlorpyrifos and carbaryl, which specifically inhibit acetylcholinesterase (AChE) in the nervous system. The aim of the study was to investigate if the pesticides can induce neurotoxic effects, when exposure occurs during a period of rapid brain growth and maturation. The results from the present study show that both compounds can affect protein levels in the developing brain and induce persistent adult behavior and cognitive impairments, in mice neonatally exposed to a single oral dose of chlorpyrifos (0.1, 1.0 or 5mg/kg body weight) or carbaryl (0.5, 5.0 or 20.0mg/kg body weight) on postnatal day 10. The results also indicate that the developmental neurotoxic effects induced are not related to the classical mechanism of acute cholinergic hyperstimulation, as the AChE inhibition level (8-12%) remained below the threshold for causing systemic toxicity. The neurotoxic effects are more likely caused by a disturbed neurodevelopment, as similar behavioral neurotoxic effects have been reported in studies with pesticides such as organochlorines, organophosphates, pyrethroids and POPs, when exposed during a critical window of neonatal brain development.

  5. Pb neurotoxicity: neuropsychological effects of lead toxicity.

    PubMed

    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.

  6. Dissecting the Influence of Two Structural Substituents on the Differential Neurotoxic Effects of Acute Methamphetamine and Mephedrone Treatment on Dopamine Nerve Endings with the Use of 4-Methylmethamphetamine and Methcathinone.

    PubMed

    Anneken, John H; Angoa-Pérez, Mariana; Sati, Girish C; Crich, David; Kuhn, Donald M

    2017-03-01

    Mephedrone (MEPH) is a β-ketoamphetamine stimulant drug of abuse that is often a constituent of illicit bath salts formulations. Although MEPH bears remarkable similarities to methamphetamine (METH) in terms of chemical structure, as well as its neurochemical and behavioral effects, it has been shown to have a reduced neurotoxic profile compared with METH. The addition of a β-keto moiety and a 4-methyl ring substituent to METH yields MEPH, and a loss of direct neurotoxic potential. In the present study, two analogs of METH, methcathinone (MeCa) and 4-methylmethamphetamine (4MM), were assessed for their effects on mouse dopamine (DA) nerve endings to determine the relative contribution of each individual moiety to the loss of direct neurotoxicity in MEPH. Both MeCa and 4MM caused significant alterations in core body temperature as well as locomotor activity and stereotypy, but 4MM was found to elicit minimal dopaminergic toxicity only at the highest dose. By contrast, MeCa caused significant reductions in all markers of DA nerve-ending damage over a range of doses. These results lead to the conclusion that ring substitution at the 4-position profoundly reduces the neurotoxicity of METH, whereas the β-keto group has much less influence on this property. Although the mechanism(s) by which the 4-methyl substituent reduces METH-induced neurotoxicity remains unclear, it is speculated that this effect is mediated by a loss of DA-releasing action in MEPH and 4MM at the synaptic vesicle monoamine transporter, an effect that is thought to be critical for METH-induced neurotoxicity.

  7. [Neurotoxic effects of cobalt: an open question].

    PubMed

    Catalani, S; Apostoli, P

    2011-01-01

    Increased cobalt levels have been associated with neurological diseases (hand tremor, incoordination, cognitive decline, depression, vertigo, hearing loss and visual changes) in addition to "classic" and known cardiac diseases (arrhythmias and cardiomyopathies) and allergic or endocrine symptoms. Cobalt neurotoxicity is reported in isolated cases: old occupational or iatrogenic exposures and more recent releases of metallic ions by prosthesis. The studies of these cases have revealed a typical symptomatology of cobalt probably due to its ability to induce oxidative stress and mitochondrial alterations.

  8. Acute, delayed neurotoxicity evaluation of two jet-engine-oil formulations. Final report, May-October 1989

    SciTech Connect

    Kinkead, E.R.; Bunger, S.R.; Wolfe, R.E.; Wall, H.G.

    1990-04-01

    This study was designed to determine the potential of two jet oils to produce acute, delayed neurotoxicity. The hydrocarbon-based ester oil formulation contained 3% tricresyl phosphate isomers, including triorthocresyl phosphate (TOCP) in one of the formulations. Hens were orally dosed over a five-day period and then observed for a total period of 30 days. All TOCP-positive control hens demonstrated signs of acute, delayed neurotoxicity. Hens from both jet engine oil groups remained asymptomatic throughout the observation period. No neurotoxic hazard would be expected for military or civilian personnel involved in the manufacture, transportation, or handling of these compounds.

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

    PubMed

    Moser, Virginia C

    2011-01-01

    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, along with motor activity, for mevinphos, monocrotophos, dicrotophos, and phosphamidon. Long-Evans hooded male rats were tested as adults and at postnatal day (PND) 17; PND11 pups were also tested with dicrotophos only. All chemicals were administered via oral gavage and tests were conducted at times intended to span peak behavioral and ChE effects. All OPs tested produced a rapid onset and recovery from the behavioral effects. There were age-related differences in the inhibition of brain, but not necessarily RBC, ChE. Mevinphos was clearly more toxic, up to 4-fold, to the young rat. On the other hand, monocrotophos, dicrotophos, and phosphamidon were somewhat more toxic to the young rat, but the magnitude of the differences was < 2-fold lower. Motor activity was consistently decreased in adults for all chemicals tested; however, there was more variability with the pups and clear age-related differences were only observed for mevinphos. These data show that three of these four OPs were only moderately more toxic in young rats, and further support findings that age-related differences in pesticide toxicity are chemical-specific.

  10. 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.

  11. Neurotoxic effects of exogenous recombinant tissue-type plasminogen activator on the normal rat brain.

    PubMed

    Goto, Hisaharu; Fujisawa, Hirosuke; Oka, Fumiaki; Nomura, Sadahiro; Kajiwara, Koji; Kato, Shoichi; Fujii, Masami; Maekawa, Tsuyoshi; Suzuki, Michiyasu

    2007-04-01

    Thrombolytic therapy with intravenous and intra-arterial recombinant tissue-type plasminogen activator (rtPA) has been established for the treatment of acute ischemic stroke. However, tPA has also been suggested to have neurotoxic effects. The purpose of this study was to examine direct neurotoxicity of rtPA in vivo. The animals (Wistar rats) were divided to the following three groups: low-dose (15 micromol/L) rtPA group (n = 6); high-dose (30 micromol/L) rtPA group (n = 6); and control (physiological saline) group (n = 6). The rtPA solution was perfused into the cortex via a microdialysis probe. The volume of the lesion was quantified histologically by image analysis of the lesions. Blood-brain barrier (BBB) disruption was evaluated by intravenous injection of Evans blue, and injury to the basal lamina was evaluated by immunohistochemistry using an anti-laminin antibody. In the rtPA-perfused animals, a pale lesion was produced around the probe, and microscopically, neurons showed necrotic changes. The volume of the lesions increased significantly as the concentration of perfused rtPA was increased. Marked extravasation of Evans blue was observed, and laminin immunoreactivity of blood vessels in the rtPA-induced lesions was lost. These results suggest that rtPA promotes acute direct neurotoxicity and participates in disruption of the microvascular basal lamina to cause BBB disruption, thereby increasing edema formation.

  12. 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

  13. 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.

  14. Calpain activation is involved in acute manganese neurotoxicity in the rat striatum in vivo.

    PubMed

    Quintanar, Liliana; Montiel, Teresa; Márquez, Maripaz; González, Alejandra; Massieu, Lourdes

    2012-01-01

    Manganese is essential for life, yet chronic exposure to this metal can cause a neurodegenerative disease named manganism that affects motor function. In the present study we have evaluated Mn neurotoxicity after its administration in the rat striatum. The participation of the calcium-dependent protease calpain and the apoptosis-related protease caspase-3, in Mn-induced cell death was monitored in the striatum and globus pallidus. Mn induced the activation of both proteases, although calpain activation seems to be an earlier event. Moreover, while the broad-spectrum caspase inhibitor QVD did not significantly prevent Mn-induced cell death, the specific calpain inhibitor MDL-28170 did. The role of NMDA glutamate receptors on calpain activity was also investigated; blockage of these receptors by MK-801 and memantine did not prevent calpain activation, nor Mn-induced cell death. Finally, studies in striatal homogenates suggest a direct activation of calpain by Mn ions. Altogether the present study suggests that additional mechanisms to excitotoxicity are involved in Mn-induced cell death, placing calpain as an important mediator of acute Mn neurotoxicity in vivo.

  15. 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

  16. 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.

  17. Differential effects of amphetamines-induced neurotoxicity on appetitive and aversive Pavlovian conditioning in mice.

    PubMed

    Achat-Mendes, Cindy; Ali, Syed F; Itzhak, Yossef

    2005-06-01

    The abuse of substituted amphetamines such as methamphetamine (METH) and 3,4-methylenedioxymethamphetamine (MDMA/Ecstasy) can result in neurotoxicity, manifested as the depletion of dopamine (DA) and 5-hydroxytriptamine (5-HT; serotonin) axon terminal markers in humans and animal models. Human METH and MDMA users exhibit impairments in memory and executive functions, which may be a direct consequence of the neurotoxic potential of amphetamines. The objective of this study was to investigate the influence of amphetamines-induced neurotoxicity on Pavlovian learning. Using mouse models of selective DA neurotoxicity (METH; 5 mg/kg x 3), selective 5-HT neurotoxicity (fenfluramine /FEN; 25 mg/kg x 4) and dual DA and 5-HT neurotoxicity (MDMA; 15 mg/kg x 4), appetitive and aversive conditioning were investigated. Dopaminergic neurotoxicity significantly impaired METH and cocaine conditioned place preference (CPP), but had no effect on LiCl-induced conditioned place aversion (CPA). In contrast, serotonergic neurotoxicity significantly enhanced CPP, and had no effect on CPA. Dual dopaminergic/serotonergic neurotoxicity had no apparent effect on CPP; however, CPA was significantly attenuated. Postmortem analysis revealed that significantly diminished levels of DA and 5-HT markers persisted in the striatum, frontal cortex, hippocampus, and amygdala. These findings suggest that amphetamines-induced dopaminergic and serotonergic neurotoxicity exert opposing influences on the affective state produced by subsequent drug reward, while dual dopaminergic/serotonergic neurotoxicity impairs associative learning of aversive conditioning. Furthermore, results revealed that amphetamines-induced DA and 5-HT neurotoxicity modulates appetitive Pavlovian conditioning similar to other DA and 5-HT neurotoxins. Modulation of Pavlovian conditioning by amphetamines-induced neurotoxicity may be relevant to compulsive drug-seeking behavior in METH and MDMA abusers.

  18. Environmental conditions modulate neurotoxic effects of psychomotor stimulant drugs of abuse.

    PubMed

    Kiyatkin, Eugene A; Sharma, Hari Shanker

    2012-01-01

    Psychomotor stimulants such as methamphetamine (METH), amphetamine, and 3,4-metylenedioxymethamphetamine (MDMA or ecstasy) are potent addictive drugs. While it is known that their abuse could result in adverse health complications, including neurotoxicity, both the environmental conditions and activity states associated with their intake could strongly enhance drug toxicity, often resulting in life-threatening health complications. In this review, we analyze results of animal experiments that suggest that even moderate increases in environmental temperatures and physiological activation, the conditions typical of human raves parties, dramatically potentiate brain hyperthermic effects of METH and MDMA. We demonstrate that METH also induces breakdown of the blood-brain barrier, acute glial activation, brain edema, and structural abnormalities of various subtypes of brain cells; these effects are also strongly enhanced when the drug is used at moderately warm environmental conditions. We consider the mechanisms underlying environmental modulation of acute drug neurotoxicity and focus on the role of brain temperature, a critical homeostatic parameter that could be affected by metabolism-enhancing drugs and environmental conditions and affect neural activity and functions.

  19. 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

  20. The neurotoxic effects of intrathecal midazolam and neostigmine in rabbits.

    PubMed

    Demirel, E; Ugur, H C; Dolgun, H; Kahilogullari, G; Sargon, M E; Egemen, N; Kecik, Y

    2006-04-01

    In parallel with improvements in understanding pain neurophysiology, many chemicals have recently been investigated for spinal anaesthesia and analgesia. However, studies discussing the effects of these drugs on neural tissue indicate that knowledge about some aspects of neurotoxicity is limited. Forty-nine New Zealand albino rabbits, weighing 2.2 +/- 0.2 kg, were randomly assigned to seven groups of seven animals each. Single dose groups received intrathecally through the atlantooccipital membrane 0.9% saline 1.5 ml; midazolam 100 microg/kg (low dose midazolam group) or 500 microg/kg (high dose midazolam group); neostigmine 10 microg/kg (low dose neostigmine group) or 50 microg/kg (high dose neostigmine group). Two groups had seven days of repeated dosing with either midazolam 100 microg/kg/day (repeat midazolam group) or 10 microg/kg/day neostigmine (repeat neostigmine group). The animals were sacrificed on day 8, and two spinal cord sections from the fourth cervical level and fourth lumbar level were removed and prepared for histopathological study. Transmission electron microscopic evaluations were performed on transverse spinal cord sections by a neuropathologist blinded to the group allocation. Twenty myelinated axons and neurones in the cervical and lumbar sections were investigated for the histopathological study. This study indicates that midazolam and neostigmine have different neurotoxic effects that depend on the dose and the repetition of dosing when these drugs are administered intrathecally.

  1. Neurotoxic behavioral effects of Lake Ontario salmon diets in rats

    SciTech Connect

    Hertzler, D.R. )

    1990-03-01

    Six experiments were conducted to examine possible neurotoxic effects of the exposure to contaminants in Lake Ontario salmon administered through the diets of rats. Rats were fed different concentrations of fish (8%, 15% or 30%) in one of three diet conditions: Lake Ontario salmon, Pacific Ocean salmon, or laboratory rat chow only. Following 20 days on the diets, rats were tested for five minutes per day in a modified open field for one or three days. Lake Ontario salmon diets consistently produced significantly lower activity, rearing, and nosepoke behaviors in comparison with ocean salmon or rat chow diet conditions. A dose-response effect for concentration of lake salmon was obtained, and the attenuation effect occurred in males, females, adult or young animals, and postweaning females, with fish sampled over a five-year period. While only two of several potential contaminants were tested, both fish and brain analyses of mirex and PCBs relate to the behavioral effects.

  2. Oxygen-inducible glutamate oxaloacetate transaminase as protective switch transforming neurotoxic glutamate to metabolic fuel during acute ischemic stroke.

    PubMed

    Rink, Cameron; Gnyawali, Surya; Peterson, Laura; Khanna, Savita

    2011-05-15

    This work rests on our previous report (J Cereb Blood Flow Metab 30: 1275-1287, 2010) recognizing that glutamate (Glu) oxaloacetate transaminase (GOT) is induced when brain tissue hypoxia is corrected during acute ischemic stroke (AIS). GOT can metabolize Glu into tricarboxylic acid cycle intermediates and may therefore be useful to harness excess neurotoxic extracellular Glu during AIS as a metabolic substrate. We report that in cultured neural cells challenged with hypoglycemia, extracellular Glu can support cell survival as long as there is sufficient oxygenation. This effect is abrogated by GOT knockdown. In a rodent model of AIS, supplemental oxygen (100% O(2) inhaled) during ischemia significantly increased GOT expression and activity in the stroke-affected brain tissue and prevented loss of ATP. Biochemical analyses and in vivo magnetic resonance spectroscopy during stroke demonstrated that such elevated GOT decreased Glu levels at the stroke-affected site. In vivo lentiviral gene delivery of GOT minimized lesion volume, whereas GOT knockdown worsened stroke outcomes. Thus, brain tissue GOT emerges as a novel target in managing stroke outcomes. This work demonstrates that correction of hypoxia during AIS can help clear extracellular neurotoxic Glu by enabling utilization of this amino acid as a metabolic fuel to support survival of the hypoglycemic brain tissue. Strategies to mitigate extracellular Glu-mediated neurodegeneration via blocking receptor-mediated excitotoxicity have failed in clinical trials. We introduce the concept that under hypoglycemic conditions extracellular Glu can be transformed from a neurotoxin to a survival factor by GOT, provided there is sufficient oxygen to sustain cellular respiration.

  3. Acrylamide neurotoxicity.

    PubMed

    Erkekoglu, Pinar; Baydar, Terken

    2014-02-01

    Acrylamide, a food contaminant, belongs to a large class of structurally similar toxic chemicals, 'type-2 alkenes', to which humans are widely exposed. Besides, occupational exposure to acrylamide has received wide attention through the last decades. It is classified as a neurotoxin and there are three important hypothesis considering acrylamide neurotoxicity: inhibition of kinesin-based fast axonal transport, alteration of neurotransmitter levels, and direct inhibition of neurotransmission. While many researchers believe that exposure of humans to relatively low levels of acrylamide in the diet will not result in clinical neuropathy, some neurotoxicologists are concerned about the potential for its cumulative neurotoxicity. It has been shown in several studies that the same neurotoxic effects can be observed at low and high doses of acrylamide, with the low doses simply requiring longer exposures. This review is focused on the neurotoxicity of acrylamide and its possible outcomes.

  4. 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...

  5. 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.

  6. Attenuated microglial activation mediates tolerance to the neurotoxic effects of methamphetamine.

    PubMed

    Thomas, David M; Kuhn, Donald M

    2005-02-01

    Methamphetamine causes persistent damage to dopamine nerve endings of the striatum. Repeated, intermittent treatment of mice with low doses of methamphetamine leads to the development of tolerance to its neurotoxic effects. The mechanisms underlying tolerance are not understood but clearly involve more than alterations in drug bioavailability or reductions in the hyperthermia caused by methamphetamine. Microglia have been implicated recently as mediators of methamphetamine-induced neurotoxicity. The purpose of the present studies was to determine if a tolerance regimen of methamphetamine would attenuate the microglial response to a neurotoxic challenge. Mice treated with a low-dose methamphetamine tolerance regimen showed minor reductions in striatal dopamine content and low levels of microglial activation. When the tolerance regimen preceded a neurotoxic challenge of methamphetamine, the depletion of dopamine normally seen was significantly attenuated. The microglial activation that occurs after a toxic methamphetamine challenge was blunted likewise. Despite the induction of tolerance against drug-induced toxicity and microglial activation, a neurotoxic challenge with methamphetamine still caused hyperthermia. These results suggest that tolerance to methamphetamine neurotoxicity is associated with attenuated microglial activation and they further dissociate its neurotoxicity from drug-induced hyperthermia.

  7. 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.

  8. 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...

  9. Alternating hemiparesis and orolingual apraxia as manifestations of methotrexate neurotoxicity in a paediatric case of acute lymphoblastic leukaemia.

    PubMed

    Yap, Siew Mei; MacEneaney, Peter; Ryan, Clodagh; O'Toole, Orna

    2016-04-25

    A 15-year-old girl with a recent diagnosis of acute lymphoblastic leukaemia was admitted to hospital with pancytopaenia after having received high-dose intrathecal methotrexate 1 day prior. During the next week she had intermittent episodes of alternating hemiparesis associated with speech arrest lasting minutes to hours at a time. The episodes were not associated with altered level of consciousness or headache. MRI of the brain showed features consistent with methotrexate encephalopathy. This report discusses the typical clinical and radiological features of methotrexate neurotoxicity in addition to differential diagnoses and the proposed pathophysiological mechanisms.

  10. Fingolimod Limits AcuteNeurotoxicity and Promotes Synaptic Versus Extrasynaptic NMDA Receptor Functionality in Hippocampal Neurons

    PubMed Central

    Joshi, Pooja; Gabrielli, Martina; Ponzoni, Luisa; Pelucchi, Silvia; Stravalaci, Matteo; Beeg, Marten; Mazzitelli, Sonia; Braida, Daniela; Sala, Mariaelvina; Boda, Enrica; Buffo, Annalisa; Gobbi, Marco; Gardoni, Fabrizio; Matteoli, Michela; Marcello, Elena; Verderio, Claudia

    2017-01-01

    Fingolimod, also known as FTY720, is an analogue of the sphingolipid sphingosine, which has been proved to be neuroprotective in rodent models of Alzheimer’s disease (AD). Several cellular and molecular targets underlying the neuroprotective effects of FTY720 have been recently identified. However, whether the drug directly protects neurons from toxicity of amyloid-beta (Aβ) still remains poorly defined. Using a combination of biochemical assays, live imaging and electrophysiology we demonstrate that FTY720 induces a rapid increase in GLUN2A-containing neuroprotective NMDARs on the surface of dendritic spines in cultured hippocampal neurons. In addition, the drug mobilizes extrasynaptic GLUN2B-containing NMDARs, which are coupled to cell death, to the synapses. Altered ratio of synaptic/extrasynaptic NMDARs decreases calcium responsiveness of neurons to neurotoxic soluble Aβ 1–42 and renders neurons resistant to early alteration of calcium homeostasis. The fast defensive response of FTY720 occurs through a Sphingosine-1-phosphate receptor (S1P-R) -dependent mechanism, as it is lost in the presence of S1P-R1 and S1P-R3 antagonists. We propose that rapid synaptic relocation of NMDARs might have direct impact on amelioration of cognitive performance in transgenic APPswe/PS1dE9 AD mice upon sub-chronic treatment with FTY720. PMID:28134307

  11. 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

  12. 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 ...

  13. 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

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

    PubMed

    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 72 kD) 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 wide-spread HSP expression in neural and glial cells examined in detail 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.

  15. [Acute and long-term effects of ecstasy].

    PubMed

    Salzmann, Julie; Marie-Claire, Cynthia; Noble, Florence

    2004-10-23

    Side effects in the short term Recreational use of Ecstasy (3,4-methylenedioxymethamphetamine or MDMA), a synthetic drug, has considerably increased over the last decade. Since its appearance it is associated with the rave culture, but its use has spread to other social settings. The drug produces euphoria and empathy, but can lead to side effects, notably acute, potentially lethal, toxicity (malignant hyperthermia and/or hepatitis). Neurotoxicity in the long-term Moreover, MDMA has been shown to induce long-term deleterious effects and provoke neurotoxic affecting the serotoninergic system. However, the psychopathological consequences of such neurotoxicity are still controversial, particularly since many ecstasy consumers are multi-drug users. A complex pharmacological profile The mechanism of action of MDMA involves various neurobiological systems (serotonin, dopamine, noradrenalin), that may all interact.

  16. Effects of potential neurotoxic pesticides on hearing loss: a review.

    PubMed

    Gatto, M P; Fioretti, M; Fabrizi, G; Gherardi, M; Strafella, E; Santarelli, L

    2014-05-01

    Several pesticides are supposed to be neurotoxic for humans, consequently, they may also affect the auditory system. This review analyzes human and experimental animal studies testing the hypothesis that exposure to pesticides is associated with hearing loss. The literature on this topic is still sparse and methodological limitations of some papers evaluated are identified. As a whole, available data indicate a possible ototoxic action of pesticides, but alternative hypotheses could not be ruled out, also considering some confounders, such as the co-exposure to noise. Therefore, further studies are necessary in order to clarify the association between pesticides exposure and hearing loss. While awaiting more evidence, for precautionary action we recommend considering pesticides as possible ototoxic agents, in particular for vulnerable targets, such as pregnant women and children during early development.

  17. Features of Neurotoxicity on Brain CT of Acutely Intoxicated Unconscious Patients

    PubMed Central

    Sanei Taheri, Morteza; Noori, Maryam; Nahvi, Vahideh; Moharamzad, Yashar

    2010-01-01

    Diagnostic imaging is a valuable device in clinical management of poisoned patients presenting to emergency units in a comatose state. Some toxic agents have adverse effects on the central nervous system (CNS). Non-contrast computed tomography (CT) of the brain, as an available diagnostic method with a high resolution, can provide useful information about structural disturbances of unconscious patients with suspected drug or chemical intoxication. The authors would describe various presentations of toxic substances detected on the brain CT scans of ten patients with acute intoxication. While non-specific, CT findings of low-attenuation lesions in the basal ganglia, infarctions in young patients, or diffuse edema should raise suspicion for poisoning or overdose. PMID:21270943

  18. 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...

  19. 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...

  20. 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...

  1. Neurotoxic effects of local anesthetics on the mouse neuroblastoma NB2a cell line.

    PubMed

    Mete, M; Aydemir, I; Tuglu, I M; Selcuki, M

    2015-04-01

    Local anesthetics are used clinically for peripheral nerve blocks, epidural anesthesia, spinal anesthesia and pain management; large concentrations, continuous application and long exposure time can cause neurotoxicity. The mechanism of neurotoxicity caused by local anesthetics is unclear. Neurite outgrowth and apoptosis can be used to evaluate neurotoxic effects. Mouse neuroblastoma cells were induced to differentiate and generate neurites in the presence of local anesthetics. The culture medium was removed and replaced with serum-free medium plus 20 μl combinations of epidermal growth factor and fibroblast growth factor containing tetracaine, prilocaine, lidocaine or procaine at concentrations of 1, 10, 25, or 100 μl prior to neurite measurement. Cell viability, iNOS, eNOS and apoptosis were evaluated. Local anesthetics produced toxic effects by neurite inhibition at low concentrations and by apoptosis at high concentrations. There was an inverse relation between local anesthetic concentrations and cell viability. Comparison of different local anesthetics showed toxicity, as assessed by cell viability and apoptotic potency, in the following order: tetracaine > prilocaine > lidocaine > procaine. Procaine was the least neurotoxic local anesthetic and because it is short-acting, may be preferred for pain prevention during short procedures.

  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. 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

  4. In vitro evaluation of anticancer effect and neurotoxicity of Styrylpyrone derivative (SPD)

    NASA Astrophysics Data System (ADS)

    Yip, Chee-Wai; Nagaoka, Yasuo; Nor, Norefrina Shafinaz Md.; Ibrahim, Nazlina

    2016-11-01

    The increasing number of death due to cancer emphasizes the need of novel anticancer agents. Styrylpyrone derivative (SPD) was previously found to have potential anticancer action towards many types of cancer. Some of the SPD-anticancer mechanisms were elucidated as induction of cancer cell apoptosis. However, more understanding on cancer cell type specific action of SPD-anticancer effects needs to be evaluated. HCT-116 cell line, a type of human colon carcinoma, was used to study SPD-anticancer effect. It was found that SPD concentration as low as 0.25 µM was able to inhibit 80% growth of cancer cells. IC50 value of SPD for HCT-116 was found to be 0.038 µM. Neurotoxicity test, carried out to determine the adverse effect of SPD towards nerve cells, gives CC50 value as 4.88 µM, thus concluded it to be a neurotoxic compound.

  5. Modulation of BDNF and TrkB expression in rat hippocampus in response to acute neurotoxicity by diethyldithiocarbamate.

    PubMed

    Micheli, M R; Bova, R; Laurenzi, M A; Bazzucchi, M; Grassi Zucconi, G

    2006-12-13

    In this study, we examined the expression profile of brain-derived neurotrophic factor (BDNF) and its receptor TrkB in adult rat hippocampus following acute administration of diethyldithiocarbamate (DDTC), a neurotoxic compound which was previously shown to induce microglia activation and cell death. Semiquantitative RT-PCR analysis detected significant variations of BDNF mRNA levels in whole hippocampus homogenates, with a peak at 24h after DDTC injection. Increased BDNF protein expression was demonstrated by immunohistochemistry in various hippocampal subfields. The most relevant increase was observed in the hilus of the dentate gyrus where BDNF levels at 120h were found to be almost four times those of basal levels. Full-length TrkB (TrkB.FL) encoding mRNA was also shown to undergo an earlier increase in the hippocampus of DDTC-treated rats. TrkB immunostaining with an antibody binding both full-length and truncated (TrkB.T) isoforms was found to increase at 120h in the hippocampal CA2 and CA3 regions. These results demonstrate that DDTC modulates the expression of BDNF and its receptor in the adult rat hippocampus and suggest a possible involvement of this neurotrophin in the protective response to DDTC-induced neuronal damage.

  6. Protective effects of ginsenoside Rg1 against colistin sulfate-induced neurotoxicity in PC12 cells.

    PubMed

    Jiang, Guo-Zheng; Li, Ji-Chang

    2014-03-01

    The present study aimed to examine the protective effect of ginsenoside Rg1 against colistin-induced neurotoxicity in cultured rat pheochromocytoma (PC12) cells. Ginsenoside Rg1 was shown to elevate cell viability, decrease levels of malondialdehyde and intracellular reactive oxygen species, enhance activity of superoxide dismutase and glutathione, and decrease the release of cytochrome-c, formation of DNA fragmentation in colistin-treated PC12 cells. Ginsenoside Rg1 also reversed the increased caspase-9 and -3 mRNA levels caused by colistin in PC12 cells. These results suggest that ginsenoside Rg1 exerts a neuroprotective effect on colistin-induced neurotoxicity in PC12 cells, at least in part, via the inhibition of oxidative stress, prevention of apoptosis mediated via mitochondria pathway. Co-administration of ginsenoside Rg1 highlights the potential to increase the therapeutic index of colistin.

  7. The Acute, Delayed Neurotoxicity Evaluation of Two Jet Engine Oil Formulations

    DTIC Science & Technology

    1990-04-01

    disir.fected with formaldehyde. The supplier indicated thaz the flock had not experienced any disease problems. TABLE 1. FLOCK VACCINATION HISTOR~a...Vaccination Agecf hen Marek’s disease I day Infectious bronchitis 2 weeks Infectious bursal cdisease 2 weeks Newcastle disease 2 weeks Infectious...bronchitis (booster) 10-12 weeks Newcastle disease (booster) 10-12 weeks Fowl pox 20-24 weeks *Provided verbally by Carey Farms, Inc., Marion. OrH ACUTE

  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. Neurotoxicity of ecstasy (MDMA): an overview.

    PubMed

    Sarkar, Sumit; Schmued, Larry

    2010-08-01

    "Ecstasy" (MDMA) is a powerful hallucinogenic drug which has raised concern worldwide because of its high abuse liability. A plethora of studies have demonstrated that MDMA has the potential to induce neurotoxicity both in human and laboratory animals. Although research on MDMA has been carried out by many different laboratories, the mechanism underlying MDMA induced toxicity has not been fully elucidated. MDMA has the ability to reduce serotonin levels in terminals of axons in the cortex of rats and mice. Recently we have shown that it also has the potential to produce degenerate neurons in discrete areas of the brain such as insular and parietal cortex, thalamus, tenia tecta and bed nucleus of stria terminalis (BST). Acute effects of MDMA can result in a constellation of changes including arrthymias, hypertension, hyperthermia, serotonin (5-HT) syndrome, liver problems, seizures and also long lasting neurocognitive impairments including mood disturbances. In human MDMA abusers, there is evidence for reduction of serotonergic biochemical markers. Several factors may contribute to the MDMA-induced neurotoxicity, especially hyperthermia. Other factors potentially influencing MDMA toxicity include monoamine oxidase metabolism of dopamine and serotonin, nitric oxide generation, glutamate excitotoxicity, serotonin 2A receptor agonism and the formation of MDMA neurotoxic metabolites. In this review we will cover the following topics: pharmacological mechanisms, metabolic pathways and acute effects in laboratory animals, as well as in humans, with special attention on the mechanism and pathology of MDMA induced neurotoxicity.

  10. The Cardiovascular and Neurotoxic Effects of the Venoms of Six Bony and Cartilaginous Fish Species

    PubMed Central

    Han, Han; Baumann, Kate; Casewell, Nicholas R.; Ali, Syed A.; Dobson, James; Koludarov, Ivan; Debono, Jordan; Cutmore, Scott C.; Rajapakse, Niwanthi W.; Jackson, Timothy N. W.; Jones, Rob; Hodgson, Wayne C.; Fry, Bryan G.; Kuruppu, Sanjaya

    2017-01-01

    Fish venoms are often poorly studied, in part due to the difficulty in obtaining, extracting, and storing them. In this study, we characterize the cardiovascular and neurotoxic effects of the venoms from the following six species of fish: the cartilaginous stingrays Neotrygon kuhlii and Himantura toshi, and the bony fish Platycephalus fucus, Girella tricuspidata, Mugil cephalus, and Dentex tumifrons. All venoms (10–100 µg/kg, i.v.), except G. tricuspidata and P. fuscus, induced a biphasic response on mean arterial pressure (MAP) in the anesthetised rat. P. fucus venom exhibited a hypotensive response, while venom from G. tricuspidata displayed a single depressor response. All venoms induced cardiovascular collapse at 200 µg/kg, i.v. The in vitro neurotoxic effects of venom were examined using the chick biventer cervicis nerve-muscle (CBCNM) preparation. N. kuhlii, H. toshi, and P. fucus venoms caused concentration-dependent inhibition of indirect twitches in the CBCNM preparation. These three venoms also inhibited responses to exogenous acetylcholine (ACh) and carbachol (CCh), but not potassium chloride (KCl), indicating a post-synaptic mode of action. Venom from G. tricuspidata, M. cephalus, and D. tumifrons had no significant effect on indirect twitches or agonist responses in the CBCNM. Our results demonstrate that envenoming by these species of fish may result in moderate cardiovascular and/or neurotoxic effects. Future studies aimed at identifying the molecules responsible for these effects could uncover potentially novel lead compounds for future pharmaceuticals, in addition to generating new knowledge about the evolutionary relationships between venomous animals. PMID:28212333

  11. 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

  12. The neuroprotective effect of tropisetron on vincristine-induced neurotoxicity.

    PubMed

    Barzegar-Fallah, Anita; Alimoradi, Houman; Mehrzadi, Saeed; Barzegar-Fallah, Niloofar; Zendedel, Adib; Abbasi, Ata; Dehpour, Ahmad Reza

    2014-03-01

    Vincristine (VCR) peripheral neuropathy is a dose-limiting side effect. Several studies have shown that tropisetron, a 5-HT3 receptor antagonist, exerts anti-inflammatory and immunomodulatory properties. Current study was designed to investigate a suppressive effect of tropisetron on VCR-induced neuropathy and whether this effect exerts through the 5-HT3 receptor or not. Neuropathy was induced in rats by administration of vincristine (0.5mg/kg, 3 intraperitoneal injections on alternate days) and in treatment group, tropisetron (3mg/kg); m-chlorophenylbiguanide (mCPBG), a selective 5-HT3 receptor agonist (15mg/kg); tropisetron (3mg/kg) plus mCPBG (15mg/kg); granisetron, another selective 5-HT3 receptor antagonist (3mg/kg) were administered intraperitoneally 1h prior to vincristine injection. Hot plate, open field tests (total distance moved, mean velocity and percentage of total duration of the movement) and motor nerve conduction velocity (MNCV) were performed to evaluate the sensory and motor neuropathy. Further, plasma levels of tumor necrosis factor-alpha (TNF-α) and interleukin-2 (IL-2) and the level of TNF-α in sciatic nerve were assessed as well as histological examination. In only VCR-treated rats hot plate latencies were significantly increased, total distance moved, mean velocity, total duration of the movement and sciatic MNCV significantly decreased compared with control. In tropisetron and tropisetron plus mCPBG groups, one injection of tropisetron prior to each VCR injection robustly diminished TNF-α and IL-2 levels, and also prevented mixed sensory-motor neuropathy, as indicated by less mortality rate, better general conditions, behavioral and electrophysiological studies. Moreover, pathological evidence confirmed the results obtained from other findings. But granisetron and mCPBG had no significant effect on the mentioned parameters. In conclusion, these studies demonstrate that tropisetron significantly suppressed VCR-induced neuropathy and could

  13. 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.

  14. Neurotoxicity effect of formaldehyde on occupational exposure and influence of individual susceptibility to some metabolism parameters.

    PubMed

    Zendehdel, Rezvan; Fazli, Zohreh; Mazinani, Mohammad

    2016-11-01

    Over the years, neurotoxicity and cognitive dysfunction have separately been associated with endogenous formaldehyde and reduction of acetylcholine signals. However, a limited number of studies have shown a relationship between cholinergic neurotransmitter and formaldehyde exposure. Therefore, the aim of this study was to assess the neurological effect on workers from melamine-dish preparation workshop, who were exposed to formaldehyde. A total of 35 formaldehyde-exposed workers were compared with 32 control employees from the food industry. Occupational exposure to formaldehyde was conducted using the National Institute of Occupational Safety and Health 3500 methods. Using the Ellman method, acetylcholinesterase (AChE) as a biomarker for neurotoxicity was analyzed in blood erythrocyte. The effects of alcohol dehydrogenase III (ADH3) and Mn-superoxide dismutase (Mn-SOD) polymorphism were used to survey the level of AChE activity. In this study, it was found that exposure to airborne formaldehyde increased from 0.024 to 0.74 ppm and the median personnel exposure was 0.057. Induction of AChE activity was observed in formaldehyde-exposed workers as compared with the control group (p < 0.01), while AChE activity increased in 64 % of the exposed subjects. Spearman's correlation (p < 0.02) was used to evaluate the association between AChE activity and occupational exposure to formaldehyde. Exposed subjects containing ADH32-2 genotype had higher AChE than others. The findings of this study suggest that the neurotoxic effect of formaldehyde depends on the AChE activity, which is affected by metabolism. It can be concluded that cholinergic signal reduction in cases of cognitive dysfunction could be associated with endogenous formaldehyde.

  15. In vitro neurotoxic and myotoxic effects of the venom from the black whip snake (Demansia papuensis).

    PubMed

    Kuruppu, S; Fry, Bryan G; Hodgson, Wayne C

    2006-04-01

    1. Black whip snakes belong to the family elapidae and are found throughout the northern coastal region of Australia. The black whip snake (Demansia papuensis) is considered to be potentially dangerous due to its size and phylogenetic distinctiveness. Previous liquid chromatography-mass spectrometry analysis of D. papuensis venom indicated a number of components within the molecular mass ranges compatible with neurotoxins. For the first time, this study examines the in vitro neurotoxic and myotoxic effects of the venom from D. papuensis. 2. Venom (10 microg/mL) caused significant inhibition of twitches elicited by stimulation (0.2 ms, 0.1 Hz, supramaximal V) of motor nerves in the chick biventer cervicis nerve-muscle preparation. This neurotoxic effect, which was postsynaptic in origin, was weak in comparison to that of most other Australian elapids. Prior addition (10 min) of polyvalent (PSAV) or tiger snake (TSAV) antivenom (5 units/mL) prevented venom-induced twitch inhibition. Addition of PSAV (5 units/mL) at t(50) failed to reverse the inhibitory effect but prevented further inhibition of nerve-mediated twitches. 3. The venom (20-50 microg/mL) is also myotoxic as indicated by a slowly developing contracture and inhibition of twitches elicited by direct stimulation (2 ms, 0.1 Hz, supramaximal V, in the presence of tubocurarine 10 micromol/L) of the chick biventer muscle. This activity was confirmed by histological examination of the muscle. 4. Fractionation and characterization of venom components is required to further investigate the reasons for the weak neurotoxic activity of D. papuensis venom.

  16. Protective effect of arctigenin on ethanol-induced neurotoxicity in PC12 cells.

    PubMed

    Huang, Jia; Xiao, Lan; Wei, Jing-Xiang; Shu, Ya-Hai; Fang, Shi-Qi; Wang, Yong-Tang; Lu, Xiu-Min

    2017-04-01

    As a neurotropic substance, ethanol can damage nerve cells through an increase in the production of free radicals, interference of neurotrophic factor signaling pathways, activation of endogenous apoptotic signals and other molecular mechanisms. Previous studies have revealed that a number of natural drugs extracted from plants offer protection of nerve cells from damage. Among these, arctigenin (ATG) is a lignine extracted from Arctium lappa (L.), which has been found to exert a neuroprotective effect on scopolamine‑induced memory deficits in mice with Alzheimer's disease and glutamate-induced neurotoxicity in primary neurons. As a result, it may offer beneficial effects on ethanol-induced neurotoxicity. However, the effects of ATG on ethanol‑induced nerve damage remain to be elucidated. To address this issue, the present study used rat pheochromocytoma PC12 cells to investigate the neuroprotective effects of ATG on ethanol-induced cell damage by performing an MTT reduction assay, cell cycle analysis, Hoechst33342/propidium iodide fluorescence staining and flow cytometry to examine apoptosis. The results showed that 10 µM ATG effectively promoted the proliferation of damaged cells, and increased the distribution ratio of the cells at the G2/M and S phases (P<0.05). In addition, the apoptosis and necrosis of the PC12 cells were significantly decreased following treatment with ATG. Therefore, it was concluded that 10 µM ATG had a protective effect on ethanol‑induced injury in PC12 cells.

  17. Neurotoxic effects of MDMA (ecstasy) on the developing rodent brain.

    PubMed

    Dzietko, M; Sifringer, M; Klaus, J; Endesfelder, S; Brait, D; Hansen, H H; Bendix, I; Felderhoff-Mueser, U

    2010-08-01

    The incidence of methamphetamine abuse is particularly high in adolescents and is a common problem among women of childbearing age, leading to an increasing number of children with prenatal exposure. MDMA (3,4-methylenedioxymethamphetamine, ecstasy) is an amphetamine-like stimulant and is known to induce apoptotic damage to fine serotonergic fibers in the adult rat brain. Little is known about toxic effects of MDMA and potential underlying molecular mechanisms in the developing brain. Here, we investigated whether MDMA exposure during the period of rapid brain growth causes neurodegeneration in the developing rat brain. MDMA significantly enhanced neuronal death in the brains of 6-day-old rat pups at a dose of 60 mg/kg, but no significant toxicity was detected at the ages of 14 and 21 days. Brain regions mainly affected were the cortex, septum, thalamus, hypothalamus and the cornu ammonis 1 region. To explore possible molecular mechanisms involved in this neurodegenerative process, we investigated the impact of MDMA on the expression of the neurotrophins brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3) and nerve growth factor. Neonatal exposure of 6-day-old rats to MDMA triggered a considerable increase in cortical BDNF and NT-3 levels. Moreover, P7 CD1/BDNF knockout mice were noticeably more sensitive to MDMA exposure as compared to their wild-type age-matched littermates. These data suggest that a single injection of MDMA causes neurodegeneration in the neonatal rat brain. The upregulation of BDNF and NT-3 expression may indicate an important compensatory mechanism leading to the survival of neuronal cells in the developing brain.

  18. 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.

  19. Nitric oxide and the neurotoxic effects of methamphetamine and 3,4-methylenedioxymethamphetamine.

    PubMed

    Taraska, T; Finnegan, K T

    1997-02-01

    The role of nitric oxide (NO) in the long-term, amine-depleting effects of methamphetamine (METH) and 3,4-methylenedioxymethamphetamine (MDMA) was investigated in the rodent central nervous system. The NO synthase inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME) antagonized the dopamine- and serotonin-depleting effects of both METH and MDMA. The protective actions of L-NAME in METH-treated mice were reversed by prior administration of the NO generator isosorbide dinitrate. However, pretreatment with N(G)-monomethyl-L-arginine or N(G)-nitro-L-arginine, two other NO synthase inhibitors, failed to block the neurotoxic effects of METH or MDMA. L-NAME was also the only NO synthase inhibitor that antagonized the hyperthermic effects of METH, reducing colonic temperatures in mice by a mean of 3 degrees C, in comparison with control. Moreover, if the hypothermic effects of L-NAME in METH-treated mice were prevented by raising the ambient room temperature, the dopamine-depleting actions of the stimulant were fully restored. The latter findings suggest that it is the hypothermic actions of L-NAME, rather than its NO inhibitory properties, that are responsible for the prevention of neurotoxicity. Together with the results of the N(G)-monomethyl-L-arginine and N(G)-nitro-L-arginine experiments, the data suggest that NO plays little or no role in the toxic mechanism of action of METH or MDMA.

  20. Vanadium carcinogenic, immunotoxic and neurotoxic effects: a review of in vitro studies.

    PubMed

    Zwolak, Iwona

    2014-01-01

    Deleterious health effects induced by inorganic vanadium compounds are linked with carcinogenic, immunotoxic and neurotoxic insults. The goal of this review is to provide a summary of mammalian cell culture studies (from the 1990s to most recent) looking into the mode of the above-mentioned adverse actions of vanadium. Regarding the carcinogenicity potential, the key cell-based studies have evidenced the ability of vanadium to induce genotoxic lesions, cell morphological transformation and anti-apoptotic effects in a certain type of cells. Two contradictory effects of vanadium on the immune functions of cells have been observed in cell culture studies. The first effect involves reduction of cell immune responses such as vanadium-dependent inhibition of cytokine-inducible functions, which may underlie the mechanism of vanadium-induced immunosuppression. The second one involves stimulation of immune activity, for example, a vanadium-mediated increase in cytokine production, which may contribute to vanadium-related inflammation. So far, an in vitro evaluation of vanadium neurotoxicity has only been reported in few articles. These papers indicate probable cytotoxic mechanisms resulting from exposure of neurons and glial cells to vanadium. In summary, this literature review collects in vitro reports on adverse vanadium effects and thus provides vanadium researchers with a single, concise source of data.

  1. Neurotoxic aspects of porphyinopathies: lead and succinylacetone

    SciTech Connect

    Silbergeld, E.K.; Hruska, R.E.; Bradley, D.; Lamon, J.M.; Frykholm, B.C.

    1982-12-01

    Neurotoxic effects of heavy metals and polyhalogenated hydrocarbons frequently occur at low levels of exposure, in some cases below those levels where direct toxic actions of these compounds have been demonstrated. Rats with acute and chronic lead exposure were compared to rats whose heme synthesis was inhibited by succinylacetone, as a semichronic model of the hereditary heme synthesis disorder, acute intermittent porphyria. Both treatments produce significant inhibition in activity of the enzyme delta-aminolevulinic acid dehydrase and elevations in the heme precursor delta-aminolevulinic acid (ALA) in tissues and urine. Associated with increased ALA is a significant inhibition of neurotransmission utilizing the amino acid ..gamma..-aminobutyric acid (GABA), expressed chemically and behaviorally. The results suggest that in addition to their direct molecular neurotoxicity, porphyrinopathic compounds such as lead may, through altering heme synthesis, adversely affect the brain at low levels of exposure.

  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.

  3. Effects of Housing on Methamphetamine-Induced Neurotoxicity and Spatial Learning and Memory.

    PubMed

    Gutierrez, Arnold; Jablonski, Sarah A; Amos-Kroohs, Robyn M; Barnes, Anna C; Williams, Michael T; Vorhees, Charles V

    2017-03-27

    Severe stress potentiates methamphetamine (MA) neurotoxicity. However, whether moderate stress increases or decreases the neurotoxic effects of MA is unknown. We assessed the effects of MA (4 × 10 mg/kg at 2 h intervals) in combination with prior barren-cage housing in adult male Sprague-Dawley rats on monoamines and glial fibrillary acid protein (GFAP) in one cohort and spatial learning and memory in the Morris water maze in another cohort. MA reduced dopamine (DA) and serotonin (5-HT) in the neostriatum and nucleus accumbens, 5-HT in the hippocampus, and increased GFAP in neostriatum and nucleus accumbens compared with saline controls. In neostriatum, barren-cage housing protected against MA-induced increases in GFAP, but it did not prevent DA and 5-HT reductions, although it did increase hippocampal norepinephrine. MA impaired spatial learning during acquisition, reversal, and shift phases and impaired reference memory on reversal and shift probe trials. Barren-cage housing enhanced performance during acquisition but not during reversal or shift or on probe trials. The data indicate that prior barren-cage housing moderates MA-induced neostriatal astrogliosis and initial spatial learning, but has no protective effect when the platform is smaller and relocated and therefore requires cognitive flexibility in relearning.

  4. Evaluating the Effects and Safety of Intravenous Lipid Emulsion on Haloperidol-Induced Neurotoxicity in Rabbit

    PubMed Central

    Moshiri, Mohammad; Mohammadpour, Amir Hooshang; Vahabzadeh, Maryam; Etemad, Leila; Memar, Bahram; Hosseinzadeh, Hossein

    2014-01-01

    There are many reports on the effect of intravenous lipid emulsion (ILE) as an antidote in drugs related toxicities. We determined the effects of ILE on neurotoxicity of haloperidol (HA), a highly lipophilic antipsychotic, as a model of antipsychotics poisoning. We used six groups of five male rabbits. Two groups received distilled water intravenously followed by infusions of either 18 mL/kg of normal saline or ILE 20%, after 30 minutes. The third group received 18 mL/kg of normal saline after HA (2.6 mg/kg) administration. The three other groups received ILE 20% solution (6, 12, and 18 mL/kg) following HA injection. Catalepsy scores, temperature, pupil size, and mortality rate were measured at 0, 0.5, 1, 2, 3, 4, 8, and 24 hours after HA administration began. Blood and tissue samples were taken from all animals at 24 hours or at death time for biochemical, cell count, and pathological studies. ILE reversed cataleptic scores, miotic pupils, and hypothermia of HA intoxication much faster than normal saline (P < 0.001). Biochemical complications and mortality rate of the animals were significantly higher in the HA + 18 mL/Kg ILE group. ILE reversed sings of HA neurotoxicity; however, synergistic effect of high dose of ILE and HA increased complications and mortality. PMID:24971362

  5. Effect of alpha lipoic acid on ifosfamide-induced central neurotoxicity in rats.

    PubMed

    Ozturk, Gulfer; Ginis, Zeynep; Kurt, Sefika Nur; Albayrak, Aynur; Bilen, Sule; Fadillioglu, Ersin

    2014-02-01

    Ifosfamide (IFOS) which is a cytotoxic alkylating agent may cause central nervous system toxicity. Alpha-lipoic acid (ALA) has a strong antioxidant effects. We hypothesized that ALA could attenuate on ifosfamide-induced central neurotoxicity in rats. Rats were divided into Control, IFOS, ALA and IFOS+ALA groups. The toxic effects of IFOS were analyzed by oxidative parameters and caspase 3 immunohistochemical examinations of brain tissue. The catalase activity of IFOS group significantly reduced in comparison with control groups (p < 0.05). The malondialdehyde (MDA) level and protein carbonyl (PC) content in brain tissue were significantly higher in IFOS group than in the other groups (p < 0.05). ALA treatments significantly prevented the increase in MDA level (p < 0.001) and PC content (p < 0.05) in brain tissue. IFOS group showed profound activation of caspase 3. The control, ALA and IFOS+ALA groups did not show caspase 3 activation. It was concluded that ALA treatments may have beneficial effects protecting neurons from central neurotoxicity caused by IFOS.

  6. Evaluating the effects and safety of intravenous lipid emulsion on haloperidol-induced neurotoxicity in rabbit.

    PubMed

    Moshiri, Mohammad; Mohammadpour, Amir Hooshang; Vahabzadeh, Maryam; Etemad, Leila; Memar, Bahram; Hosseinzadeh, Hossein

    2014-01-01

    There are many reports on the effect of intravenous lipid emulsion (ILE) as an antidote in drugs related toxicities. We determined the effects of ILE on neurotoxicity of haloperidol (HA), a highly lipophilic antipsychotic, as a model of antipsychotics poisoning. We used six groups of five male rabbits. Two groups received distilled water intravenously followed by infusions of either 18 mL/kg of normal saline or ILE 20%, after 30 minutes. The third group received 18 mL/kg of normal saline after HA (2.6 mg/kg) administration. The three other groups received ILE 20% solution (6, 12, and 18 mL/kg) following HA injection. Catalepsy scores, temperature, pupil size, and mortality rate were measured at 0, 0.5, 1, 2, 3, 4, 8, and 24 hours after HA administration began. Blood and tissue samples were taken from all animals at 24 hours or at death time for biochemical, cell count, and pathological studies. ILE reversed cataleptic scores, miotic pupils, and hypothermia of HA intoxication much faster than normal saline (P < 0.001). Biochemical complications and mortality rate of the animals were significantly higher in the HA + 18 mL/Kg ILE group. ILE reversed sings of HA neurotoxicity; however, synergistic effect of high dose of ILE and HA increased complications and mortality.

  7. Effects of the neurotoxic thionophosphate pesticide chlorpyrifos on differentiating alternative models.

    PubMed

    Amaroli, Andrea; Aluigi, Maria Grazia; Falugi, Carla; Chessa, Maria Giovanna

    2013-02-01

    Studies by researchers worldwide have revealed that, even in industrialised nations, people, infants and the aged in particular, are even more exposed to neurotoxic drugs as a consequence of the increased quantity of pesticide residues in food. This phenomenon, as underlined by The Worldwatch Institute (2006), is linked to the exponential increase in the use of these toxic compounds over the last 40 years, up from 0.49 kg per hectare in 1961 to 2 kg in 2004, with the result that these substances are found in the daily diet. Many studies have demonstrated how the assumption of pesticides in the neonatal period and early infancy can alter the development and function of the nervous, immune, endocrine and reproductive apparatuses. Moreover, the unequivocal relationship between brain tumours, infant leukemia and pesticides are well recognised. On the basis of the above information, the effects of the neurotoxic thionophosphate pesticide chlorpyrifos (CPF) have been tested, considering biomarkers of toxicity and toxicity endpoint, on the biological models Dictyostelium discoideum, Paracentrotus lividus, and NTera2 Cells, as they are compatible with the 3Rs strategy (Reduction, Replacement, and Refinement in animal experiments). Our results have revealed that developing organisms are particularly sensitive to the toxic effects of CPF.

  8. 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.

  9. Neuroprotective effect of thymoquinone in acrylamide-induced neurotoxicity in Wistar rats

    PubMed Central

    Mehri, Soghra; Shahi, Mehran; Razavi, Bibi Marjan; Hassani, Faezeh Vahdati; Hosseinzadeh, Hossein

    2014-01-01

    Objective(s): Acrylamide (ACR) has broad applications in different industries. It also forms in food during heating process. Oxidative stress has a critical role in ACR-induced neurotoxicity in both in vitro and in vivo models; therefore, the aim of the current study was the evaluation of effects of thymoquinone, the main constituent of volatile oil from Nigella sativa seeds in ACR-induced neurotoxicity. Materials and Methods: Male Wistar rats were treated with ACR (50 mg/kg IP) alone or with thymoquinone (TQ) (2.5, 5, 10 mg/kg IP) for 11 days. Two protocols were used in this study, A: in this one TQ and ACR were used simultaneously, B: Administration of TQ was started 1 week before ACR treatment and continued during exposure to ACR. At the end of the treatment, behavioral index (gait score) was examined for rats. After that, rats were sacrificed and molondialdehyde (MDA) as a marker of lipid peroxidation and glutathione (GSH) content were determined in cerebral cortex. Results: Exposure to ACR led to severe gait abnormalities and treatment with TQ significantly decreased abnormalities. Level of MDA was elevated in cerebral cortex after exposure to ACR while TQ treatment significantly and in a dose-dependent manner reduced lipid peroxidation. Results clearly showed that there is no significant difference between two protocols of administration of TQ. Conclusion: It suggests the neuroprotective effect of TQ in this model in part, may be because of due the antioxidant activity of this natural compound. PMID:25859305

  10. The Neurotoxic Effects of Manganese on the Dopaminergic Innervation of the Gill of the Bivalve Mollusc, Crassostrea virginica

    PubMed Central

    Martin, Kesha; Huggins, Turkesha; King, Candice; Carroll, Margaret A.; Catapane, Edward J.

    2008-01-01

    We examined effects of manganese on the nervous system and innervation of lateral cilia of Crassostrea virginica. While essential in trace amounts, tissue manganese accumulation is neurotoxic, inducing Manganism, a Parkinson’s-like disease in humans. Lateral cilia of the gill of C. virginica are controlled by a reciprocal serotonergic-dopaminergic innervation from their ganglia. Oysters were incubated 3 days in the presence of up to 1 mM manganese, followed by superfusion of the cerebral ganglia, visceral ganglia or gill with dopamine or serotonin. Beating rates of cilia were measured by stroboscopic microscopy of isolated gill preparations or gill preparations with the ipsilateral cerebral and/or visceral ganglia attached. Acute manganese treatments impaired the dopaminergic, cilio-inhibitory system, while having no effect on the serotonergic, cilio-excitatory system, which is in agreement with the proposed mechanism of manganese toxicity in humans. Manganese treatments also decreased endogenous dopamine levels in the cerebral and visceral ganglia, and gills, but not serotonin levels. We demonstrated that manganese disrupts the animal’s dopaminergic system, and also that this preparation can be used to investigate mechanisms that underlie manganese neurotoxcity. It also may serve as a model in pharmacological studies of drugs to treat or prevent Manganism and other dopaminergic cell disorders. PMID:18547869

  11. Neurotoxicity of FireMaster 550® in zebrafish (Danio rerio): Chronic developmental and acute adolescent exposures

    PubMed Central

    Bailey, J.M.; Levin, E.D.

    2015-01-01

    BACKGROUND FireMaster® 550 (FM 550) is the second most commonly used flame retardant (FR) product in consumer goods and has been detected in household dust samples. However, neurobehavioral effects associated with exposure have not been characterized in detail. We investigated the behavioral effects of FM 550 in zebrafish to facilitate the integration of the cellular and molecular effects of FM 550 with its behavioral consequences. The effects of developmental FM 550 exposure on zebrafish larvae swimming shortly after the end of exposure as well as the persisting effects of this exposure on adolescent behavior were studied. In addition, the acute effects of FM 550 on behavior with exposure during adolescence in zebrafish were studied. METHODS Developmental exposure to 0, 0.01, 0.1 or 1 mg/L of FM 550 via immersion spanned 0–5 days post fertilization, with larval testing on day 6 and adolescent testing on days 40–45. Acute adolescent (45 dpf) exposure was to 0, 1.0 or 3.0 mg/L of FM 550 via immersion, for 24 hrs, with testing 2 hr or 1 week later. The vehicle condition was colony tank water with .0004% (developmental) or .0012% (adolescent) DMSO. Zebrafish behavior was characterized across several domains including learning, social affiliation, sensorimotor function, predator escape, and novel environment exploration. RESULTS Persisting effects of developmental FM 550 exposure included a significant (p < 0.01) reduction in social behavior among all dose groups. Acute FM550 exposure during adolescence caused hypoactivity and reduced social behavior (p’s < 0.05) when the fish were tested 2 hr after exposure. These effects were attenuated at the 1 week post exposure testing point. DISCUSSION Taken together, these data indicate that FM 550 may cause persisting neurobehavioral alterations to social behavior in the absence of perturbations along other behavioral domains and that developmental exposure is more costly to the organism than acute adolescent exposure

  12. 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.

  13. Neurotoxic effect of linamarin in rats associated with cassava (Manihot esculenta Crantz) consumption.

    PubMed

    Rivadeneyra-Domínguez, Eduardo; Vázquez-Luna, Alma; Rodríguez-Landa, Juan Francisco; Díaz-Sobac, Rafael

    2013-09-01

    Cassava (Manihot esculenta Crantz) is a plant widely used for food consumption in different processed products in rural areas of Africa, Asia, and Latin America. Cassava is a good source of carbohydrates and micronutrients. However, if it is not adequately processed or the consumer has nutritional deficiencies, then its cyanogenic glycoside (i.e., linamarin and lotaustralin) content makes it potentially neurotoxic. In the present study, the neurotoxic effects of different concentrations of linamarin (0.075, 0.15, 0.22, and 0.30 mg/kg) contained in cassava juice were evaluated in the open field and swim tests to identify locomotor alterations in adult male Wistar rats. The linamarin concentration in cassava juice was determined by high-performance liquid chromatography, and the juice was administered intraesophageally for 28 days. The results suggested that the consumption of linamarin in cassava juice increased the number of crossings and rearings in the open field test and caused behavioral deficiency, reflected by lateral swimming, in the swim test on days 21 and 28 of treatment. These alterations are possibly related to neuronal damage caused by linamarin in cassava juice in structures of the central nervous system involved in motor processing.

  14. Neurotoxicity of acrylamide and its analogues and effects of these analogues and other agents on acrylamide neuropathy.

    PubMed Central

    Edwards, P M

    1975-01-01

    N-Hydroxymethylacrylamide, N-methylacrylamide, and N,N-diethylacrylamide produce peripheral neuropathy in rats. Seven other compounds related to acrylamide do not produce neuropathy. Rats given one of the three neurotoxic compounds are more susceptible to acrylamide. A regime for testing acrylamide analogues for neuro-toxicity is suggested. DDT, phenobarbitone, or high dietary concentrations of vitamin A or E have no effect on the development of acrylamide neuropathy in rats. Acrylamide produces neuropathy in hens but not in frogs or goldfish. PMID:164879

  15. Ameliorating effects of aged garlic extracts against Aβ-induced neurotoxicity and cognitive impairment

    PubMed Central

    2013-01-01

    Background In vitro antioxidant activities and neuron-like PC12 cell protective effects of solvent fractions from aged garlic extracts were investigated to evaluate their anti-amnesic functions. Ethyl acetate fractions of aged garlic had higher total phenolics than other fractions. Methods Antioxidant activities of ethyl acetate fractions from aged garlic were examined using 2,2'-azino-bis(3-ethylbenzthiazoline-6-sulfonic acid) diammonium salt (ABTS) and malondialdehyde (MDA) inhibitory effect using mouse whole brain homogenates. Levels of cellular oxidative stress as reactive oxygen species (ROS) accumulation were measured using 2',7'-dichlorofluorescein diacetate (DCF-DA). PC12 cell viability was investigated by 3-[4,5-dimethythiazol-2-yl]-2,5-diphenyl tetrazolium bromide (MTT) and lactate dehydtrogenase (LDH) assay. The learning and memory impairment in institute of cancer research (ICR) mice was induced by neurotoxic amyloid beta protein (Aβ) to investigate in vivo anti-amnesic effects of aged garlic extracts by using Y-maze and passive avoidance tests. Results We discovered that ethyl acetate fractions showed the highest ABTS radical scavenging activity and MDA inhibitory effect. Intracellular ROS accumulation resulting from Aβ treatment in PC12 cells was significantly reduced when ethyl acetate fractions were presented in the medium compare to PC12 cells which was only treated with Aβ only. Ethyl acetate fractions from aged garlic extracts showed protection against Aβ-induced neurotoxicity. Pre-administration with aged garlic extracts attenuated Aβ-induced learning and memory deficits in both in vivo tests. Conclusions Our findings suggest that aged garlic extracts with antioxidant activities may improve cognitive impairment against Aβ-induced neuronal deficit, and possess a wide range of beneficial activities for neurodegenerative disorders, notably Alzheimer's disease (AD). PMID:24134394

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

    ClinicalTrials.gov

    2017-04-05

    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

  17. 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...

  18. Effect of Selenium on Neurotoxicity in Adult Male Mice Exposed to Formaldehyde

    PubMed Central

    Mohammadi, Shabnam

    2014-01-01

    Background: Formaldehyde is used in medicine and industry, and it is known to have detrimental effects on various systems including the nervous system, by increasing oxidative stress. However, data are scarce related to substances that can protect against the neurotoxicity induced by formaldehyde. Therefore, this study was designed to assess the protective effects of selenium against the toxic effect of this compound. Methods: A total of 48 adult male mice were divided randomly into six groups, i.e., (1) control, (2) treated with formaldehyde, (3) treated with formaldehyde plus 0.1 mg/kg selenium, (4) treated with formaldehyde plus 0.2 mg/kg selenium, (5) treated with formaldehyde plus 0.4 mg/kg selenium, and (6) treated with formaldehyde plus 0.8 mg/kg selenium. At the end of 14 days, the cerebellums were removed for histological evaluation. Morphological changes were examined using Image J software. The data were analyzed using SPSS software version 20.0 and analysis of variance (ANOVA). Results: Formaldehyde caused a reduction in the numbers and sizes of Purkinje cells and granular cells; in addition, the thickness of the granular layer was thinner than that in the control mice (P < 0.05). Treatment with 0.1 mg/kg selenium resulted in an increase in the number of Purkinje cells as well as the area of the gray matter compared to those of the control mice. Conclusion: Formaldehyde-induced neuronal damage was prevented by the administration of 0.1 mg/kg selenium, hence this treatment shows therapeutic potential for the treatment of neurotoxicity PMID:25763172

  19. Neurotoxic exposures and effects: gender and sex matter! Hänninen Lecture 2011.

    PubMed

    Mergler, Donna

    2012-08-01

    Although males and females differ both biologically and in their social and power relations throughout their life span, research in environmental and occupational neurotoxicology often ignore sex and/or gender as a characteristic that requires in-depth consideration. The neurotoxicology literature continues to confuse the terms sex (biological attributes) and gender (socially constructed roles and behavior) and the words are still used interchangeably. Throughout the lifespan, sex and gender are in interaction and both may play a role in influencing exposure and effect. Studies that have examined both males and females, provide evidence for sex differences in toxicokinetics and responses to neurotoxic assault as well as gender differences in exposure patterns, biomarkers of exposure, neurobehavioral performance and social consequences. Integrating sex and gender considerations into research in neurotoxicology would not only provide us with a better understanding of the mechanisms and pathways that lead to toxic assault, but also provide a means to improve preventive intervention strategies.

  20. 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.

  1. Clarithromycin-induced neurotoxicity in adults.

    PubMed

    Bandettini di Poggio, M; Anfosso, Sandra; Audenino, Daniela; Primavera, Alberto

    2011-03-01

    Clarithromycin is a relatively new antibiotic of the macrolide family heralded for an improved side effect profile, dosing schedule, and microbiological activity relative to its parent compound, erythromycin. We review the literature on clarithromycin-induced neurotoxicity in adults and present an illustrative case. A total of 38 patients with clarithromycin-induced neurotoxicity have been reported. The average age of patients was 51.3 years (range: 19-87 years) with females comprising 52.6% of patients. Psychiatric illness was the most common comorbidity, while only two patients had renal failure. Clarithromycin had been prescribed for respiratory infections in most patients, and only two patients were receiving more than 1000 mg/day of antibiotic. The symptoms started 1 day to 10 days after starting clarithromycin (mean: 5 days). A total of 71% of patients were under treatment with concomitant medication, and eight patients were undergoing treatment with psychoactive drugs. Patients had a very good outcome after clarithromycin was discontinued, but medication with neuroleptics or benzodiazepine was required for 58% of patients in the acute phase. Only four patients underwent an electroencephalogram (EEG). Our illustrative patient was a 74-year-old woman with clarithromycin-induced delirium due to non-convulsive status epilepticus (NCSE). Her clinical symptoms and electroencephalogram (EEG) readings dramatically improved after discontinuation of clarithromycin. The mechanism underlying the central nervous system side effects remains unclear. We suggest including an EEG in the diagnostic procedures of patients under treatment with clarithromycin who develop features of neurotoxicity because an EEG can help to differentiate patients with psychiatric illness from those with encephalopathy or epilepsy. Because of the widespread use of clarithromycin, clinicians should be aware of its neurotoxicity. Early detection of clarithromycin-induced neurotoxicity and

  2. Effects of Hypericum perforatum extract on oxaliplatin-induced neurotoxicity: in vitro evaluations.

    PubMed

    Cinci, Lorenzo; Di Cesare Mannelli, Lorenzo; Maidecchi, Anna; Mattoli, Luisa; Ghelardini, Carla

    2017-02-04

    Hypericum perforatum L. has been used for centuries as a natural remedy for the treatment of many disorders. Neuropathic pain is a common side effect of oxaliplatin-based chemotherapy and often the cause of therapy discontinuation. Thanks to its anti-inflammatory and analgesic effects, the use of H. perforatum may be a novel therapeutic strategy for neuropathy. The aim of this paper was to evaluate the effect of H. perforatum hydrophilic extract on an in vitro model of oxaliplatin-induced neurotoxicity. The antioxidant potential of extract was first evaluated in cell-free models by the thiobarbituric acid-reactive substances assay and nitro blue tetrazolium oxidation test; the ability of H. perforatum extract to reduce oxaliplatin-induced caspase-3 activity in rat astrocytes and its potential interference with the cytotoxic effects of oxaliplatin in a colorectal cancer in vitro model (HT-29 cells) were also evaluated. The extract showed a significant antioxidant effect and was able to reduce caspase-3 activity in rat astrocytes. Of note, the extract alone exerted a cytotoxic effect in HT-29 cells and did not reduce the cytotoxicity of oxaliplatin in HT-29 cells. These data suggest that H. perforatum could be used as a novel therapeutic strategy for counteracting chemotherapy-induced neuropathy.

  3. Evaluating the neurotoxic effects of lactational exposure to persistent organic pollutants (POPs) in Spanish children.

    PubMed

    Gascon, Mireia; Verner, Marc-André; Guxens, Mònica; Grimalt, Joan O; Forns, Joan; Ibarluzea, Jesús; Lertxundi, Nerea; Ballester, Ferran; Llop, Sabrina; Haddad, Sami; Sunyer, Jordi; Vrijheid, Martine

    2013-01-01

    Although the brain continues developing in the postnatal period, epidemiological studies on the effects of postnatal exposure to neurotoxic POPs through breast-feeding remain mostly inconclusive. Failure to detect associations between postnatal exposure and health outcomes may stem from the limitations of commonly employed approaches to assess lactational exposure. The aim of the present study was to assess whether lactational exposure to polychlorinated biphenyl-153 (PCB-153), dichlorodiphenyldichloroethylene (DDE), or hexachlorobenzene (HCB) as estimated with a physiologically based pharmacokinetic (PBPK) model, is associated with decrements in mental and psychomotor development scores of the Bayley Scales of Infant Development (BSID) test in children aged around 14-months of a subsample (N=1175) of the Spanish INMA birth cohort, and to compare this with the effects of prenatal exposure. Although in the present study population PCB-153, DDE and HCB exposure increased within the first months of postnatal life, no associations were found between different periods of postnatal exposure to these compounds and mental or psychomotor scores. Increasing prenatal PCB-153 concentrations were associated with worse mental and psychomotor scores, although significance was only reached for psychomotor development (β [95%CI]=-1.36 [-2.61, -0.11]). Indeed, the association between exposure and effects observed during prenatal life weakened gradually across periods of postnatal life. Results of the present study suggest that, although breastfeeding increases children's blood persistent organic pollutants (POPs) levels during postnatal life, deleterious effects of PCB-153 on neuropsychological development are mainly attributable to prenatal exposure.

  4. 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.

  5. [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.

  6. Neuroprotective effects of sodium hydrosulfide against β-amyloid-induced neurotoxicity

    PubMed Central

    Li, Xiao-Hui; Deng, Yuan-Yuan; Li, Fei; Shi, Jing-Shan; Gong, Qi-Hai

    2016-01-01

    Alzheimer's disease (AD) is known to be caused by the accumulation of amyloid-β peptide (Aβ). The accumulation of Aβ has been shown to cause learning and memory impairment in rats, and it has been shown that hydrogen sulfide donors, such as sodium hydrosulfide (NaHS) can attenuate these effects. However, the underlying mechanisms have not yet been fully eludicated. This study was designed to investigate whether NaHS attenuates the inflammation and apoptosis induced by Aβ. We demonstrated that NaHS attenuated Aβ25–35-induced neuronal reduction and apoptosis, and inhibited the activation of pro-caspase-3. It also decreased the protein expresion of phosphodiesterase 5 (PDE5) in the hippocampus of the rats. In addition, NaHS upregulated the expression of peroxisome proliferator-activated receptor (PPAR)-α and PPAR-γ, but it did not affect the expression of PPAR-β. Moreover, the Aβ25–35-exposed rats exhibited a decrease in IκB-α degradation and an increase in nuclear factor-κB (NF-κB) p65 phosphorylation levels, whereas these effects were attenuated by NaHS. Our data suggest that NaHS prevents Aβ-induced neurotoxicity via the upregulation of PPAR-α and PPAR-γ and the inhibition of PDE5. Hence NaHS may prove to be beneficial in the treatment of AD. PMID:27511125

  7. 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.

  8. IDENTIFICATION AND INTERPRETATION OF DEVELOPMENTAL NEUROTOXICITY EFFECTS: A REPORT FROM THE ILSI RESEARCH FOUNDATION/RISK SCIENCE INSTITUTE EXPERT WORKING GROUP ON NEURODEVELOPMENTAL ENDPOINTS

    EPA Science Inventory

    The reliable detection, measurement, and interpretation of treatment-related developmental neurotoxicity (DNT) effects depend on appropriate study design and execution, using scientifically established methodologies, with appropriate controls to minimize confounding factors. App...

  9. 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.

  10. Effects of L-cysteine on lead acetate induced neurotoxicity in albino mice.

    PubMed

    Mahmoud, Y I; Sayed, S S

    2016-07-01

    Lead is a toxic heavy metal that adversely affects nervous tissues; it often occurs as an environmental pollutant. We investigated histological changes in the cerebral cortex, hippocampus and cerebellum of adult albino mice following exposure to lead acetate. We also studied the possible ameliorative effect of the chelating agent, L-cysteine, on lead-induced neurotoxicity. We divided albino mice into six groups: 1) vehicle-only control, 2) L-cysteine control, 3 and 4) treated for 7 days with 20 and 40 mg/kg lead acetate, respectively, and 5 and 6) treated for 7 days with 20 and 40 mg/kg lead acetate, respectively, followed by 50 mg/kg L-cysteine for 7 days. Lead acetate administration caused disorganization of cell layers, neuronal loss and degeneration, and neuropil vacuolization. Brain sections from lead-intoxicated mice treated with L-cysteine showed fewer pathological changes; the neuropil showed less vacuolization and the neurons appeared less damaged. L-cysteine at the dose we used only marginally alleviated lead-induced toxicity.

  11. 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

  12. Potential protective effect of taurine against dibromoacetonitrile-induced neurotoxicity in rats.

    PubMed

    Sayed, Rabab H; Salem, Hesham A; El-Sayeh, Bahia M

    2012-11-01

    Dibromoacetonitrile (DBAN) is a disinfection by-product of water chlorination. Epidemiological studies indicate that it might present a potential hazard to human health. The present study aimed to investigate the possible neurotoxicity of DBAN in rats and possible protection by taurine. Based on initial dose-response experiment, DBAN (60 mg/kg) was administrated orally for 7 days. DBAN administration significantly impaired behavior of rats. Further, DBAN produced significant decrease of monoamines, γ-aminobutyric acid (GABA), glutamate contents, acetylcholinestrase (AChE) and aspartate aminotransferase (AST) activities, in rat brain. On the other hand, a significant increase in malondialdehyde (MDA), nitric oxide (NO) contents and lactic dehydrogenase (LDH) activity was observed. Co-administration of taurine (200mg/kg, i.p.) with DBAN mitigated most tested parameters. In conclusion, the present study indicates that DBAN has the propensity to cause significant oxidative damage in rat brain. However, taurine has a promising role in attenuating the obtained hazardous effects of DBAN.

  13. 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

  14. Neurotoxic effect of dermally-applied chlorpyrifos and cypermethrin in Wistar rats.

    PubMed

    Latuszyńska, J; Luty, S; Raszewski, G; Tokarska-Rodak, M; Przebirowska, D; Przylepa, E; Haratym-Maj, A

    2001-01-01

    The aim of the study was to evaluate the neurotoxic effect of a dermally-applied mixture of chlorpyrifos and cypermethrin in rats based on cognitive function, activity of the blood cholinesterase and brain acetylcholinesterase, as well as histologic brain examination. Nurelle D 550 EC (500 g of chlorpyrifos and 50 g of cypermethrin) was used in the study. The application liquid was in the form of a water solution. The investigation covered eight groups of animals: six experimental groups and two control groups, of 15 rats each. Experimental groups received 5.6 mg/cm2 chlorpyrifos and 0.5 mg/cm2 cypermethrin, or 27.8 mg/cm2 chlorpyrifos and 2.7 mg/cm2 cypermethrin dermally, for one day, one week and four weeks, except for Saturdays and Sundays. The preparations examined were applied to the tail skin of rats. The animals were anaesthetized at the end of exposure period. Plasma cholinesterase and brain acetylcholinesterase activities were determined. The brain for histological examination was perfused with a solution of methanol, formalin and glacial acetic acid, and the sections stained by the Nissel method. The behaviour of the animals was evaluated in the open field test four times: before exposure, and after one, two and four weeks of the experiment. The results of the study showed that chlorpyrifos and cypermethrin applied in a mixture caused an inhibition of cholinesterase and acetylcholinesterase activity and elicited the pycnosis of brain neurocytes.

  15. Calcitriol protects against the dopamine- and serotonin-depleting effects of neurotoxic doses of methamphetamine.

    PubMed

    Cass, Wayne A; Smith, Michael P; Peters, Laura E

    2006-08-01

    Repeated methamphetamine (METH) administration to animals can result in long-lasting decreases in brain dopamine (DA) and serotonin (5-HT) content. Calcitriol, the active metabolite of vitamin D, has potent effects on brain cells, both in vitro and in vivo, including the ability to upregulate trophic factors and protect against various lesions. The present experiments were designed to examine the ability of calcitriol to protect against METH-induced reductions in striatal and nucleus accumbens levels of DA and 5-HT. Male Fischer-344 rats were administered vehicle or calcitriol (1 microg/kg, s.c.) once a day for eight consecutive days. After the seventh day of treatment the animals were given METH (5 mg/kg, s.c.) or saline four times in 1 day at 2-h intervals. Seven days later the striata and accumbens were harvested from the animals for high-performance liquid chromatography (HPLC) analysis of monoamines and metabolites. In animals treated with vehicle and METH, there were significant reductions in DA, 5-HT, and their metabolites in both the striatum and accumbens. In animals treated with calcitriol and METH, the magnitude of the METH-induced reductions in DA, 5-HT, and metabolites was substantially and significantly attenuated. The calcitriol treatments did not reduce the hyperthermia associated with multiple injections of METH, indicating that the neuroprotective effects of calcitriol are not due to the prevention of increases in body temperature. These results suggest that calcitriol can provide significant protection against the DA- and 5-HT-depleting effects of neurotoxic doses of METH.

  16. Cross-neutralisation of the neurotoxic effects of Egyptian cobra venom with commercial tiger snake antivenom.

    PubMed

    Kornhauser, Rachelle; Isbister, Geoffrey K; O'Leary, Margaret A; Mirtschin, Peter; Dunstan, Nathan; Hodgson, Wayne C

    2013-02-01

    Cross-neutralisation has been demonstrated for haemorrhagic venoms including Echis spp. and Cerastes spp. and for Australia elapid procoagulant toxins. A previous study showed that commercial tiger snake antivenom (TSAV) was able to neutralise the systemic effects of the Egyptian cobra, Naja haje, in vivo but it is unclear if this was true cross-neutralisation. The aim of the current study was to determine whether TSAV can neutralise the in vitro neurotoxic effects of N. haje venom. Both Notechis scutatus (10 μg/ml) and N. haje (10 μg/ml) venoms caused inhibition of indirect (supramaximal V, 0.1 Hz, 0.2 msec.) twitches of the chick biventer cervicis nerve-muscle preparation with t(90) values (i.e. the time to produce 90% inhibition of the original twitch height) of 26 ± 1 min. (n = 4) and 36 ± 4 min.; (n = 4). This effect at 10 μg/ml was significantly attenuated by the prior addition of TSAV (5 U/ml). A comparison of the reverse-phase HPLC profiles of both venoms showed some similarities with peak elution times, and SDS-PAGE analysis elucidated comparable bands across both venoms. Further analysis using Western immunoblotting indicated TSAV was able to detect N. haje venom, and enzyme immunoassay showed that in-house biotinylated polyclonal monovalent N. scutatus antibodies were able to detect N. haje venom. These findings demonstrate cross-neutralisation between different and geographically separated snakes supporting potential immunological similarities in snake toxin groups for a large range of snakes. This provides more evidence that antivenoms could be developed against specific toxin groups to cover a large range of snakes.

  17. 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.

  18. In vitro neurotoxic effects of Pseudechis spp. venoms: A comparison of avian and murine skeletal muscle preparations.

    PubMed

    Hart, Andrew J; Isbister, Geoffrey K; Hodgson, Wayne C

    2013-03-01

    Two common in vitro skeletal muscle preparations used for the study of venom neurotoxicity are the indirectly stimulated chick isolated biventer cervicis nerve-muscle preparation and the rat isolated phrenic nerve-diaphragm preparation. The aim of the current study was to compare the in vitro neurotoxicity of six Pseudechis spp. (Black snakes) venoms in both avian (chicken) and mammalian (rat) skeletal muscle preparations to determine differences in sensitivity. All Pseudechis spp. venoms significantly inhibited indirect twitches, in both preparations, indicating the presence of post synaptic neurotoxins. The inhibitory effects of all venoms were more rapid in the avian preparation, except for Pseudechis colletti venom where no significant difference was seen between the murine and avian muscles. Time taken to produce 50% reduction in stimulated twitches (i.e. t(50)) was markedly shorter in the avian preparation. We have shown that the avian in vitro preparation is more sensitive to the neurotoxic activity of Pseudechis spp. than the murine preparation. This difference is likely to be due to species differences in the interaction between the neurotoxins and the nicotinic receptor binding sites as well as differences in the 'safety factor' between the preparations.

  19. Possible ameliorative effects of antioxidants on propionic acid / clindamycin - induced neurotoxicity in Syrian hamsters

    PubMed Central

    2013-01-01

    Background Propionic acid (PA) found in some foods and formed as a metabolic product of gut bacteria has been reported to mimic/mediate the effects of autism. The present study was undertaken to compare the effect of orally administered PA with that of clindamycin-induced PA-microbial producers in inducing persistent biochemical autistic features in hamsters. The neuroprotective potency of carnosine and carnitine supplements against PA toxicity was also investigated. Methods The following groups were studied. 1. Control group, which received phosphate buffered saline orally, 2. Propionic acid treated group which were given PA at a dose of 250 mg/kg body weight/day for 3 days orally, 3. Clindamycin treated group which received a single dose of the antibiotic orogastrically at a dose of 30 mg/kg on the day of the experiment, 4. Carnosine-treated group which were given carnosine at a dose of 10 mg/kg body weight/day orally for one week, 5. Carnitine treated group given 50 mg/kg body weight/day carnitine orally daily for one week. Group 6. Carnosine followed by PA, Group 7. Carnitine followed by PA. Dopamine, adrenaline and noradrenaline, serotonin and Gamma amino-butyric acid (GABA) were measured in the cortex and medulla of the nine studied groups. Results PA administration caused significant decrease in the neurotransmitters in the brains of treated hamsters while clindamycin caused a significant decrease only in dopamine in hamster brains (cortex and medulla) and GABA in the cerebral cortex of the treated hamsters. Administration of carnosine and carnitine which are known antioxidants caused no significant changes in the levels of neurotransmitters when administered alone to hamsters. However when administered with PA both carnosine and carnitine restored the altered neurotransmitters to near normal levels. Conclusion Carnosine and carnitine may be used as supplements to protect against PA neurotoxicity. PMID:24188374

  20. Restorative effects of GDNF on striatal dopamine release in rats treated with neurotoxic doses of methamphetamine.

    PubMed

    Cass, W A; Manning, M W; Bailey, S L

    2000-09-01

    Repeated methamphetamine (METH) administration to animals can result in long-lasting decreases in striatal dopamine (DA) release and content. Glial cell line-derived neurotrophic factor (GDNF) has pronounced effects on dopaminergic systems in vivo, including neuroprotective effects against METH. The present experiments were designed to examine the ability of GDNF to reverse, or accelerate recovery from, METH-induced alterations in striatal DA release. Male Fischer-344 rats were administered METH (5 mg/kg, s.c.) or saline 4 times in one day at 2-hour intervals. Seven days later the animals were anesthetized and given a single injection of 10 microg GDNF, or vehicle, into the right striatum. Three weeks later microdialysis experiments were carried out in both the right and left striata to examine basal and evoked levels of DA and its metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA). In animals treated with METH followed by vehicle 7 days later, there were significant reductions in potassium- and amphetamine-evoked overflow of DA, and in basal levels of DOPAC and HVA, compared to control animals. In rats treated with METH followed 7 days later with GDNF, there were significant increases in potassium- and amphetamine-evoked overflow of DA on the right, GDNF-treated, side of the brain compared to the left side. Basal levels of DOPAC and HVA were also elevated on the GDNF-treated side of the brain. These results suggest that GDNF can accelerate recovery of dopaminergic release processes in the striatum of rats treated with neurotoxic doses of METH.

  1. Antiperoxidative and antiinflammatory effect of Sida cordifolia Linn. on quinolinic acid induced neurotoxicity.

    PubMed

    Swathy, S S; Panicker, Seema; Nithya, R S; Anuja, M M; Rejitha, S; Indira, M

    2010-09-01

    Sida cordifolia is a plant belonging to the Malvaceae family used in many ayurvedic preparations. This study aimed at assessing the effects of ethanolic extract of Sida cordifolia root on quinolinic acid (QUIN) induced neurotoxicity and to compare its effect with the standard drug deprenyl in rat brain. Rats were divided into six groups: (1) control group (2) QUIN (55 microg/100 g bwt/day) (3) 50% ethanolic plant extract treated group (50 mg/100 g bwt/day) (4) Deprenyl (100 microg/100 g bwt/day) (5) QUIN (55 microg/100 g bwt/day) + 50% ethanolic plant extract treated group (50 mg/100 g bwt/day) (6) QUIN (55 microg/100 g bwt/day) + Deprenyl (100 microg/100 g bwt/day). At the end of the experimental period a status of lipid peroxidation products, protein peroxidation product, activities of the scavenging enzymes and the activities of the inflammatory markers were analyzed. Results revealed that the lipid peroxidation products decreased and the activities of the scavenging enzymes increased significantly in the brain of the plant extract treated group, deprenyl treated group and also in the coadminstered groups. The activities of markers of inflammatory responses such as cyclooxygenase and lipoxygenase were found to be significantly increased in the QUIN treated rats and this was decreased upon the administration of plant extract and deprenyl. In short, the study revealed that 50% ethanolic extract of Sida cordifolia has got potent antioxidant and antiinflammatory activity and the activity is comparable with the standard drug deprenyl.

  2. 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

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

    PubMed Central

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

    2015-01-01

    ABSTRACT 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

  4. 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.

  5. 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.

  6. Intermingled modulatory and neurotoxic effects of thimerosal and mercuric ions on electrophysiological responses to GABA and NMDA in hippocampal neurons.

    PubMed

    Wyrembek, P; Szczuraszek, K; Majewska, M D; Mozrzymas, J W

    2010-12-01

    The organomercurial, thimerosal, is at the center of medical controversy as a suspected factor contributing to neurodevelopmental disorders in children. Many neurotoxic effects of thimerosal have been described, but its interaction with principal excitatory and inhibitory neurotransmiter systems is not known. We examined, using electrophysiological recordings, thimerosal effects on GABA and NMDA-evoked currents in cultured hippocampal neurons. After brief (3 to 10 min) exposure to thimerosal at concentrations up to 100 μM, there was no significant effect on GABA or NMDA-evoked currents. However, following exposure for 60-90 min to 1 or 10 μM thimerosal, there was a significant decrease in NMDA-induced currents (p<0.05) and GABAergic currents (p<0.05). Thimerosal was also neurotoxic, damaging a significant proportion of neurons after 60-90 min exposure; recordings were always conducted in the healthiest looking neurons. Mercuric chloride, at concentrations 1 μM and above, was even more toxic, killing a large proportion of cells after just a few minutes of exposure. Recordings from a few sturdy cells revealed that micromolar mercuric chloride markedly potentiated the GABAergic currents (p<0.05), but reduced NMDA-evoked currents (p<0.05). The results reveal complex interactions of thimerosal and mercuric ions with the GABA(A) and NMDA receptors. Mercuric chloride act rapidly, decreasing electrophysiological responses to NMDA but enhancing responses to GABA, while thimerosal works slowly, reducing both NMDA and GABA responses. The neurotoxic effects of both mercurials are interwoven with their modulatory actions on GABA(A) and NMDA receptors, which most likely involve binding to these macromolecules.

  7. Long-Term Neurotoxic Effects of Early Life Exposure to Tetrachloroethylene-contaminated Drinking Water

    PubMed Central

    Aschengrau, Ann; Janulewicz, Patricia A.; White, Roberta F.; Vieira, Veronica M.; Gallagher, Lisa G.; Getz, Kelly D.; Webster, Thomas F.; Ozonoff, David M.

    2016-01-01

    Background Tetrachloroethene (PCE) is a common environmental and occupational contaminant and an acknowledged neurotoxicant. From 1968 through 1983 widespread contamination of public drinking water supplies with PCE occurred in the Cape Cod region of Massachusetts. The source of the contamination was a vinyl liner applied to the inner surface of water distribution pipes. Objectives A retrospective cohort study (“the Cape Cod Health Study”) was undertaken to examine possible health consequences of early life exposure to PCE-contaminated drinking water. This review describes the study methods and findings regarding the impact of prenatal and childhood exposure on neurological outcomes during early adulthood, including vision, neuropsychological functioning, brain structure, risky behaviors, and mental illness. The review also describes the strengths and challenges of conducting population-based epidemiological research in this unique setting. Methods Subjects were identified by cross-matching birth certificate and water system data. Information on health outcomes and confounding variables was collected from self-administered surveys (N= 1,689), neuropsychological tests (N=63), vision exam (N=63), and magnetic resonance imaging (N=42). Early life exposure to PCE was estimated using a leaching and transport model. The data analysis compared the occurrence of each health outcome among subjects with prenatal and early childhood PCE exposure to unexposed subjects while considering the impact of confounding variables. Results The study found evidence that early life exposure to PCE-contaminated drinking water has long-term neurotoxic effects. The strongest associations were seen with illicit drug use, bipolar disorder, and post-traumatic stress disorder. Key strengths of the study were availability of historical data on affected water systems, a relatively high exposure prevalence and wide range of exposure levels, and little confounding. Challenges arose mainly from

  8. 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.

  9. Effect of acrylamide-induced neurotoxicity in a primary astrocytes/microglial co-culture model.

    PubMed

    Zhao, Mengyao; Wang, Fu Sheng Lewis; Hu, Xiao Song; Chen, Fang; Chan, Hing Man

    2017-03-01

    Acrylamide (AA), is a common food contaminant generated by heat processing. Astrocytes and microglia are the two major glial cell types in the brain that play pivotal but different roles in maintaining optimal brain function. The objective of this study is to investigate the neurotoxicity of AA, using a primary astrocytes/microglia co-culture model. Co-cultural cells obtained from Balb/c mice were cultured and treated with 0-1.0mM AA for 24-96h. Cell viability, reactive oxygen species (ROS) generation, oxidative end produces formation and glutathione (GSH) levels were measured. The expression of nuclear-E2-related factor 2(Nrf2), and nuclear factor kappa-beta (NF-κB) and selected down-stream genes were measured. Results showed that AA treatment led toa dose-dependent toxicity. Oxidative stress was induced as indicated by an increase of ROS, a decrease of GSH levels, and an increase in the formation of 4-hydroxynonenal-adduct and 8-hydroxy-2-deoxyguanosine-adduct. Both Nrf2 and NF-κB pathway contributed to the initiation of oxidative stress but the timing of two factors was different. Nrf2 and its related downstream genes were activated earlier than that in NF-κB pathway. In conclusion, AA-induced neurotoxicity attribute to oxidative stress via Nrf2 and NF-κB pathway. Moreover, the co-culture cell model was proven to be a viable model to study AA neurotoxicity.

  10. Protection by GDNF and other trophic factors against the dopamine-depleting effects of neurotoxic doses of methamphetamine.

    PubMed

    Cass, Wayne A; Peters, Laura E; Harned, Michael E; Seroogy, Kim B

    2006-08-01

    Repeated methamphetamine (METH) administration to animals can result in long-lasting decreases in striatal dopamine (DA) content. It has previously been shown that glial cell line-derived neurotrophic factor (GDNF) can reduce the DA-depleting effects of neurotoxic doses of METH. However, there are several other trophic factors that are protective against dopaminergic toxins. Thus, the present experiments further investigated the protective effect of GDNF as well as the protective effects of several other trophic factors. Male Fischer-344 rats were given an intracerebral injection of trophic factor (2-10 microg) 1 day before METH (5 mg/kg, s.c., 4 injections at 2-h intervals). Seven days later DA levels in the striatum were measured using high-performance liquid chromatography (HPLC). Initial experiments indicated that only intrastriatal GDNF, and not intranigral GDNF, was protective. Thereafter, all other trophic factors were administered into the striatum. Members of the GDNF family (GDNF, neurturin, and artemin) all provided significant protection against the DA-depleting effects of METH, with GDNF providing the greatest protection. Brain-derived neurotrophic factor, neurotrophin-3, acidic fibroblast growth factor, basic fibroblast growth factor, ciliary neurotrophic factor, transforming growth factor-alpha (TGF-alpha), heregulin beta1 (HRG-beta1), and amphiregulin (AR) provided no significant protection at the doses examined. These results suggest that the GDNF family of trophic factors can provide significant protection against the DA-depleting effects of neurotoxic doses of METH.

  11. 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.

  12. 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.

  13. Effect of neurotoxic lesion of pedunculopontine nucleus in nigral and striatal redox balance and motor performance in rats.

    PubMed

    Jimenez-Martin, J; Blanco-Lezcano, L; González-Fraguela, M E; Díaz-Hung, M-L; Serrano-Sánchez, T; Almenares, J L; Francis-Turner, L

    2015-03-19

    Early degeneration of pedunculopontine nucleus (PPN) is considered part of changes that characterize premotor stages of Parkinson's disease (PD). In this paper, the effects of unilateral neurotoxic lesion of the PPN in motor execution and in the development of oxidative stress events in striatal and nigral tissues in rats were evaluated. The motor performance was assessed using the beam test (BT) and the cylinder test (CT). Nigral and striatal redox balance, was studied by means of biochemical indicators such as malondialdehyde (MDA), nitric oxide (NO) and the catalase enzymatic activity (CAT EA). Lesioned rats showed fine motor dysfunction expressed both as an increase in the length (p<0.001) and deviation (p<0.001) of the traveled path and also in the time spent (p<0.01) in the circular small beam (CBS) (p<0.01) in comparison with control groups. In addition, the lesioned rats group presented a right asymmetry index greater than 0.5 which is consistent with a significant increase in the percentage of use of the right forelimb (ipsilateral to the lesion), compared with the control group (p<0.05). Biochemical studies revealed that after 48-h PPN neurotoxic injury, the CAT EA showed a significant increase in the subtantia nigra pars compacta (SNpc) (p<0.05). This significant increase of CAT EA persisted in the nigral tissue (p<0.001) and reached the striatal tissue (p<0.001) seven days after PPN injury. Also at seven days post-injury PPN, increased concentrations of MDA (p<0.01) and a tendency to decrease in the concentrations of NO in both structures (SNpc and striatum) were found. The events associated with the generation of free radicals at nigral and striatal levels, can be part of the physiological mechanisms underlying motor dysfunction in rats with unilateral PPN neurotoxic lesion.

  14. 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.

  15. Neurotoxic lesions of the medial mediodorsal nucleus of the thalamus disrupt reinforcer devaluation effects in rhesus monkeys.

    PubMed

    Mitchell, Anna S; Browning, Philip G F; Baxter, Mark G

    2007-10-17

    The mediodorsal thalamus is a major input to the prefrontal cortex and is thought to modulate cognitive functions of the prefrontal cortex. Damage to the medial, magnocellular part of the mediodorsal thalamus (MDmc) impairs cognitive functions dependent on prefrontal cortex, including memory. The contribution of MDmc to other aspects of cognition dependent on prefrontal cortex has not been determined. The ability of monkeys to adjust their choice behavior in response to changes in reinforcer value, a capacity impaired by lesions of orbital prefrontal cortex, can be tested in a reinforcer devaluation paradigm. In the present study, rhesus monkeys with bilateral neurotoxic MDmc lesions were tested in the devaluation procedure. Monkeys learned visual discrimination problems in which each rewarded object is reliably paired with one of two different food rewards and then were given choices between pairs of rewarded objects, one associated with each food. Selective satiation of one of the food rewards reduces choices of objects associated with that food in normal monkeys. Monkeys with bilateral neurotoxic lesions of MDmc learned concurrently presented visual discrimination problems as quickly as unoperated control monkeys but showed impaired reinforcer devaluation effects. This finding suggests that the neural circuitry for control of behavioral choice by changes in reinforcer value includes MDmc.

  16. 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.

  17. 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

  18. 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.

  19. A review of the neurotoxicity risk of selected hydrocarbon fuels.

    PubMed

    Ritchie, G D; Still, K R; Alexander, W K; Nordholm, A F; Wilson, C L; Rossi, J; Mattie, D R

    2001-01-01

    Over 1.3 million civilian and military personnel are occupationally exposed to hydrocarbon fuels, emphasizing gasoline, jet fuel, diesel fuel, or kerosene. These exposures may occur acutely or chronically to raw fuel, vapor, aerosol, or fuel combustion exhaust by dermal, respiratory inhalation, or oral ingestion routes, and commonly occur concurrently with exposure to other chemicals and stressors. Hydrocarbon fuels are complex mixtures of 150-260+ aliphatic and aromatic hydrocarbon compounds containing varying concentrations of potential neurotoxicants including benzene, n-hexane, toluene, xylenes, naphthalene, and certain n-C9-C12 fractions (n-propylbenzene, trimethylbenzene isomers). Due to their natural petroleum base, the chemical composition of different hydrocarbon fuels is not defined, and the fuels are classified according to broad performance criteria such as flash and boiling points, complicating toxicological comparisons. While hydrocarbon fuel exposures occur typically at concentrations below permissible exposure limits for their constituent chemicals, it is unknown whether additive or synergistic interactions may result in unpredicted neurotoxicity. The inclusion of up to six performance additives in existing fuel formulations presents additional neurotoxicity challenge. Additionally, exposures to hydrocarbon fuels, typically with minimal respiratory or dermal protection, range from weekly fueling of personal automobiles to waist-deep immersion of personnel in raw fuel during maintenance of aircraft fuel tanks. Occupational exposures may occur on a near daily basis for from several months to over 20 yr. A number of published studies have reported acute or persisting neurotoxic effects from acute, subchronic, or chronic exposure of humans or animals to hydrocarbon fuels, or to certain constituent chemicals of these fuels. This review summarizes human and animal studies of hydrocarbon fuel-induced neurotoxicity and neurobehavioral consequences. It is

  20. Chronic exposure to corticosterone enhances the neuroinflammatory and neurotoxic responses to methamphetamine.

    PubMed

    Kelly, Kimberly A; Miller, Diane B; Bowyer, John F; O'Callaghan, James P

    2012-09-01

    Up-regulation of proinflammatory cytokines and chemokines in brain ("neuroinflammation") accompanies neurological disease and neurotoxicity. Previously, we documented a striatal neuroinflammatory response to acute administration of a neurotoxic dose of methamphetamine (METH), i.e. one associated with evidence of dopaminergic terminal damage and activation of microglia and astroglia. When we used minocycline to suppress METH-induced neuroinflammation, indices of dopaminergic neurotoxicity were not affected, but suppression of neuroinflammation was incomplete. Here, we administered the classic anti-inflammatory glucocorticoid, corticosterone (CORT), in an attempt to completely suppress METH-related neuroinflammation. METH alone caused large increases in striatal proinflammatory cytokine/chemokine mRNA and subsequent astrocytic hypertrophy, microglial activation, and dopaminergic nerve terminal damage. Pre-treatment of mice with acute CORT failed to prevent neuroinflammatory responses to METH. Surprisingly, when mice were pre-treated with chronic CORT in the drinking water, an enhanced striatal neuroinflammatory response to METH was observed, an effect that was accompanied by enhanced METH-induced astrogliosis and dopaminergic neurotoxicity. Chronic CORT pre-treatment also sensitized frontal cortex and hippocampus to mount a neuroinflammatory response to METH. Because the levels of chronic CORT used are associated with high physiological stress, our data suggest that chronic CORT therapy or sustained physiological stress may sensitize the neuroinflammatory and neurotoxicity responses to METH.

  1. An In Vitro Study of the Neurotoxic Effects of N-Benzylpiperazine: A Designer Drug of Abuse.

    PubMed

    Persona, Karolina; Polus, Anna; Góralska, Joanna; Gruca, Anna; Dembińska-Kieć, Aldona; Piekoszewski, Wojciech

    2016-05-01

    Recently, the number of new psychoactive substances has significantly increased. Despite the systematic introduction of prohibition in trade of medicinal products which mimic the effects of illegal drugs, the problem concerning this group of drugs is still important although knowledge about the mechanism of action of those types of substances is scarce. This study aimed to follow the neurotoxic effect of N-benzylpiperazine (BZP), the central nervous system psychostimulant, using the human cancer LN-18 cell model. The statistically significant elevation of LDH levels, increased mitochondrial membrane potential, decreased ATP and increased ROS production, increased levels of DNA damage marker (8-OHdG) and activation of caspases: -3 and -9 confirmed by Real-Time PCR imply the activation of mitochondrial proapoptotic pathways induced by BZP after 24 h incubation. This study is a novel, preliminary attempt to explain the toxicity of one of the most popular designer drug of abuse at the cellular level.

  2. 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

  3. The protective effect of Rho-associated kinase inhibitor on aluminum-induced neurotoxicity in rat cortical neurons.

    PubMed

    Chen, Tsan-Ju; Hung, Hui-Shan; Wang, Dean-Chuan; Chen, Shun-Sheng

    2010-07-01

    Aluminum (Al) is a neurotoxicant and is implicated in several neurodegenerative diseases, including Alzheimer's disease (AD). In AD brains, one of the pathological hallmarks is the extracellular deposition of senile plaques, which are mainly composed of aggregated amyloid-beta (Abeta). Endoproteolysis of the amyloid-beta precursor protein (AbetaPP) by the beta-secretase and the gamma-secretase generates Abeta. AbetaPP can also be cleaved by the alpha-secretase within the Abeta region, which releases a soluble fragment sAPPalpha and precludes the formation of Abeta. Al has been reported to increase the level of Abeta, promote Abeta aggregation, and increase Abeta neurotoxicity. In contrast, small G protein Rho and its effector, Rho-associated kinase (ROCK), are known to negatively regulate the amount of Abeta. Inhibition of the Rho-ROCK pathway may underlie the ability of nonsteroidal anti-inflammatory drugs and statins to reduce Abeta production. Whether the Rho-ROCK pathway is involved in Al-induced elevation and aggregation of Abeta is unknown. In the present study, cultured rat cortical neurons were treated with Al(malt)(3) in the absence or presence of ROCK inhibitor Y-27632. After the treatment of Al(malt)(3), the cell viability and the level of sAPPalpha were reduced, whereas the amyloid fibrils in the conditioned media were increased. Treatment with Y-27632 prevented these adverse effects of Al(malt)(3) and thus maintained neuronal survival. These results reveal that the activation of the Rho-ROCK signaling pathway was involved in Al-induced effects in terms of the cell viability, the production of sAPPalpha, and the formation of amyloid fibril, which provides a novel mechanism underlying Al-induced neurotoxicity.

  4. 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.

  5. 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...

  6. Exacerbation of Methamphetamine Neurotoxicity in Cold and Hot Environments: Neuroprotective Effects of an Antioxidant Compound H-290/51.

    PubMed

    Sharma, Hari Shanker; Kiyatkin, Eugene A; Patnaik, Ranjana; Lafuente, José Vicente; Muresanu, Dafin F; Sjöquist, Per-Ove; Sharma, Aruna

    2015-10-01

    In this study, we examined the influence of cold and hot environments on methamphetamine (METH) neurotoxicity in both drug-naive rats and animals previously exposed to different types of nanoparticles (NPs). Since METH induces oxidative stress, we also examined how a potential chain-breaking antioxidant H-290/51 (Astra-Zeneca, Mölndal, Sweden) affects METH-induced neurotoxicity. Exposure of drug-naive rats to METH (9 mg/kg, s.c.) at 4, 21, or 34 °C for 3 h resulted in breakdown of the blood-brain barrier (BBB), brain edema, and neuronal injuries, which all differed in severity depending upon ambient temperatures. The changes were moderate at 21 °C, 120-180 % larger at 34 °C, and almost absent at 4 °C. In rats chronically treated with NPs (SiO2, Cu, or Ag; 50-60 nm, 50 mg/kg, i.p. for 7 days), METH-induced brain alterations showed a two- to fourfold increase at 21 °C, a four- to sixfold increase at 34 °C, and three- to fourfold increase at 4 °C. SiO2 exposure showed the most pronounced METH-induced brain pathology at all temperatures followed by Ag and Cu NPs. Pretreatment with a potent antioxidant compound H-290/51 (50 mg/kg, p.o., 30 min before METH) significantly reduced brain pathology in naive animals exposed to METH at 21 and 34 °C. In NPs-treated animals, however, attenuation of METH-induced brain pathology occurred only after repeated exposure of H-290/51 (-30 min, 0 min, and +30 min). These observations are the first to show that NPs exacerbate METH-induced brain pathology in both cold and hot environments and demonstrate that timely intervention with antioxidant H-290/51 could have neuroprotective effects.

  7. Phenotypic screening for developmental neurotoxicity ...

    EPA Pesticide Factsheets

    There are large numbers of environmental chemicals with little or no available information on their toxicity, including developmental neurotoxicity. Because of the resource-intensive nature of traditional animal tests, high-throughput (HTP) methods that can rapidly evaluate chemicals for the potential to affect the developing brain are being explored. Typically, HTP screening uses biochemical and molecular assays to detect the interaction of a chemical with a known target or molecular initiating event (e.g., the mechanism of action). For developmental neurotoxicity, however, the mechanism(s) is often unknown. Thus, we have developed assays for detecting chemical effects on the key events of neurodevelopment at the cellular level (e.g., proliferation, differentiation, neurite growth, synaptogenesis, network formation). Cell-based assays provide a test system at a level of biological complexity that encompasses many potential neurotoxic mechanisms. For example, phenotypic assessment of neurite outgrowth at the cellular level can detect chemicals that target kinases, ion channels, or esterases at the molecular level. The results from cell-based assays can be placed in a conceptual framework using an Adverse Outcome Pathway (AOP) which links molecular, cellular, and organ level effects with apical measures of developmental neurotoxicity. Testing a wide range of concentrations allows for the distinction between selective effects on neurodevelopmental and non-specific

  8. 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...

  9. 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

  10. 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.

  11. 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.

  12. 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.

  13. Neurotoxicity of organomercurial compounds.

    PubMed

    Sanfeliu, Coral; Sebastià, Jordi; Cristòfol, Rosa; Rodríguez-Farré, Eduard

    2003-01-01

    Mercury is a ubiquitous contaminant, and a range of chemical species is generated by human activity and natural environmental change. Elemental mercury and its inorganic and organic compounds have different toxic properties, but all them are considered hazardous in human exposure. In an equimolecular exposure basis, organomercurials with a short aliphatic chain are the most harmful compounds and they may cause irreversible damage to the nervous system. Methylmercury (CH(3)Hg(+)) is the most studied following the neurotoxic outbreaks identified as Minamata disease and the Iraq poisoning. The first description of the CNS pathology dates from 1954. Since then, the clinical neurology, the neuropathology and the mechanisms of neurotoxicity of organomercurials have been widely studied. The high thiol reactivity of CH(3)Hg(+), as well as all mercury compounds, has been suggested to be the basis of their harmful biological effects. However, there is clear selectivity of CH(3)Hg(+) for specific cell types and brain structures, which is not yet fully understood. The main mechanisms involved are inhibition of protein synthesis, microtubule disruption, increase of intracellular Ca(2+) with disturbance of neurotransmitter function, oxidative stress and triggering of excitotoxicity mechanisms. The effects are more damaging during CNS development, leading to alterations of the structure and functionality of the nervous system. The major source of CH(3)Hg(+) exposure is the consumption of fish and, therefore, its intake is practically unavoidable. The present concern is on the study of the effects of low level exposure to CH(3)Hg(+) on human neurodevelopment, with a view to establishing a safe daily intake. Recommendations are 0.4 micro g/kg body weight/day by the WHO and US FDA and, recently, 0.1 micro g/kg body weight/day by the US EPA. Unfortunately, these levels are easily attained with few meals of fish per week, depending on the source of the fish and its position in the

  14. 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...

  15. Effect of melatonin on methamphetamine- and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced dopaminergic neurotoxicity and methamphetamine-induced behavioral sensitization.

    PubMed

    Itzhak, Y; Martin, J L; Black, M D; Ali, S F

    1998-06-01

    Methamphetamine (METH)- and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced dopaminergic neurotoxicity is thought to be associated with the formation of free radicals. Since evidence suggests that melatonin may act as a free radical scavenger and antioxidant, the present study was undertaken to investigate the effect of melatonin on METH- and MPTP-induced neurotoxicity. In addition, the effect of melatonin on METH-induced locomotor sensitization was investigated. The administration of METH (5 mg kg(-1) x 3) or MPTP (20 mg kg(-1) x 3) to Swiss Webster mice resulted in 45-57% depletion in the content of striatal dopamine and its metabolites, 3,4-dihydroxyphenylacetic acid and homovanillic acid, and 57-59% depletion in dopamine transporter binding sites. The administration of melatonin (10 mg kg(-1)) before each of the three injections of the neurotoxic agents (on day 1), and thereafter for two additional days, afforded a full protection against METH-induced depletion of dopamine and its metabolites and dopamine transporter binding sites. In addition, melatonin significantly diminished METH-induced hyperthermia. However, the treatment with melatonin had no significant effect on MPTP-induced depletion of the dopaminergic markers tested. In the set of behavioral experiments, we found that the administration of 1 mg kg(-1) METH to Swiss Webster mice for 5 days resulted in marked locomotor sensitization to a subsequent challenge injection of METH, as well as context-dependent sensitization (conditioning). The pretreatment with melatonin (10 mg kg(-1)) prevented neither the sensitized response to METH nor the development of conditioned locomotion. Results of the present study indicate that melatonin has a differential effect on the dopaminergic neurotoxicity produced by METH and MPTP. Since it is postulated that METH-induced hyperthermia is related to its neurotoxic effect, while regulation of body temperature is unrelated to MPTP-induced neurotoxicity or METH

  16. Acute neurobehavioural effects of toluene.

    PubMed Central

    Echeverria, D; Fine, L; Langolf, G; Schork, A; Sampaio, C

    1989-01-01

    An acute inhalation chamber study of 42 college students was performed to investigate the relation between exposure to 0, 75, and 150 ppm of toluene and changes in central nervous system function and symptoms. Paid subjects were exposed for seven hours over three days. Verbal and visual short term memory (Sternberg, digit span, Benton, pattern memory); perception (pattern recognition); psychomotor skill (simple reaction time, continuous performance, digit symbol, hand-eye coordination, finger tapping, and critical tracking); manual dexterity (one hole); mood (profile of mood scales (POMS]; fatigue (fatigue checklist); and verbal ability were evaluated at 0800, 1200, and 1600 hours. Voluntary symptoms and observations of sleep were collected daily. An analysis of variance and test for trend was performed on the difference and score for each concentration reflecting an eight hour workday where each subject was their own control. A 3 x 3 Latin square study design evaluated toluene effects simultaneously, controlling for learning across the three days and the solvent order. Intersubject variation in solvent uptake was monitored in breath and urine. A 5-10% decrement in performance was considered significant if it was consistent with a linear trend at p less than 0.05. Adverse performance at 150 ppm toluene was found at 6.0% for digit span, 12.1% for pattern recognition (latency), 5.0% for pattern memory (number correct), 6.5% for one hole, and 3.0% for critical tracking. The number of headaches and eye irritation also increased in a dose response manner. The greatest effect was found for an increasing number of observations of sleep. Overall, no clear pattern of neurobehavioural effects was found consistent with the type 1 central nervous system as classified by the World Health Organisation. Subtle acute effects, however, were found just below and above the ACGIH TLV of 100 ppm toluene, supporting the position that the guideline be lowered since the biological

  17. 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.

  18. Stem cell mobilization chemotherapy with gemcitabine is effective and safe in myeloma patients with bortezomib-induced neurotoxicity.

    PubMed

    Mueller, Beatrice U; Keller, Sandra; Seipel, Katja; Mansouri Taleghani, Behrouz; Rauch, Daniel; Betticher, Daniel; Egger, Thomas; Pabst, Thomas

    2016-05-01

    Vinorelbine chemotherapy with granulocyte-colony stimulating factor (G-CSF) stimulation is a widely applied non-myelosuppressive mobilization regimen in Switzerland for myeloma patients, but its neurotoxic potential limits its use in patients with bortezomib-induced polyneuropathy. In this single-center study, we alternatively evaluated safety and effectiveness of gemcitabine chemotherapy with G-CSF for mobilization of autologous stem cells. Between March 2012 and February 2013, all bortezomib-pretreated myeloma patients planned to undergo first-line high-dose melphalan chemotherapy received a single dose of 1250 mg/m2 gemcitabine, with G-CSF started on day 4. The 24 patients in this study had received a median of four cycles of bortezomib-dexamethason-based induction. Bortezomib-related polyneuropathy was identified in 21 patients (88%) by clinical evaluation and a standardized questionnaire. Administration of gemcitabine mobilization did not induce new or aggravate pre-existing neuropathy. Stem cell mobilization was successful in all 24 patients, with a single day of apheresis being sufficient in 19 patients (78%). The median yield was 9.51×10(6) CD34+ cells/kg. Stem collection could be accomplished at day 8 in 67%. Our data suggest that single-dose gemcitabine together with G-CSF is an effective mobilization regimen in myeloma patients and a safe alternative non-myelosuppressive mobilization chemotherapy for myeloma patients with bortezomib-induced polyneuropathy.

  19. Ester Hydrolysis Differentially Reduces Aconitine-Induced Anti-hypersensitivity and Acute Neurotoxicity: Involvement of Spinal Microglial Dynorphin Expression and Implications for Aconitum Processing

    PubMed Central

    Li, Teng-Fei; Gong, Nian; Wang, Yong-Xiang

    2016-01-01

    Aconitines, including bulleyaconitine A, probably the most bioactive and abundant alkaloids in Aconitum plant, are a group of diester C19-diterpenoid alkaloids with one acetylester group attached to C8 of the diterpenoid skeleton and one benzoylester group to C14. Hydrolysis of both groups is involved in the processing of Aconitum, a traditional Chinese medicinal approach. We recently demonstrated that bulleyaconitine A produced anti-hypersensitivity, which was mediated by stimulation of spinal microglial dynorphin A expression. This study aimed to elucidate whether the acetylester and benzoylester groups are involved in aconitine-induced dynorphin A expression, anti-hypersensitivity, neurotoxicity in neuropathic rats. Intrathecal administration of aconitine and benzoylaconine (but not aconine) attenuated mechanical allodynia and heat hyperalgesia, with normalized ED50 values of 35 pmol and 3.6 nmol, respectively. Aconitine and benzoylaconine anti-allodynia was completely blocked by the microglial inhibitor, dynorphin A antiserum, and κ-opioid receptor antagonist. Aconitine and benzoylaconine, but not aconine, stimulated dynorphin A expression in cultured primary spinal microglia, with EC50 values of 32 nM and 3 μM, respectively. Intrathecal aconitine, benzoylaconine and aconine induced flaccid paralysis and death, with normalized TD50 values of 0.5 nmol, 0.2 μmol, and 1.6 μmol, respectively. The TD50/ED50 ratios of aconitine and benzolyaconine were 14:1 and 56:1. Our results suggest that both the C8-acetyl and C14-benzoyl groups are essential for aconitine to stimulate spinal microglial dynorphin A expression and subsequent anti-hypersensitivity, which can be separated from neurotoxicity, because both benzoylaconine and aconine differentially produced anti-hypersensitivity and neurotoxicity due to their different stimulatory ability on dynorphin A expression. Our results support the scientific rationale for Aconitum processing, but caution should be taken to

  20. Ameliorative effect of 1,2-benzenedicarboxylic acid dinonyl ester against amyloid beta peptide-induced neurotoxicity.

    PubMed

    Jung Choi, Soo; Kim, Mi Jeong; Jin Heo, Ho; Kim, Jae Kyeum; Jin Jun, Woo; Kim, Hye Kyung; Kim, Eun-Ki; Ok Kim, Myeong; Yon Cho, Hong; Hwang, Han-Joon; Jun Kim, Young; Shin, Dong-Hoon

    2009-03-01

    Amyloid beta peptide (Abeta)-induced oxidative stress may be linked to neurodegenerative disease. Ethanol extracts of Rosa laevigata protected PC12 cells from hydrogen peroxide-induced oxidative stress. (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide) reduction assays revealed a significant increase in cell viability when oxidatively stressed PC12 cells were treated with R. laevigata extract. The effect of R. laevigata on oxidative stress-induced cell death was further investigated by lactate dehydrogenase release assays and trypan blue exclusion assays. Administration of 1,2-benzenedicarboxylic acid dinonyl ester from R. laevigata extract to mice infused with Abeta significantly reversed learning and memory impairment in behavioural tests. After behavioural testing, the mice were sacrificed and brains were collected for the examination of lipid peroxidation, catalase activity and acetylcholinesterase (AchE) activity. These results suggest that 1,2-benzenedicarboxylic acid dinonyl ester from R. laevigata extract may be able to reduce Abeta-induced neurotoxicity, possibly by reducing oxidative stress. Therefore, R. laevigata extract may be useful for the prevention of oxidative stress-induced neurodegenerative disorders.

  1. 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

  2. Urinary delta-ALA: a potential biomarker of exposure and neurotoxic effect in rats co-treated with a mixture of lead, arsenic and manganese.

    PubMed

    Andrade, Vanda; Mateus, M Luísa; Batoréu, M Camila; Aschner, Michael; dos Santos, A P Marreilha

    2013-09-01

    Lead (Pb), arsenic (As) and manganese (Mn) are neurotoxic elements that often occur in mixtures for which practically no information is available on biomarkers (BMs) for the evaluation of exposure/effects. Exposures to these metals may increase delta-aminolevulinic acid (delta-ALA), which in itself may potentiate neurotoxicity. The objective of this study was to investigate the utility of urinary delta-ALA (delta-ALA-U) levels as BM of exposure and/or neurotoxic effects induced by this mixture. Five groups of Wistar rats were treated for 8 days with Pb (5mg/kg), As (60mg/L), Mn (10mg/kg), the 3-metal mixture (same doses of the single metals), and control group. Motor activity was evaluated and 24-h urine collected before and after the treatment. 24-hours (h) after the last dose, the rats were sacrificed and the brains removed for analyses. Delta-ALA and metal levels were determined in brain and urine. Co-treated rats showed a significant (p<0.05) correlation between increased Pb, As, Mn and delta-ALA levels in the brain and decreased motor activity. Delta-ALA-U concentrations were higher in the mixture-treated group than the sum of the delta-ALA-U levels in each single-treated groups and discriminated (p<0.05) between the mixture and untreated rats. Moreover, delta-ALA-U was correlated (p<0.05) with brain delta-ALA levels. These results establish that treatments with this metal mixture exacerbate behavioral dysfunction, increasing most prominently brain Pb levels. This study is the first to establish that delta-ALA-U levels represent a sensitive BM of exposure/neurotoxic effect to this metal mixture.

  3. Urinary delta-ALA: a potential biomarker of exposure and neurotoxic effect in rats co-treated with a mixture of lead, arsenic and manganese

    PubMed Central

    Andrade, Vanda; Mateus, M. Luísa; Batoréu, M. Camila; Aschner, Michael; Marreilha dos Santos, A.P.

    2013-01-01

    Lead (Pb), arsenic (As) and manganese (Mn) are neurotoxic elements that often occur in mixtures for which practically no information is available on biomarkers (BMs) for the evaluation of exposure/effects. Exposures to these metals may increase delta-aminolevulinic acid (delta-ALA), which in itself may potentiate neurotoxicity. The objective of this study was to investigate the utility of urinary delta-ALA (delta-ALA-U) levels as BM of exposure and/or neurotoxic effects induced by this mixture. Five groups of Wistar rats were treated for 8 days with Pb (5 mg/kg), As (60 mg/L), Mn (10 mg/kg), the 3-metal mixture (same doses of the single metals), and control group. Motor activity was evaluated and 24-h urine collected before and after the treatment. 24-hours (h) after the last dose, the rats were sacrificed and the brains removed for analyses. Delta-ALA and metal levels were determined in brain and urine. Co-treated rats showed a significant (p<0.05) correlation between increased Pb, As, Mn and delta-ALA levels in the brain and decreased motor activity. Delta-ALA-U concentrations were higher in the mixture-treated group than the sum of the delta-ALA-U levels in each single-treated groups and discriminated (p<0.05) between the mixture and untreated rats. Moreover, delta-ALA-U was correlated (p<0.05) with brain delta-ALA levels. These results establish that treatments with this metal mixture exacerbate behavioral dysfunction, increasing most prominently brain Pb levels. This study is the first to establish that delta-ALA-U levels represent a sensitive BM of exposure/neurotoxic effect to this metal mixture. PMID:23764341

  4. 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.

  5. Evaluation of Early and Prolonged Effects of Acute Neurotoxicity and Neuroprotection Using Novel Functional Imaging Techniques

    DTIC Science & Technology

    2004-08-01

    100mg/kg dose, indicative of neuronal sparing. Histological analysis confirmed cystamine induced neuroprotection of striatal and cortical neurons. Nissl ...washing in PBS. Histochemistry: Sections were stained for Nissl substance and the presence of the enzyme nicotinamide adenine dinucleotide phosphate... Nissl staining reveals that following cystamine treatment (100 mg/kg), striatal cells are more numerous and depict a healthier appearance (e) closely

  6. [Neurotoxic effect of toluene on background of prenatal hypoxic brain damage to white rats].

    PubMed

    Vokina, V A; Sosedova, L M; Rukavishnikov, V S; Iakimova, N L; Lizarev, A V

    2014-01-01

    Comparative study covered influence of toluene on behavioral parameters, cognitive abilities and brain bioelectric activity in white rats with normal embryonic development or with prenatal hypoxia. Prenatal hypoxia was simulated by subcutaneous injection of 50 mg/kg sodium nitrite into female white rats on day 13-14 of gestation. The offspring at the age of 2, 5-3 months was exposed to toluene (concentration of 560 mg/m3, 4 hours per day, 5 days per week, over 4 weeks). After the exposure, the animals were estimated for individual and intraspecific behaviour in "open fields and "resident-intruder" tests, for cognitive abilities in "radial maze" training, EEG with visual and auditory evoked potentials. Acute hypoxia at early stages of organogenesis appeared to be burdening factor and to influence consequences of toluene intoxication.

  7. The A2a adenosine receptor modulates the reinforcement efficacy and neurotoxicity of MDMA.

    PubMed

    Ruiz-Medina, Jessica; Ledent, Catherine; Carretón, Olga; Valverde, Olga

    2011-04-01

    Adenosine is an endogenous purine nucleoside that plays a neuromodulatory role in the central nervous system. A2a adenosine receptors have been involved in reward-related processes, inflammatory phenomena and neurotoxicity reactions. In the present study, we investigated the role of A2a adenosine receptors on the acute pharmacological effects, reinforcement and neuroinflammation induced by MDMA administration. First, the acute effects of MDMA on body temperature, locomotor activity and anxiety-like responses were measured in A2a knockout mice and wild-type littermates. Second, MDMA reinforcing properties were evaluated using the intravenous self-administration paradigm. Finally, we assessed striatal astrogliosis and microgliosis as markers of MDMA neurotoxicity. Our results showed that acute MDMA produced a biphasic effect on body temperature and increased locomotor activity and anxiogenic-like responses in both genotypes. However, MDMA reinforcing properties were dramatically affected by the lack of A2a adenosine receptors. Thus, wild-type mice maintained MDMA self-administration under a fixed ratio 1 reinforcement schedule, whereas the operant response appeared completely abolished in A2a knockout mice. In addition, the MDMA neurotoxic regime produced an enhanced inflammatory response in striatum of wild-type mice, revealed by a significant increase in glial expression, whereas such activation was attenuated in mutant mice. This is the first report indicating that A2a adenosine receptors play a key role in reinforcement and neuroinflammation induced by the widely used psychostimulant.

  8. 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.

  9. Short and long-term effects of three neurotoxic insecticides on biological and behavioural attributes of the orb-web spider Alpaida veniliae (Araneae, Araneidae): implications for IPM programs.

    PubMed

    Benamú, Marco A; Schneider, Marcela I; González, Alda; Sánchez, Norma E

    2013-09-01

    Soybean pest control in Argentina is done just by chemical control using broad-spectrum pesticides. Alpaida veniliae (Araneae, Araneidae) is one of the most abundant spider species of the orb web weaver guild in soybean, and it is considered a very important polyphagous predator, attacking different insects' families. The objective of this study was to determine if neurotoxic insecticides commonly used in soybean crops and a new active ingredient registered in Argentina (spinosad) adversely affected survival, prey consumption, mating behaviour, web building and reproductive capacity of A. veniliae females, under standard laboratory conditions. Spinosad was the most harmful insecticide due to high acute toxicity, even at lower concentrations than those registered for its field use and for its sublethal effects also. Cypermethrin caused several sublethal effects although its acute toxicity on spider was lower than other insecticides. It reduced prey consumption, affected web building, caused abnormalities in eggs sacs and decreased drastically the fecundity and fertility at sublethal concentrations. Endosulfan did not reduce prey consumption but it affected web building, caused abnormalities in eggs sacs and egg masses, and decreased the fecundity and fertility. Spinosad was also the compound with the most drastic effect on web building, it did not reduce prey consumption and fecundity, but fertility was reduced and abnormalities in egg sacs and egg masses were observed. The use of these insecticides in IPM programs according to their potential toxicity on spider communities is discussed.

  10. 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.

  11. 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

  12. Developmental neurotoxicity of industrial chemicals.

    PubMed

    Grandjean, P; Landrigan, P J

    2006-12-16

    Neurodevelopmental disorders such as autism, attention deficit disorder, mental retardation, and cerebral palsy are common, costly, and can cause lifelong disability. Their causes are mostly unknown. A few industrial chemicals (eg, lead, methylmercury, polychlorinated biphenyls [PCBs], arsenic, and toluene) are recognised causes of neurodevelopmental disorders and subclinical brain dysfunction. Exposure to these chemicals during early fetal development can cause brain injury at doses much lower than those affecting adult brain function. Recognition of these risks has led to evidence-based programmes of prevention, such as elimination of lead additives in petrol. Although these prevention campaigns are highly successful, most were initiated only after substantial delays. Another 200 chemicals are known to cause clinical neurotoxic effects in adults. Despite an absence of systematic testing, many additional chemicals have been shown to be neurotoxic in laboratory models. The toxic effects of such chemicals in the developing human brain are not known and they are not regulated to protect children. The two main impediments to prevention of neurodevelopmental deficits of chemical origin are the great gaps in testing chemicals for developmental neurotoxicity and the high level of proof required for regulation. New, precautionary approaches that recognise the unique vulnerability of the developing brain are needed for testing and control of chemicals.

  13. 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.

  14. [Hyperhomocysteinemia: atherothrombosis and neurotoxicity].

    PubMed

    Fridman, O

    1999-01-01

    The positive correlation existing between hyperhomocyst(e)inemia [HH(e)] and vascular disease has firmly been established through data derived from numerous epidemiological and experimental observations. Clinical data corroborate that homocysteine (Hcy) is an independent risk factor for coronary, cerebral and peripheral arterial occlusive disease or peripheral venous thrombosis. Hcy is a sulfhydryl-containing amino acid that is formed by the demethylation of methionine. It is normally catalyzed to cystathionine by cystathionine beta-synthase a pyridoxal phosphate-dependent enzyme. Hcy is also remethylated to methionine by 5-methyltetrahydrofolate-Hcy methyltransferase (methionine synthase), a vitamin B12 dependent enzyme and by betaine-Hcy methyltransferase. Nutritional status such as vitamin B12, or vitamin B6, or folate deficiencies and genetic defects such as cystathionine beta-synthase or methylene-tetrahydrofolate reductase may contribute to increasing plasma homocysteine levels. The pathogenesis of Hcy-induced vascular damage may be multifactorial, including direct Hcy damage to the endothelium, stimulation of proliferation of smooth muscle cells, enhanced low-density lipoprotein peroxidation, increase of platelet aggregation, and effects on the coagulation system. Besides adverse effects on the endothelium and vessel wall, Hcy exert a toxic action on neuronal cells trough the stimulation of N-methyl-D-aspartate (NMDA) receptors. Under these conditions, neuronal damage derives from excessive calcium influx and reactive oxygen generation. This mechanism may contribute to the cognitive changes and markedly increased risk of cerebrovascular disease in children and young adults with homocystunuria. Moreover, during stroke, in hiperhomocysteinemic patients, disruption of the blood-brain barrier results in exposure of the brain to near plasma levels of Hcy. The brain is exposed to 15-50 microM H(e). Thus, the neurotoxicity of Hcy acting through the overstimulation

  15. 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.

  16. Characterization of the effects of anti-aging medicine Fructus lycii on beta-amyloid peptide neurotoxicity.

    PubMed

    Yu, Man-Shan; Lai, Cora Sau-Wan; Ho, Yuen-Shan; Zee, Sze-Yong; So, Kwok-Fai; Yuen, Wai-Hung; Chang, Raymond Chuen-Chung

    2007-08-01

    Alzheimer's disease (AD) is an age-related neurodegenerative disease. There are increasing lines of evidence showing that the molecular signaling pathways in aged cells are altered so that cells are susceptible to injury. We and other laboratories have demonstrated the significant involvement of double-stranded RNA-dependent protein kinase (PKR) in beta-amyloid (A beta) peptide neurotoxicity and in AD. Fructus lycii (the fruit of Lycium barbarum) has long been used in oriental medicine as an anti-aging agent. Our previous studies demonstrated that the aqueous extract isolated from L. barbarum exhibited significant protection on cultured neurons against harmful chemical toxins such as A beta and dithiothreitol. We also showed that the polysaccharide-containing extract (LBP) from L. barbarum exhibited neuroprotective effects in the retina against ocular hypertension in a laser-induced glaucoma animal model. In this study, we aimed to investigate whether LBP can elicit neuroprotection to neurons stressed by A beta peptides. Furthermore, we planned to isolate and identify the neuroprotective agent from LBP using chromatographic methods. Our results showed that pretreatment of LBP effectively protected neurons against A beta-induced apoptosis by reducing the activity of both caspase-3 and -2, but not caspase-8 and -9. A new arabinogalactan-protein (LBP-III) was isolated from LBP and attenuated A beta peptide-activated caspase-3-like activity. LBP-III markedly reduced the phosphorylation of PKR triggered by A beta peptide. Since the phosphorylation state of PKR increased with age, reduction of its phosphorylation triggered by A beta peptide may implicate that LBP-III from Fructus lycii is a potential neuroprotective agent in AD. As herbal medicine has received increasing attention for the treatment of AD, our study will open a window for the development of a neuroprotective agent for anti-aging from Chinese medicine.

  17. 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

  18. Central Neurotoxicity of Immunomodulatory Drugs in Multiple Myeloma

    PubMed Central

    Patel, Urmeel H.; Mir, Muhammad A.; Sivik, Jeffrey K.; Raheja, Divisha; Pandey, Manoj K.; Talamo, Giampaolo

    2015-01-01

    Immunomodulatory drugs (IMiDs) currently used in the treatment of multiple myeloma, are thalidomide, lenalidomide and pomalidomide. One of the most common side effects of thalidomide is neurotoxicity, predominantly in the form of peripheral neuropathy. We report 6 cases of significant central neurotoxicity associated with IMiD therapy. Treatment with thalidomide (1 patient), lenalidomide (4 patients), and pomalidomide (1 patient) was associated with various clinical manifestations of central neurotoxicity, including reversible coma, amnesia, expressive aphasia, and dysarthria. Central neurotoxicity should be recognized as an important side effect of IMiD therapy. PMID:25852850

  19. A comparison of the potency of newly developed oximes (K027, K048) and commonly used oximes (obidoxime, HI-6) to counteract tabun-induced neurotoxicity in rats.

    PubMed

    Kassa, Jirí; Kunesova, Gabriela

    2006-01-01

    The neuroprotective effects of newly developed oximes (K027, K048) and currently available oximes (obidoxime, HI-6) in combination with atropine in rats poisoned with tabun at a sublethal dose (170 microg kg(-1) i.m.; 80% of LD(50) value) were studied. The tabun-induced neurotoxicity was monitored using a functional observational battery and an automatic measurement of motor activity. The neurotoxicity of tabun was monitored at 24 h and 7 days following tabun challenge. The results indicate that the oxime HI-6 in combination with atropine was not able to protect the rats from the lethal effects of tabun. Two non-treated tabun-poisoned rats and one tabun-poisoned rat treated with atropine combined with HI-6 died within 2 h. On the other hand, all other tested oximes combined with atropine allowed all the tabun-poisoned rats to survive 7 days following tabun challenge. Both newly developed oximes combined with atropine seem to be sufficiently effective antidotes for a decrease in tabun-induced neurotoxicity in the case of sublethal poisoning although they are not able to eliminate tabun-induced neurotoxicity completely. The neuroprotective efficacy of obidoxime in combination with atropine approached the potency of newly developed oximes but the ability of the oxime HI-6 to counteract tabun-induced acute neurotoxicity was significantly lower, especially at 24 h after tabun poisoning. Due to their neuroprotective effects, both newly developed oximes appear to be suitable oximes for the antidotal treatment of acute tabun poisoning.

  20. Elucidation of mechanisms underlying the protective effects of olive leaf extract against lead-induced neurotoxicity in Wistar rats.

    PubMed

    Seddik, Leila; Bah, Thierno Madjou; Aoues, Abdelkader; Slimani, Miloud; Benderdour, Mohamed

    2011-01-01

    Recently, we identified that olive leaf extract (OLE) prevents lead (Pb)-induced abnormalities in behavior and neurotransmitters production in chronic Pb exposure in rats. The aim of the present study was to provide additional evidence that OLE acts as an anti-apoptotic, anti-inflammatory, and antioxidant mediator in Pb exposed rats. 4-weeks old Wistar rats were exposed or not to 250 mg/l Pb for 13-weeks and then exposed to tap water containing or not 0.1% OLE for additional 2-weeks. Atomic absorption spectrophotometry showed significantly elevated Pb levels in the hippocampus and serum and reaches 5 and 42 µg/mg tissue, respectively. In the hippocampus, the examination of markers of apoptosis and inflammation revealed an increase in caspase-3 activity and DNA fragmentation as well as tumor necrosis factor alpha, interleukin-1 beta and prostaglandin E2 in Pb-exposed rats. In addition, our findings showed that Pb induced 4-hydroxynonenal production and inhibited antioxidant-related enzyme activity, such as glutathione-S-transferase as wells as energy metabolism-related enzyme activity, such as NADP-isocitrate dehydrogenase and glucose transporter. Upon examination of signaling pathways involved in apoptosis process, we found that Pb induced p38 mitogen activated protein kinase (MAPK) and Akt phosphorylation, but in contrast, inhibited that of ERK(1/2). Interestingly, OLE administration diminished tissue Pb deposition and prevented all Pb effects. In the frontal cortex, our data also showed that OLE-abolished Pb-induced caspase-3 activity and DNA fragmentation. Collectively, these data support the use of OLE by traditional medicine to counter Pb neurotoxicity.

  1. Neuroprotective effects of anti-aging oriental medicine Lycium barbarum against beta-amyloid peptide neurotoxicity.

    PubMed

    Yu, Man-Shan; Leung, Sarana Ka-Yan; Lai, Sau-Wan; Che, Chi-Ming; Zee, Sze-Yong; So, Kwok-Fai; Yuen, Wai-Hung; Chang, Raymond Chuen-Chung

    2005-01-01

    As aged population dramatically increases in these decades, efforts should be made on the intervention for curing age-associated neurodegenerative diseases such as Alzheimer's disease (AD). Natural plant extracts of Lycium barbarum are well-known to exhibit anti-aging effects. We therefore hypothesized that they exhibit neuroprotective effects against toxins in aging-related neurodegenerative diseases. In this study, we aimed to investigate whether extracts from L. barbarum have neuroprotective effects against toxicity of fibrillar Abeta(1-42) and Abeta(25-35) fragments. Primary rat cortical neurons exposed to Abeta peptides resulted in apoptosis and necrosis. Pre-treatment with extract isolated from L. barbarum significantly reduced the release of lactate dehydrogenase (LDH). In addition, it attenuated Abeta peptide-activated caspases-3-like activity. The extract elicited a typical dose-dependent neuroprotective effect. Effective dosage of this extract was wider than that of a well-known western neuroprotective medicine lithium chloride (LiCl). We have further examined the underlying mechanisms of the neuroprotective effects. In agreement with other laboratories, Abeta peptides induce a rapid activation of c-Jun N-terminal kinase (JNK) by phosphorylation. Pre-treatment of aqueous extract markedly reduced the phosphorylation of JNK-1 (Thr183/Tyr185) and its substrates c-Jun-I (Ser 73) and c-Jun-II (Ser 63). Taken together, we have proved our hypothesis by showing neuroprotective effects of the extract from L. barbarum. Study on anti-aging herbal medicine like L. barbarum may open a new therapeutic window for the prevention of AD.

  2. Sex-, tissue-, and exposure duration-dependent effects of imidacloprid modulated by piperonyl butoxide and menadione in rats. Part I: oxidative and neurotoxic potentials.

    PubMed

    Yardimci, Mustafa; Sevgiler, Yusuf; Rencuzogullari, Eyyup; Arslan, Mehmet; Buyukleyla, Mehmet; Yilmaz, Mehmet

    2014-12-01

    Earlier research has evidenced the oxidative and neurotoxic potential of imidacloprid, a neonicotinoid insecticide, in different animal species. The primary aim of this study was to determine how metabolic modulators piperonyl butoxide and menadione affect imidacloprid's adverse action in the liver and kidney of Sprague-Dawley rats of both sexes. The animals were exposed to imidacloprid alone (170 mg kg⁻¹) or in combination with piperonyl butoxide (100 mg kg⁻¹) or menadione (25 mg kg⁻¹) for 12 and 24 h. Their liver and kidney homogenates were analysed spectrophotometrically for glutathione peroxidase, glutathione S-transferase, catalase, total cholinesterase specific activities, total glutathione, total protein content, and lipid peroxidation levels. Imidacloprid displayed its prooxidative and neurotoxic effects predominantly in the kidney of male rats after 24 h of exposure. Our findings suggest that the observed differences in prooxidative and neurotoxic potential of imidacloprid could be related to differences in its metabolism between the sexes. Co-exposure (90-min pre-treatment) with piperonyl butoxide or menadione revealed tissue-specific effect of imidacloprid on total cholinesterase activity. Increased cholinesterase activity in the kidney could be an adaptive response to imidacloprid-induced oxidative stress. In the male rat liver, co-exposure with piperonyl butoxide or menadione exacerbated imidacloprid toxicity. In female rats, imidacloprid+menadione co-exposure caused prooxidative effects, while no such effects were observed with imidacloprid alone or menadione alone. In conclusion, sex-, tissue-, and duration-specific effects of imidacloprid are remarkable points in its toxicity.

  3. Neuroprotective effects of three different sizes nanochelating based nano complexes in MPP(+) induced neurotoxicity.

    PubMed

    Maghsoudi, Amirhossein; Fakharzadeh, Saideh; Hafizi, Maryam; Abbasi, Maryam; Kohram, Fatemeh; Sardab, Shima; Tahzibi, Abbas; Kalanaky, Somayeh; Nazaran, Mohammad Hassan

    2015-03-01

    Parkinson's disease (PD) is the world's second most common dementia, which the drugs available for its treatment have not had effects beyond slowing the disease process. Recently nanotechnology has induced the chance for designing and manufacturing new medicines for neurodegenerative disease. It is demonstrated that by tuning the size of a nanoparticle, the physiological effect of the nanoparticle can be controlled. Using novel nanochelating technology, three nano complexes: Pas (150 nm), Paf (100 nm) and Pac (40 nm) were designed and in the present study their neuroprotective effects were evaluated in PC12 cells treated with 1-methyl-4-phenyl-pyridine ion (MPP (+)). PC12 cells were pre-treated with the Pas, Paf or Pac nano complexes, then they were subjected to 10 μM MPP (+). Subsequently, cell viability, intracellular free Calcium and reactive oxygen species (ROS) levels, mitochondrial membrane potential, catalase (CAT) and superoxide dismutase (SOD) activity, Glutathione (GSH) and malondialdehyde (MDA) levels and Caspase 3 expression were evaluated. All three nano complexes, especially Pac, were able to increase cell viability, SOD and CAT activity, decreased Caspase 3 expression and prevented the generation of ROS and the loss of mitochondrial membrane potential caused by MPP(+). Pre-treatment with Pac and Paf nano complexes lead to a decrease of intracellular free Calcium, but Pas nano complex could not decrease it. Only Pac nano complex decreased MDA levels and other nano complexes could not change this parameter compared to MPP(+) treated cells. Hence according to the results, all nanochelating based nano complexes induced neuroprotective effects in an experimental model of PD, but the smallest nano complex, Pac, showed the best results.

  4. 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.

  5. The neuroprotective effect of lovastatin on MPP(+)-induced neurotoxicity is not mediated by PON2.

    PubMed

    Aguirre-Vidal, Yoshajandith; Montes, Sergio; Tristan-López, Luis; Anaya-Ramos, Laura; Teiber, John; Ríos, Camilo; Baron-Flores, Verónica; Monroy-Noyola, Antonio

    2015-05-01

    Parkinson's disease (PD) is a neurodegenerative disorder characterized by loss of the pigmented dopaminergic neurons in the substantia nigra pars compacta with subsequent striatal dopamine (DA) deficiency and increased lipid peroxidation. The etiology of the disease is still unclear and it is thought that PD may be caused by a combination of genetic and environmental factors. In the search of new pharmacological options, statins have been recognized for their potential application to treat PD, due to their antioxidant effect. The aim of this work is to contribute in the characterization of the neuroprotective effect of lovastatin in a model of PD induced by 1-methyl-4-phenylpyridinium (MPP(+)). Male Wistar rats (200-250 g) were randomly allocated into 4 groups and administered for 7 days with different pharmacological treatments. Lovastatin administration (5 mg/kg) diminished 40% of the apomorphine-induced circling behavior, prevented the striatal DA depletion and lipid peroxides formation by MPP(+) intrastriatal injection, as compared to the group of animals treated only with MPP(+). Lovastatin produced no change in paraoxonase-2 (PON2) activity. It is evident that lovastatin conferred neuroprotection against MPP(+)-induced protection but this effect was not associated with the induction of PON2 in the rat striatum.

  6. In vitro neurotoxic hazard characterization of different tricresyl phosphate (TCP) isomers and mixtures.

    PubMed

    Duarte, Daniel J; Rutten, Joost M M; van den Berg, Martin; Westerink, Remco H S

    2016-02-03

    Exposure to tricresyl phosphates (TCPs), via for example contaminated cabin air, has been associated with health effects including the so-called aerotoxic syndrome. While TCP neurotoxicity is mainly attributed to ortho-isomers like tri-ortho-cresyl phosphate (ToCP), recent exposure and risk assessments indicate that ToCP levels in cabin air are very low. However, the neurotoxic potential of non-ortho TCP isomers and TCP mixtures is largely unknown. We therefore measured effects of exposure (up to 48h) to different TCP isomers, mixtures and the metabolite of ToCP (CBDP: cresyl saligenin phosphate) on cell viability and mitochondrial activity, spontaneous neuronal electrical activity, and neurite outgrowth in primary rat cortical neurons. The results demonstrate that exposure to TCPs (24-48h, up to 10μM) increases mitochondrial activity, without affecting cell viability. Effects of acute TCP exposure (30min) on neuronal electrical activity are limited. However, electrical activity is markedly decreased for the majority of TCPs (10μM) following 48h exposure. Additional preliminary data indicate that exposure to TCPs (48h, 10μM) did not affect the number of neurites per cell or average neurite length, except for TmCP and the analytical TCP mixture (Sigma) that induced a reduction of average neurite length. The combined neurotoxicity data demonstrate that the different TCPs, including ToCP, are roughly equipotent and a clear structure-activity relation is not apparent for the studied endpoints. The no-observed-effect-concentrations (1μM) are well above current exposure levels indicating limited neurotoxic health risk, although exposures may have been higher in the past. Moreover, prolonged and/or repeated exposure to TCPs may exacerbate the observed neurotoxic effects, which argues for additional research.

  7. 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.

  8. Anti-inflammatory effects of catechols in lipopolysaccharide-stimulated microglia cells: inhibition of microglial neurotoxicity.

    PubMed

    Zheng, Long Tai; Ryu, Geun-Mu; Kwon, Byoung-Mog; Lee, Won-Ha; Suk, Kyoungho

    2008-06-24

    Microglial activation plays a pivotal role in the pathogenesis of neurodegenerative diseases by producing various proinflammatory cytokines and nitric oxide (NO). In the present study, the anti-inflammatory and subsequent neuroprotective effects of catechol and its derivatives including 3-methylcatechol, 4-methylcatechol, and 4-tert-butylcatechol were investigated in microglia and neuroblastoma cells in culture. The four catechol compounds showed anti-inflammatory effects with different potency. The catechols significantly decreased lipopolysaccharide (LPS)-induced NO and tumor necrosis factor (TNF)-alpha production in BV-2 microglia cells. The catechols also inhibited the expression of inducible nitric oxide synthase (iNOS) and TNF-alpha at mRNA or protein levels in the LPS-stimulated BV-2 cells. In addition, the catechols inhibited LPS-induced nuclear translocation of p65 subunit of nuclear factor (NF)-kappaB, IkappaB degradation, and phosphorylation of p38 mitogen-activated protein kinase (MAPK) in BV-2 cells. Moreover, the catechols attenuated the cytotoxicity of LPS-stimulated BV-2 microglia toward co-cultured rat B35 neuroblastoma cells. The catechols, however, did not protect B35 cells against H(2)O(2) toxicity, indicating that the compounds exerted the neuroprotective effect by inhibiting the inflammatory activation of microglia in the co-culture. The anti-inflammatory and neuroprotective properties of the catechols in cultured microglia and neuroblastoma cells suggest a therapeutic potential of these compounds for the treatment of neurodegenerative diseases that are associated with an excessive microglial activation.

  9. Morphologic and neurotoxic effects of ethanol vary with timing of exposure in vitro.

    PubMed

    Lindsley, Tara A; Comstock, Laura L; Rising, Lisa J

    2002-11-01

    Results of investigations with animal models of fetal alcohol syndrome (FAS) seem to indicate that neuronal vulnerability to ethanol-induced cell death may be correlated with specific developmental events. In the present study, we sought to test this observation in a cell culture model of neuronal development in which morphogenesis as well as survival could be assessed. Using embryonic rat hippocampal pyramidal neurons in primary cultures, we compared the sensitivity of neurons to ethanol added, at 400 mg/dl, to the medium at different times relative to the development of axons and dendrites. Quantitative morphometric analysis was performed by using phase contrast at 12 h (0.5 day) and 24 h (1 day), or fluorescence microscopy after microtubule-associated protein-2 (MAP2) immunostaining at 6 and 14 days. Survival was assessed by counting the number of neurons per unit area of the substrate at 14 days. Addition of ethanol 1 day after plating, when most neurons had developed an axon, had no effect on survival up to 14 days in vitro, but resulted in significantly shorter, less branched dendrites than observed when ethanol was added 2 h after plating. Despite the shorter duration of ethanol exposure, the addition of ethanol on day 6, after rapid growth of dendrites and synapses had begun, resulted in loss of all but about one third of the neurons by 14 days. This supports the suggestion that increased neuronal vulnerability to the morphoregulatory effects of ethanol is correlated with the establishment of polarity, but that the sensitivity of neurons to the cytotoxic effects of ethanol occurs later, when dendrites and synapses are rapidly forming.

  10. The neurotoxic effect of monosodium glutamate (MSG) on the retinal ganglion cells of the albino rat.

    PubMed

    van Rijn, C M; Marani, E; Rietveld, W J

    1986-07-01

    Monosodium glutamate (MSG) administered postnatally to the albino rat causes extensive destruction of the retina. This MSG effect does not result in complete blindness. Ganglion cells surviving the MSG treatment are healthy and functional. Using retrogradely transported HRP and Nissl staining in whole mounted retinas, it was found that the ganglion cells left after MSG treatment are not smaller than those in controls, that these cells do not belong to one cell size group, and that no cells size group is selectively missed. The results explain why photic entrainment of MSG treated animals is still possible.

  11. 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...

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

    PubMed Central

    Lv, Wenting; Huang, Qiaoling; Fu, Mengsi; Cai, Minxuan; He, Qiangqiang

    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

  13. 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.

  14. 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.

  15. 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.

  16. Neurotoxicity of traffic-related air pollution.

    PubMed

    Costa, Lucio G; Cole, Toby B; Coburn, Jacki; Chang, Yu-Chi; Dao, Khoi; Roqué, Pamela J

    2017-03-01

    The central nervous system is emerging as an important target for adverse health effects of air pollution, where it may contribute to neurodevelopmental and neurodegenerative disorders. Air pollution comprises several components, including particulate matter (PM) and ultrafine particulate matter (UFPM), gases, organic compounds, and metals. An important source of ambient PM and UFPM is represented by traffic-related air pollution, primarily diesel exhaust (DE). Human epidemiological studies and controlled animal studies have shown that exposure to air pollution, and to traffic-related air pollution or DE in particular, may lead to neurotoxicity. In particular, air pollution is emerging as a possible etiological factor in neurodevelopmental (e.g. autism spectrum disorders) and neurodegenerative (e.g. Alzheimer's disease) disorders. The most prominent effects caused by air pollution in both humans and animals are oxidative stress and neuro-inflammation. Studies in mice acutely exposed to DE (250-300μg/m(3) for 6h) have shown microglia activation, increased lipid peroxidation, and neuro-inflammation in various brain regions, particularly the hippocampus and the olfactory bulb. An impairment of adult neurogenesis was also found. In most cases, the effects of DE were more pronounced in male mice, possibly because of lower antioxidant abilities due to lower expression of paraoxonase 2.

  17. Neurotoxic effects of rubber factory environment. An auditory evoked potential study.

    PubMed

    Kumar, V; Tandon, O P

    1997-01-01

    The effects of rubber factory environment on functional integrity of auditory pathway have been studied in forty rubber factory workers using Brainstem Auditory Evoked Potentials (BAEPs) technique to detect early subclinical impairments. Results indicate that 47 percent of the workers showed abnormalities in prolongations of either peak latencies or interpeak latencies when compared with age and sex matched control subjects not exposed to rubber factory environment. The percent distribution of abnormalities (ears affected) were in the order of extrusion and calendering (75%) > vulcanising (41.66%) > mixing (28.57%) > loading and dispatch (23.07%) > tubing (18.75%) sections of the factory. This incidence of abnormalities may be attributed to solvents being used in these units of rubber factory. These findings suggest that rubber factory environment does affect auditory pathway in the brainstem.

  18. Mechanisms involved in the neurotoxic, cognitive, and neurobehavioral effects of alcohol consumption during adolescence.

    PubMed

    Guerri, Consuelo; Pascual, María

    2010-02-01

    Studies over the last decade demonstrate that adolescence is a brain maturation period from childhood to adulthood. Plastic and dynamic processes drive adolescent brain development, creating flexibility that allows the brain to refine itself, specialize, and sharpen its functions for specific demands. Maturing connections enable increased communication among brain regions, allowing greater integration and complexity. Compelling evidence has shown that the developing brain is vulnerable to the damaging effects of ethanol. It is possible to infer, therefore, that alcohol exposure during the critical adolescent developmental stages could disrupt the brain plasticity and maturation processes, resulting in behavioral and cognitive deficits. Recent neuroimaging studies have provided evidence of the impact of human adolescent drinking in brain structure and functions. Findings in experimental animals have also given new insight into the potential mechanisms of the toxic effects of ethanol on both adolescent brain maturation and the short- and long-term cognitive consequences of adolescent drinking. Adolescence is also characterized by the rapid maturation of brain systems mediating reward and by changes in the secretion of stress-related hormones, events that might participate in the increasing in anxiety and the initiation pattern of alcohol and drug consumption. Studies in human adolescents demonstrate that drinking at early ages can enhance the likelihood of developing alcohol-related problems. Experimental evidence suggests that early exposure to alcohol sensitizes the neurocircuitry of addiction and affects chromatin remodeling, events that could induce abnormal plasticity in reward-related learning processes that contribute to adolescents' vulnerability to drug addiction. In this article, we review the potential mechanisms by which ethanol impacts brain development and lead to brain impairments and cognitive and behavioral dysfunctions as well as the neurobiological

  19. Effect of Gestational Intake of Fisetin (3,3',4',7-Tetrahydroxyflavone) on Developmental Methyl Mercury Neurotoxicity in F1 Generation Rats.

    PubMed

    Jacob, Sherin; Thangarajan, Sumathi

    2016-11-04

    Methyl mercury (MeHg) is a developmental neurotoxin that causes irreversible cognitive damage in offspring of gestationally exposed mothers. Currently, no preventive drugs are established against MeHg developmental neurotoxicity. The neuroprotective effect of gestational administration of a flavanoid against in utero toxicity of MeHg is not explored much. Hence, the present study validated the effect of a bioactive flavanoid, fisetin, on MeHg developmental neurotoxicity outcomes in rat offspring at postnatal weaning age. Pregnant Wistar rats were simultaneously given MeHg (1.5 mg/kg b.w.) and two doses of fisetin (10 and 50 mg/kg b.w. in two separate groups) orally from gestational day (GD) 5 till parturition. Accordingly, after parturition, on postnatal day (PND) 24, weaning F1 generation rats were studied for motor and cognitive behavioural changes. Biochemical and histopathological changes were also studied in the cerebral cortex, cerebellum and hippocampus on PND 25. Administration of fisetin during pregnancy prevented behavioural impairment due to transplacental MeHg exposure in weaning rats. Fisetin decreased the levels of oxidative stress markers, increased enzymatic and non-enzymatic antioxidant levels and increased the activity of membrane-bound ATPases and cholinergic function in F1 generation rats. In light microscopic studies, fisetin treatment protected the specific offspring brain regions from significant morphological aberrations. Between the two doses of fisetin studied, 10 mg/kg b.w. was found to be more satisfactory and effective than 50 mg/kg b.w. The present study shows that intake of fisetin during pregnancy in rats ameliorated in utero MeHg exposure-induced neurotoxicity outcomes in postnatal weaning F1 generation rats.

  20. Acetyl-L-carnitine provides effective in vivo neuroprotection over 3,4-methylenedioximethamphetamine-induced mitochondrial neurotoxicity in the adolescent rat brain.

    PubMed

    Alves, E; Binienda, Z; Carvalho, F; Alves, C J; Fernandes, E; de Lourdes Bastos, M; Tavares, M A; Summavielle, T

    2009-01-23

    3,4-Methylenedioximethamphetamine (MDMA, ecstasy) is a worldwide abused stimulant drug, with persistent neurotoxic effects and high prevalence among adolescents. The massive release of 5-HT from pre-synaptic storage vesicles induced by MDMA followed by monoamine oxidase B (MAO-B) metabolism, significantly increases oxidative stress at the mitochondrial level. l-Carnitine and its ester, acetyl-l-carnitine (ALC), facilitate the transport of long chain free fatty acids across the mitochondrial membrane enhancing neuronal anti-oxidative defense. Here, we show the potential of ALC against the neurotoxic effects of MDMA exposure. Adolescent male Wistar rats were assigned to four groups: control saline solution, isovolumetric to the MDMA solution, administered i.p.; MDMA (4x10 mg/kg MDMA, i.p.); ALC/MDMA (100 mg/kg 30 min of ALC prior to MDMA, i.p.) and ALC (100 mg/kg, i.p.). Rats were killed 2 weeks after exposure and brains were analyzed for lipid peroxidation, carbonyl formation, mitochondrial DNA (mtDNA) deletion and altered expression of the DNA-encoded subunits of the mitochondrial complexes I (NADH dehydrogenase, NDII) and IV (cytochrome c oxidase, COXI) from the respiratory chain. Levels of 5-HT and 5-hydroxyindoleacetic acid (5-HIAA) were also assessed. The present work is the first to successfully demonstrate that pretreatment with ALC exerts effective neuroprotection against the MDMA-induced neurotoxicity at the mitochondrial level, reducing carbonyl formation, decreasing mtDNA deletion, improving the expression of the respiratory chain components and preventing the decrease of 5-HT levels in several regions of the rat brain. These results indicate potential benefits of ALC application in the prevention and treatment of neurodegenerative disorders.

  1. Protective effects of statins on L-DOPA neurotoxicity due to the activation of phosphatidylinositol 3-kinase and free radical scavenging in PC12 cell culture.

    PubMed

    Koh, Seong-Ho; Park, Hyun-Hee; Choi, Na-Young; Lee, Kyu-Yong; Kim, Sangjae; Lee, Young Joo; Kim, Hee-Tae

    2011-01-25

    Neurotoxic effects have been suggested for l-3,4-dihydroxyphenylalanine (L-DOPA), while neuroprotective effects have been proposed for statins. We investigated whether certain statins (simvastatin or pitavastatin) could inhibit L-DOPA neurotoxicity. Neuronally-differentiated PC12 (nPC12) cells were treated with L-DOPA and/or statins for 24h, and their viabilities were measured using a cell counting kit, trypan blue staining, and 4',6-diamidino-2-phenylindole (DAPI) staining. Free radical and specific intracellular signaling protein levels were measured with 2',7'-dichlorodihydrofluorescein diacetate (DCFH-DA) and Western blotting, respectively. High concentrations of l-DOPA reduced nPC12 cell viability, but combined treatment with statins restored viability. Treatment with 200 μM L-DOPA increased free radical and hydroxyl radical levels, but combined treatment with 5 μM statins decreased these levels. Survival-related signaling proteins were decreased in nPC12 cells treated with 200 μM L-DOPA, but combined treatment with 5μM statins significantly increased the levels of these proteins. Treatment with 200 μM L-DOPA significantly increased death-related signaling proteins, while combined treatment with 5 μM statins reduced the levels of these proteins. Pretreatment with LY294002, a phosphatidylinositol 3 kinase (PI3K) inhibitor, before combined treatment with statins and L-DOPA almost completely blocked the protective effects of statins. These results indicate that statins reduce L-DOPA neurotoxicity by lowering oxidative stress and by enhancing survival signals and inhibiting death signals via activation of the PI3K pathway.

  2. Protective Effect of Edaravone on Glutamate-Induced Neurotoxicity in Spiral Ganglion Neurons

    PubMed Central

    Bai, Xiaohui; Zhang, Chi; Chen, Aiping; Liu, Wenwen; Li, Jianfeng; Sun, Qian

    2016-01-01

    Glutamate is an important excitatory neurotransmitter in mammalian brains, but excessive amount of glutamate can cause “excitotoxicity” and lead to neuronal death. As bipolar neurons, spiral ganglion neurons (SGNs) function as a “bridge” in transmitting auditory information from the ear to the brain and can be damaged by excessive glutamate which results in sensorineural hearing loss. In this study, edaravone, a free radical scavenger, elicited both preventative and therapeutic effects on SGNs against glutamate-induced cell damage that was tested by MTT assay and trypan blue staining. Ho.33342 and PI double staining revealed that apoptosis as well as necrosis took place during glutamate treatment, and apoptosis was the main type of cell death. Oxidative stress played an important role in glutamate-induced cell damage but pretreatment with edaravone alleviated cell death. Results of western blot demonstrated that mechanisms underlying the toxicity of glutamate and the protection of edaravone were related to the PI3K pathway and Bcl-2 protein family. PMID:27957345

  3. Neurotoxic effects of DSP-4 on the central noradrenergic system in male zebra finches.

    PubMed

    Waterman, Susanna A; Harding, Cheryl F

    2008-04-09

    When administered systemically, the noradrenergic neurotoxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4) appears to target the noradrenergic innervation originating in the locus coeruleus causing long-term decrements in noradrenergic function. In songbirds, DSP-4-treatment decreased female-directed singing by males and copulation solicitation responses of females to male songs. However, DSP-4 treatment in songbirds did not lower measures of NE function in the brain to the same extent as it does in mammals. The current study had two goals: determining if two DSP-4 treatments 10 days apart would cause significant decrements in noradrenergic function in male zebra finches and determining if, as in other species, the noradrenergic innervation of midbrain and cortical areas would be profoundly affected while hypothalamic areas were spared. Dopamine-beta-hydroxylase immunoreactivity (DBH-ir) was quantified in thirteen brain regions (five vocal control nuclei, one auditory nucleus, two hypothalamic nuclei, and five additional areas that demonstrated high DBH labeling in controls). Within 20 days, DSP-4 treatment profoundly reduced the number of DBH-ir cells in both the locus coeruleus and ventral subcoeruleus. Unlike a previous study, DBH labeling delineated four out of five vocal control nuclei and an auditory nucleus. As expected, DSP-4 treatment significantly decreased DBH labeling in all areas examined in the mesencephalon and telencephalon without significantly affecting DBH-ir in hypothalamic areas. This double treatment regime appears to be much more effective in decreasing noradrenergic function in songbirds than the single treatment typically used.

  4. Evaluation of the potency of two novel bispyridinium oximes (K456, K458) in comparison with oxime K203 and trimedoxime to counteract tabun-induced neurotoxicity in rats.

    PubMed

    Kassa, Jiri; Misik, Jan; Karasova, Jana Z

    2013-09-01

    The ability of two newly developed bispyridinium oximes (K456, K458) to reduce tabun-induced acute neurotoxic signs and symptoms was compared with oxime K203 and trimedoxime using the functional observational battery. The neuroprotective effects of the oximes studied combined with atropine on rats poisoned with tabun at a sublethal dose (200 μg/kg i.m.; 85% of LD50 value) were evaluated. Tabun-induced neurotoxicity was monitored by the functional observational battery and automatic measurement of motor activity at 2 hr after tabun challenge. The results indicate that all tested oximes combined with atropine enable tabun-poisoned rats to survive till the end of experiment. Both newly developed oximes (K456, K458) combined with atropine were able to decrease tabun-induced neurotoxicity in the case of sublethal poisonings although they did not eliminate all tabun-induced acute neurotoxic signs and symptoms. Their ability to decrease tabun-induced acute neurotoxicity was slightly higher than that of trimedoxime and oxime K203, but the difference in neuroprotective efficacy among all oximes studied is not large enough to make a decision about replacement of commonly used oximes (especially trimedoxime and obidoxime) in the treatment of acute tabun poisonings.

  5. Neuroprotective effects of α-iso-cubebenol on glutamate-induced neurotoxicity.

    PubMed

    Park, Sun Young; Choi, Yung Hyun; Park, Geuntae; Choi, Young-Whan

    2015-09-01

    α-Iso-cubebenol is a natural compound isolated from Schisandra chinensis, and is reported to have beneficial bioactivity including anti-inflammatory and anti-tumor activities. Glutamate-induced oxidative neuronal damage has been implicated in a variety of neurodegenerative disorders. Here we investigated the mechanisms of α-iso-cubebenol protection of mouse hippocampus-derived neuronal cells (HT22 cells) from apoptotic cell death induced by the major excitatory neurotransmitter, glutamate. Pretreatment with α-iso-cubebenol markedly attenuated glutamate-induced loss of cell viability and release of lactate dehydrogenase), in a dose-dependent manner. α-Iso-cubebenol significantly reduced glutamate-induced intracellular reactive oxygen species and calcium accumulation. Strikingly, α-iso-cubebenol inhibited glutamate-induced mitochondrial depolarization, which releases apoptosis-inducing factor from mitochondria. α-Iso-cubebenol also suppressed glutamate-induced phosphorylation of extracellular-signal-regulated kinases. Furthermore, α-iso-cubebenol induced CREB phosphorylation and Nrf-2 nuclear accumulation and increased the promoter activity of ARE and CREB in HT22 cells. α-Iso-cubebenol also upregulated the expression of phase-II detoxifying/antioxidant enzymes such as HO-1 and NQO1. Subsequent studies revealed that the inhibitory effects of α-iso-cubebenol on glutamate-induced apoptosis were abolished by small interfering RNA-mediated knockdown of CREB and Nrf-2. These findings suggest that α-iso-cubebenol prevents excitotoxin-induced oxidative damage to neurons by inhibiting apoptotic cell death, and might be a potential preventive or therapeutic agent for neurodegenerative disorders.

  6. Developing methods for assessing neurotoxic effects in Hispanic non-English speaking children.

    PubMed

    Rohlman, Diane S; Bodner, Todd; Arcury, Thomas A; Quandt, Sara A; McCauley, Linda

    2007-03-01

    Many factors affect the growth and development of children, including chemicals in the environment. Children have greater exposure to toxicants than adults due to both behavior and their increased food: body-mass ratio. Furthermore, the developing brain and organ systems of infants and children and their immature metabolism also make them more vulnerable to environmental toxins. Children from all cultures and backgrounds are at risk. However, minorities may be at greatest risk. In order to evaluate the impact of environmental exposures on neurodevelopment it is necessary to have effective methods that will allow accurate conclusions to be drawn. We have developed a battery to assess neurobehavioral performance in non-English speaking Hispanic children ages 4 years and older. This paper will examine the associations between age and performance and present test-retest correlations. Two hundred and forty one Hispanic children between the ages of 4 and 9 years completed a neurobehavioral test battery twice, approximately 1 month apart. The battery consists of computerized tests from the Behavioral Assessment and Research System, tests selected from the Pediatric Environmental Neurobehavioral Test Battery, and the Object Memory Test. Multiple regression was used to examine the association between age, gender and mother's education on performance. All of the tests, except for Continuous Performance, showed that performance improved as the child gets older. Gender differences were found on several tests with females generally performing worse than males. Correlation coefficients on performance retest measures ranged from .51 to .88. This study has demonstrated the utility of using this test battery to assess cognitive and motor performance in non-English speaking Hispanic children. Tests in the battery assess a range of functions and the measures are sensitive to differences in ages. Test-retest correlations show the reliability of the battery. These support the use of

  7. Possible mechanism for the neuroprotective effects of L-carnitine on methamphetamine-evoked neurotoxicity.

    PubMed

    Virmani, Ashraf; Gaetani, Franco; Imam, Syed; Binienda, Zbigniew; Ali, Syed

    2003-05-01

    Some of the damage to the CNS that is observed following amphetamine and methamphetamine (METH) administration is known to be linked to increased formation of free radicals. This increase could be, in part, related to mitochondrial dysfunction and/or cause damage to the mitochondria, thereby leading to a failure of cellular energy metabolism and an increase in secondary excitotoxicity. The actual neuronal damage that occurs with METH-induced toxicity seems to affect dopaminergic cells in particular. METH-induced toxicity is related to an increase in the generation of both reactive oxygen (hydroxyl, superoxide, peroxide) and nitrogen (nitric oxide) species. Peroxynitrite (ONOO(-)), which is a reaction product of either superoxide or nitric oxide, is the most damaging radical. It can be reduced by antioxidants such as selenium, melatonin, and the selective nNOS inhibitor, 7-nitroindazole. METH-induced toxicity has been previously shown to increase production of the peroxynitrite stress marker, 3-nitrotyrosine (3-NT), in vitro, in cultured PC12 cells, and also in vivo, in the striatum of adult male mice. Pre- and post-treatment of mice with l-carnitine (LC) significantly attenuated the production of 3-NT in the striatum after METH exposure. LC is a mitochondriotropic compound in that it carries long-chain fatty acyl groups into mitochondria for beta-oxidation. It was shown also to play a protective role against various mitochondrial toxins, such as 3-nitropropionic acid. The protective effects of LC against METH-induced toxicity could be related to its prevention of possible metabolic compromise produced by METH and the resulting energy deficits. In particular, LC may be maintaining the mitochondrial permeability transition (MPT) and modulating the activation of the mitochondrial permeability transition pores (mPTP), especially the cyclosporin-dependent mPTP. The possible neuroprotective mechanism of LC against METH-toxicity and the role of the mitochondrial

  8. 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.

  9. 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...

  10. Mechanisms underlying the neurotoxicity induced by glyphosate-based herbicide in immature rat hippocampus: involvement of glutamate excitotoxicity.

    PubMed

    Cattani, Daiane; de Liz Oliveira Cavalli, Vera Lúcia; Heinz Rieg, Carla Elise; Domingues, Juliana Tonietto; Dal-Cim, Tharine; Tasca, Carla Inês; Mena Barreto Silva, Fátima Regina; Zamoner, Ariane

    2014-06-05

    Previous studies demonstrate that glyphosate exposure is associated with oxidative damage and neurotoxicity. Therefore, the mechanism of glyphosate-induced neurotoxic effects needs to be determined. The aim of this study was to investigate whether Roundup(®) (a glyphosate-based herbicide) leads to neurotoxicity in hippocampus of immature rats following acute (30min) and chronic (pregnancy and lactation) pesticide exposure. Maternal exposure to pesticide was undertaken by treating dams orally with 1% Roundup(®) (0.38% glyphosate) during pregnancy and lactation (till 15-day-old). Hippocampal slices from 15 day old rats were acutely exposed to Roundup(®) (0.00005-0.1%) during 30min and experiments were carried out to determine whether glyphosate affects (45)Ca(2+) influx and cell viability. Moreover, we investigated the pesticide effects on oxidative stress parameters, (14)C-α-methyl-amino-isobutyric acid ((14)C-MeAIB) accumulation, as well as glutamate uptake, release and metabolism. Results showed that acute exposure to Roundup(®) (30min) increases (45)Ca(2+) influx by activating NMDA receptors and voltage-dependent Ca(2+) channels, leading to oxidative stress and neural cell death. The mechanisms underlying Roundup(®)-induced neurotoxicity also involve the activation of CaMKII and ERK. Moreover, acute exposure to Roundup(®) increased (3)H-glutamate released into the synaptic cleft, decreased GSH content and increased the lipoperoxidation, characterizing excitotoxicity and oxidative damage. We also observed that both acute and chronic exposure to Roundup(®) decreased (3)H-glutamate uptake and metabolism, while induced (45)Ca(2+) uptake and (14)C-MeAIB accumulation in immature rat hippocampus. Taken together, these results demonstrated that Roundup(®) might lead to excessive extracellular glutamate levels and consequently to glutamate excitotoxicity and oxidative stress in rat hippocampus.

  11. NEUROTOXICITY PRODUCED BY DIBROMOACETIC ACID IN DRINKING WATER OF RATS.

    EPA Science Inventory

    This manuscript examines the neurotoxic potential of a commonly found disinfection by-product (DBP), dibromoacetic acid (DBA). While the Safe Drinking Water Act requires evaluation of DBPs for noncancer health effects, surprisingly few have been tested for neurotoxicity. Rats e...

  12. 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

  13. Oxidative and nitrosative stress in ammonia neurotoxicity.

    PubMed

    Skowrońska, Marta; Albrecht, Jan

    2013-04-01

    Increased ammonia accumulation in the brain due to liver dysfunction is a major contributor to the pathogenesis of hepatic encephalopathy (HE). Fatal outcome of rapidly progressing (acute) HE is mainly related to cytotoxic brain edema associated with astrocytic swelling. An increase of brain ammonia in experimental animals or treatment of cultured astrocytes with ammonia generates reactive oxygen and nitrogen species in the target tissues, leading to oxidative/nitrosative stress (ONS). In cultured astrocytes, ammonia-induced ONS is invariably associated with the increase of the astrocytic cell volume. Interrelated mechanisms underlying this response include increased nitric oxide (NO) synthesis which is partly coupled to the activation of NMDA receptors and increased generation of reactive oxygen species by NADPH oxidase. ONS and astrocytic swelling are further augmented by excessive synthesis of glutamine (Gln) which impairs mitochondrial function following its accumulation in there and degradation back to ammonia ("the Trojan horse" hypothesis). Ammonia also induces ONS in other cell types of the CNS: neurons, microglia and the brain capillary endothelial cells (BCEC). ONS in microglia contributes to the central inflammatory response, while its metabolic and pathophysiological consequences in the BCEC evolve to the vasogenic brain edema associated with HE. Ammonia-induced ONS results in the oxidation of mRNA and nitration/nitrosylation of proteins which impact intracellular metabolism and potentiate the neurotoxic effects. Simultaneously, ammonia facilitates the antioxidant response of the brain, by activating astrocytic transport and export of glutathione, in this way increasing the availability of precursors of neuronal glutathione synthesis.

  14. Inhibitory effect of curcumin on the Al(III)-induced Aβ₄₂ aggregation and neurotoxicity in vitro.

    PubMed

    Jiang, Teng; Zhi, Xiu-Ling; Zhang, Yue-Hong; Pan, Luan-Feng; Zhou, Ping

    2012-08-01

    The pathogenesis of Alzheimer's disease (AD) involves a key event which changes the morphology of amyloid-β 42 (Aβ)₄₂ peptide from its soluble monomeric form into the fibrillated aggregates in the brain. Aluminum ion, Al(III), is known to act as a pathological chaperone of the Aβ₄₂ in this process; curcumin, a natural phenolic compound, is considered capable of binding Al(III) and Aβ₄₂; nevertheless, little is known about the combined action of curcumin and Al(III) on the Aβ₄₂ fibrillation and neurotoxicity. Here, combinations of circular dichroism spectroscopy, thioflavin T fluorescence, atomic force microscopy, Bradford and MTT assays, it is demonstrated that although Al(III) can promote the Aβ₄₂ fibrillation dose-dependently, leading to the high neurotoxicity to PC12 cells, curcumin can inhibit the events. Besides, we found that curcumin is able not only to inhibit the formation of Al(III)-induced Aβ₄₂ fibrillation, but also to form the Al(III)-curcumin complexes which in turn can remold the preformed, mature, ordered Aβ₄₂ fibrils into the low toxic amorphous aggregates. These findings suggest that curcumin could block the binding of Al(III) with Aβ₄₂ and form the Al(III)-curcumin complexes, so as to inhibit the Al(III)-induced Aβ₄₂ fibrillation and neurotoxicity. The Al(III)-curcumin complexes are worth potentially developing as a therapy agent against the neurodegenerative disorders in the future.

  15. 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...

  16. Beneficial Effects of a Protein Rich Diet on Coping Neurotrans-mitter Levels During Ampicillin-Induced Neurotoxicity Compared to Propionic-Acid Induced Autistic Biochemical Features

    PubMed Central

    Bhat, Ramesa Shafi; Chandrul, Kaushal Kishore; El-Ansary, Afaf

    2016-01-01

    This study examined the effects of a protein rich diet on coping neurotransmitter levels in orally administered ampicillin–induced neurotoxic rats compared with propionic acid (PA) models of autism. 40 young male western albino rats were divided into four groups. The first group served as control and received phosphate buffered saline orally; the second group serving as autistic model was treated with oral dose of PA (250 mg/kg body weight/day for 3 days); the third group was treated with the neurotoxic dose of ampicillin (50 mg/kg for three weeks); the fourth group received the same dose of ampicillin and was fed with special protein rich diets. Noradrenaline, dopamine, serotonin glutamate, glutamine and interleukin 6 (IL-6) were measured in the brain homogenate of all tested groups. Specified doses of PA and ampicillin significantly (P<0.001) decreased noradrenaline, dopamine, and serotonin levels when compared to control. Also glutamate, IL-6 levels were significantly (P<0.001) increased in PA treated group while non-significant increase was found in ampicillin treated group. Non-significant increase of glutamine was found in PA treated group with a significant increase in ampicillin treated group. The effects of ampicillin on these parameters were found to be potentiated when the rats were fed on a protein rich diet. Our results end with the conclusion that dietary protein level may be a useful tool to find out a path to restrict neurotransmitter alterations in neurodevelopmental disorders like autism. PMID:27942501

  17. 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

  18. 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

  19. Unexpected Neuroprotective Effects of Loganin on 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine-Induced Neurotoxicity and Cell Death in Zebrafish.

    PubMed

    Yao, Li; Peng, Shi-Xiao; Xu, Yi-Da; Lin, Stanley Li; Li, Yu-Hong; Liu, Chun-Jie; Zhao, Hou-De; Wang, Lin-Fang; Shen, Yan-Qin

    2017-03-01

    1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP), which induces the pathological characteristics of Parkinson's disease in rodents, also specifically targets dopaminergic neurons in zebrafish embryos and larvae. Loganin, a traditional Chinese drug, was reported to regulate immune function and possess anti-inflammatory and anti-shock effects. Here, we investigate the role of loganin in MPTP-induced Parkinson-like abnormalities in zebrafish. MPTP treatment-induced abnormal development, in larvae, such as pericardium edema, increased yolk color, yolk sac edema, and retarded yolk sac resorption, as well as defects in brain development. Loganin could block MPTP-induced defects, with little toxicity to the eggs. Results of whole mount in situ hybridization showed loganin prevented the loss of both dopaminergic neurons and locomotor activity, exhibited by larvae treated with MPTP. In addition, loganin significantly rescued MPTP-induced neurotoxicity on PC12 cells, possibly through the suppression of PI3K/Akt/mTOR axis and JNK signaling pathways. In conclusion, loganin blocks MPTP-induced neurotoxicity and abnormal development in zebrafish. J. Cell. Biochem. 118: 615-628, 2017. © 2016 Wiley Periodicals, Inc.

  20. Nitric oxide neurotoxicity.

    PubMed

    Dawson, V L; Dawson, T M

    1996-06-01

    Derangements in glutamate neurotransmission have been implicated in several neurodegenerative disorders including, stroke, epilepsy, Huntington's disease, Alzheimer's disease, and amyotrophic lateral sclerosis (ALS). Activation of the N-methyl-D-aspartate (NMDA) receptor subtype of glutamate receptors results in the influx of calcium which binds calmodulin and activates neuronal nitric oxide synthase (nNOS), to convent L-arginine to citrulline and nitric oxide (NO). NO has many roles in the central nervous system as a messenger molecule, however, when generated in excess NO can be neurotoxic. Excess NO is in part responsible for glutamate neurotoxicity in primary neuronal cell culture and in animal models of stroke. It is likely that most of the neurotoxic actions of NO are mediated by peroxynitrite (ONOO-), the reaction product from NO and superoxide anion. In pathologic conditions, peroxynitrite and oxygen free radicals can be generated in excess of a cell antioxidant capacity resulting in severe damage to cellular constituents including proteins, DNA and lipids. The inherent biochemical and physiological characteristics of the brain, including high lipid concentrations and energy requirements, make it particularly susceptible to free radical and oxidant mediated insult. Increasing evidence indicates that many neurologic disorders may have components of free radical and oxidative stress induced injury.

  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

    2015-08-05

    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.

  2. 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...

  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.

  4. 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.

  5. A comparison of the potency of newly developed oximes (K074, K075) and commonly used oximes (obidoxime, HI-6) to counteract tabun-induced neurotoxicity in rats.

    PubMed

    Kassa, Jiri; Karasova, Jana

    2007-01-05

    The neuroprotective effects of newly developed oximes (K074, K075) and currently available oximes (obidoxime, HI-6) in combination with atropine in rats poisoned with tabun at a sublethal dose (180 micro g/kg i.m.; 80% LD(50)) were studied. The tabun-induced neurotoxicity was monitored using a functional observational battery and an automatic measurement of motor activity. The neurotoxicity of tabun was monitored at 24h and 7 days following tabun challenge. The results indicate that all oximes studied in combination with atropine allow all tabun-poisoned rats to survive within 7 days following tabun challenge while two non-treated tabun-poisoned rats died within 2h. Both newly developed oximes combined with atropine seem to be effective antidotes for a decrease in tabun-induced neurotoxicity in the case of sublethal poisoning although they are not able to eliminate tabun-induced neurotoxicity completely. The oxime K075 showed a higher neuroprotective efficacy against tabun than K074 according to the number of eliminated tabun-induced neurotoxic signs at 24h as well as 7 days after tabun challenge. The neuroprotective efficacy of obidoxime in combination with atropine is similar to the potency of newly developed oxime K075 but the ability of the oxime HI-6 to counteract tabun-induced acute neurotoxicity is significantly lower at 24h as well as 7 days after tabun poisoning. Due to their neuroprotective effects, both newly developed oximes (especially K075) appear to be more suitable oximes for the antidotal treatment of acute tabun poisonings than the oxime HI-6.

  6. Silver nanoparticles induced neurotoxicity through oxidative stress in rat cerebral astrocytes is distinct from the effects of silver ions.

    PubMed

    Sun, Cheng; Yin, Nuoya; Wen, Ruoxi; Liu, Wei; Jia, Yanxia; Hu, Ligang; Zhou, Qunfang; Jiang, Guibin

    2016-01-01

    The rapid development of silver nanoparticles (AgNPs) based products has raised increasing concerns in view of their potential hazardous risks to the environment and human health. The roles of the released silver ions in AgNPs induced cytotoxicities are being hotly debated. Using rat cerebral astrocytes, the neurotoxicological effects of AgNPs and silver ions were investigated. Acute toxicity based on Alamar Blue assay showed that silver ions were considerably more toxic than AgNPs. Comparative studies indicated that AgNPs increased caspase activities and induced cell apoptosis under cytotoxic level of exposures, while silver ions compromised cell membrane integrity and dominantly caused cell necrosis. Cellular internalization of silver provided the basis for the cytotoxicities of these two silver species. In contrast to silver ions, intracellular reactive oxygen species (ROS) generation occurred in time- and concentration-dependent manners in astrocytes upon AgNPs stimulation, which caused subsequent c-Jun N-terminal kinases (JNK) phosphorylation and promoted the programmed cell death. Non-cytotoxic level of AgNPs exposure increased multiple cytokines secretion from the astrocytes, indicating that AgNPs were potentially involved in neuroinflammation. This effect was independent of silver ions as well. The distinct toxicological effects caused by AgNPs and silver ions provided the solid proofs for the particle-specific effects which should be concerned regarding the accurate assessment of AgNPs exposure risks.

  7. 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...

  8. 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.

  9. MDMA-induced neurotoxicity: long-term effects on 5-HT biosynthesis and the influence of ambient temperature.

    PubMed

    O'Shea, Esther; Orio, Laura; Escobedo, Isabel; Sanchez, Veronica; Camarero, Jorge; Green, Alfred Richard; Colado, Maria Isabel

    2006-07-01

    1. 3,4-Methylenedioxymethamphetamine (MDMA or 'ecstasy') decreases the 5-HT concentration, [3H]-paroxetine binding and tryptophan hydroxylase activity in rat forebrain, which has been interpreted as indicating 5-HT neurodegeneration. This has been questioned, particularly the 5-HT loss, as MDMA can also inhibit tryptophan hydroxylase. We have now evaluated the validity of these parameters as a reflection of neurotoxicity. 2. Male DA rats were administered MDMA (12.5 mg kg(-1), i.p.) and killed up to 32 weeks later. 5-HT content and [3H]-paroxetine binding were measured in the cortex, hippocampus and striatum. Parallel groups of treated animals were administered NSD-1015 for determination of in vivo tryptophan hydroxylase activity and 5-HT turnover rate constant. 3. Tissue 5-HT content and [3H]-paroxetine binding were reduced in the cortex (26-53%) and hippocampus (25-74%) at all time points (1, 2, 4, 8 and 32 weeks). Hydroxylase activity was similarly reduced up to 8 weeks, but had recovered at 32 weeks. The striatal 5-HT concentration and [3H]-paroxetine binding recovered by week 4 and hydroxylase activity after week 1. In all regions, the reduction in 5-HT concentration did not result in an altered 5-HT synthesis rate constant. 4. Administering MDMA to animals when housed at 4 degrees C prevented the reduction in [3H]-paroxetine binding and hydroxylase activity observed in rats housed at 22 degrees C, but not the reduction in 5-HT concentration. 5. These data indicate that MDMA produces long-term damage to serotoninergic neurones, but this does not produce a compensatory increase in 5-HT synthesis in remaining terminals. It also highlights the fact that measurement of tissue 5-HT concentration may overestimate neurotoxic damage.

  10. Alcohol Acute Effects in Aircrew

    DTIC Science & Technology

    1990-06-01

    we derive the name "whiskey." In the Elizabethan era the physiological effects were known to Shakespeare , who in Hamlet noted that alcohol provoked...the Elizabethan era the physiological effects were alluded to by Porter in Hamlet , who noted alcohol provoked only "nose-painting, sleep and urine" (8...atlas of wine. London: Mitchell Beazley Pub, 1985. 7. Lord T. The World Guide to Spirits. pp. 6-27, 1979. 8. Shakespeare W. Macbeth. Act II, Scene 3

  11. Neurotoxicity of anhydroecgonine methyl ester, a crack cocaine pyrolysis product.

    PubMed

    Garcia, Raphael Caio Tamborelli; Dati, Livia Mendonça Munhoz; Fukuda, Suelen; Torres, Larissa Helena Lobo; Moura, Sidnei; de Carvalho, Nathalia Delazeri; Carrettiero, Daniel Carneiro; Camarini, Rosana; Levada-Pires, Adriana Cristina; Yonamine, Mauricio; Negrini-Neto, Osvaldo; Abdalla, Fernando Maurício Francis; Sandoval, Maria Regina Lopes; Afeche, Solange Castro; Marcourakis, Tania

    2012-07-01

    Smoking crack cocaine involves the inhalation of cocaine and its pyrolysis product, anhydroecgonine methyl ester (AEME). Although there is evidence that cocaine is neurotoxic, the neurotoxicity of AEME has never been evaluated. AEME seems to have cholinergic agonist properties in the cardiovascular system; however, there are no reports on its effects in the central nervous system. The aim of this study was to investigate the neurotoxicity of AEME and its possible cholinergic effects in rat primary hippocampal cell cultures that were exposed to different concentrations of AEME, cocaine, and a cocaine-AEME combination. We also evaluated the involvement of muscarinic cholinergic receptors in the neuronal death induced by these treatments using concomitant incubation of the cells with atropine. Neuronal injury was assessed using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and lactate dehydrogenase (LDH) assays. The results of the viability assays showed that AEME is a neurotoxic agent that has greater neurotoxic potential than cocaine after 24 and 48 h of exposure. We also showed that incubation for 48 h with a combination of both compounds in equipotent concentrations had an additive neurotoxic effect. Although both substances decreased cell viability in the MTT assay, only cocaine increased LDH release. Caspase-3 activity was increased after 3 and 6 h of incubation with 1mM cocaine and after 6 h of 0.1 and 1.0mM AEME exposure. Atropine prevented the AEME-induced neurotoxicity, which suggests that muscarinic cholinergic receptors are involved in AEME's effects. In addition, binding experiments confirmed that AEME has an affinity for muscarinic cholinergic receptors. Nevertheless, atropine was not able to prevent the neurotoxicity produced by cocaine and the cocaine-AEME combination, suggesting that these treatments activated other neuronal death pathways. Our results suggest a higher risk for neurotoxicity after smoking crack cocaine than after

  12. p38/Sp1/Sp4/HDAC4/BDNF Axis Is a Novel Molecular Pathway of the Neurotoxic Effect of the Methylmercury

    PubMed Central

    Guida, Natascia; Laudati, Giusy; Mascolo, Luigi; Valsecchi, Valeria; Sirabella, Rossana; Selleri, Carmine; Di Renzo, Gianfranco; Canzoniero, Lorella M. T.; Formisano, Luigi

    2017-01-01

    The molecular pathways involved in methylmercury (MeHg)-induced neurotoxicity are not fully understood. Since pan-Histone deacetylases (HDACs) inhibition has been found to revert the neurodetrimental effect of MeHg, it appeared of interest to investigate whether the pattern of HDACs isoform protein expression is modified during MeHg-induced neurotoxicity and the transcriptional/transductional mechanisms involved. SH-SY5Y neuroblastoma cells treated with MeHg 1 μM for 12 and 24 h showed a significant increase of HDAC4 protein and gene expression, whereas the HDACs isoforms 1–3, 5, and 6 were unmodified. Furthermore, MeHg-induced HDAC4 increase was reverted when cells were transfected with siRNAs against specificity protein 1 (Sp1) and Sp4, that were both increased during MeHg exposure. Next we studied the role of extracellular-signal-regulated kinases 1/2 (ERK1/2), c-Jun N-terminal kinases (JNK), and p38 mitogen-activated protein kinases (MAPKs) in MeHg—induced increase of Sp1, Sp4, and HDAC4 expression. As shown by Western Blot analysis MeHg exposure increased the phosphorylation of p38, but not of ERK and JNK. Notably, when p38 was pharmacologically blocked, MeHg-induced Sp1, Sp4 protein expression, and HDAC4 protein and gene expression was reverted. In addition, MeHg exposure increased the binding of HDAC4 to the promoter IV of the Brain-derived neurotrophic factor (BDNF) gene, determining its mRNA reduction, that was significantly counteracted by HDAC4 knocking down. Furthermore, rat cortical neurons exposed to MeHg (1 μM/24 h) showed an increased phosphorylation of p38, in parallel with an up-regulation of Sp1, Sp4, and HDAC4 and a down-regulation of BDNF proteins. Importantly, transfection of siRNAs against p38, Sp1, Sp4, and HDAC4 or transfection of vector overexpressing BDNF significantly blocked MeHg-induced cell death in cortical neurons. All these results suggest that p38/Sp1-Sp4/HDAC4/BDNF may represent a new pathway involved in Me

  13. Arsenic neurotoxicity--a review.

    PubMed

    Vahidnia, A; van der Voet, G B; de Wolff, F A

    2007-10-01

    Arsenic (As) is one of the oldest poisons known to men. Its applications throughout history are wide and varied: murder, make-up, paint and even as a pesticide. Chronic As toxicity is a global environmental health problem, affecting millions of people in the USA and Germany to Bangladesh and Taiwan. Worldwide, As is released into the environment by smelting of various metals, combustion of fossil fuels, as herbicides and fungicides in agricultural products. The drinking water in many countries, which is tapped from natural geological resources, is also contaminated as a result of the high level of As in groundwater. The environmental fate of As is contamination of surface and groundwater with a contaminant level higher than 10 particle per billion (ppb) as set by World Health Organization (WHO). Arsenic exists in both organic and inorganic species and either form can also exist in a trivalent or pentavalent oxidation state. Long-term health effects of exposure to these As metabolites are severe and highly variable: skin and lung cancer, neurological effects, hypertension and cardiovascular diseases. Neurological effects of As may develop within a few hours after ingestion, but usually are seen in 2-8 weeks after exposure. It is usually a symmetrical sensorimotor neuropathy, often resembling the Guillain-Barré syndrome. The predominant clinical features of neuropathy are paresthesias, numbness and pain, particularly in the soles of the feet. Electrophysiological studies performed on patients with As neuropathy have revealed a reduced nerve conduction velocity, typical of those seen in axonal degeneration. Most of the adverse effects of As, are caused by inactivated enzymes in the cellular energy pathway, whereby As reacts with the thiol groups of proteins and enzymes and inhibits their catalytic activity. Furthermore, As-induced neurotoxicity, like many other neurodegenerative diseases, causes changes in cytoskeletal protein composition and hyperphosphorylation

  14. 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.

  15. 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

  16. Acute and Developmental Behavioral Effects of Flame ...

    EPA Pesticide Factsheets

    As polybrominated diphenyl ethers are phased out, numerous compounds are emerging as potential replacement flame retardants for use in consumer and electronic products. Little is known, however, about the neurobehavioral toxicity of these replacements. This study evaluated the neurobehavioral effects of acute or developmental exposure to t-butylphenyl diphenyl phosphate (BPDP), 2-ethylhexyl diphenyl phosphate (EHDP), isodecyl diphenyl phosphate (IDDP), isopropylated phenyl phosphate (IPP), tricresyl phosphate (TMPP; also abbreviated TCP), triphenyl phosphate (TPHP; also abbreviated TPP), tetrabromobisphenol A (TBBPA), tris (2-chloroethyl) phosphate (TCEP), tris (1,3-dichloroisopropyl) phosphate (TDCIPP; also abbreviated TDCPP), tri-o-cresyl phosphate (TOCP), and 2,2-,4,4’-tetrabromodiphenyl ether (BDE-47) in zebrafish (Danio rerio) larvae. Larvae (n≈24 per dose per compound) were exposed to test compounds (0.4 - 120 µM) at sub-teratogenic concentrations either developmentally or acutely, and locomotor activity was assessed at 6 days post fertilization. When given developmentally, all chemicals except BPDP, IDDP and TBBPA produced behavioral effects. When given acutely, all chemicals produced behavioral effects, with TPHP, TBBPA, EHDP, IPP, and BPDP eliciting the most effects at the most concentrations. The results indicate that these replacement flame retardants may have developmental or pharmacological effects on the vertebrate nervous system. This study

  17. 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.

  18. 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.

  19. 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.

  20. 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...

  1. Relative neurotoxicity of ivermectin and moxidectin in Mdr1ab (-/-) mice and effects on mammalian GABA(A) channel activity.

    PubMed

    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 (LD(50)) in wild-type mice). Survival was evaluated over 14-days. In Mdr1ab(-/-) mice, LD(50) 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 LD(50) 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.

  2. Delayed treatment of hemoglobin neurotoxicity.

    PubMed

    Regan, Raymond F; Rogers, Bret

    2003-01-01

    Hemoglobin is an oxidative neurotoxin that may contribute to cell injury after CNS trauma and hemorrhagic stroke. Prior studies have demonstrated that concomitant treatment with iron-chelating antioxidants prevents its neurotoxicity. However, the efficacy of these agents when applied hours after hemoglobin has not been determined, and is the subject of the present investigation. Consistent with prior observations, an increase in reactive oxygen species generation, detected by 2',7'-dichlorofluorescin oxidation, was observed when mixed neuronal/astrocyte cultures prepared from mouse cortex were exposed to hemoglobin alone. However, this oxidative stress developed slowly. A significant increase in the dichlorofluorescein signal compared with control, untreated cultures was not observed until four hours after addition of hemoglobin, and was followed by loss of membrane integrity and propidium iodide staining. Treating cultures with the 21-aminosteroid U74500A or the ferric iron chelator deferoxamine four hours after initiating hemoglobin treatment markedly attenuated reactive oxygen species production within 2 h. Continuous exposure to 5 micro M hemoglobin for 24 h resulted in death of about three-quarters of neurons, without injuring astrocytes. Most neuronal loss was prevented by concomitant treatment with U74500A; its effect was not significantly attenuated if treatment was delayed for 2-4 h, and it still prevented over half of neuronal death if treatment was delayed for 8 h. Similar neuroprotection was produced by delayed treatment with deferoxamine or the lipid-soluble iron chelator phenanthroline. None of these agents had any effect on neuronal death when added to cultures 12 h after hemoglobin. These results suggest that hemoglobin is a potent but slowly-acting neurotoxin. The delayed onset of hemoglobin neurotoxicity may make it an attractive target for therapeutic intervention.

  3. 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

  4. Role of p75 Neurotrophin Receptor in the Neurotoxicity by β-amyloid Peptides and Synergistic Effect of Inflammatory Cytokines

    PubMed Central

    Perini, Giovanni; Della-Bianca, Vittorina; Politi, Valeria; Della Valle, Giuliano; Dal-Pra, Ilaria; Rossi, Filippo; Armato, Ubaldo

    2002-01-01

    The neurodegenerative changes in Alzheimer's disease (AD) are elicited by the accumulation of β-amyloid peptides (Aβ), which damage neurons either directly by interacting with components of the cell surface to trigger cell death signaling or indirectly by activating astrocytes and microglia to produce inflammatory mediators. It has been recently proposed that the p75 neurotrophin receptor (p75NTR) is responsible for neuronal damage by interacting with Aβ. By using neuroblastoma cell clones lacking the expression of all neurotrophin receptors or engineered to express full-length or various truncated forms of p75NTR, we could show that p75NTR is involved in the direct signaling of cell death by Aβ via the function of its death domain. This signaling leads to the activation of caspases-8 and -3, the production of reactive oxygen intermediates and the induction of an oxidative stress. We also found that the direct and indirect (inflammatory) mechanisms of neuronal damage by Aβ could act synergistically. In fact, TNF-α and IL-1β, cytokines produced by Aβ-activated microglia, could potentiate the neurotoxic action of Aβ mediated by p75NTR signaling. Together, our results indicate that neurons expressing p75NTR, mostly if expressing also proinflammatory cytokine receptors, might be preferential targets of the cytotoxic action of Aβ in AD. PMID:11927634

  5. Chronic subarachnoid administration of 1-(4chlorobenzoyl)-5methoxy-2methyl-1H-indole-3 acetic acid (indomethacin): an evaluation of its neurotoxic effects in an animal model.

    PubMed

    Guevara-López, Uriah; Covarrubias-Gómez, Alfredo; Gutierrez-Acar, Hilario; Aldrete, J Antonio; López-Muñoz, Francisco J; Martínez-Benítez, Braulio

    2006-07-01

    Neuraxial administration of nonsteroid antiinflammatory drugs has been suggested as an alternative in the management of intractable pain, but there is little evidence that the neurotoxic effects of indomethacin by this route of administration have been evaluated. In this study, we evaluated histological neurotoxicity of indomethacin after its subarachnoid administration in guinea pigs. The hypothesis tested was "Does subarachnoid administration of indomethacin produce damage in the spinal cord of guinea pigs?" Ten male guinea pigs were anesthetized, and a polyamide catheter connected to a subcutaneous osmotic micro-pump was implanted at the L2-3 level. Animals were randomly assigned in 2 groups of 5 animals each. Indomethacin or saline solution was administered by continuous infusion (0.5 microL/h) for 14 days. Neurotoxicity was determined by spinal cord histopathology. There was no evidence of toxicity in the histological examinations of either group. These data suggest that subarachnoid administration of indomethacin infusion, at these doses, did not produce lesions typical of neurotoxicity in the spinal cord. We have concluded that epidural administration of indomethacin may be considered an alternative for application in human pain management, although more studies to determine its safety are required.

  6. Piperacillin/tazobactam-induced neurotoxicity in a hemodialysis patient: a case report.

    PubMed

    Neves, Precil Diego M M; Freitas, Fernanda M; Kojima, Christiane A; Carmello, Beatriz L; Bazan, Rodrigo; Barretti, Pasqual; Martin, Luis C

    2015-01-01

    Antibiotics are potentially a cause of neurotoxicity in dialysis patients, the most common are the beta-lactams as ceftazidime and cefepime, and few cases have been reported after piperacillin/tazobactam use. This report presents a case of a hypertensive and diabetic 67-year-old woman in regular hemodialysis, which previously had a stroke. She was hospitalized presenting pneumonia, which was initially treated with cefepime. Two days after treatment, she presented dysarthria, left hemiparesis, ataxia, and IX and X cranial nerves paresis. Computed tomography showed no acute lesions and cefepime neurotoxicity was hypothesized, and the antibiotic was replaced by piperacillin/tazobactam. The neurologic signs disappeared; however, 4 days after with piperacillin/tazobactam treatment, the neurological manifestations returned. A new computed tomography showed no new lesions, and the second antibiotic regimen withdrawn. After two hemodialysis sessions, the patient completely recovered from neurological manifestations. The patient presented sequentially neurotoxicity caused by two beta-lactams antibiotics. This report meant to alert clinicians that these antibiotics have dangerous neurological effects in chronic kidney disease patients.

  7. 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.

  8. 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

  9. 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.

  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.

  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. 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

  13. Guidelines for Neurotoxicity Risk Assessment

    EPA Pesticide Factsheets

    These Guidelines set forth principles and procedures to guide EPA scientists in evaluating environmental contaminants that may pose neurotoxic risks, and inform Agency decision makers and the public about these procedures.

  14. 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...

  15. Neuroprotective effects of nicotinamide and 1-methylnicotinamide in acute excitotoxicity in vitro.

    PubMed

    Slomka, Marta; Zieminska, Elzbieta; Salinska, Elzbieta; Lazarewicz, Jerzy W

    2008-01-01

    Nicotinamide (NAM), an important cofactor in many metabolic pathways, exhibits at high doses neuroprotective abilities of an unclear mechanism. In the present study we evaluated the unknown protective capability of its immediate metabolite 1-methylnicotinamide (MNA) in comparison to NAM in primary cultures of rat cerebellar granule cells (CGC) submitted to acute excitotoxicity. Neurotoxicity was evaluated with propidium iodide staining 24 h after 30 min exposure to glutamate (GLU) and NMDA. NAM and MNA reduced NMDA toxicity only at 25 mM concentration, while neurotoxicity of 0.5 mM GLU was slightly diminished only by 25 mM NAM. Both compounds at 25 mM reduced GLU-induced 45Ca uptake and dose-dependently inhibited NMDA-induced 45Ca accumulation. Neither NAM nor MNA interfered with GLU-evoked intracellular calcium transients evaluated with calcium orange fluorescent probe or inhibited [3H]MK-801 binding to rat cortical membranes. NAM and MNA failed to change GLU-evoked decrease in mitochondrial membrane potential monitored using the fluorescent dye rhodamine 123. Analysis with a hydroperoxide-sensitive fluorescent probe demonstrated significant reduction by 20 and 25 mM MNA, but not NAM, of oxidative stress in cultures after 1 h treatment with GLU. CGC accumulated radiolabelled NAM and MNA in a time and concentration dependent manner, NAM being transported more rapidly. These findings demonstrate that weak neuroprotective ability of MNA in excitotoxicity, accompanied by incomplete stabilization of calcium imbalance and lessening of oxidative stress, is not connected with direct inhibition of NMDA receptors. The exact mechanisms of these effects require further investigation.

  16. 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.

  17. Glutathione and N-acetylcysteine conjugates of alpha-methyldopamine produce serotonergic neurotoxicity: possible role in methylenedioxyamphetamine-mediated neurotoxicity.

    PubMed

    Bai, F; Lau, S S; Monks, T J

    1999-12-01

    Direct injection of either 3,4-(+/-)-methylenedioxymethamphetamine (MDMA) or 3,4-(+/-)-methylenedioxyamphetamine (MDA) into the brain fails to reproduce the serotonergic neurotoxicity seen following peripheral administration. The serotonergic neurotoxicity of MDA and MDMA therefore appears to be dependent upon the generation of a neurotoxic metabolite, or metabolites, the identity of which remains unclear. alpha-Methyldopamine (alpha-MeDA) is a major metabolite of both MDA and MDMA. We have shown that intracerebroventricular (icv) injection of 2,5-bis(glutathion-S-yl)-alpha-methyldopamine [2, 5-bis(glutathion-S-yl)-alpha-MeDA] causes decreases in serotonin concentrations in the striatum, cortex, and hippocampus, and neurobehavioral effects similar to those seen following MDA and MDMA administration. In contrast, although 5-(glutathion-S-yl)-alpha-methyldopamine [5-(glutathion-S-yl)-alpha-MeDA] and 5-(N-acetylcystein-S-yl)-alpha-methyldopamine [5-(N-acetylcystein-S-yl)-alpha-MeDA] produce neurobehavioral changes similar to those seen with MDA and MDMA, and acute changes in brain 5-HT and dopamine concentrations, neither conjugate caused long-term decreases in 5-HT concentrations. We now report that direct intrastriatal or intracortical administration of 5-(glutathion-S-yl)-alpha-MeDA (4 x 200 or 4 x 400 nmol), 5-(N-acetylcystein-S-yl)-alpha-MeDA (4 x 7 or 4 x 20 nmol), and 2, 5-bis(glutathion-S-yl)-alpha-MeDA (4 x 150 or 4 x 300 nmol) causes significant decreases in striatal and cortical 5-HT concentrations (7 days following the last injection). Interestingly, intrastriatal injection of 5-(glutathion-S-yl)-alpha-MeDA or 2, 5-bis(glutathion-S-yl)-alpha-MeDA, but not 5-(N-acetylcystein-S-yl)-alpha-methyldopamine, also caused decreases in 5-HT concentrations in the ipsilateral cortex. The same pattern of changes was seen when the conjugates were injected into the cortex. The effects of the thioether conjugates of alpha-MeDA were confined to 5-HT nerve terminal fields

  18. 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

  19. Estrogenic protection against gp120 neurotoxicity: role of microglia.

    PubMed

    Zemlyak, Ilona; Brooke, Sheila; Sapolsky, Robert

    2005-06-07

    HIV infection of the nervous system can cause neurotoxicity, and the glycoprotein gp120 of HIV seems to play a key role in this. gp120 is neurotoxic through a multi-cellular pathway, stimulating microglia to release excitotoxins, cytokines and reactive oxygen species, which then damage neurons. We have previously shown that estrogen decreases the neurotoxicity of gp120 in mixed neuronal/glial cultures. In this study, we determine whether estrogen a) decreases the collective neurotoxicity of the factors released by gp120-treated microglia, and/or b) enhances the ability of neurons to survive such factors. To do so, we established microglial cultures, mixed neuronal/glial hippocampal cultures, and neuron-enriched cultures, independently manipulating gp120 and estrogen exposure in each type of culture, and inducing neurotoxicity in neuron-containing cultures by introducing conditioned media from gp120-treated microglial cultures. We observe that estrogen can exert some small protective effects at the level of bolstering neuronal resistance, but that the bulk of its protective effects arise at the level of decreasing the neurotoxicity of factors released by microglia.

  20. Neuroprotective effects of Salidroside and its analogue tyrosol galactoside against focal cerebral ischemia in vivo and H2O2-induced neurotoxicity in vitro.

    PubMed

    Shi, Tian-yao; Feng, Shu-fang; Xing, Jiang-hao; Wu, Yu-mei; Li, Xiao-qiang; Zhang, Nan; Tian, Zhen; Liu, Shui-bing; Zhao, Ming-gao

    2012-05-01

    Salidroside (Sal) is a natural antioxidant extracted from the root of Rhodiola rosea L. that elicits neuroprotective effects in vivo and in vitro. Tyrosol galactoside (Tyr), an analog of Sal, was recently synthesized in our laboratory. The purpose of the current study was to investigate and compare the neuroprotective effects of Sal and Tyr against focal cerebral ischemia in vivo and H(2)O(2)-induced neurotoxicity in vitro. Sal and Tyr significantly prevented a cerebral ischemic injury induced by a 2 h middle cerebral artery occlusion and a 24 h reperfusion in rats in vivo. Furthermore, the oxidative insult was markedly attenuated by treatments of Sal and Tyr in the cultured rat cortical neurons after a 30 min exposure to 50 μM of H(2)O(2). Western blot analysis revealed that Sal and Tyr decreased the expression of Bax and restored the balance of pro- and anti-apoptotic proteins. The neuroprotective effects of these two analogues show that Tyr has a better antioxidative action compared with Sal both in vivo and in vitro, and suggest that the antioxidant activity of Sal and Tyr may be partly due to their different substituents in their glycosyl groups. This gives a new insight into the development of therapeutic natural antioxidants against oxidative stress.

  1. 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.

  2. 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

  3. Ifosfamide-induced neurotoxicity reversal with continuous veno-venous hemodialysis. A case report.

    PubMed

    Cherry, Mohamad A; Bhardwaj, Himanshu; Hopps, Sarah; Srour, Samer; Pant, Shubham

    2013-09-01

    Ifosfamide is an alkylating agent used to treat different types of malignancies including lymphomas, sarcomas and germinal cell tumors. Symptoms of ifosfamide neurotoxicity can range from mild confusion, dizziness and hallucination to overt encephalopathy. Various treatment options like methylene blue, albumin infusion and rarely hemodialysis have been used to treat ifosfamide neurotoxicity. We hereby report a case of a patient with relapsed diffuse large B cell lymphoma who received methylene blue after experiencing acute renal failure and encephalopathy due to ifosfamide with no improvement. The prompt use of hemodialysis in this case has led to reversal of both renal failure and neurotoxicity.

  4. Assessing the Developmental Neurotoxicity of 27 ...

    EPA Pesticide Factsheets

    Assessing the Developmental Neurotoxicity of 27 Organophosphorus Pesticides Using a Zebrafish Behavioral Assay, Waalkes, M., Hunter, D.L., Jarema, K., Mundy, W., and S. Padilla. The U.S. Environmental Protection Agency is evaluating methods to screen and prioritize organophosphorus pesticides for developmental neurotoxicity. As such, we are exploring a behavioral testing paradigm that can assess the effects of sublethal and subteratogenic concentrations of developmental neurotoxicants on zebrafish (Danio rerio). This in vivo assay quantifies the locomotor response to light stimuli under tandem light and dark conditions in a 96-well plate using a video tracking system on 6 day post fertilization zebrafish larvae. Each of twenty-seven organophosphorus pesticides was tested for their developmental neurotoxic potential by exposing zebrafish embryos/larvae to the pesticide at several concentrations (≤ 100 μM nominal concentration) during the first five days of development, followed by 24 hours of depuration and then behavioral testing. Approximately 22% of the chemicals (Acephate, Dichlorvos, Diazoxon, Bensulide,Tribufos, Tebupirimfos) did not produce any behavioral changes after developmental exposure, while many (Malaoxon Fosthiazate, Dimethoate, Dicrotophos, Ethoprop, Malathion, Naled, Diazinon, Methamidophos, Terbufos, Trichlorfon, Phorate, Pirimiphos-methyl, Profenofos, Z-Tetrachlorvinphos, Chlorpyrifos, Coumaphos, Phosmet, Omethoate) produced changes in swi

  5. Kallikrein 6 Signals through PAR1 and PAR2 to Promote Neuron Injury and Exacerbate Glutamate Neurotoxicity

    PubMed Central

    Yoon, Hyesook; Radulovic, Maja; Wu, Jianmin; Blaber, Sachiko I.; Blaber, Michael; Fehlings, Michael G.; Scarisbrick, Isobel A.

    2014-01-01

    CNS trauma generates a proteolytic imbalance contributing to secondary injury, including axonopathy and neuron degeneration. Kallikrein 6 (Klk6) is a serine protease implicated in neurodegeneration and here we investigate the role of protease activated receptors 1 (PAR1) and PAR2 in mediating these effects. First we demonstrate Klk6 and the prototypical activator of PAR1, thrombin, as well as PAR1 and PAR2, are each elevated in murine experimental traumatic spinal cord injury (SCI) at acute or subacute time points. Recombinant Klk6 triggered ERK1/2 signaling in cerebellar granule neurons and in the NSC34 spinal cord motoneuron cell line, in a PI3K and MEK-dependent fashion. Importantly, lipopeptide inhibitors of PAR1 or PAR2, and PAR1 genetic deletion, each reduced Klk6-ERK1/2 activation. In addition, Klk6 and thrombin promoted degeneration of cerebellar neurons and exacerbated glutamate neurotoxicity. Moreover, genetic deletion of PAR1 blocked thrombin-mediated cerebellar neurotoxicity and reduced the neurotoxic effects of Klk6. Klk6 also increased glutamate-mediated Bim signaling, PARP cleavage and lactate dehydrogenase (LDH) release in NSC34 motoneurons and these effects were blocked by PAR1 and PAR2 lipopeptide inhibitors. Taken together these data point to a novel Klk6-signaling axis in CNS neurons that is mediated by PAR1 and PAR2 and is positioned to contribute to neurodegeneration. PMID:23647384

  6. 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

  7. Acyclovir-Induced Neurotoxicity: A Case Report and Review of Literature.

    PubMed

    Chowdhury, Mohammed Andaleeb; Derar, Nada; Hasan, Syed; Hinch, Bryan; Ratnam, Shoba; Assaly, Ragheb

    2016-01-01

    Neurotoxicity can develop as a side effect of intravenous acyclovir use in patients with renal impairment. It is underreported in clinical practice and often confused with worsening herpes encephalitis. We present a 69-year-old woman with end-stage renal disease on hemodialysis with acyclovir neurotoxicity treated with daily extended hemodialysis sessions. Daily hemodialysis for extended period may shorten the neurotoxicity period and can help with faster return to normal mentation. A high index of suspicion is warranted to diagnose acyclovir-induced neurotoxicity.

  8. Acute and chronic effects of parathion and 2,4 D on the oxygen consumption of Chasmagnathus granulata (Decapoda, Brachyura).

    PubMed

    Rodríguez, E M; Monserrat, J M

    1991-01-01

    The effect of two pesticides widely used in Argentina on the oxygen consumption of the estuarine crab Chasmagnathus granulata was studied. Constant pressure respirometers were employed to estimate the rate of oxygen consumption per weight unit of animals treated previously with each pesticide, both acute (96 h) and chronically (15 and 30 days). Crabs exposed to parathion -an organophosphorate insecticide that causes the inhibition of acetylcholinesterase- show an increase of oxygen consumption at 0.5 ppm under acute exposure, and at 10 ppb under a chronic one. On the other hand, crabs exposed to 2,4 D (an herbicide) did not show changes in their consumption after an acute exposure, but those exposed chronically did show an increase at low concentration (5 ppm) followed by a relative decrease at the highest concentration (50 ppm). The results obtained for parathion are in accordance with the abnormal cholinergic excitation that it may exert on crustacean nervous system. The effect of 2,4 D was consistent with its uncoupler action at respiratory chain level, at low concentrations, while a possible Krebs cycle enzymes inhibition might be occurring at higher concentrations of that pesticide, as in other crustacean species. The faster action of parathion, respect to 2,4 D, is explained by its neurotoxic nature.

  9. 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.

  10. Studies on striatal neurotoxicity caused by the 3,4-methylenedioxymethamphetamine/ malonate combination: implications for serotonin/dopamine interactions.

    PubMed

    Goñi-Allo, Beatriz; Ramos, Mar'a; Herv'as, Isabel; Lasheras, Berta; Aguirre, Norberto

    2006-03-01

    The amphetamine derivative 3,4-methylenedioxymethamphetamine (MDMA) produces long-term toxicity to serotonin (5-HT) neurones in rats, which is exacerbated when combined with the mitochondrial inhibitor malonate. Moreover, MDMA, which does not produce dopamine depletion in the rat, potentiates malonate-induced striatal dopamine toxicity. Because the malonate/MDMA combination acutely causes a synergistic increase of 5-HT and dopamine release, in this study we sought to determine whether pharmacological blockade of MDMA- and/or malonate-induced dopamine release prevents neurotoxicity. Fluoxetine, given 30 min prior to the malonate/MDMA combination, afforded complete protection against 5-HT depletion and reversed MDMA-induced exacerbation of dopamine toxicity found in the malonate/MDMA treated rats. Protection afforded by fluoxetine was not related to changes in MDMA-induced hyperthermia. Similarly, potentiation of malonate-induced dopamine toxicity caused by MDMA was not observed in p-chlorophenylalanine-5-HT depleted rats. Finally, the dopamine transporter inhibitor GBR 12909 completely prevented dopamine neurotoxicity caused by the malonate/MDMA combination and reversed the exacerbating toxic effects of malonate on MDMA-induced 5-HT depletion without significantly altering the hyperthermic response. Overall, these results suggest that the synergic release of dopamine caused by the malonate/MDMA combination plays an important role in the long-term toxic effects. A possible mechanism of neurotoxicity and protection is proposed.

  11. 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

  12. Pharmacological Effects of Niacin on Acute Hyperlipemia.

    PubMed

    la Paz, Sergio Montserrat-de; Bermudez, Beatriz; Naranjo, M Carmen; Lopez, Sergio; Abia, Rocio; Muriana, Francisco J G

    2016-01-01

    The well-known changes in modern lifestyle habits including over nutrition and physical inactivity have led to striking adverse effects on public health (e.g., obesity, diabetes, and metabolic syndrome) over recent decades. One noticeable consequence is exaggerated and prolonged state of postprandial hyperlipemia due to the ingestion of multiple fat-enriched meals during the course of a day. Postprandial (non-fasting) hyperlipemia is characterized by increased blood levels of exogenous triglycerides (TG) in the form of apolipoprotein (apo) B48-containing TG-rich lipoproteins (TRL), which have a causal role in the pathogenesis and progression of cardiovascular disease (CVD). The cardiovascular benefits of lifestyle modification (healthy diet and exercise) and conventional lipid-lowering therapies (e.g., statins, fibrates, and niacin) could involve their favourable effects on postprandial metabolism. Pharmacologically, niacin has been used as an athero-protective drug for five decades. Studies have since shown that niacin may decrease fasting levels of plasma verylow- density lipoproteins (VLDL), low-density lipoprotein cholesterol (LDL-C), and lipoprotein [a] (Lp[a]), while may increase high-density lipoprotein cholesterol (HDL-C). Herein, the purpose of this review was to provide an update on effects and mechanisms related to the pharmacological actions of niacin on acute hyperlipemia.

  13. 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.

  14. In vitro and in vivo comparisons of the effects of the fruiting body and mycelium of Antrodia camphorata against amyloid β-protein-induced neurotoxicity and memory impairment.

    PubMed

    Wang, Li-Chun; Wang, Shen-En; Wang, Jyh-Jye; Tsai, Tsung-Yu; Lin, Chun-Hong; Pan, Tzu-Ming; Lee, Chun-Lin

    2012-06-01

    Antrodia camphorata is a particular and precious medicinal mushroom, and its fruiting body was found to provide more efficient protection from oxidative stress and inflammation than its mycelium because of its higher content of triterpenoids, total phenols, and so on. In the previous in vitro studies, the mycelium of A. camphorata is proven to provide strong neuroprotection in neuron cells and suggested to have the potential of protection against neurotoxicity of amyloid β-protein (Aβ) known as the risk factor toward Alzheimer's disease (AD) development. However, the in vivo study and the comparison study with the fruiting body have not yet been investigated. This study compared the effect of the fruiting body and mycelium of A. camphorata on alleviating the Aβ40-induced neurocytotoxicity in the in vitro Aβ-damaged neuron cell model (PC-12 cell treated with Aβ40) and memory impairment in the in vivo AD animal model induced with a continuous brain infusion of Aβ40. In the results of in vitro and in vivo studies, the fruiting body possessed stronger anti-oxidative and anti-inflammatory abilities for inhibiting neurocytotoxicity in Aβ40-treated PC-12 cells and Aβ40 accumulation in Aβ40-infused brain than mycelium. Moreover, hyperphosphorylated tau (p-tau) protein expression, known as an important AD risk factor, was suppressed by the treatment of fruiting body rather than that of mycelium in the in vitro and in vivo studies. These comparisons supported the reasons why the fruiting body resulted in a more significant improvement effect on working memory ability than mycelium in the AD rats.

  15. Neuroprotective effect of aqueous extract of Selaginella delicatula as evidenced by abrogation of rotenone-induced motor deficits, oxidative dysfunctions, and neurotoxicity in mice.

    PubMed

    Chandran, Girish; Muralidhara

    2013-10-01

    Oxidative stress is one of the mechanisms implicated to play a significant role in the pathophysiology of Parkinson's disease. Previously, we showed that an aqueous extract of Selaginella delicatula (SDAE) offered robust neuroprotection against rotenone (ROT) in a Drosophila model. In furtherance in the present study, we validated the neuroprotective efficacy of SDAE in a chronic ROT exposure model in mice. Initially, we assessed the propensity of SDAE to modulate the levels of endogenous markers in striatal region of mice. Subsequently, the neuroprotective efficacy of SDAE (100 mg/kg bw, 21 d) to mitigate ROT-induced striatal motor deficits, oxidative stress, and neurotoxicity was examined employing a co-exposure paradigm. We found significant attenuation of ROT-induced motor deficits (stride length and landing foot spread distance) among mice given SDAE supplements. Biochemical analysis revealed that ROT-induced elevation in the levels of oxidative markers in cytosol/mitochondria of striatum were normalized with SDAE supplements. In addition, SDAE also restored the ROT-induced elevation in the levels of oxidized and nitrated proteins. Further, SDAE also restored the activities of acetylcholinesterase and butyrylcholinesterase indicating its effect on cholinergic function. While ROT exposure caused significant perturbations in the activity levels of mitochondrial electron transport chain enzymes (complex I/II), membrane potential and activity of ATPases, these functions were restored to normalcy among mice receiving SDAE suggesting its effects on mitochondrial function. Since these data corroborate our previous findings in Drosophila system, we propose that the neuroprotective property of SDAE may be largely attributed to the antioxidant properties and its ability to attenuate mitochondrial dysfunction. However, studies employing dopaminergic cell models would enable us to identify specific molecular mechanism, by which SDAE exerts neuroprotective action.

  16. 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.

  17. 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.

  18. Pharmacognostical Analysis and Protective Effect of Standardized Extract and Rizonic Acid from Erythrina velutina against 6-Hydroxydopamine-Induced Neurotoxicity in SH-SY5Y Cells

    PubMed Central

    Silva, Aline H.; Fonseca, Francisco Noé; Pimenta, Antônia T. A.; Lima, MaryAnne S.; Silveira, Edilberto Rocha; Viana, Glauce S. B.; Vasconcelos, Silvânia M. M.; Leal, Luzia Kalyne A. M.

    2016-01-01

    Background: Erythrina velutina is a tree common in the northeast of Brazil extensively used by traditional medicine for the treatment of central nervous system disorders. Objective: To develop a standardized ethanol extract of E. velutina (EEEV) and to investigate the neuroprotective potential of the extract and rizonic acid (RA) from E. velutina on neuronal cells. Materials and methods: The plant drug of E. velutina previously characterized was used for the production of EEEV. Three methods were evaluated in order to obtain an extract with higher content of phenols. The neuroprotective effect of standardized EEEV (HPLC-PDA) and RA was investigated on SH-SY5Y cell exposure to the neurotoxin 6-hydroxydopamine (6-OHDA). Results: The powder of the plant drug was classified as moderately coarse and several quality control parameters were determined. EEEV produced by percolation gave the highest phenol content when related to others extractive methods, and its HPLC-PDA analysis allowed to identify four flavonoids and RA, some reported for the first time for the species. EEEV and RA reduced significantly the neurotoxicity induced by 6-OHDA in SH-SY5Y cells determined by the MTT assay and the nitrite concentration. EEEV also showed a free radical scavenging activity. Conclusion: This is the first pharmacological study about E. velutina which used a controlled standardized extract since the preparation of the herbal drug. This extract and RA, acting as an antioxidant, presents a neuroprotective effect suggesting that they have potential for future development as a therapeutic agent in neurodegenerative disease as Parkinson. SUMMARY The powder of Erythrina velutina was classified as moderately coarse and several quality-control parameters were determined.Ethanolic extract from E. velutina (EEEV) produced by percolation gave the highest phenol content when related to others extractive methods and its HPLC–PDA analysis of EEEV allowed to identify four flavonoids and rizonic

  19. 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

  20. Acute effects of solar particle event radiation

    PubMed Central

    Kennedy, Ann R.; Weissman, Drew; Sanzari, Jenine K.; Krigsfeld, Gabriel S.; Wan, X. Steven; Romero-Weaver, Ana L.; Diffenderfer, Eric S.; Lin, L.; Cengel, K.

    2014-01-01

    A major solar particle event (SPE) may place astronauts at significant risk for the acute radiation syndrome (ARS), which may be exacerbated when combined with other space flight stressors, such that the mission or crew health may be compromised. The National Space Biomedical Research Institute (NSBRI) Center of Acute Radiation Research (CARR) is focused on the assessment of risks of adverse biological effects related to the ARS in animals exposed to space flight stressors combined with the types of radiation expected during an SPE. The CARR studies are focused on the adverse biological effects resulting from exposure to the types of radiation, at the appropriate energies, doses and dose-rates, present during an SPE (and standard reference radiations: gamma rays or electrons). All animal studies described have been approved by the University of PA IACUC. Some conclusions from recent CARR investigations are as follows: (i) the relative biological effectiveness (RBE) values for SPE-like protons compared with standard reference radiations (gammas or electrons) for white blood cells (WBCs) vary greatly between mice, ferrets and pigs, with the RBE values being greater in ferrets than those in mice, and considerably greater in pigs compared with those in ferrets or mice [1, 2]. This trend for the data suggests that the RBE values for WBCs in humans could be considerably greater than those observed in small mammals, and SPE proton radiation may be far more hazardous to humans than previously estimated from small animal studies. (ii) Very low doses of SPE proton radiation (25 cGy) increase blood clotting times in ferrets, and the low SPE-like dose rate has more severe effects than high dose rate radiation [3]. (iii) Results from pig and ferret studies suggest that disseminated intravascular coagulation is a major cause of death at doses near the LD50 level for SPE-like proton and gamma radiation. (iv) Exposure to SPE-like proton or gamma radiation, in combination with

  1. 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.

  2. Glucose Effect in the Acute Porphyrias

    MedlinePlus

    ... 2017 Apr 05, 2017 National Porphyria Awareness Week! Mar 23, 2017 National Porphyria Awareness Week is ONE ... 2017 National Porphyria Awareness Week (NPAW) 2017 date: Mar 1, 2017 FDA Meeting for Acute Porphyrias is ...

  3. Phantom limb pain as a manifestation of paclitaxel neurotoxicity.

    PubMed

    Khattab, J; Terebelo, H R; Dabas, B

    2000-07-01

    Paclitaxel is a chemotherapeutic agent with activity directed against several malignancies. It has multiple adverse effects including neurotoxicity. We describe 2 patients with prior amputation who experienced phantom limb pain (PLP) after receiving paclitaxel therapy. A third patient experienced disabling neurotoxicity in the extremity of a prior ulnar nerve and tendon transposition after receiving paclitaxel. This unique syndrome should be identified as a direct causal effect of paclitaxel. In this report, we review the pathophysiology of PLP and treatment options. Physicians should be aware that PLP can occur after initiation of paclitaxel.

  4. 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

  5. Effects of petrochemical contamination on caged marine mussels using a multi-biomarker approach: Histological changes, neurotoxicity and hypoxic stress.

    PubMed

    Maisano, Maria; Cappello, Tiziana; Natalotto, Antonino; Vitale, Valeria; Parrino, Vincenzo; Giannetto, Alessia; Oliva, Sabrina; Mancini, Giuseppe; Cappello, Simone; Mauceri, Angela; Fasulo, Salvatore

    2016-03-31

    This work was designed to evaluate the biological effects of petrochemical contamination on marine mussels. Mytilus galloprovincialis, widely used as sentinel organisms in biomonitoring studies, were caged at the "Augusta-Melilli-Priolo" industrial site (eastern Sicily, Italy), chosen as one of the largest petrochemical areas in Europe, and Brucoli, chosen as reference site. Chemical analyses of sediments at the polluted site revealed high levels of PAHs and mercury, exceeding the national and international guideline limits. In mussels from the polluted site, severe morphological alterations were observed in gills, mainly involved in nutrient uptake and gas exchange. Changes in serotonergic and cholinergic systems, investigated through immunohistochemical, metabolomics and enzymatic approaches, were highlighted in gills, as well as onset of hypoxic adaptive responses with up-regulation of hypoxia-inducible factor transcript. Overall, the application of a multi-biomarker panel results effective in assessing the biological effects of petrochemical contamination on the health of aquatic organisms.

  6. 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.

  7. Neuroprotection against diisopropylfluorophosphate in acute hippocampal slices

    PubMed Central

    Ferchmin, P. A.; Pérez, Dinely; Cuadrado, Brenda L.; Carrasco, Marimée; Martins, Antonio H.; Eterović, Vesna A.

    2015-01-01

    Diisopropylfluorophosphate (DFP) is an irreversible inhibitor of acetylcholine esterase (AChE) and a surrogate of the organophosphorus (OP) nerve agent sarin. The neurotoxicity of DFP was assessed as a reduction of population spike (PS) area elicited by synaptic stimulation in acute hippocampal slices. Two classical antidotes, atropine, and pralidoxime, and two novel antidotes, 4R-cembranotriene-diol (4R) and a caspase 9 inhibitor, were tested. Atropine, pralidoxime, and 4R significantly protected when applied 30 min after DFP. The caspase inhibitor was neuroprotective when applied 5–10 min before or after DFP, suggesting that early synaptic apoptosis is responsible for the loss of PSs. It is likely that apoptosis starts at the synapses and, if antidotes are not applied, descends to the cell bodies, causing death. The acute slice is a reliable tool for mechanistic studies, and the assessment of neurotoxicity and neuroprotection with PS areas is, in general, pharmacologically congruent with in vivo results and predicts the effect of drugs in vivo. 4R was first found to be neuroprotective in slices and later we demonstrated that 4R is neuroprotective in vivo. The mechanism of neurotoxicity of OPs is not well understood, and there is a need for novel antidotes that could be discovered using acute slices. PMID:26438150

  8. Protective effects of dibenzocyclooctadiene lignans from Schisandra chinensis against beta-amyloid and homocysteine neurotoxicity in PC12 cells.

    PubMed

    Song, Ju-Xian; Lin, Xiang; Wong, Ricky Ngok-Shun; Sze, Stephen Cho-Wing; Tong, Yao; Shaw, Pang-Chui; Zhang, Yan-Bo

    2011-03-01

    Aggregated beta-amyloid (Aβ) and elevated plasma levels of homocysteine have been implicated as critical factors in the pathogenesis of Alzheimer's disease. The neuroprotective effects and possible mechanism of four structurally similar dibenzocyclooctadiene lignans (namely schisandrin, schisantherin A, schisandrin B and schisandrin C) isolated from the fruit of Schisandra chinensis (Turcz.) Baill. (Schisandraceae) against Aβ₂₅₋₃₅ and homocysteine toxicity in PC12 cells was studied. Exposure of PC12 cells to 0.5 µm Aβ₂₅₋₃₅ caused significant cell death, increased the number of apoptotic cells, elevated reactive oxygen species, increased the levels of the pro-apoptotic protein Bax and caspase-3 activation. All these effects induced by Aβ₂₅₋₃₅ were markedly reversed by schisandrin B and schisandrin C pretreatment, while schisandrin and schisantherin A had no obvious effects. Meanwhile, schisandrin B and schisandrin C reversed homocysteine-induced cytotoxicity. The results indicated that schisandrin B and schisandrin C protected PC12 cells against Aβ toxicity by attenuating ROS production and modulating the apoptotic signal pathway through Bax and caspase-3. Further structure-activity analysis of Schisandra lignans and evaluations of their neuroprotective effects using AD animal models are warranted.

  9. 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...

  10. Neuroprotective effects of α-tocotrienol on kainic acid-induced neurotoxicity in organotypic hippocampal slice cultures.

    PubMed

    Jung, Na Young; Lee, Kyung Hee; Won, Ran; Lee, Bae Hwan

    2013-09-05

    Vitamin E, such as alpha-tocopherol (ATPH) and alpha-tocotrienol (ATTN), is a chain-breaking antioxidant that prevents the chain propagation step during lipid peroxidation. In the present study, we investigated the effects of ATTN on KA-induced neuronal death using organotypic hippocampal slice culture (OHSC) and compared the neuroprotective effects of ATTN and ATPH. After 15 h KA (5 µM) treatment, delayed neuronal death was detected in the CA3 region and reactive oxygen species (ROS) formation and lipid peroxidation were also increased. Both co-treatment and post-treatment of ATPH (100 µM) or ATTN (100 µM) significantly increased the cell survival and reduced the number of TUNEL-positive cells in the CA3 region. Increased dichlorofluorescein (DCF) fluorescence and levels of thiobarbiturate reactive substances (TBARS) were decreased by ATPH and ATTN treatment. These data suggest that ATPH and ATTN treatment have protective effects on KA-induced cell death in OHSC. ATTN treatment tended to be more effective than ATPH treatment, even though there was no significant difference between ATPH and ATTN in co-treatment or post-treatment.

  11. The Cardiovascular and Neurotoxic Effects of the  Venoms of Six Bony and Cartilaginous Fish Species.

    PubMed

    Han, Han; Baumann, Kate; Casewell, Nicholas R; Ali, Syed A; Dobson, James; Koludarov, Ivan; Debono, Jordan; Cutmore, Scott C; Rajapakse, Niwanthi W; Jackson, Timothy N W; Jones, Rob; Hodgson, Wayne C; Fry, Bryan G; Kuruppu, Sanjaya

    2017-02-16

    Fish venoms are often poorly studied, in part due to the difficulty in obtaining, extracting, and storing them. In this study, we characterize the cardiovascular and neurotoxic effects of the venoms from the following six species of fish: the cartilaginous stingrays Neotrygon kuhlii and Himantura toshi, and the bony fish Platycephalus fucus, Girella tricuspidata, Mugil cephalus, and Dentex tumifrons. All venoms (10-100 μg/kg, i.v.), except G. tricuspidata and P. fuscus, induced a biphasic response on mean arterial pressure (MAP) in the anesthetised rat. P. fucus venom exhibited a hypotensive response, while venom from G. tricuspidata displayed a single depressor response. All venoms induced cardiovascular collapse at 200 μg/kg, i.v. The in vitro neurotoxic effects of venom were examined using the chick biventer cervicis nerve-muscle (CBCNM) preparation. N. kuhlii, H. toshi, and P. fucus venoms caused concentration-dependent inhibition of indirect twitches in the CBCNM preparation. These three venoms also inhibited responses to exogenous acetylcholine (ACh) and carbachol (CCh), but not potassium chloride (KCl), indicating a post-synaptic mode of action. Venom from G. tricuspidata, M. cephalus, and D. tumifrons had no significant effect on indirect twitches or agonist responses in the CBCNM. Our results demonstrate that envenoming by these species of fish may result in moderate cardiovascular and/or neurotoxic effects. Future studies aimed at identifying the molecules responsible for these effects could uncover potentially novel lead compounds for future pharmaceuticals, in addition to generating new knowledge about the evolutionary relationships between venomous animals.

  12. 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

  13. Intraocular pressure, ocular toxicity and neurotoxicity after administration of delta 9-tetrahydrocannabinol or cannabichromene.

    PubMed

    Colasanti, B K; Powell, S R; Craig, C R

    1984-01-01

    delta-9-Tetrahydrocannabinol (delta 9-THC) or cannabichromene, a structurally diverse naturally occurring cannabinoid, was delivered unilaterally to the corneas of cats either acutely by application of single drops or chronically via osmotic minipumps over a period of nine days. While delta 9-THC only reduced intraocular pressure (IOP) minimally after acute administration, this cannabinoid produced substantial reductions in ocular tension during the entire period of chronic administration. Ocular toxicity during chronic treatment, however, was pronounced; conjunctival chemosis, erythema, and hyperemia were sustained, and corneal opacities approximating the site of drug delivery became evident within three to five days. In contrast, cannabichromene did not significantly alter IOP either acutely or during the nine days of chronic administration, and ocular toxicity was not apparent. After systemic administration of delta 9-THC to rats, a dose-related increase in the appearance of 8-13 Hz polyspike discharges became evident in the electrocorticogram during wakefulness and behavioral depression. These polyspikes subsequently reappeared during rapid eye movement (REM) sleep episodes. Cannabichromene was devoid of this effect. These results indicate that, in contrast with acute administration, chronic delivery of delta 9-THC to cat eyes produces substantial reductions in IOP. The tension lowering effect, however, is accompanied by considerable ocular toxicity and neurotoxicity. As cannabichromene lacked these activities, the terpenoid portion of the cannabinoid structure appears to be important for their mediation.

  14. 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.

  15. Acute toxicity of the pesticide methomyl on the topmouth gudgeon (Pseudorasbora parva): mortality and effects on four biomarkers.

    PubMed

    Li, Huixian; Jiang, Hui; Gao, Xiwu; Wang, Xiaojun; Qu, Weigang; Lin, Ronghua; Chen, Jiao

    2008-09-01

    In this study, the acute toxicity of the pesticide methomyl on the topmouth gudgeon (Pseudorasbora parva) was evaluated using mortality and the activity of the enzymes acetylcholinesterase (AChE), glutathione S-transferases (GSTs), glutamic oxaloacetic transaminase (GOT) and glutamic pyruvic transaminase (GPT) as endpoints. LC50 values were 1.228, 0.782, 0.538, and 0.425 mg/l at 24, 48, 72, and 96 h of exposure, respectively. Methomyl caused a sharp decrease in specific activity of brain AChE around 48% at concentrations between 0.043 and 0.213 mg/l. A reduction higher than 40% in liver GST activity at concentrations between 0.085 and 0.213 mg/l was found, whereas no significant effects were observed in intestinal GST. A significant concentration-dependent decrease of GOT activity was found after 24 h of exposure to the pesticide but not after 96 h. No significant effects on GPT activity were observed. These results indicate that at the concentrations tested, methomyl is acutely toxic to the species P. parva, causing mortality, neurotoxic effects, and changes in some hepatic enzymes.

  16. 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.

  17. 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

  18. 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

  19. Effects of curcumin and tannic acid on the aluminum- and lead-induced oxidative neurotoxicity and alterations in NMDA receptors.

    PubMed

    Tüzmen, Münire Nalan; Yücel, Nilgün Candan; Kalburcu, Tülden; Demiryas, Nazan

    2015-02-01

    Exposure to aluminum (Al) and lead (Pb) can cause brain damage. Also, Pb and Al exposure alters N-methyl-d-aspartate receptor (NMDAR) subunit expression. Polyphenols such as tannic acid and curcumin are very efficient chelator for metals. The effects of curcumin and tannic acid (polyphenols) on Al(3+)- and Pb(2+)-induced oxidative stress were examined by investigating lipid peroxidation (LPO) levels, antioxidant enzyme activities, acetyl cholinesterase (AChE) activity and also NMDA receptor subunits 2A and 2B concentrations in the brain tissue of rats sub-chronically. Rats were divided into seven groups as control, Al, Pb, aluminum-tannic acid treatment (AlT), aluminum-curcumin treatment (AlC), lead-tannic acid treatment (PbT) and lead-curcumin treatment (PbC). After 16 weeks of treatment, LPO levels in the brain and hippocampus were higher in Al(3+)-exposed rats than that of Pb(2+)-exposed group. Superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activities in brain tissue of Al- and Pb-exposed rats increased significantly compared with control, while catalase (CAT) and AChE activities decreased. It was observed that metal exposure affected NR2A concentrations more than NR2B concentrations and also that polyphenol treatments increased these receptor protein concentrations.

  20. Bioaccumulation and effects of metals on oxidative stress and neurotoxicity parameters in the frogs from the Pelophylax esculentus complex.

    PubMed

    Prokić, Marko D; Borković-Mitić, Slavica S; Krizmanić, Imre I; Mutić, Jelena J; Trifković, Jelena Đ; Gavrić, Jelena P; Despotović, Svetlana G; Gavrilović, Branka R; Radovanović, Tijana B; Pavlović, Slađan Z; Saičić, Zorica S

    2016-10-01

    Metals are involved in the formation of reactive oxygen species and can induce oxidative stress. The aim of this study was to assess the effects of several metals on oxidative stress in the skin and muscle of the Pelophylax esculentus "complex" frogs (parental species Pelophylax ridibundus, Pelophylax lessonae, and their hybrid Pelophylax esculentus) that inhabit the wetland Obedska Bara in Serbia, and the potential use of these species as bioindicator organisms in biomonitoring studies. The biomarkers of oxidative stress (SOD, CAT, GSH-Px, GR, GST activities and GSH, SH concentrations) and cholinesterase activity were investigated. The concentrations of nine metals (Fe, Cu, Zn, As, Cd, Cr, Hg, Ni, and Pb) were measured in the water and tissues. Correlations were established between metals and biomarkers in the tissues. The results of metal accumulation distinguished the skin of P. lessonae and muscle of P. ridibundus from other P. esculentus complex species. The oxidative stress biomarkers observed in P. ridibundus and P. esculentus had greater similarity than in P. lessonae. The P. lessonae displayed the highest number of correlations between biomarkers and metals. The results of tissue responses revealed that skin was more susceptible to metal-induced oxidative stress, with only exception of As. In the light of these findings, we can suggest the use of P. esculentus complex species as a biomonitoring species in studies of metal accumulation and metal-induced oxidative stress, but with special emphasis on P. lessonae.

  1. 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.

  2. Effect of a synbiotic on infantile acute gastroenteritis.

    PubMed

    Gundogdu, Z

    2013-09-01

    Acute gastroenteritis is still a common disease worldwide. Synbiotics are being used to alleviate the effects of acute gastroenteritis-related diarrhoea. The objective of this study was to determine the efficacy of a synbiotic in reducing the duration of diarrhoea in children with acute gastroenteritis. The study has been carried out on data gathered from children with acute gastroenteritis between the age of three months and 14 years seen in paediatric polyclinics between August 2009 and April 2010. While synbiotic group patients got a sachet containing Bifidobacterium lactis 2211 with a minimum of 5×10⁶ cfu active bacteria and 900 mg chicory inulin twice daily for five days together with an oral rehydration solution, the control group only received an oral rehydration solution. Therapy with synbiotic plus an oral rehydration solution shortened the duration of acute diarrhoea in children by approximately one day compared to oral rehydration solution only.

  3. Synthesis, pharmacological assessment, and molecular modeling of acetylcholinesterase/butyrylcholinesterase inhibitors: effect against amyloid-β-induced neurotoxicity.

    PubMed

    Silva, Daniel; Chioua, Mourad; Samadi, Abdelouahid; Agostinho, Paula; Garção, Pedro; Lajarín-Cuesta, Rocío; de Los Ríos, Cristobal; Iriepa, Isabel; Moraleda, Ignacio; Gonzalez-Lafuente, Laura; Mendes, Eduarda; Pérez, Concepción; Rodríguez-Franco, María Isabel; Marco-Contelles, José; Carmo Carreiras, M

    2013-04-17

    The synthesis, molecular modeling, and pharmacological analysis of phenoxyalkylamino-4-phenylnicotinates (2-7), phenoxyalkoxybenzylidenemalononitriles (12, 13), pyridonepezils (14-18), and quinolinodonepezils (19-21) are described. Pyridonepezils 15-18 were found to be selective and moderately potent regarding the inhibition of hAChE, whereas quinolinodonepezils 19-21 were found to be poor inhibitors of hAChE. The most potent and selective hAChE inhibitor was ethyl 6-(4-(1-benzylpiperidin-4-yl)butylamino)-5-cyano-2-methyl-4-phenylnicotinate (18) [IC(50) (hAChE) = 0.25 ± 0.02 μM]. Pyridonepezils 15-18 and quinolinodonepezils 20-21 are more potent selective inhibitors of EeAChE than hAChE. The most potent and selective EeAChE inhibitor was ethyl 6-(2-(1-benzylpiperidin-4-yl)ethylamino)-5-cyano-2-methyl-4-phenylnicotinate (16) [IC(50) (EeAChE) = 0.0167 ± 0.0002 μM], which exhibits the same inhibitory potency as donepezil against hAChE. Compounds 2, 7, 13, 17, 18, 35, and 36 significantly prevented the decrease in cell viability caused by Aβ(1-42). All compounds were effective in preventing the enhancement of AChE activity induced by Aβ(1-42). Compounds 2-7 caused a significant reduction whereas pyridonepezils 17 and 18, and compound 16 also showed some activity. The pyrazolo[3,4-b]quinolines 36 and 38 also prevented the upregulation of AChE induced by Aβ(1-42). Compounds 2, 7, 12, 13, 17, 18, and 36 may act as antagonists of voltage sensitive calcium channels, since they significantly prevented the Ca(2+) influx evoked by KCl depolarization. Docking studies show that compounds 16 and 18 adopted different orientations and conformations inside the active-site gorges of hAChE and hBuChE. The structural and energetic features of the 16-AChE and 18-AChE complexes compared to the 16-BuChE and 18-BuChE complexes account for a higher affinity of the ligand toward AChE. The present data indicate that compounds 2, 7, 17, 18, and 36 may represent attractive multipotent

  4. Methamphetamine- and 1-methyl-4-phenyl- 1,2,3, 6-tetrahydropyridine-induced dopaminergic neurotoxicity in inducible nitric oxide synthase-deficient mice.

    PubMed

    Itzhak, Y; Martin, J L; Ali, S F

    1999-12-15

    Previous studies have suggested a role for the retrograde messenger, nitric oxide (NO), in methamphetamine (METH)- and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)- induced dopaminergic neurotoxicity. Since evidence supported the involvement of the neuronal nitric oxide synthase (nNOS) isoform in the dopaminergic neurotoxicity, the present study was undertaken to investigate whether the inducible nitric oxide synthase (iNOS) isoform is also associated with METH- and MPTP-induced neurotoxicity. The administration of METH (5mg/kg x 3) to iNOS deficient mice [homozygote iNOS(-/-)] and wild type mice (C57BL/6) resulted in significantly smaller depletion of striatal dopaminergic markers in the iNOS(-/-) mice compared with the wild-type mice. METH-induced hyperthermia was also significantly lower in the iNOS(-/-) mice than in wild-type mice. In contrast to the outcome of METH administration, MPTP injections (20 mg/kg x 3) resulted in a similar decrease in striatal dopaminergic markers in iNOS(-/-) and wild-type mice. In the set of behavioral experiments, METH-induced locomotor sensitization was investigated. The acute administration of METH (1.0 mg/kg) resulted in the same intensity of locomotor activity in iNOS(-/-) and wild-type mice. Moreover, 68 to 72 h after the exposure to the high-dose METH regimen (5 mg/kg x 3), a marked sensitized response to a challenge injection of METH (1.0 mg/kg) was observed in both the iNOS(-/-) and wild-type mice. The finding that iNOS(-/-) mice were unprotected from MPTP-induced neurotoxicity suggests that the partial protection against METH-induced neurotoxicity observed was primarily associated with the diminished hyperthermic effect of METH seen in the iNOS(-/-) mice. Moreover, in contrast to nNOS deficiency, iNOS deficiency did not affect METH-induced behavioral sensitization.

  5. 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.

  6. Effects of metabolic modifiers such as carnitines, coenzyme Q10, and PUFAs against different forms of neurotoxic insults: metabolic inhibitors, MPTP, and methamphetamine.

    PubMed

    Virmani, Ashraf; Gaetani, Franco; Binienda, Zbigniew

    2005-08-01

    A number of strategies using the nutritional approach are emerging for the protection of the brain from damage caused by metabolic toxins, age, or disease. Neural dysfunction and metabolic imbalances underlie many diseases, and the inclusion of metabolic modifiers may provide an alternative and early intervention approach that may prevent further damage. Various models have been developed to study the impact of metabolism on brain function. These have also proven useful in expanding our understanding of neurodegeneration processes. For example, the metabolic compromise induced by inhibitors such as 3-nitropropionic acid (3-NPA), rotenone, and 1-methyl-4-phenylpyridinium (MPP+) can cause neurodegeneration in animal models and these models are thought to simulate the processes that may lead to diseases such as Huntington's and Parkinson's diseases. These inhibitors of metabolism are thought to selectively kill neurons by inhibiting various mitochondrial enzymes. However, the eventual cell death is attributed to oxidative stress damage of selectively vulnerable cells, especially highly differentiated neurons. Various studies indicate that the neurotoxicity resulting from these types of metabolic compromise is related to mitochondrial dysfunction and may be ameliorated by metabolic modifiers such as L-carnitine (L-C), creatine, and coenzyme Q10, as well as by antioxidants such as lipoic acid, vitamin E, and resveratrol. Mitochondrial function and cellular metabolism are also affected by the dietary intake of essential polyunsaturated fatty acids (PUFAs), which may regulate membrane composition and influence cellular processes, especially the inflammatory pathways. Cellular metabolic function may also be ameliorated by caloric restriction diets. L-C is a naturally occurring quaternary ammonium compound that is a vital cofactor for the mitochondrial entry and oxidation of fatty acids. Any factors affecting L-C levels may also affect ATP levels. This endogenous compound

  7. Mitochondrial Toxin 3-Nitropropionic Acid Induces Cardiac and Neurotoxicity Differentially in Mice

    PubMed Central

    Gabrielson, Kathleen L.; Hogue, Barbara A.; Bohr, Vilhelm A.; Cardounel, A. J.; Nakajima, Waco; Kofler, Julia; Zweier, Jay L.; Rodriguez, E. Rene; Martin, Lee J.; de Souza-Pinto, Nadja C.; Bressler, Joseph

    2001-01-01

    We investigated the effects of 3-nitropropionic acid (3NPA), a previously characterized neurotoxin, in four strains of mice to better understand the molecular basis of variable host responses to this agent. Unexpectedly, we found significant cardiac toxicity that always accompanied the neurotoxicity in all strains of mice in acute and subacute/chronic toxicity testing. Caudate putamen infarction never occurred without cardiac toxicity. All mouse strains tested are sensitive to 3NPA although the C57BL/6 and BALB/c mice require more exposure than 129SVEMS and FVB/n mice. Cardiac toxicity alone was found in 50% of symptomatic mice tested and morphologically, the cardiac toxicity is characterized by diffuse swelling of cardiomyocytes and multifocal coagulative contraction band necrosis. In subacute to chronic exposure, atrial thrombosis, cardiac mineralization, cell loss, and fibrosis are combined with cardiomyocyte swelling and necrosis. Ultrastructurally, mitochondrial swelling occurs initially, followed by disruption of myofilaments. Biochemically, isolated heart mitochondria from the highly sensitive 129SVEMS mice have a significant reduction of succinate dehydrogenase activity, succinate oxygen consumption rates, and heart adenosine triphosphate after 3NPA treatment. The severity of morphological changes parallels the biochemical alterations caused by 3NPA, consistent with cardiac toxicity being a consequence of the effects of 3NPA on succinate dehydrogenase. These experiments show, for the first time, that 3NPA has important cardiotoxic effects as well as neurotoxic effects, and that cardiac toxicity possibly resulting from inhibition of the succinate dehydrogenase in heart mitochondria, contributes to the cause of death in 3NPA poisoning in acute and subacute/chronic studies in mice. PMID:11583977

  8. Occupational Neurotoxic Diseases in Taiwan

    PubMed Central

    Liu, Chi-Hung; Huang, Chu-Yun

    2012-01-01

    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

  9. Hemodynamic effects of acute digitalization several months after acute myocardial infarction.

    PubMed

    Ressl, J; Jandová, R; Jebavý, P; Kasalický, J; Widimský, J

    1975-01-01

    Left ventricular function was investigated at rest and during exercise by heart catheterization in 15 patients 3-5 months after acute myocardial infarction. The effect of 1 mg digoxin i.v. in ten patients was correlated to placebo (saline solution) in five patients. A significant decrease of the left ventricular enddiastolic pressure, increase of left ventricular systolic ejection fraction and a shift of the left ventricular function curve to left upwards was found after digoxin with no changes in the placebo group. This beneficial effect of acute digitalization in patients convalescing from uncomplicated myocardial infarction without clinical signs of manifest heart failure could have therapeutic implication.

  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. Acute and long term health effects of radiation

    SciTech Connect

    Voelz, G.L.

    1986-11-19

    This paper covers selected aspects of the acute and long term health effects excluding acute radiation syndrome and carcinogenesis, resulting from exposure to ionizing radiation. The changes addressed in this paper are those witnessed within an organ or whole body rather than at the molecular or even cellular level. They include acute and late health effects. Some of these effects are threshold effects, meaning that the dose must exceed a certain threshold before one sees these effects. Less than the threshold dose results in no observable organ or whole body effect. The severity of the effects correlate directly with the amount of cell damage or cell death that has occurred. 15 refs., 4 figs., 8 tabs.

  12. 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

    2015-12-05

    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.

  13. A curious case of oxaliplatin-induced neurotoxicity: recurrent, self-limiting dysarthria.

    PubMed

    Joseph, Ranjit; Dasanu, Constantin A

    2014-10-01

    This report presents a unique case of oxaliplatin-induced neurotoxicity featuring acute, recurrent, self-limiting dysarthria following multiple subsequent infusions of oxaliplatin. A 65-year-old man started chemotherapy for metastatic pancreatic adenocarcinoma with oxaliplatin-irinotecan-leucovorin-5-fluorouracil (FOLFIRINOX). During the first and subsequent infusions of oxaliplatin, the patient developed episodes of dysarthria that lasted between 2 and 4 h after oxaliplatin infusions, followed by their complete and uneventful resolution. A thorough neurological examination showed no new neurologic deficits except for very fine tongue fasciculations. Recognizing this self-limiting toxic effect of oxaliplatin is important in order to avoid dose reductions that may affect clinical outcomes.

  14. Acute and long-term effects of a single dose of MDMA on aggression in Dark Agouti rats.

    PubMed

    Kirilly, Eszter; Benko, Anita; Ferrington, Linda; Ando, Romeo D; Kelly, Paul A T; Bagdy, Gyorgy

    2006-02-01

    MDMA causes selective depletion of serotonergic terminals in experimental animals and the consequent decrease in synaptic 5-HT may, inter alia, increase impulsivity. To study the effects of MDMA upon brain function, the behaviour of male Dark Agouti rats exposed to MDMA (15 mg/kg i.p.), two 5-HT1B agonists (CGS-12066A and CP-94,253, both 5 mg/kg i.p.) or saline were investigated in the resident-intruder test. Studies were performed in drug-naive rats and also in rats exposed to MDMA (15 mg/kg i.p.) 21 d earlier. In parallel experiments the functional neuroanatomy of MDMA effects were assessed using 2-deoxyglucose imaging of local cerebral metabolic rate of glucose utilization (LCMRGlu) and neurotoxicity was assessed by measuring [3H]paroxetine binding. There was no significant difference in aggressive behaviour (biting, boxing, wrestling and their latencies) between drug-naive rats and rats previously exposed to MDMA 21 d earlier, despite reduced social behaviour, decreased LCMRGlu in several brain areas involved in aggression, and reductions in paroxetine binding by 30-60% in the forebrain. CGS-12066A, CP-94,253 and acute MDMA produced marked decreases in aggressive behaviours, especially in biting, boxing and kicking found in drug-naive rats. In animals previously exposed to the drug, acute anti-aggressive effects of MDMA were, in general, preserved as were MDMA-induced increases in LCMRGlu. Our studies provide evidence that in the resident-intruder test, where social isolation is a requirement, aggressive behaviour and acute anti-aggressive effects of MDMA and 5-HT1B receptor agonists remain intact 3 wk after a single dose of the drug despite significant damage to the serotonergic system.

  15. 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

    1999-07-09

    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

  16. Assessment of therapeutic potential of amantadine in methamphetamine induced neurotoxicity.

    PubMed

    Thrash-Williams, Bessy; Ahuja, Manuj; Karuppagounder, Senthilkumar S; Uthayathas, Subramaniam; Suppiramaniam, Vishnu; Dhanasekaran, Muralikrishnan

    2013-10-01

    Methamphetamine epidemic has a broad impact on world's health care system. Its abusive potential and neurotoxic effects remain a challenge for the anti-addiction therapies. In addition to oxidative stress, mitochondrial dysfunction and apoptosis, excitotoxicity is also involved in methamphetamine induced neurotoxicity. The N-methyl-D-aspartate (NMDA) type of glutamate receptor is thought to be one of the predominant mediators of excitotoxicity. There is growing evidence that NMDA receptor antagonists could be one of the therapeutic options to manage excitotoxicity. Amantadine, a well-tolerated and modestly effective antiparkinsonian agent, was found to possess NMDA antagonistic properties and has shown to release dopamine from the nerve terminals. The current study aimed to evaluate the effect of amantadine pre-treatment against methamphetamine induced neurotoxicity. Results showed that methamphetamine treatment had depleted striatal dopamine, generated of reactive oxygen species and decreased activity of complex I in the mitochondria. Interestingly, amantadine, at high dose (10 mg/kg), did not prevent dopamine depletion moreover it exacerbated the behavioral manifestations of methamphetamine toxicity such as akinesia and catalepsy. Only lower dose of amantadine (1 mg/kg) produced significant scavenging of the reactive oxygen species induced by methamphetamine. Overall results from the present study suggest that amantadine should not be used concomitantly with methamphetamine as it may results in excessive neurotoxicity.

  17. Effects of Acute Confinement Stress-induced Hypothalamic-Pituitary Adrenal Axis Activation and Concomitant Peripheral and Central Transforming Growth Factor-β1 Measures in Nonhuman Primates

    PubMed Central

    Coplan, Jeremy D.; Gopinath, Srinath; Abdallah, Chadi G.; Margolis, Jeffrey; Chen, Wei; Scharf, Bruce A.; Rosenblum, Leonard A.; Batuman, Olcay A.; Smith, Eric L. P.

    2017-01-01

    Transforming growth factor-β1 (TGF-β1) is a multifunctional cytokine with anti-inflammatory, immunosuppressive and neuroprotective properties. The hypothalamic-pituitary-adrenal (HPA) axis and immune system exert bidirectional influences on each other, via cortisol and TGF-β1, but the exact nature of the interaction is not well characterized. The current study examined the effects, in bonnet macaques (Macaca radiata), of two consecutive acute confinement stress periods in an unfamiliar room while mildly restrained, first without and then with dexamethasone pretreatment (0.01 mg/kg IM). Preceding the confinement studies, a non-stress control condition obtained contemporaneous levels of cortisol and TGF-β1 in both plasma and cerebrospinal fluid (CSF) to match the confinement stress studies. Subjects were reared under either normative or variable foraging demand (VFD) conditions. Since there were no rearing effects at baseline or for any of the conditions tested -- either for cortisol or TGF-β -- the study analyses were conducted on the combined rearing groups. The stress condition increased both plasma and CSF cortisol levels whereas dexamethasone pretreatment decreased cortisol concentrations to below baseline levels despite stress. The stress condition decreased TGF-β1 concentrations only in CSF but not in serum. Together the data suggested that stress-induced reductions of a centrally active neuroprotective cytokine occurs in the face of HPA axis activation, potentially facilitating glucocortoid-induced neurotoxicity. Stress-induced reductions of neuroprotective cytokines prompts exploration of protective measures against glucocorticoid-induced neurotoxicity.

  18. Neurotoxicity of Ammonia.

    PubMed

    Oja, Simo S; Saransaari, Pirjo; Korpi, Esa R

    2017-03-01

    Abnormal liver function has dramatic effects on brain functions. Hyperammonemia interferes profoundly with brain metabolism, astrocyte volume regulation, and in particular mitochondrial functions. Gene expression in the brain and excitatory and inhibitory neurotransmission circuits are also affected. Experiments with a number of pertinent animal models have revealed several potential mechanisms which could underlie the pathological phenomena occurring in hepatic encephalopathy.

  19. 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.

  20. 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

  1. Herpes zoster encephalopathy or acyclovir neurotoxicity: a management dilemma.

    PubMed

    Sacchetti, Daniel; Alawadhi, Aydah; Albakour, Mustafa; Rapose, Alwyn

    2014-04-28

    This is a case report of a 69-year-old morbidly obese woman who presented with mental status changes after she was treated with acyclovir for shingles. The predominant symptoms were word-finding difficulties and visual hallucinations. Complicating her presentation was acyclovir-induced acute renal injury causing her creatinine level to rise up to 7.4 mg/dL. Acyclovir was discontinued on the suspicion of acyclovir neurotoxicity. Even though PCR for varicella zoster virus in the cerebrospinal fluid was positive, acyclovir was not restarted and the patient continued to improve and returned to her baseline.

  2. 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.

  3. 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

  4. Prospective, longitudinal assessment of developmental neurotoxicity.

    PubMed Central

    Jacobson, J L; Jacobson, S W

    1996-01-01

    Methodological issues in the design of prospective, longitudinal studies of developmental neurotoxicity in humans are reviewed. A comprehensive assessment of potential confounding influences is important in these studies because inadequate assessment of confounders can threaten the validity of causal inferences drawn from the data. Potential confounders typically include demographic background variables, alcohol and smoking during pregnancy, the quality of parental stimulation, the child's age at test, and the examiner. Exposure to other substances is assessed where significant exposure is expected in the target population. In most studies, control variables even weakly related to outcome are included in all multivariate statistical analyses, and a toxic effect is inferred only if the effect of exposure is significant after controlling for the potential confounders. Once a neurotoxic effect has been identified, suspected mediating variables may be added to the analysis to examine underlying processes or mechanisms through which the exposure may impact on developmental outcome. Individual differences in vulnerability may be examined in terms of either an additive compensatory model or a synergistic "risk and resilience" approach. Failure to detect real effects (Type II error) is of particular concern in these studies because public policy considerations make it likely that negative findings will be interpreted to mean that the exposure is safe. Important sources of Type II error include inadequate representation of highly exposed individuals, overcontrol for confounders, and inappropriate correction for multiple comparisons. Given the high cost and complexity of prospective, longitudinal investigations, cross-sectional pilot studies focusing on highly exposed individuals can be valuable for the initial identification of salient domains of impairment. PMID:9182034

  5. Effects of an Acute Seizure on Associative Learning and Memory

    PubMed Central

    Holley, Andrew J.; Lugo, Joaquin N.

    2015-01-01

    Past studies have demonstrated that inducing several seizures or continuous seizures in neonatal or adult rats results in impairments in learning and memory. The impact of a single acute seizure on learning and memory has not been investigated in mice. In this study, we exposed an adult 129SvEvTac mouse to the inhalant flurothyl until a behavioral seizure was induced. Our study consisted of 4 experiments where we examined the effect of one seizure before or after delay fear conditioning. We also included a separate cohort of animals that was tested in the open field after a seizure to rule out changes in locomotor activity influencing the results of memory tests. Mice that had experienced a single seizure 1 hour, but not 6 hours, prior to training showed a significant impairment in associative conditioning to the conditioned stimulus when compared to controls 24 hours later. There were no differences in freezing one day later for animals that experienced a single seizure 1 hour after associative learning. We also found that an acute seizure reduced activity levels in an open field test 2 hours but not 24 hours later. These findings suggest that an acute seizure occurring immediately before learning can have an effect on the recall of events occurring shortly after that seizure. In contrast, an acute seizure occurring shortly after learning appears to have little or no effect on long-term memory. These findings have implications for understanding the acute effects of seizures on the acquisition of new knowledge. PMID:26655449

  6. Research advances on potential neurotoxicity of quantum dots.

    PubMed

    Wu, Tianshu; Zhang, Ting; Chen, Yilu; Tang, Meng

    2016-03-01

    With rapid development of nanotechnology, quantum dots (QDs) as advanced nanotechnology products have been widely used in biological and biomedical studies, including neuroscience, due to their superior optical properties. In recent years, there has been intense concern regarding the toxicity of QDs with a growing number of studies. However, the knowledge of neurotoxic consequences of QDs applied in living organisms is lagging behind their development, while a potential risk of neurotoxicity arises if mass production of QDs leads to increased exposure and distribution in the nervous system. Owing to the quantum size effect of QDs, they are capable of crossing the blood-brain barrier or moving along neural pathways and entering the brain. Nevertheless, the interactions of QDs with cells and tissues in the central nervous system are not well understood. This review highlighted research advances on the neurotoxicity of QDs in the central nervous system, including oxidative stress injury, elevated cytoplasmic Ca(2+) levels and autophagy to damage in vitro neural cells, and impairments of synaptic transmission and plasticity as well as brain functions in tested animals, with the hope of throwing light on future research directions of QD neurotoxicity, which is a demanding topic that requires further exploration.

  7. Neuroinflammation and Microglia: Considerations and approaches for neurotoxicity assessment

    PubMed Central

    Harry, G. Jean; Kraft, Andrew D.

    2009-01-01

    Background The impact of an inflammatory response, as well as interactions between the immune and nervous systems, are rapidly assuming major roles in neurodegenerative disease and injury. However, it is now appreciated that the exact nature of such responses can differ with each type of insult and interaction. More recently, neuroinflammation and the associated cellular response of microglia are being considered for their contribution to neurotoxicity of environmental agents; yet, to date, the inclusion of inflammatory endpoints into neurotoxicity assessment have relied primarily on relatively limited measures or driven by in vitro models of neurotoxicity. Objective To present background information on relevant biological considerations of neuroinflammation and the microglia response demonstrating the complex integrative nature of these biological processes and raising concern with regards to translation of effects demonstrated in vitro to the in vivo situation. Specific points are addressed that would influence the design and interpretation of neuroinflammation with regards to neurotoxicology assessment. Conclusion There is a complex and dynamic response in the brain to regulate inflammatory processes and maintain a normal homeostatic level. The classification of such responses as beneficial or detrimental is an oversimplification. Neuroinflammation should be considered as a balanced network of processes where subtle modifications can shift the cells toward disparate outcomes. The tendency to over-interpret data obtained in an isolated culture system should be discouraged. Rather, the use of cross-disciplinary approaches to evaluate multiple endpoints should be incorporated into the assessment of inflammatory contributions to the neurotoxicity of environmental exposures. PMID:18798697

  8. Teriflunomide and monomethylfumarate target HIV-induced neuroinflammation and neurotoxicity.

    PubMed

    Ambrosius, Björn; Faissner, Simon; Guse, Kirsten; von Lehe, Marec; Grunwald, Thomas; Gold, Ralf; Grewe, Bastian; Chan, Andrew

    2017-03-11

    HIV-associated neurocognitive disorders (HAND) affect about 50% of infected patients despite combined antiretroviral therapy (cART). Ongoing compartmentalized inflammation mediated by microglia which are activated by HIV-infected monocytes has been postulated to contribute to neurotoxicity independent from viral replication. Here, we investigated effects of teriflunomide and monomethylfumarate on monocyte/microglial activation and neurotoxicity. Human monocytoid cells (U937) transduced with a minimal HIV-Vector were co-cultured with human microglial cells (HMC3). Secretion of pro-inflammatory/neurotoxic cytokines (CXCL10, CCL5, and CCL2: p < 0.001; IL-6: p < 0.01) by co-cultures was strongly increased compared to microglia in contact with HIV-particles alone. Upon treatment with teriflunomide, cytokine secretion was decreased (CXCL10, 3-fold; CCL2, 2.5-fold; IL-6, 2.2-fold; p < 0.001) and monomethylfumarate treatment led to 2.9-fold lower CXCL10 secretion (p < 0.001). Reduced toxicity of co-culture conditioned media on human fetal neurons by teriflunomide (29%, p < 0.01) and monomethylfumarate (27%, p < 0.05) indicated functional relevance. Modulation of innate immune functions by teriflunomide and monomethylfumarate may target neurotoxic inflammation in the context of HAND.

  9. 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...

  10. Up-regulation of protein tyrosine nitration in methamphetamine-induced neurotoxicity through DDAH/ADMA/NOS pathway.

    PubMed

    Zhang, Fu; Chen, Ling; Liu, Chao; Qiu, Pingming; Wang, Aifeng; Li, Lizeng; Wang, Huijun

    2013-06-01

    Protein tyrosine nitration is an important post-translational modification mediated by nitric oxide (NO) associated oxidative stress, occurring in a variety of neurodegenerative diseases. In our previous study, an elevated level of dimethylarginine dimethylaminohydrolase 1 (DDAH1) protein was observed in different brain regions of acute methamphetamine (METH) treated rats, indicating the possibility of an enhanced expression of protein nitration that is mediated by excess NO through the DDAH1/ADMA (Asymmetric Dimethylated l-arginine)/NOS (Nitric Oxide Synthase) pathway. In the present study, proteomic methods, including stable isotope labeling with amino acids in cell culture (SILAC) and two dimensional electrophoresis, were used to determine the relationship between protein nitration and METH induced neurotoxicity in acute METH treated rats and PC12 cells. We found that acute METH administration evokes a positive activation of DDAH1/ADMA/NOS pathway and results in an over-production of NO in different brain regions of rat and PC12 cells, whereas the whole signaling could be repressed by DDAH1 inhibitor N(ω)-(2-methoxyethyl)-arginine (l-257). In addition, enhanced expressions of 3 nitroproteins were identified in rat striatum and increased levels of 27 nitroproteins were observed in PC12 cells. These nitrated proteins are key factors for Cdk5 activation, cytoskeletal structure, ribosomes function, etc. l-257 also displayed significant protective effects against METH-induced protein nitration, apoptosis and cell death. The overall results illustrate that protein nitration plays a significant role in the acute METH induced neurotoxicity via the activation of DDAH1/ADMA/NOS pathway.

  11. 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...

  12. 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...

  13. An investigation of the effect of thiamine pyrophosphate on cisplatin-induced oxidative stress and DNA damage in rat brain tissue compared with thiamine: thiamine and thiamine pyrophosphate effects on cisplatin neurotoxicity.

    PubMed

    Turan, M I; Cayir, A; Cetin, N; Suleyman, H; Siltelioglu Turan, I; Tan, H

    2014-01-01

    This study investigated the effects of thiamine pyrophosphate (TPP) at dosages of 10 and 20 mg/kg on oxidative stress induced in rat brain tissue with cisplatin and compared this with thiamine. Cisplatin neurotoxicity represents one of the main restrictions on the drug being given in effective doses. Oxidative stress is considered responsible for cisplatin toxicity. Our results showed that cisplatin increased the levels of oxidant parameters such as lipid peroxidation (thio barbituric acid reactive substance (TBARS)) and myeloperoxidase (MPO) in brain tissue and suppressed the effects of antioxidants such as total glutathione (GSH) and superoxide dismutase (SOD). TPP, especially at a dosage of 20 mg/kg, significantly reduced TBARS and MPO levels that increase with cisplatin administration compared with the thiamine group, while TPP significantly increases GSH and SOD levels. In addition, the level of 8-Gua (guanine), a product of DNA damage, was 1.7 ± 0.12 8-hydroxyl guanine (8-OH Gua)/105 Gua in brain tissue in the control group receiving cisplatin, compared with 0.97 ± 0.03 8-OH Gua/105 Gua in the thiamine pyrophosphate (20 mg/kg) group and 1.55 ± 0.11 8-OH Gua/105 Gua in the thiamine (20 mg/kg) group. These results show that thiamine pyrophosphate significantly prevents oxidative damage induced by cisplatin in brain tissue, while the protective effect of thiamine is insignificant.

  14. Rechallenging With Intrathecal Methotrexate After Developing Subacute Neurotoxicity in Children With Hematologic Malignancies.

    PubMed

    Badke, Colleen; Fleming, Amy; Iqbal, Asneha; Khilji, Ohmed; Parhas, Sophia; Weinstein, Joanna; Morgan, Elaine; Hijiya, Nobuko

    2016-04-01

    Methotrexate is associated with neurologic side effects. It is recommended that patients who developed neurotoxicity be rechallenged with methotrexate, but little is known about the safety of this approach. We performed a chart review to identify patients who received high-dose or intrathecal (IT) methotrexate. Twenty-one of 298 patients (7%) experienced neurologic symptoms attributed to methotrexate treatment in the premaintenance phase. Seventeen of these patients were rechallenged with IT methotrexate and 13 (76%) had no further neurotoxic events. No patients rechallenged during maintenance (n = 9) experienced recurrence of neurotoxic events. It is safe to rechallenge with IT methotrexate in maintenance.

  15. 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

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

    PubMed

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

    2008-05-01

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

  17. Subchronic neurotoxicity of chlorpyrifos, carbaryl, and their combination in rats.

    PubMed

    Wang, Hui-Ping; Liang, Yu-Jie; Sun, Ying-Jian; Hou, Wei-Yuan; Chen, Jia-Xiang; Long, Ding-Xin; Xu, Ming-Yuan; Wu, Yi-Jun

    2014-10-01

    Anticholinesterase pesticides have been widely used in agricultural and domestic settings and can be detected in the environment after long-term use. Although the acute toxic effects of chlorpyrifos and carbaryl have been well described, little is known about the chronic toxicity of the pesticides mixture. To investigate their chronic neurotoxicity, Wistar rats were exposed to chlorpyrifos, carbaryl, and their mixture (MIX) for 90 consecutive days. The activities of serum cholinesterase (ChE) as well as acetylcholinesterase (AChE) and neuropathy target esterase (NTE) in nerve tissues were determined. Furthermore, the histopathological examination was carried out. The results showed that ChE activity significantly decreased in all treated rats except the rats treated with low dose carbaryl. Treatment with middle- and high-dose chlorpyrifos and MIX in rats significantly inhibited AChE activity in the central nervous tissues, whereas treatment with carbaryl alone did not. In sciatic nerve, AChE activity was significantly inhibited by high-dose carbaryl and MIX, but not by chlorpyrifos alone. No significant NTE inhibition was observed in all treatment groups. Histopathological examination revealed that both chlorpyrifos and MIX treatment induced hippocampal damage. However, no obvious hippocampal damage was found in carbaryl-treated rats. Carbaryl and MIX, but not chlorpyrifos alone, induced pathological damage of sciatic nerve. Taken together, all of the results indicated that chlorpyrifos and carbaryl have different toxicological target tissues in nervous system and showed corresponding effects in the nervous tissues, which may reflect the different sensitivity of central and peripheral nervous tissues to different pesticides individually and in combination.

  18. Air Force Health Study (Project RANCH HAND II). An Epidemiologic Investigation of Health Effects in Air Force Personnel Following Exposure to Herbicides. Baseline Morbidity Study Results

    DTIC Science & Technology

    1984-02-24

    exposure (Dudley, 1972). While these effects have only been demonstrated acutely following heavy .exposures, complaints of peripheral neuropathy are...patients in the Registry had complaints compatible with symptoms of peripheral neuropathy . The recognized acute neurotoxicity of these chemicals and the...unclear at this time. There were no distinct patterns of Increasing abnormality with increasing exposure. Table XII-7 PERIPHERAL NEUROPATHY BY EXPOSURE

  19. Neurotoxicity

    MedlinePlus

    ... Strategy Current Research Research Funded by NINDS Basic Neuroscience Clinical Research Translational Research Research at NINDS Focus ... Information Current Research Research Funded by NINDS Basic Neuroscience Clinical Research Translational Research Research at NINDS Focus ...

  20. Effect of acute ethanol and acute allopregnanolone on spatial memory in adolescent and adult rats.

    PubMed

    Chin, Vivien S; Van Skike, Candice E; Berry, Raymond B; Kirk, Roger E; Diaz-Granados, Jamie; Matthews, Douglas B

    2011-08-01

    The effects of ethanol differ in adolescent and adult rats on a number of measures. The evidence of the effects of ethanol on spatial memory in adolescents and adults is equivocal. Whether adolescents are more or less sensitive to ethanol-induced impairment of spatial memory acquisition remains unclear; with regard to the effects of acute ethanol on spatial memory retrieval there is almost no research looking into any age difference. Thus, we examined the effects of acute ethanol on spatial memory in the Morris Watermaze in adolescents and adults. Allopregnanolone (ALLO) is a modulator of the GABA(A) receptor and has similar behavioral effects as ethanol. We sought to also determine the effects of allopreganolone on spatial memory in adolescent and adults. Male adolescent (post natal [PN]28-30) and adult (PN70-72) rats were trained in the Morris Watermaze for 6 days and acute doses of ethanol (saline, 1.5 and 2.0 g/kg) or ALLO (vehicle, 9 and 18 mg/kg) were administered on Day 7. A probe trial followed on Day 8. As expected, there were dose effects; higher doses of both ethanol and ALLO impaired spatial memory. However, in both the ethanol and ALLO conditions adolescents and adults had similar spatial memory impairments. The current results suggest that ethanol and ALLO both impair hippocampal-dependent spatial memory regardless of age in that once learning has occurred, ethanol or ALLO does not differentially impair the retrieval of spatial memory in adolescents and adults. Given the mixed results on the effect of ethanol on cognition in adolescent rats, additional research is needed to ascertain the factors critical for the reported differential results.

  1. Endoplasmic Reticulum Stress and Ethanol Neurotoxicity.

    PubMed

    Yang, Fanmuyi; Luo, Jia

    2015-10-14

    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.

  2. Fumonisin B(1): a neurotoxic mycotoxin.

    PubMed

    Domijan, Ana-Marija

    2012-12-01

    Fumonisin B(1) (FB(1)) is a mycotoxin produced by Fusarium spp. moulds that contaminate crop, predominantly maize, all around the world. More than 15 types of fumonisins have been indentified so far, but FB(1) is the most abundant and toxicologically the most significant one. FB(1) has a wide range of toxic effects, depending on animal species. In horses FB(1) causes equine leukoencephalomalacia (ELEM), in pigs pulmonary oedema and in experimental rodents nephrotoxicity and hepatotoxicity. In humans exposure to FB(1) is linked with higher incidence of primary liver cancer and oesophageal cancer, which are frequent in certain regions of the world (such as Transkei region in South Africa) where maize is staple food. The occurrence of neural tube defect in children in some countries of Central America (such as Mexico and Honduras) is connected with the consumption of FB(1)-contaminated maize-based food. However, possible involvement of FB(1) in the development of human diseases is not clear. Nevertheless, the International Agency for Research on Cancer (IARC) has classified FB(1) as a possible carcinogen to humans (group 2B). FB(1) is a causative agent of ELEM, a brain disorder in equines, indicating that brain is a target organ of FB(1) toxicity. Several studies on experimental animals or on cell cultures of neural origin have established that FB(1) has a neurodegenerative potential, although the mechanism of its neurotoxicity is still vague. The aim of this article is to give an overview of available literature on FB(1) neurotoxicity and involved mechanisms, and to offer a new perspective for future studies.

  3. Study of neurotoxic intracellular calcium signalling triggered by amyloids.

    PubMed

    Villalobos, Carlos; Caballero, Erica; Sanz-Blasco, Sara; Núñez, Lucía

    2012-01-01

    Neurotoxicity in Alzheimer's disease (AD) is associated to dishomeostasis of intracellular Ca(2+) induced by amyloid β peptide (Aβ) species. Understanding of the effects of Aβ on intracellular Ca(2+) homeostasis requires preparation of the different Aβ assemblies including oligomers and fibrils and the testing of their effects on cytosolic and mitochondrial Ca(2+) in neurons. Procedures for cerebellar granule cell culture, preparation of Aβ species as well as fluorescence and bioluminescence imaging of cytosolic and mitochondrial Ca(2+) in neurons are described.

  4. N-acetyl cysteine (NAC) treatment reduces mercury-induced neurotoxicity in the developing rat hippocampus

    PubMed Central

    Falluel-Morel, Anthony; Lin, Lulu; Sokolowski, Katie; McCandlish, Elizabeth; Buckley, Brian; DiCicco-Bloom, Emanuel

    2011-01-01

    Mercury is an environmental toxicant that can disrupt brain development. However, while progress has been made in defining its neurotoxic effects, we know far less about available therapies that can effectively protect brain in exposed individuals. We previously developed an animal model in which we defined the sequence of events underlying neurotoxicity: Methylmercury (MeHg) injection in postnatal rat acutely induced inhibition of mitosis and stimulated apoptosis in the hippocampus, that later resulted in intermediate term deficits in structure size and cell number. NAC is the N-acetyl derivative of L-cysteine used clinically for treatment of drug intoxication. Here, based on its known efficacy in promoting MeHg urinary excretion, we evaluated NAC for protective effects in the developing brain. In immature neurons and precursors MeHg (3µM) induced a >50% decrease in DNA synthesis at 24hr, an effect that was completely blocked by NAC co-incubation. In vivo, injection of MeHg (5µg/gbw) into 7 day-old rats induced a 22% decrease in DNA synthesis in whole hippocampus and a 4-fold increase in activated caspase-3 immunoreactive cells at 24hr, and reduced total cell numbers by 13% at 3 weeks. Treatment of MeHg exposed rats with repeated injections of NAC abolished MeHg toxicity. NAC prevented the reduction in DNA synthesis and the marked increase in caspase-3 immunoreactivity. Moreover, the intermediate term decrease in hippocampal cell number provoked by MeHg was fully blocked by NAC. Altogether, these results suggest that MeHg toxicity in the perinatal brain can be ameliorated by using NAC, opening potential avenues for therapeutic intervention. PMID:22420031

  5. 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…

  6. 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…

  7. Effects of melatonin on gallbladder neuromuscular function in acute cholecystitis.

    PubMed

    Gomez-Pinilla, Pedro J; Camello, Pedro J; Pozo, María J

    2007-10-01

    Gallbladder stasis is associated to experimental acute cholecystitis. Impaired contractility could be, at least in part, the result of inflammation-induced alterations in the neuromuscular function. This study was designed to determine the changes in gallbladder neurotransmission evoked by acute inflammation and to evaluate the protective and therapeutic effects of melatonin. Experimental acute cholecystitis was induced in guinea pigs by common bile duct ligation for 2 days, and then the neuromuscular function was evaluated using electrical field stimulation (EFS; 5-40 Hz). In a group of animals with the bile duct ligated for 2 days, a deligation of the duct was performed, and after 2 days, the neuromuscular function was studied. The EFS-evoked isometric gallbladder contraction was significantly lower in cholecystitic tissue. In addition, inflammation changed the pharmacological profile of these contractions that were insensitive to tetrodotoxin but sensitive to atropine and omega-conotoxin, indicating that acute cholecystitis affects action potential propagation in the intrinsic nerves. Nitric oxide (NO)-mediated neurotransmission was reduced by inflammation, which also increased the reactivity of sensitive fibers. Melatonin treatment prevented qualitative changes in gallbladder neurotransmission, but it did not improve EFS-induced contractility. The hormone recovered gallbladder neuromuscular function once the biliary obstruction was resolved, even when the treatment was started after the onset of gallbladder inflammation. These findings show for the first time the therapeutic potential of melatonin in the recovery of gallbladder neuromuscular function during acute cholecystitis.

  8. [Usefulness of color vision test for early detection of neurological damages by neurotoxic substances].

    PubMed

    Lee, Eun-Hee; Choi, Kyungho; Chae, Hong Jae; Paek, Domyung

    2008-11-01

    This paper reviews the published literature that is concerned with color vision impairment from industrial and environmental exposure to neurotoxic substances, and we evaluated whether testing for color vision impairment could be an affordable procedure for assessing these neurotoxic effects. In general, most cases of congenital color vision impairment are red-green, and blue-yellow impairment is extremely rare. However, most of the acquired color vision impairment that is related to age, alcohol or environmental factors is blue-yellow impairment. Therefore, many studies have been performed to identify this relationship between exposure to neurotoxic substances, such as organic solvents and heavy metals, and the prevalence of blue-yellow color vision impairment. The test for color vision impairment is known to be very sensitive to the early signs of nervous system dysfunction and this can be useful for making the early diagnosis of neurotoxic effects from exposure to very low concentrations of toxic substances.

  9. Neurotoxicity of manganese oxide nanomaterials

    NASA Astrophysics Data System (ADS)

    Stefanescu, Diana M.; Khoshnan, Ali; Patterson, Paul H.; Hering, Janet G.

    2009-11-01

    Manganese (Mn) toxicity in humans has been observed as manganism, a disease that resembles Parkinson's disease. The mechanism of Mn toxicity and the chemical forms that may be responsible for its neurotoxicity are not well understood. We examined the toxicity of Mn oxide nanomaterials in a neuronal precursor cell model, using the MTS assay to evaluate mitochondrial function in living cells and the LDH assay to quantify the release of the enzyme lactate dehydrogenase as a result of damage to the cell membrane. Both assays show that the toxicity of Mn is dependent on the type of Mn oxide nanomaterial and its concentration as well as on the state of cell differentiation. Following exposure to Mn oxide nanomaterials, reactive oxygen species (ROS) are generated, and flow cytometry experiments suggest that cell death occurred through apoptosis. During exposure to Mn oxide nanomaterials, increased levels of the transcription factor NF-κB (which mediates the cellular inflammatory response) were observed.

  10. Is racecadotril effective for acute diarrhea in children? -First update.

    PubMed

    Sáez, Josefina; Cifuentes, Lorena

    2016-05-06

    This article updates the December 2015 Living FRISBEE (Living FRISBEE: Living FRIendly Summary of the Body of Evidence using Epistemonikos), based on the detection of two systematic reviews not identified in the previous version. Gastroenteritis or acute watery diarrhea is usually a self-limited disease, but it is still associated to substantial healthcare costs and remains a frequent demand for medical care. Racecadotril, an intestinal enkephalinase inhibitor, has been used as treatment because it would decrease the duration of acute diarrhea and fluid loss. However there is still no evidence supporting its routine use. Searching in Epistemonikos database, which is maintained by screening 30 databases, we identified five systematic reviews including nine randomized trials relevant for our question. We combined the evidence using meta-analysis and generated a summary of findings table following the GRADE approach. We concluded racecadotril probably reduces the duration of acute diarrhea in pediatric patients, without increasing adverse effects.

  11. Effect of acute pesticide exposure on bee spatial working memory using an analogue of the radial-arm maze

    NASA Astrophysics Data System (ADS)

    Samuelson, Elizabeth E. W.; Chen-Wishart, Zachary P.; Gill, Richard J.; Leadbeater, Ellouise

    2016-12-01

    Pesticides, including neonicotinoids, typically target pest insects by being neurotoxic. Inadvertent exposure to foraging insect pollinators is usually sub-lethal, but may affect cognition. One cognitive trait, spatial working memory, may be important in avoiding previously-visited flowers and other spatial tasks such as navigation. To test this, we investigated the effect of acute thiamethoxam exposure on spatial working memory in the bumblebee Bombus terrestris, using an adaptation of the radial-arm maze (RAM). We first demonstrated that bumblebees use spatial working memory to solve the RAM by showing that untreated bees performed significantly better than would be expected if choices were random or governed by stereotyped visitation rules. We then exposed bees to either a high sub-lethal positive control thiamethoxam dose (2.5 ng‑1 bee), or one of two low doses (0.377 or 0.091 ng‑1) based on estimated field-realistic exposure. The high dose caused bees to make more and earlier spatial memory errors and take longer to complete the task than unexposed bees. For the low doses, the negative effects were smaller but statistically significant, and dependent on bee size. The spatial working memory impairment shown here has the potential to harm bees exposed to thiamethoxam, through possible impacts on foraging efficiency or homing.

  12. Effect of acute pesticide exposure on bee spatial working memory using an analogue of the radial-arm maze

    PubMed Central

    Samuelson, Elizabeth E. W.; Chen-Wishart, Zachary P.; Gill, Richard J.; Leadbeater, Ellouise

    2016-01-01

    Pesticides, including neonicotinoids, typically target pest insects by being neurotoxic. Inadvertent exposure to foraging insect pollinators is usually sub-lethal, but may affect cognition. One cognitive trait, spatial working memory, may be important in avoiding previously-visited flowers and other spatial tasks such as navigation. To test this, we investigated the effect of acute thiamethoxam exposure on spatial working memory in the bumblebee Bombus terrestris, using an adaptation of the radial-arm maze (RAM). We first demonstrated that bumblebees use spatial working memory to solve the RAM by showing that untreated bees performed significantly better than would be expected if choices were random or governed by stereotyped visitation rules. We then exposed bees to either a high sub-lethal positive control thiamethoxam dose (2.5 ng−1 bee), or one of two low doses (0.377 or 0.091 ng−1) based on estimated field-realistic exposure. The high dose caused bees to make more and earlier spatial memory errors and take longer to complete the task than unexposed bees. For the low doses, the negative effects were smaller but statistically significant, and dependent on bee size. The spatial working memory impairment shown here has the potential to harm bees exposed to thiamethoxam, through possible impacts on foraging efficiency or homing. PMID:27958350

  13. Effect of acute pesticide exposure on bee spatial working memory using an analogue of the radial-arm maze.

    PubMed

    Samuelson, Elizabeth E W; Chen-Wishart, Zachary P; Gill, Richard J; Leadbeater, Ellouise

    2016-12-13

    Pesticides, including neonicotinoids, typically target pest insects by being neurotoxic. Inadvertent exposure to foraging insect pollinators is usually sub-lethal, but may affect cognition. One cognitive trait, spatial working memory, may be important in avoiding previously-visited flowers and other spatial tasks such as navigation. To test this, we investigated the effect of acute thiamethoxam exposure on spatial working memory in the bumblebee Bombus terrestris, using an adaptation of the radial-arm maze (RAM). We first demonstrated that bumblebees use spatial working memory to solve the RAM by showing that untreated bees performed significantly better than would be expected if choices were random or governed by stereotyped visitation rules. We then exposed bees to either a high sub-lethal positive control thiamethoxam dose (2.5 ng(-1) bee), or one of two low doses (0.377 or 0.091 ng(-1)) based on estimated field-realistic exposure. The high dose caused bees to make more and earlier spatial memory errors and take longer to complete the task than unexposed bees. For the low doses, the negative effects were smaller but statistically significant, and dependent on bee size. The spatial working memory impairment shown here has the potential to harm bees exposed to thiamethoxam, through possible impacts on foraging efficiency or homing.

  14. Effects of acute hypoxia on cerebrovascular responses to carbon dioxide.

    PubMed

    Ogoh, Shigehiko; Nakahara, Hidehiro; Ueda, Shinya; Okazaki, Kazunobu; Shibasaki, Manabu; Subudhi, Andrew W; Miyamoto, Tadayoshi

    2014-06-01

    In normoxic conditions, a reduction in arterial carbon dioxide tension causes cerebral vasoconstriction, thereby reducing cerebral blood flow and modifying dynamic cerebral autoregulation (dCA). It is unclear to what extent these effects are altered by acute hypoxia and the associated hypoxic ventilatory response (respiratory chemoreflex). This study tested the hypothesis that acute hypoxia attenuates arterial CO2 tension-mediated regulation of cerebral blood flow to help maintain cerebral O2 homeostasis. Eight subjects performed three randomly assigned respiratory interventions following a resting baseline period, as follows: (1) normoxia (21% O2); (2) hypoxia (12% O2); and (3) hypoxia with wilful restraint of the respiratory chemoreflex. During each intervention, 0, 2.0, 3.5 or 5.0% CO2 was sequentially added (8 min stages) to inspired gas mixtures to assess changes in steady-state cerebrovascular CO2 reactivity and dCA. During normoxia, the addition of CO2 increased internal carotid artery blood flow and middle cerebral artery mean blood velocity (MCA Vmean), while reducing dCA (change in phase = -0.73 ± 0.22 rad, P = 0.005). During acute hypoxia, internal carotid artery blood flow and MCA Vmean remained unchanged, but cerebrovascular CO2 reactivity (internal carotid artery, P = 0.003; MCA Vmean, P = 0.031) and CO2-mediated effects on dCA (P = 0.008) were attenuated. The effects of hypoxia were not further altered when the respiratory chemoreflex was restrained. These findings support the hypothesis that arterial CO2 tension-mediated effects on the cerebral vasculature are reduced during acute hypoxia. These effects could limit the degree of hypocapnic vasoconstriction and may help to regulate cerebral blood flow and cerebral O2 homeostasis during acute periods of hypoxia.

  15. 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.

  16. 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.

  17. 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

  18. Anti-inflammatory and anti-apoptotic effects of (RS)-glucoraphanin bioactivated with myrosinase in murine sub-acute and acute MPTP-induced Parkinson's disease.

    PubMed

    Galuppo, Maria; Iori, Renato; De Nicola, Gina Rosalinda; Bramanti, Placido; Mazzon, Emanuela

    2013-09-01

    This study was focused on the possible neuroprotective role of (RS)-glucoraphanin, bioactivated with myrosinase enzyme (bioactive RS-GRA), in an experimental mouse model of Parkinson's disease (PD). RS-GRA is one of the most important glucosinolates, a thiosaccharidic compound found in Brassicaceae, notably in Tuscan black kale seeds. RS-GRA was extracted by one-step anion exchange chromatography, further purified by gel-filtration and analyzed by HPLC. Following, pure RS-GRA was characterized by (1)H and (13)C NMR spectrometry and the purity was assayed by HPLC analysis of the desulfo-derivative according to the ISO 9167-1 method. The obtained purity has been of 99%. To evaluate the possible pharmacological efficacy of bioactive RS-GRA (administrated at the dose of 10mg/kg, ip +5μl/mouse myrosinase enzyme), C57BL/6 mice were used in two different sets of experiment (in order to evaluate the neuroprotective effects in different phases of the disease), according to an acute (2 injections·40mg/kg MPTP) and a sub-acute (5 injections·20mg/kg MPTP) model of PD. Behavioural test, body weight changes measures and immunohistochemical localization of the main PD markers were performed and post-hoc analysis has shown as bioactive RS-GRA is able to reduce dopamine transporter degradation, tyrosine hydroxylase expression, IL-1β release, as well as the triggering of neuronal apoptotic death pathway (data about Bax/Bcl-2 balance and dendrite spines loss) and the generation of radicalic species by oxidative stress (results focused on nitrotyrosine, Nrf2 and GFAP immunolocalization). These effects have been correlated with the release of neurotrophic factors, such as GAP-43, NGF and BDNF, that, probably, play a supporting role in the neuroprotective action of bioactive RS-GRA. Moreover, after PD-induction mice treated with bioactive RS-GRA are appeared more in health than animals that did not received the treatment both for phenotypic behaviour and for general condition

  19. The Acute and Chronic Biochemical and Behavioral Effects of Cyclotrimethylenetrinitramine

    DTIC Science & Technology

    1975-03-31

    Behavioral Studies - Barbiturate slieptimes were determined using hexabar- bital according to the standard technique used in our labora- tory, in which rats...the in vitro study (Table 4 D). - These results show that CMT does not produce an acute effect on Ouptake of duration over 6 hours. Nor does chronic...results of a study of the toxic effects of cyclomethylenetrinitramine on the brain after chronic admin.istration to male rats. In 1973 the Department

  20. 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.

  1. Valdecoxib provides effective pain relief following acute ankle sprain.

    PubMed

    Diaz, J A; Cuervo, C; Valderrama, A M; Kohles, J

    2006-01-01

    We sought to determine whether valdecoxib is as effective as diclofenac in treating acute ankle sprain. Patients (n=202) with acute first- and second-degree ankle sprain were randomized to valdecoxib (40 mg twice daily on day 1 followed by 40 mg once daily on days 2-7) or diclofenac (75 mg twice daily). The primary efficacy end-point was the Patient's Assessment of Ankle Pain visual analogue scale (VAS, 0-100 mm) value on day 4. Valdecoxib was as efficacious as diclofenac in treating the signs and symptoms of acute ankle sprain. The mean VAS reduction in ankle pain on day 4 was not different between groups; the two-sided 95% confidence interval for the between-group difference was within the prespecified limit for non-inferiority (10 mm). There were no significant differences between groups for all secondary efficacy end-points. The two treatments were similarly effective and well tolerated for treatment of acute ankle sprain.

  2. 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

  3. 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

  4. 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.

  5. 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

  6. Toxicity testing of neurotoxic pesticides in Caenorhabditis elegans.

    PubMed

    Meyer, Dean; Williams, Phillip L

    2014-01-01

    The use of pesticides is ubiquitous worldwide, and these chemicals exert adverse effects on both target and nontarget species. Understanding the modes of action of pesticides, as well as quantifying exposure concentration and duration, is an important goal of clinicians and environmental health scientists. Some chemical exposures result in adverse effects on the nervous system. The nematode Caenorhabditis elegans (C. elegans) is a model lab organism well established for studying neurotoxicity, since the components of its nervous system are mapped and known, and most of its neurotransmitters correspond to human homologs. This review encompasses published studies in which C. elegans nematodes were exposed to pesticides with known neurotoxic actions. Endpoints measured include changes in locomotion, feeding behavior, brood size, growth, life span, and cell death. From data presented, evidence indicates that C. elegans can serve a role in assessing the effects of neurotoxic pesticides at the sublethal cellular level, thereby advancing our understanding of the mechanisms underlying toxicity induced by these chemicals. A proposed toxicity testing scheme for water-soluble chemicals is also included.

  7. Peripheral ammonia as a mediator of methamphetamine neurotoxicity.

    PubMed

    Halpin, Laura E; Yamamoto, Bryan K

    2012-09-19

    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 [4-(8-methyl-9H-1,3-dioxolo[4,5-h][2,3]benzodiazepin-5-yl)-benzamine hydrochloride], 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.

  8. 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

  9. Neurotoxicity Questions Regarding Common Peripheral Nerve Block Adjuvants in Combination with Local Anesthetics

    PubMed Central

    Knight, Joshua B.; Schott, Nicholas J.; Kentor, Michael L.; Williams, Brian A.

    2015-01-01

    Purpose of Review Outline the analgesic role of perineural adjuvants for local anesthetic nerve block injections, and evaluate current knowledge regarding whether adjuvants modulate the neurocytologic properties of local anesthetics. Recent Findings Perineural adjuvant medications such as dexmedetomidine, clonidine, buprenorphine, dexamethasone, and midazolam play unique analgesic roles. The dosing of these medications to prevent neurotoxicity is characterized in various cellular and in vivo models. Much of this mitigation may be via reducing the dose of local anesthetic used while achieving equal or superior analgesia. Dose-concentration animal models have shown no evidence of deleterious effects. Clinical observations regarding blocks with combined bupivacaine-clonidine-buprenorphine-dexamethasone have shown beneficial effects on block duration and rebound pain without long-term evidence of neurotoxicity. In vitro and in vivo studies of perineural clonidine and dexmedetomidine show attenuation of perineural inflammatory responses generated by local anesthetics. Summary Dexmedetomidine added as a peripheral nerve blockade adjuvant improves block duration without neurotoxic properties. The combined adjuvants clonidine, buprenorphine, and dexamethasone do not appear to alter local anesthetic neurotoxicity. Midazolam significantly increases local anesthetic neurotoxicity in vitro, but when combined with clonidine-buprenorphine-dexamethasone (sans local anesthetic) produces no in vitro or in vivo neurotoxicity. Further larger-species animal testing and human trials will be required to reinforce the clinical applicability of these findings. PMID:26207854

  10. Neurotoxicity produced by dibromoacetic acid in drinking water of rats.

    PubMed

    Moser, V C; Phillips, P M; Levine, A B; McDaniel, K L; Sills, R C; Jortner, B S; Butt, M T

    2004-05-01

    An evaluation of potential adverse human health effects of disinfection byproducts requires study of both cancer and noncancer endpoints; however, no studies have evaluated the neurotoxic potential of a common haloacetic acid, dibromoacetic acid (DBA). This study characterized the neurotoxicity of DBA during 6-month exposure in the drinking water of rats. Adolescent male and female Fischer 344 rats were administered DBA at 0, 0.2, 0.6, and 1.5 g/l. On a mg/kg/day basis, the consumed dosages decreased greatly over the exposure period, with average intakes of 0, 20, 72, and 161 mg/kg/day. Weight gain was depressed in the high-concentration group, and concentration-related diarrhea and hair loss were observed early in exposure. Testing with a functional observational battery and motor activity took place before dosing and at 1, 2, 4, and 6 months. DBA produced concentration-related neuromuscular toxicity (mid and high concentrations) characterized by limb weakness, mild gait abnormalities, and hypotonia, as well as sensorimotor depression (all concentrations), with decreased responses to a tail-pinch and click. Other signs of toxicity at the highest concentration included decreased activity and chest clasping. Neurotoxicity was evident as early as one month, but did not progress with continued exposure. The major neuropathological finding was degeneration of spinal cord nerve fibers (mid and high concentrations). Cellular vacuolization in spinal cord gray matter (mostly) and in white matter (occasionally) tracts was also observed. No treatment-related changes were seen in brain, eyes, peripheral nerves, or peripheral ganglia. The lowest-observable effect level for neurobehavioral changes was 20 mg/kg/day (produced by 0.2 g/l, lowest concentration tested), whereas this dosage was a no-effect level for neuropathological changes. These studies suggest that neurotoxicity should be considered in the overall hazard evaluation of haloacetic acids.

  11. 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

  12. 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.

  13. Effect of solcoseryl on antitumour action and acute toxicity of some antineoplastic drugs.

    PubMed

    Danysz, A; Sołtysiak-Pawluczuk, D; Czyzewska-Szafran, H; Jedrych, A; Jastrzebski, Z

    1991-01-01

    The in vivo effect of Solcoseryl on the antitumour activity and acute toxicity of some antineoplastic drugs was examined. It was found that Solcoseryl does not inhibit the antineoplastic effectiveness of the drugs against transplantable P 388 leukaemia in mice. Studies of the effect of Solcoseryl on acute toxicity of selected antineoplastic drugs in mice revealed that the biostimulator could exert a modifying influence. The prior administration of Solcoseryl significantly decreases the acute toxicity of methotrexate but has no effect on acute toxicity of 5-fluorouracil, increases the acute toxicity of bleomycin and vinblastine and has no effect on acute toxicity of methotrexate and mitoxantron. On the other hand, Solcoseryl administered simultaneously with the antineoplastic drugs increases acute toxicity of 5-fluorouracil, bleomycin and mitoxantron. The protective effect of the biostimulator noted exclusively against acute toxicity of 5-fluorouracil was also observed after multiple administration of this anticancer drug.

  14. Perceived Control Alters the Effect of Acute Stress on Persistence

    PubMed Central

    Bhanji, Jamil P.; Kim, Eunbin S.; Delgado, Mauricio R.

    2015-01-01

    We often encounter setbacks while pursuing our goals. Success requires that we cope with these negative outcomes and choose to persist in spite of them. For example, learners may be more likely to continue a course after failing an assessment if they control their emotional reactions to the setback and study harder. However, the ability to effectively cope with the negative emotion inherent in such setbacks can be compromised by acute stress present in daily life (e.g., struggles in the household), which can subsequently lead to problems with persisting with a goal. The present study examined whether increasing the perception of control over setbacks (e.g., belief that a setback was caused by a correctable mistake rather than uncontrollable factors) can guard against the influence of a prior acute stressor on reactions to setbacks. Participants underwent a socially-evaluated cold water stress or a non-stress control procedure. Afterwards, they performed a behavioral task designed to measure persistence through controllable and uncontrollable setbacks. We observed that exposure to an acute stressor led to a detrimental effect on decision making by decreasing persistence behavior. Importantly, we also observed that the perception of control protected against the effect of preexisting stress and helped promote persistence. That is, stress impaired persistence through uncontrollable setbacks, but the impairment was alleviated by presenting setbacks as controllable. The findings demonstrate a potential avenue for improving the maintenance of goals aimed at behavior change, which can be susceptible to effects of stress. PMID:26726915

  15. Acute effects of aerobic exercise promote learning.

    PubMed

    Perini, Renza; Bortoletto, Marta; Capogrosso, Michela; Fertonani, Anna; Miniussi, Carlo

    2016-05-05

    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.

  16. Translating neurobehavioural endpoints of developmental neurotoxicity tests into in vitro assays and readouts.

    PubMed

    van Thriel, Christoph; Westerink, Remco H S; Beste, Christian; Bale, Ambuja S; Lein, Pamela J; Leist, Marcel

    2012-08-01

    The developing nervous system is particularly vulnerable to chemical insults. Exposure to chemicals can result in neurobehavioural alterations, and these have been 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.

  17. Effects of acute exercise on long-term memory.

    PubMed

    Labban, Jeffrey D; Etnier, Jennifer L

    2011-12-01

    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 three groups: exercise prior to exposure, exercise after exposure, or no-exercise. Exercise consisted of 30 min on a cycle ergometer including 20 min at moderate intensity. Only the exercise prior group recalled significantly more than the control group (p < .05). Differences among the exercise groups failed to reach significance (p = .09). Results indicated that acute exercise positively influenced recall and that exercise timing relative to memory task may have an impact on this effect.

  18. 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

  19. The effect of menthol on acute experimental colitis in rats.

    PubMed

    Ghasemi-Pirbaluti, Masoumeh; Motaghi, Ehsan; Bozorgi, Homan

    2017-03-18

    Menthol is an aromatic compound with high antiinflammatory activity. The purpose of the current research is to investigate the effectiveness of menthol on acetic acid induced acute colitis in rats. Animals were injected with menthol (20 and 50 and 80mg/kg, i.p.) 24h prior to induction of colitis for 3 consecutive days. Menthol at medium and higher doses similar to dexamethasone as a reference drug significantly reduced body weight loss, macroscopic damage score, ulcer area, colon weight, colon length and improved hematocrit in rats with colitis. The histopathological examination also confirmed anti-colitic effects of menthol. Menthol also reduced significantly the colonic levels of tumor necrosis factor-α (TNF-α), interleukin 1β (IL-1β), interleukin 6 (IL-6) and myeloperoxidase (MPO) activity in inflamed colons. Thus, the findings of the current study provide evidence that menthol may be beneficial in patients suffering from acute ulcerative colitis.

  20. 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.

  1. 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.

  2. 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

  3. 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

  4. The acute (cerebro)vascular effects of statins.

    PubMed

    Prinz, Vincent; Endres, Matthias

    2009-08-01

    The introduction of 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors, i.e., statins, constitutes a milestone in the prevention of cardio- and cerebrovascular disease. The effects of statins extend far beyond their effects on cholesterol levels: pleiotropic effects include vasoprotective mechanisms, comprising improved endothelial function, increased bioavailability of nitric oxide, immunomodulatory and antiinflammatory properties, stabilization of atherosclerotic plaques, as well as antioxidant and stem cell-regulating capacities. Large clinical trials have clearly demonstrated that statins reduce the risk of myocardial infarction and stroke. Recent experimental and clinical data have demonstrated that in addition to risk reduction, statins may also improve outcome after stroke and myocardial infarction, even when statins were administered after the event. Moreover, abrupt discontinuation of statin therapy after acute cardio- or cerebrovascular events may impair vascular function and increase morbidity and mortality. Beyond stroke, statin treatment also has been shown to provide protective effects in critically ill patients, e.g., after major surgery, sepsis, or in patients at high-vascular risk. However, although large randomized controlled trials are missing, ongoing trials will clarify the impact of acute statin treatment in these conditions. Although evidence is presently limited, acute statin therapy is emerging as a new therapeutic avenue for the treatment of the critically ill. Until now, statins were only available as oral drugs. An IV formulation may be warranted for acute treatment of severely ill patients, for example, those who are unable to swallow or scheduled for surgery. Hydrophilic statins would be suitable for an IV formulation and have been safely tested in healthy volunteers.

  5. Effect of roxithromycin on acute toxoplasmosis in mice.

    PubMed Central

    Chang, H R; Pechere, J C

    1987-01-01

    Roxithromycin effectively treated acute peritoneal murine toxoplasmosis. After five doses, starting 24 h after challenge, the 100 and 50% survival doses were 540 and 336 mg/kg per day, respectively. After 14 doses, starting 3 h after challenge, the 50% survival dose was 360 mg/kg per day. Toxoplasma gondii was recovered from the brain in 59 and 28% of surviving mice treated with 5 and 14 doses, respectively. PMID:3662475

  6. Microglial activation is a pharmacologically specific marker for the neurotoxic amphetamines.

    PubMed

    Thomas, David M; Dowgiert, Jennifer; Geddes, Timothy J; Francescutti-Verbeem, Dina; Liu, Xiuli; Kuhn, Donald M

    2004-09-09

    Neurotoxic amphetamines cause damage to monoamine nerve terminals of the striatum by unknown mechanisms. Microglial activation contributes to the neuronal damage that accompanies injury, disease, and inflammation, but a role for these cells in amphetamine-induced neurotoxicity has received little attention. We show presently that D-methamphetamine, 3,4-methylenedioxymethamphetamine (MDMA), D-amphetamine, and p-chloroamphetamine, each of which has been linked to dopamine (DA) or serotonin nerve terminal damage, result in microglial activation in the striatum. The non-neurotoxic amphetamines l-methamphetamine, fenfluramine, and DOI do not have this effect. All drugs that cause microglial activation also increase expression of glial fibrillary acidic protein (GFAP). At a minimum, microglial activation serves as a pharmacologically specific marker for striatal nerve terminal damage resulting only from those amphetamines that exert neurotoxicity. Because microglia are known to produce many of the reactive species (e.g., nitric oxide, superoxide, cytokines) that mediate the neurotoxicity of the amphetamine-class of drugs, their activation could represent an early and essential event in the neurotoxic cascade associated with high-dose amphetamine intoxication.

  7. Effects of Acute Stress on Decision Making.

    PubMed

    Wemm, Stephanie E; Wulfert, Edelgard

    2017-03-01

    The study examined the effects of a social stressor (Trier Social Stress Test) on 24 male and 32 female college students' affective and physiological reactivity and their subsequent performance on a decision-making task (Iowa Gambling Task). The 56 participants were randomly assigned to a social stressor or a control condition. Compared to controls, participants in the stress condition responded with higher heart rates and skin conductance responses, reported more negative affect, and on the decision-making task made less advantageous choices. An exploratory regression analysis revealed that among men higher levels of heart rate were positively correlated with riskier choices on the Iowa Gambling Task, whereas for women this relationship was curvilinear. Exploratory correlational analyses showed that lower levels of skin conductance within the stress condition were associated with greater levels of substance use and gambling. The results suggest that the presence of a stressor may generally result in failure to attend to the full range of possible consequences of a decision. The relationship pattern between the degree of stress responding and successful decision making may be different for men and women.

  8. Glucocorticoid therapy-induced memory deficits: acute versus chronic effects.

    PubMed

    Coluccia, Daniel; Wolf, Oliver T; Kollias, Spyros; Roozendaal, Benno; Forster, Adrian; de Quervain, Dominique J-F

    2008-03-26

    Conditions with chronically elevated glucocorticoid levels are usually associated with declarative memory deficits. Considerable evidence suggests that long-term glucocorticoid exposure may cause cognitive impairment via cumulative and long-lasting influences on hippocampal function and morphology. However, because elevated glucocorticoid levels at the time of retention testing are also known to have direct impairing effects on memory retrieval, it is possible that such acute hormonal influences on retrieval processes contribute to the memory deficits found with chronic glucocorticoid exposure. To investigate this issue, we examined memory functions and hippocampal volume in 24 patients with rheumatoid arthritis who were treated either chronically (5.3 +/- 1.0 years, mean +/- SE) with low to moderate doses of prednisone (7.5 +/- 0.8 mg, mean +/- SE) or without glucocorticoids. In both groups, delayed recall of words learned 24 h earlier was assessed under conditions of either elevated or basal glucocorticoid levels in a double-blind, placebo-controlled crossover design. Although the findings in this patient population did not provide evidence for harmful effects of a history of chronic prednisone treatment on memory performance or hippocampal volume per se, acute prednisone administration 1 h before retention testing to either the steroid or nonsteroid group impaired word recall. Thus, these findings indicate that memory deficits observed under chronically elevated glucocorticoid levels result, at least in part, from acute and reversible glucocorticoid effects on memory retrieval.

  9. Effects of acute hippocampal stimulation on EEG dynamics.

    PubMed

    Nair, Sandeep P; Sackellares, J Chris; Shiau, Deng-Shan; Norman, Wendy M; Dance, Linda K; Pardalos, Panos M; Principe, Jose C; Carney, Paul R

    2006-01-01

    Progressive preictal dynamical convergence and postictal divergence of dynamical EEG descriptors among brain regions has been reported in human temporal lobe epilepsy (TLE) and in a rodent model of TLE. There are also reports of anticonvulsant effects of high frequency stimulation of the hippocampus in humans. We postulate that this anticonvulsant effect is due to dynamical resetting by the electrical stimulation. The following study investigated the effects of acute hippocampal electrical stimulation on dynamical transitions in the brain of a spontaneously seizing animal model of TLE to test the hypothesis of divergence in dynamical values by electrical stimulation of the hippocampus.

  10. Neurotoxicity in Preclinical Models of Occupational Exposure to Organophosphorus Compounds

    PubMed Central

    Voorhees, Jaymie R.; Rohlman, Diane S.; Lein, Pamela J.; Pieper, Andrew A.

    2017-01-01

    Organophosphorus (OPs) compounds are widely used as insecticides, plasticizers, and fuel additives. These compounds potently inhibit acetylcholinesterase (AChE), the enzyme that inactivates acetylcholine at neuronal synapses, and acute exposure to high OP levels can cause cholinergic crisis in humans and animals. Evidence further suggests that repeated exposure to lower OP levels insufficient to cause cholinergic crisis, frequently encountered in the occupational setting, also pose serious risks to people. For example, multiple epidemiological studies have identified associations between occupational OP exposure and neurodegenerative disease, psychiatric illness, and sensorimotor deficits. Rigorous scientific investigation of the basic science mechanisms underlying these epidemiological findings requires valid preclinical models in which tightly-regulated exposure paradigms can be correlated with neurotoxicity. Here, we review the experimental models of occupational OP exposure currently used in the field. We found that animal studies simulating occupational OP exposures do indeed show evidence of neurotoxicity, and that utilization of these models is helping illuminate the mechanisms underlying OP-induced neurological sequelae. Still, further work is necessary to evaluate exposure levels, protection methods, and treatment strategies, which taken together could serve to modify guidelines for improving workplace conditions globally. PMID:28149268

  11. Neurotoxicity in Preclinical Models of Occupational Exposure to Organophosphorus Compounds.

    PubMed

    Voorhees, Jaymie R; Rohlman, Diane S; Lein, Pamela J; Pieper, Andrew A

    2016-01-01

    Organophosphorus (OPs) compounds are widely used as insecticides, plasticizers, and fuel additives. These compounds potently inhibit acetylcholinesterase (AChE), the enzyme that inactivates acetylcholine at neuronal synapses, and acute exposure to high OP levels can cause cholinergic crisis in humans and animals. Evidence further suggests that repeated exposure to lower OP levels insufficient to cause cholinergic crisis, frequently encountered in the occupational setting, also pose serious risks to people. For example, multiple epidemiological studies have identified associations between occupational OP exposure and neurodegenerative disease, psychiatric illness, and sensorimotor deficits. Rigorous scientific investigation of the basic science mechanisms underlying these epidemiological findings requires valid preclinical models in which tightly-regulated exposure paradigms can be correlated with neurotoxicity. Here, we review the experimental models of occupational OP exposure currently used in the field. We found that animal studies simulating occupational OP exposures do indeed show evidence of neurotoxicity, and that utilization of these models is helping illuminate the mechanisms underlying OP-induced neurological sequelae. Still, further work is necessary to evaluate exposure levels, protection methods, and treatment strategies, which taken together could serve to modify guidelines for improving workplace conditions globally.

  12. 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

  13. 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

    2016-03-08

    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.

  14. Cadmium neurotoxicity to a freshwater planarian.

    PubMed

    Wu, Jui-Pin; Lee, Hui-Ling; Li, Mei-Hui

    2014-11-01

    Although freshwater planarians are evolutionarily primitive, they are some of the simplest bilateral animals possessing integrated neural networks similar to those in vertebrates. We attempted to develop planarian Dugesia japonica as a model for investigating the neurotoxicity of environmental pollutants such as cadmium (Cd). This study was therefore designed to study the effects of Cd on the locomotor activity, neurobehavior, and neurological enzymes of D. japonica. After planarians were exposed to Cd at high concentrations, altered neurobehavior was observed that exhibited concentration-dependent patterns. Morphological alterations in Cd-treated planarians included irregular shape, body elongation, screw-like hyperkinesia, and bridge-like position. To study the direct effects of Cd on neurological enzymes, tissue homogenates of planarians were incubated in vitro with Cd before their activity was measured. Results showed that acetylcholinesterase (AChE), adenosine triphosphatase (ATPase), and monoamine oxidase A (MAO-A) activities were inhibited in a concentration-dependent manner. MAO-B activity was significantly induced by Cd at low concentrations and inhibited at high concentrations. Changes in the in vivo activity of AChE and ATPase were also found after planarians were treated with Cd at a sublethal concentration (5.56 μM). These observations indicate that neurotransmission systems in planarians are disturbed after Cd exposure.

  15. The effects of acute sleep deprivation during residency training.

    PubMed

    Bartle, E J; Sun, J H; Thompson, L; Light, A I; McCool, C; Heaton, S

    1988-08-01

    Verbal and symbol concentration, learning, problem solving, clear thinking, manual skills, and memory were tested in 42 surgical residents to assess the effects of acute sleep deprivation on specific neuropsychological parameters. A series of eight neuropsychological tests--digit symbols, digit vigilance, story memory, trail making, PASAT, Raven matrices, delayed story, and pegboard--and a questionnaire on mood states were completed by the residents both when fatigued (less than 4 hours of sleep: mean, 2.0 +/- 1.5 hours) and when rested (more than 4 hours of sleep: mean, 6.5 +/- 1.0 hours), with at least 7 days between tests. In order to eliminate the effects of learning from the first test series, randomization of residents was performed so that one half were first evaluated when rested and one half when fatigued. ANOVA, multiple regression analysis, and the Student t test were used to assess differences. In the acute sleep-deprived state, residents were less vigorous and more fatigued, depressed, tense, confused, and angry (p less than 0.05) than they were in rested state. Despite these changes in mood, however, the responses on all of the functional tests were no different statistically in those who were rested and those who were fatigued (even in those with less than 2 hours' sleep). We conclude that acute sleep deprivation of less than 4 hours alters mood state but does not change performance in test situations in which concentration, clear thinking, and problem solving are important.

  16. Effects of acute ingestion of salbutamol during submaximal exercise.

    PubMed

    Collomp, K; Candau, R; Collomp, R; Carra, J; Lasne, F; Préfaut, C; De Ceaurriz, J

    2000-10-01

    To assess the eventual effects of acute oral salbutamol intake on performance and metabolism during submaximal exercise, nine healthy volunteers completed two cycling trials at a power corresponding to 80-85% VO2max, after either placebo (Pla) or salbutamol (Sal, 6 mg) treatment, according to a double-blind randomized protocol. Blood samples were collected both at rest and during exercise (5 min-, 10 min-, 15 min-exhaustion) for C-peptide, FFA, lactate and blood glucose measurements. Cycling performance was significantly improved in the Sal vs. Pla trials (p < 0.05). After Sal intake, resting C-peptide, lactate, FFA and blood glucose values were higher whereas exercise lactate and free fatty acid concentrations were greater during and at the conclusion of the exercise period (p < 0.05). These results suggest that acute salbutamol ingestion improved performance during submaximal exercise probably through an enhancement of the overall contribution to energy production from both aerobic and anaerobic metabolisms.

  17. Cross-Neutralisation of In Vitro Neurotoxicity of Asian and Australian Snake Neurotoxins and Venoms by Different Antivenoms

    PubMed Central

    Silva, Anjana; Hodgson, Wayne C.; Isbister, Geoffrey K.

    2016-01-01

    venom in an in vitro preparation, cross-neutralization of neurotoxicity means that antivenoms from one region may be effective in other regions which do not have effective antivenoms. TCAV only neutralized post-synaptic neurotoxicity and is potentially useful in distinguishing pre-synaptic and post-synaptic effects in the chick biventer cervicis preparation. PMID:27763543

  18. Hormetic Effects of Acute Methylmercury Exposure on Grp78 Expression in Rat Brain Cortex

    PubMed Central

    Zhang, Ye; Lu, Rongzhu; Liu, Wenshuai; Wu, Ying; Qian, Hai; Zhao, Xiaowu; Wang, Suhua; Xing, Guangwei; Yu, Feng; Aschner, Michael

    2013-01-01

    This study aims to explore the expression of GRP78, a marker of endoplasmic reticulum (ER) stress, in the cortex of rat brains acutely exposed to methylmercury (MeHg). Thirty Sprague-Dawley (SD) rats were randomly divided into six groups, and decapitated 6 hours (h) after intraperitoneal (i.p.) injection of MeHg (2, 4, 6, 8 or 10 mg/kg body weight) or normal saline. Protein and mRNA expression of Grp78 were detected by western blotting and real-time PCR, respectively. The results showed that a gradual increase in GRP78 protein expression was observed in the cortex of rats acutely exposed to MeHg (2, 4 or 6 mg/kg). Protein levels peaked in the 6 mg/kg group (p < 0.05 vs. controls), decreased in the 8 mg/kg group, and bottomed below the control level in the 10 mg/kg group. Parallel changes were noted for Grp78 mRNA expression. It may be implied that acute exposure to MeHg induced hormetic dose-dependent changes in Grp78 mRNA and protein expression, suggesting that activation of ER stress is involved in MeHg-induced neurotoxicity. Low level MeHg exposure may induce GRP78 protein expression to stimulate endogenous cytoprotective mechanisms. PMID:23549286

  19. Assessing the Effects of Acute Amyloid β Oligomer Exposure in the Rat

    PubMed Central

    Wong, Ryan S.; Cechetto, David F.; Whitehead, Shawn N.

    2016-01-01

    Alzheimer’s disease (AD) is the most common form of dementia, yet there are no therapeutic treatments that can either cure or delay its onset. Currently, the pathogenesis of AD is still uncertain, especially with respect to how the disease develops from a normal healthy brain. Amyloid β oligomers (AβO) are highly neurotoxic proteins and are considered potential initiators to the pathogenesis of AD. Rat brains were exposed to AβO via bilateral intracerebroventricular injections. Rats were then euthanized at either 1, 3, 7 or 21-days post surgery. Rat behavioural testing was performed using the Morris water maze and open field tests. Post-mortem brain tissue was immunolabelled for Aβ, microglia, and cholinergic neurons. Rats exposed to AβO showed deficits in spatial learning and anxiety-like behaviour. Acute positive staining for Aβ was only observed in the corpus callosum surrounding the lateral ventricles. AβO exposed rat brains also showed a delayed increase in activated microglia within the corpus callosum and a decreased number of cholinergic neurons within the basal forebrain. Acute exposure to AβO resulted in mild learning and memory impairments with co-concomitant white matter pathology within the corpus callosum and cholinergic cell loss within the basal forebrain. Results suggest that acute exposure to AβO in the rat may be a useful tool in assessing the early phases for the pathogenesis of AD. PMID:27563885

  20. Current Challenges in Neurotoxicity Risk Assessment ...

    EPA Pesticide Factsheets

    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 complex animal models that better replicate human behavior and a wider array of molecular and mechanistic data relevant to interpreting the underlying cause(s) of toxicity. However, modern neurotoxicology studies are often more nuanced and complicated than traditional studies, and they often vary considerably in evaluation methods from one study to the next, impeding comparisons. This can pose particular difficulties for risk assessors, especially given the recent demand for chemical risk assessments to be more systematic and transparent. This presentation will introduce and provide some examples of specific challenges in neurotoxicity assessments of environmental chemicals. Some of these challenges are relatively new to the field, such as the incorporation of data on neuron-supportive glial cells into hazard characterization, while other challenges have persisted for several decades, but only recently are studies being designed to evaluate them, including analyses of latent neurotoxicity. The examples provided illustrate some future research areas of interest for scientists and risk assessors examining human neurotoxicity risk. This abstract will be presented to internal U.S. Food and Drug A

  1. Effects of acute bouts of exercise on cognition.

    PubMed

    Tomporowski, Phillip D

    2003-03-01

    A review was conducted of studies that assessed the effects of acute bouts of physical activity on adults' cognitive performance. Three groups of studies were constituted on the basis of the type of exercise protocol employed. Each group was then evaluated in terms of information-processing theory. It was concluded that submaximal aerobic exercise performed for periods up to 60 min facilitate specific aspects of information processing; however, extended exercise that leads to dehydration compromises both information processing and memory functions. The selective effects of exercise on cognitive performance are explained in terms of Sanders' [Acta Psychol. 53 (1983) 61] cognitive-energetic model.

  2. 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

  3. Remote effects of acute kidney injury in a porcine model.

    PubMed

    Gardner, David S; De Brot, Simone; Dunford, Louise J; Grau-Roma, Llorenc; Welham, Simon J M; Fallman, Rebecca; O'Sullivan, Saoirse E; Oh, Weng; Devonald, Mark A J

    2016-02-15

    Acute kidney injury (AKI) is a common and serious condition with no specific treatment. An episode of AKI may affect organs distant from the kidney, further increasing the morbidity associated with AKI. The mechanism of organ cross talk after AKI is unclear. The renal and immune systems of pigs and humans are alike. Using a preclinical animal (porcine) model, we tested the hypothesis that early effects of AKI on distant organs is by immune cell infiltration, leading to inflammatory cytokine production, extravasation, and edema. In 29 pigs exposed to either sham surgery or renal ischemia-reperfusion (control, n = 12; AKI, n = 17), we assessed remote organ (liver, lung, brain) effects in the short (from 2- to 48-h reperfusion) and longer term (5 wk later) using immunofluorescence (for leukocyte infiltration, apoptosis), a cytokine array, tissue elemental analysis (e.g., electrolytes), blood hematology and chemistry (e.g., liver enzymes), and PCR (for inflammatory markers). AKI elicited significant, short-term (∼24 h) increments in enzymes indicative of acute liver damage (e.g. , AST: ALT ratio; P = 0.02) and influenced tissue biochemistry in some remote organs (e.g., lung tissue [Ca(2+)] increased; P = 0.04). These effects largely resolved after 48 h, and no further histopathology, edema, apoptosis, or immune cell infiltration was noted in the liver, lung, or hippocampus in the short and longer term. AKI has subtle biochemical effects on remote organs in the short term, including a transient increment in markers of acute liver damage. These effects resolved by 48 h, and no further remote organ histopathology, apoptosis, edema, or immune cell infiltration was noted.

  4. Protection from MPTP-induced neurotoxicity in differentiating mouse N2a neuroblastoma cells.

    PubMed

    De Girolamo, L A; Hargreaves, A J; Billett, E E

    2001-02-01

    We have shown previously that subcytotoxic concentrations of MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) inhibit axon outgrowth and are associated with increased neurofilament heavy chain (NF-H) phosphorylation in differentiating mouse N2a neuroblastoma cells while higher doses (> 100 microM) cause cell death. In this work we assessed the ability of potential neuroprotective agents to alleviate both MPTP-induced cell death (cytotoxicity) and MPTP-induced NF-H phosphorylation/reduction in axon outgrowth (neurotoxicity) in N2a cells induced to differentiate by dbcAMP. The neurotoxic effects of MPTP occurred in the absence of significant alterations in energy status or mitochondrial membrane potential. The hormone oestradiol (100 microM) reduced the cytotoxic effect of MPTP, but blocked di-butyryl cyclic AMP (dbcAMP)-induced differentiation, i.e. axon outgrowth. Both the cytotoxic and neurotoxic effects of MPTP were reduced by the monoamine oxidase (MAO) inhibitors deprenyl and, to a lesser extent, clorgyline. Alleviation of both neurotoxicity and cytotoxicity was also achieved by conditioned medium derived from rat C6 glioma cells. In contrast, whilst the p38 MAP kinase inhibitor, SB202190, protected cells against MPTP-induced neurotoxicity, it could not maintain cell viability at high MPTP exposures. In each case neuroprotection involved maintenance of the differentiating phenotype linked with attenuation of NF-H hyper-phosphorylation; the latter may represent a mechanism by which neuronal cells can moderate MPTP-induced neurotoxicity. The use of a simplified neuronal cell model, which expresses subtle biochemical changes following neurotoxic insult, could therefore provide a valuable tool for the identification of potential neuroprotective agents.

  5. Downregulation of miR-210 protected bupivacaine-induced neurotoxicity in dorsal root ganglion.

    PubMed

    Wang, Yiheng; Ni, Hongxia; Zhang, Wenrui; Wang, Xiu; Zhang, Haishan

    2016-04-01

    Local anesthetic may cause neurotoxicity in developing neurons. In this study, we examined the molecular mechanisms of microRNA-210 (miR-210) in regulating bupivacaine-induced dorsal root ganglia (DRG) neurotoxicity in vitro. Young mouse (P30) DRG explants were cultured in vitro and treated with 5 mM bupivacaine to induce neurotoxicity. QRT-PCR was used to evaluate the expression profiles of miRNAs within 24 h after bupivacaine treatment. MiR-210 was downregulated in DRG, and its effects on bupivacaine-induced neurotoxicity were evaluated by apoptosis and neurite growth assays, respectively. Putative downstream target of miR-210 in DRG, BDNF, was evaluated by dual-luciferase assay, qRT-PCR, and western blot, respectively. BDNF was then knocked down by siRNA to assess its associated effects in regulating DRG neurotoxicity. Within the initial 24 h after bupivacaine treatment, various patterns of miRNA expression were observed, whereas miR-210 was constantly upregulated. Application of miR-210 inhibitor efficiently downregulated endogenous miR-210, protected apoptosis and neurite retraction in bupivacaine damaged DRG neurons. Using dual-luciferase assay, qRT-PCR, and western blot, BDNF was confirmed to the downstream target of miR-210 in DRG. SiRNA-mediated BDNF downregulation reversed the effect of miR-210 downregulation in DRG neurotoxicity. MiR-210, through the regulation of BDNF, plays important role in anesthetics-induced DRG neurotoxicity.

  6. Effects of diazoxide in experimental acute necrotizing pancreatitis

    PubMed Central

    de Oliveira Andrade, Roberta; Kunitake, Tiago; Koike, Marcia Kiyomi; Machado, Marcel C C; Souza, Heraldo Possolo

    2017-01-01

    OBJECTIVE: We aimed to assess the effects of diazoxide on the mortality, pancreatic injury, and inflammatory response in an experimental model of acute pancreatitis. METHODS: Male Wistar rats (200–400 g) were divided randomly into two groups. Fifteen minutes before surgery, animals received physiological (0.9%) saline (3 mL/kg) (control group) or 45 mg/kg diazoxide (treatment group) via the intravenous route. Acute pancreatitis was induced by injection of 2.5% sodium taurocholate via the biliopancreatic duct. Mortality (n=38) was observed for 72 h and analyzed by the Mantel–Cox Log-rank test. To study pancreatic lesions and systemic inflammation, rats (10 from each group) were killed 3 h after acute pancreatitis induction; ascites volume was measured and blood as well as pancreases were collected. Pancreatic injury was assessed according to Schmidt’s scale. Cytokine expression in plasma was evaluated by the multiplex method. RESULTS: Mortality at 72 h was 33% in the control group and 60% in the treatment group (p=0.07). Ascites volumes and plasma levels of cytokines between groups were similar. No difference was observed in edema or infiltration of inflammatory cells in pancreatic tissues from either group. However, necrosis of acinar cells was lower in the treatment group compared to the control group (3.5 vs. 3.75, p=0.015). CONCLUSIONS: Treatment with diazoxide can reduce necrosis of acinar cells in an experimental model of acute pancreatitis, but does not affect the inflammatory response or mortality after 72 h. PMID:28273237

  7. 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

  8. Acute effects of ethanol on renal folate clearance in rats

    SciTech Connect

    Eisenga, B.H.; McMartin, K.E.

    1986-03-05

    Studies of the renal clearance of folic acid in primates demonstrate net reabsorption of folate by a saturable system. The acute administration of ethanol to rats causes a significant increase in urinary folate excretion. The mechanism for this effect is unknown and thus the effect of acute administration of ethanol on the renal absorption and urinary clearance of folate was studied in rats. Folic acid was administered to male Sprague-Dawley rats via continuous intravenous infusion in doses ranging from 3-75 micromoles/kg and renal clearance relative to inulin was determined. The effects of various dose levels of ethanol on these parameters were then determined. At a dose of 15 micromoles/kg, the renal clearance of folate relative to that of inulin was about 0.65 mg/min. At a plasma ethanol level about 100 mg/dl, the renal clearance of folate was not markedly altered. These results suggests that there is net reabsorption of folate in the rat kidney and that moderate doses of ethanol have little effect on renal effect on renal folate reabsorption.

  9. 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.

  10. A 21st Century Update on Neurotoxicity Risk Assessment

    EPA Science Inventory

    In 1998, EPA published Guidelines for Neurotoxicity Risk Assessment as the basis for interpreting neurotoxicity results. At that time, the focus was on traditional toxicity testing and human clinical /epidemiological data. More recently, a change in approach to toxicity testing ...

  11. 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...

  12. Nucleus accumbens invulnerability to methamphetamine neurotoxicity.

    PubMed

    Kuhn, Donald M; Angoa-Pérez, Mariana; Thomas, David M

    2011-01-01

    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.

  13. Death Adder Envenoming Causes Neurotoxicity Not Reversed by Antivenom - Australian Snakebite Project (ASP-16)

    PubMed Central

    Johnston, Christopher I.; O'Leary, Margaret A.; Brown, Simon G. A.; Currie, Bart J.; Halkidis, Lambros; Whitaker, Richard; Close, Benjamin; Isbister, Geoffrey K.

    2012-01-01

    Background Death adders (Acanthophis spp) are found in Australia, Papua New Guinea and parts of eastern Indonesia. This study aimed to investigate the clinical syndrome of death adder envenoming and response to antivenom treatment. Methodology/Principal Findings Definite death adder bites were recruited from the Australian Snakebite Project (ASP) as defined by expert identification or detection of death adder venom in blood. Clinical effects and laboratory results were collected prospectively, including the time course of neurotoxicity and response to treatment. Enzyme immunoassay was used to measure venom concentrations. Twenty nine patients had definite death adder bites; median age 45 yr (5–74 yr); 25 were male. Envenoming occurred in 14 patients. Two further patients had allergic reactions without envenoming, both snake handlers with previous death adder bites. Of 14 envenomed patients, 12 developed neurotoxicity characterised by ptosis (12), diplopia (9), bulbar weakness (7), intercostal muscle weakness (2) and limb weakness (2). Intubation and mechanical ventilation were required for two patients for 17 and 83 hours. The median time to onset of neurotoxicity was 4 hours (0.5–15.5 hr). One patient bitten by a northern death adder developed myotoxicity and one patient only developed systemic symptoms without neurotoxicity. No patient developed venom induced consumption coagulopathy. Antivenom was administered to 13 patients, all receiving one vial initially. The median time for resolution of neurotoxicity post-antivenom was 21 hours (5–168). The median peak venom concentration in 13 envenomed patients with blood samples was 22 ng/mL (4.4–245 ng/mL). In eight patients where post-antivenom bloods were available, no venom was detected after one vial of antivenom. Conclusions/Significance Death adder envenoming is characterised by neurotoxicity, which is mild in most cases. One vial of death adder antivenom was sufficient to bind all circulating venom. The

  14. Fingerprinting of neurotoxic compounds using a mouse embryonic stem cell dual luminescence reporter assay.

    PubMed

    Colaianna, Marilena; Ilmjärv, Sten; Peterson, Hedi; Kern, Ilse; Julien, Stephanie; Baquié, Mathurin; Pallocca, Giorgia; Bosgra, Sieto; Sachinidis, Agapios; Hengstler, Jan G; Leist, Marcel; Krause, Karl-Heinz

    2017-01-01

    Identification of neurotoxic drugs and environmental chemicals is an important challenge. However, only few tools to address this topic are available. The aim of this study was to develop a neurotoxicity/developmental neurotoxicity (DNT) test system, using the pluripotent mouse embryonic stem cell line CGR8 (ESCs). The test system uses ESCs at two differentiation stages: undifferentiated ESCs and ESC-derived neurons. Under each condition, concentration-response curves were obtained for three parameters: activity of the tubulin alpha 1 promoter (typically activated in early neurons), activity of the elongation factor 1 alpha promoter (active in all cells), and total DNA content (proportional to the number of surviving cells). We tested 37 compounds from the ESNATS test battery, which includes polypeptide hormones, environmental pollutants (including methylmercury), and clinically used drugs (including valproic acid and tyrosine kinase inhibitors). Different classes of compounds showed distinct concentration-response profiles. Plotting of the lowest observed adverse effect concentrations (LOAEL) of the neuronal promoter activity against the general promoter activity or against cytotoxicity, allowed the differentiation between neurotoxic/DNT substances and non-neurotoxic controls. Reporter activity responses in neurons were more susceptible to neurotoxic compounds than the reporter activities in ESCs from which they were derived. To relate the effective/toxic concentrations found in our study to relevant in vivo concentrations, we used a reverse pharmacokinetic modeling approach for three exemplary compounds (teriflunomide, geldanamycin, abiraterone). The dual luminescence reporter assay described in this study allows high-throughput, and should be particularly useful for the prioritization of the neurotoxic potential of a large number of compounds.

  15. 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.

  16. Mefloquine neurotoxicity is mediated by non-receptor tyrosine kinase.

    PubMed

    Milatovic, Dejan; Jenkins, Jerry W; Hood, Jonathan E; Yu, Yingchun; Rongzhu, Lu; Aschner, Michael

    2011-10-01

    Among several available antimalarial drugs, mefloquine has proven to be effective against drug-resistant Plasmodium falciparum and remains the drug of choice for both therapy and chemoprophylaxis. However, mefloquine is known to cause adverse neurological and/or psychiatric symptoms, which offset its therapeutic advantage. The exact mechanisms leading to the adverse neurological effects of mefloquine are poorly defined. Alterations in neurotransmitter release and calcium homeostasis, the inhibition of cholinesterases and the interaction with adenosine A(2A) receptors have been hypothesized to play prominent roles in mediating the deleterious effects of this drug. Our recent data have established that mefloquine can also trigger oxidative damage and subsequent neurodegeneration in rat cortical primary neurons. Furthermore, we have utilized a system biology-centered approach and have constructed a pathway model of cellular responses to mefloquine, identifying non-receptor tyrosine kinase 2 (Pyk2) as a critical target in mediating mefloquine neurotoxicity. In this study, we sought to establish an experimental validation of Pyk2 using gene-silencing techniques (siRNA). We have examined whether the downregulation of Pyk2 in primary rat cortical neurons alters mefloquine neurotoxicity by evaluating cell viability, apoptosis and oxidative stress. Results from our study have confirmed that mefloquine neurotoxicity is associated with apoptotic response and oxidative injury, and we have demonstrated that mefloquine affects primary rat cortical neurons, at least in part, via Pyk2. The implication of these findings may prove beneficial in suppressing the neurological side effects of mefloquine and developing effective therapeutic modalities to offset its adverse effects.

  17. Pramipexole prevents neurotoxicity induced by oligomers of beta-amyloid.

    PubMed

    Uberti, Daniela; Bianchi, Irene; Olivari, Luca; Ferrari-Toninelli, Giulia; Canonico, PierLuigi; Memo, Maurizio

    2007-08-27

    Here we demonstrate that pramipexole, an antiparkinsonian dopamine receptor agonist drug, exerts neuroprotective effects against beta-amyloid neurotoxicity. Using a specific protocol to test individually oligomers, fibrils, or unaggregated amyloid beta-peptide, we found pramipexole able to protect cells against oligomers and fibrils. Unaggregated amyloid beta-peptide was found unable to cause cell death. Fibrils and oligomers were also found to produce elevated amount of free radicals, and this effect was prevented by pramipexole. We propose pramipexole may become in the future a coadjuvant in the treatment of neuropathologies, besides Parkinson's disease, where amyloid beta-peptide-mediated oxidative injury exerts a relevant role.

  18. 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

  19. 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.

  20. 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.

  1. Plant terpenoids: acute toxicities and effects on flight motor activity and wing beat frequency in the blow fly Phaenicia sericata.

    PubMed

    Waliwitiya, Ranil; Belton, Peter; Nicholson, Russell A; Lowenberger, Carl A

    2012-02-01

    We evaluated the acute toxicities and the physiological effects of plant monoterpenoids (eugenol, pulegone, citronellal and alpha-terpineol) and neuroactive insecticides (malathion, dieldrin and RH3421) on flight muscle impulses (FMI) and wing beat signals (WBS) of the blow fly (Phaenicia sericata). Topically-applied eugenol, pulegone, citronellal, and alpha-terpineol produced neurotoxic symptoms, but were less toxic than malathion, dieldrin, or RH3421. Topical application of eugenol, pulegone, and citronellal reduced spike amplitude in one of the two banks of blow fly dorsolongitudinal flight muscles within 6-8 min, but with citronellal, the amplitude of FMIs reverted to a normal pattern within 1 hr. In contrast to pulegone and citronellal, where impulse frequency remained relatively constant, eugenol caused a gradual increase, then a decline in the frequency of spikes in each muscle bank. Wing beating was blocked permanently within 6-7 min of administering pulegone or citronellal and within 16 mins with eugenol. alpha-Terpineol-treated blow flies could not beat their wings despite normal FMI patterns. The actions of these monoterpenoids on blow fly flight motor patterns are discussed and compared with those of dieldrin, malathion, RH3421, and a variety of other neuroactive substances we have previously investigated in this system. Eugenol, pulegone and citronellal readily penetrate blow fly cuticle and interfere with flight muscle and/or central nervous function. Although there were differences in the effects of these compounds, they mainly depressed flight-associated responses, and acted similarly to compounds that block sodium channels and facilitate GABA action.

  2. Neurotoxicity From Chronic Exposure to Depleted Uranium

    DTIC Science & Technology

    2006-04-01

    these response magnitudes. This suggests that UO2 +2 does not possess Ca+2-mimetic properties, but it could also be explained if the...intrasynaptosomal UO2 +2 concentrations did not achieve sufficient levels during the acute exposure to manifest such an effect. The uranium species involved in the...effect on glutamate exocytosis is not known. Uranyl ion ( UO2 +2) – the most common form produced in the body from all forms of the metal – is

  3. Protective effects of endothelin-1 on acute pancreatitis in rats.

    PubMed

    Kogire, M; Inoue, K; Higashide, S; Takaori, K; Echigo, Y; Gu, Y J; Sumi, S; Uchida, K; Imamura, M

    1995-06-01

    Endothelin-1, a 21-residue peptide isolated from vascular endothelial cells, has a broad spectrum of actions. To clarify the involvement of endothelin-1 in acute pancreatitis, we examined the effects of endothelin-1 and its receptor antagonist BQ-123 on cerulein-induced pancreatitis in rats. Rats were infused intravenously with heparin-saline (control), endothelin-1 (100 pmol/kg/hr), cerulein (5 micrograms/kg/hr), or cerulein plus endothelin-1 for 3.5 hr. In another experiment, cerulein or cerulein plus BQ-123 (3 mg/kg/hr) was infused. Infusion of cerulein caused hyperamylasemia and pancreatic edema. Endothelin-1, when infused with cerulein, decreased the extent of pancreatic edema with a significant increase in the pancreatic dry- to wet-weight ratio. Histological changes induced by cerulein were markedly attenuated when endothelin-1 was given with cerulein. In contrast, endothelin-receptor blockade with BQ-123 further augmented pancreatic edema caused by cerulein. The extent of inflammatory cell infiltration was greater than BQ-123 was given with cerulein. Endothelin-1 or BQ-123 had no influence on hyperamylasemia. This study suggests that endothelin-1 has protective effects on experimental acute pancreatitis.

  4. Acute effects of a glucose energy drink on behavioral control.

    PubMed

    Howard, Meagan A; Marczinski, Cecile A

    2010-12-01

    There has been a dramatic rise in the consumption of glucose energy drinks (e.g., Amp, Monster, and Red Bull) in the past decade, particularly among high school and college students. However, little laboratory research has examined the acute objective and subjective effects of energy drinks. The purpose of this study was to investigate the acute effects of a glucose energy drink (Red Bull) on cognitive functioning. Participants (N = 80) were randomly assigned to one of five conditions: 1.8 ml/kg energy drink, 3.6 ml/kg energy drink, 5.4 ml/kg energy drink, placebo beverage, or no drink. Participants completed a well-validated behavioral control task (the cued go/no-go task) and subjective measures of stimulation, sedation, and mental fatigue both before and 30 minutes following beverage administration. The results indicated that compared with the placebo and no drink conditions, the energy drink doses decreased reaction times on the behavioral control task, increased subjective ratings of stimulation and decreased ratings of mental fatigue. Greatest improvements in reaction times and subjective measures were observed with the lowest dose and improvements diminished as the dose increased. The findings suggest that energy drink consumption can improve cognitive performance on a behavioral control task, potentially explaining the dramatic rise in popularity of these controversial new beverages.

  5. Manganese neurotoxicity: a focus on the neonate.

    PubMed

    Erikson, Keith M; Thompson, Khristy; Aschner, Judy; Aschner, Michael

    2007-02-01

    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/m(3)) 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.

  6. 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

  7. A Current Review of Cypermethrin-Induced Neurotoxicity and Nigrostriatal Dopaminergic Neurodegeneration

    PubMed Central

    Singh, Anand Kumar; Tiwari, Manindra Nath; Prakash, Om; Singh, Mahendra Pratap

    2012-01-01

    Cypermethrin, a class II pyrethroid pesticide, is used to control insects in the household and agricultural fields. Despite beneficial roles, its uncontrolled and repetitive applications lead to unintended effects in non-target organisms. Cypermethrin crosses the blood-brain barrier and induces neurotoxicity and motor deficits. Cypermethrin prolongs the opening of sodium channel, a major site of its action, leading to hyper-excitation of the central nervous system. In addition to sodium channel, cypermethrin modulates chloride, voltage-gated calcium and potassium channels, alters the activity of glutamate and acetylcholine receptors and adenosine triphosphatases and induces DNA damage and oxidative stress in the neuronal cells. Cypermethrin also modulates the level of neurotransmitters, including gamma-aminobutyric acid and dopamine. It is one of the most commonly used pesticides in neurotoxicology research not only because of its variable responses depending upon the doses, time and routes of exposure and strain, age, gender and species of animals used across multiple studies but also owing to its ability to induce the nigrostriatal dopaminergic neurodegeneration. This article describes the effect of acute, chronic, developmental and adulthood exposures to cypermethrin in experimental animals. The article sheds light on cypermethrin-induced changes in the central nervous system, including its contribution in the onset of specific features, which are associated with the nigrostriatal dopaminergic neurodegeneration. Resemblances and dissimilarities of cypermethrin-induced nigrostriatal dopaminergic neurodegeneration with sporadic and chemicals-induced disease models along with its advantages and pitfalls are also discussed. PMID:22942879

  8. Acute and neuropathic orofacial antinociceptive effect of eucalyptol.

    PubMed

    Melo Júnior, José de Maria de Albuquerque de; Damasceno, Marina de Barros Mamede Vidal; Santos, Sacha Aubrey Alves Rodrigues; Barbosa, Talita Matias; Araújo, João Ronielly Campêlo; Vieira-Neto, Antonio Eufrásio; Wong, Deysi Viviana Tenazoa; Lima-Júnior, Roberto César Pereira; Campos, Adriana Rolim

    2017-04-01

    Terpenes have a wide range of pharmacological properties, including antinociceptive action. The anti-inflammatory and antinociceptive effects of eucalyptol are well established. The purpose of this study was to evaluate the antinociceptive effect of eucalyptol on acute and neuropathic orofacial pain in rodent models. Acute orofacial and corneal nociception was induced with formalin, capsaicin, glutamate and hypertonic saline in mice. In another series, animals were pretreated with capsazepine or ruthenium red to evaluate the involvement of TRPV1 receptors in the effect of eucalyptol. In a separate experiment, perinasal tissue levels of IL-1β, TNF-α and IFN-γ were measured. Rats were pretreated with eucalyptol before induction of temporomandibular joint pain with formalin or mustard oil. In another experiment, rats were submitted to infraorbital nerve transection (IONX) to induce chronic pain, followed by induction of mechanical hypersensitivity using Von Frey hairs. Locomotor performance was evaluated with the open-field test, and molecular docking was conducted on the TRPV1 channel. Pretreatment with eucalyptol significantly reduced formalin-induced nociceptive behaviors in all mouse strains, but response was more homogenous in the Swiss strain. Eucalyptol produced antinociceptive effects in all tests. The effect was sensitive to capsazepine but not to ruthenium red. Moreover, eucalyptol significantly reduced IFN-γ levels. Matching the results of the experiment in vivo, the docking study indicated an interaction between eucalyptol and TRPV1. No locomotor activity changes were observed. Our study shows that eucalyptol may be a clinically relevant aid in the treatment of orofacial pain, possibly by acting as a TRPV1 channel antagonist.

  9. 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.

  10. Successful treatment of hydromorphone-induced neurotoxicity and hyperalgesia.

    PubMed

    Chung, Keun Sam; Carson, Shawn; Glassman, David; Vadivelu, Nalini

    2004-10-01

    There has been an increase in opioid consumption world wide in the last decade. There has also been a disturbing increase in the number of reports of neuroexcitatory opioid-related side effects observed in patients receiving large doses of systemically administered morphine and its structural analogue, hydromorphone. It is now becoming clearer that patients receiving long-term opioid therapy can develop unexpected pain. We describe an interesting case of successful management of hydromorphone-induced neurotoxicity and hyperalgesia produced by short-term therapy with rapidly escalating doses of systemic hydromorphone.

  11. 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...

  12. 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

  13. alpha7 Nicotinic acetylcholine receptor knockout selectively enhances ethanol-, but not beta-amyloid-induced neurotoxicity.

    PubMed

    de Fiebre, Nancyellen C; de Fiebre, Christopher M

    2005-01-03

    The alpha7 subtype of nicotinic acetylcholine receptor (nAChR) has been implicated as a potential site of action for two neurotoxins, ethanol and the Alzheimer's disease related peptide, beta-amyloid. Here, we utilized primary neuronal cultures of cerebral cortex from alpha7 nAChR null mutant mice to examine the role of this receptor in modulating the neurotoxic properties of subchronic, "binge" ethanol and beta-amyloid. Knockout of the alpha7 nAChR gene selectively enhanced ethanol-induced neurotoxicity in a gene dosage-related fashion. Susceptibility of cultures to beta-amyloid induced toxicity, however, was unaffected by alpha7 nAChR gene null mutation. Further, beta-amyloid did not inhibit the binding of the highly alpha7-selective radioligand, [(125)I]alpha-bungarotoxin. On the other hand, in studies in Xenopus oocytes ethanol efficaciously inhibited alpha7 nAChR function. These data suggest that alpha7 nAChRs modulate the neurotoxic effects of binge ethanol, but not the neurotoxicity produced by beta-amyloid. It is hypothesized that inhibition of alpha7 nAChRs by ethanol provides partial protection against the neurotoxic properties of subchronic ethanol.

  14. Interrelationships of undernutrition and neurotoxicity: food for thought and research attention.

    PubMed

    Spencer, Peter S; Palmer, Valerie S

    2012-06-01

    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/or mineral undernutrition are associated with a range of neurodevelopmental, neurological and psychiatric disorders, commonly with involvement of both the central and the 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 with low incomes 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, or 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 increase the risk of fetal and infant undernutrition and chemical interactions therewith.

  15. Age-related differences in pulmonary effects of acute and ...

    EPA Pesticide Factsheets

    Ozone (O3) is known to induce adverse pulmonary and systemic health effects. Importantly, children and older persons are considered at-risk populations for O3-induced dysfunction, yet the mechanisms accounting for the age-related pulmonary responses to O3 are uncertain. In this study, we examined age-related susceptibility to O3 using 1 mo (adolescent), 4 mo (young adult), 12 mo (adult) and 24 mo (senescent) male Brown Norway rats exposed to filtered air or O3 (0.25and 1.00 ppm), 6 h/day, two days/week for 1 week (acute) or 13 weeks (subchronic). Ventilatory function, assessed by whole-body plethysmography, and bronchoalveolar lavage fluid (BALF) biomarkers of injury and inflammation were used to examine O3-induced pulmonary effects.Relaxation time declined in all ages following the weekly exposures; however, this effect persisted only in the 24 mo rats following a five days recovery, demonstrating an inability to induce adaptation commonly seen with repeated O3 exposures. PenH was increased in all groups with an augmented response in the 4 mo rats following the subchronic O3 exposures. O3 led to increased breathing frequency and minute volume in the 1 and 4 mo animals. Markers ofpulmonary permeability were increased in all age groups. Elevations in BALF γ-glutamyl transferase activity and lung inflammation following an acute O3 exposure were noted in only the 1 and 4 mo rats, which likely received an increased effective O3 dose. These data demonstrate that ado

  16. Inhibitory effect of anethole in nonimmune acute inflammation.

    PubMed

    Domiciano, Talita Perdigão; Dalalio, Márcia Machado de Oliveira; Silva, Expedito Leite; Ritter, Alessandra Mileni Versuti; Estevão-Silva, Camila Fernanda; Ramos, Fernando Seara; Caparroz-Assef, Silvana Martins; Cuman, Roberto Kenji Nakamura; Bersani-Amado, Ciomar Aparecida

    2013-04-01

    Anethole [1-methoxy-4-(1-propenyl)benzene] occurs naturally as a major component of the essential oil of star anise (Illicium verum Hook.f., family Illiciaceae), comprising more than 90 % of its volatile components. Studies showed that this substance has antioxidant, antibacterial, antifungal, and anesthetic properties. In this study, the anti-inflammatory properties of anethole in animal models of nonimmune acute inflammation such as croton oil-induced ear edema and carrageenan-induced pleurisy were investigated. The investigated parameters were edema formation, leukocyte migration, and inflammatory mediators involved. Oral administration of anethole at a dose of 250 and 500 mg/kg reduced both the volume of pleural exudates and the number of migrated leukocytes. Levels of nitric oxide (NO) and prostaglandins (PGE2) in the inflammatory exudate were reduced by treatment with anethole, but levels of tumor necrosis factor-α and interleukin-1β were not significantly altered. In ear edema, the oral treatment with anethole inhibited the formation of exudate and the activity of myeloperoxidase, but not after topical administration. These results suggest that the anethole may be effective in controlling some nonimmune acute inflammation-related disease, probably by an inhibitory action on production and/or release of PGE2 and NO.

  17. Effect of dexamethasone on brain oedema following acute ischemic stroke.

    PubMed

    Shaikh, A K; Mohammad, Q D; Ullah, M A; Ahsan, M M; Rahman, A; Shakoor, M A

    2011-07-01

    A randomized clinical trial was conducted to asses the effects of dexamethasone on brain oedema following acute ischemic stroke in the departments of Medicine of different hospitals from July, 2003 to December, 2006. A total of 60 patients were included in the study. They were divided into two groups keeping the similarity regarding the age, sex and severity of the stroke between two groups. There were 30 patients in experimental group and 30 in control group. The level of consciousness was compared by Glasgow Coma Scale (GCS) on 3rd, 7th and 10th day of intervention and improvement was found in both the groups, but the improvement of level of consciousness was statistically significant in Dexamethasone treated group. The volume of hypodense area did not differ significantly in two groups in CT scans before and after treatment (p=0.74). The study results demonstrate that Dexamethasone improves the level of consciousness in acute ischemic stroke associated with brain oedema but did not reduce volume of hypodense area.

  18. Effects of clotrimazol on the acute necrotizing pancreatitis in rats.

    PubMed

    Cekic, Arif Burak; Alhan, Etem; Usta, Arif; Türkyılmaz, Serdar; Kural, Birgül Vanizor; Erçin, Cengiz

    2013-12-01

    This study aims to investigate the influence of clotrimazol (CLTZ) on acute necrotizing pancreatitis (ANP) induced by glycodeoxycholic acid in rats. Rats were divided into five groups as sham + saline, sham + CLTZ, sham + polyethylene glycol, ANP + saline, and ANP + CLTZ. ANP in rats was induced by glycodeoxycholic acid. The extent of acinar cell injury, mortality, systemic cardiorespiratory variables, functional capillary density (FCD), renal/hepatic functions, and changes in some enzyme markers for pancreatic and lung tissue were investigated during ANP in rats. The use of CLTZ after the induction of ANP resulted in a significant decrease in the mortality rate, pancreatic necrosis, and serum activity of amylase, alanine aminotransferase, interleukin-6, lactate dehydrogenase in bronchoalveolar lavage fluid, serum concentration of urea, and tissue activity of myeloperoxidase, and malondialdehyde in the pancreas and lung and a significant increase in concentrations of calcium, blood pressure, urine output, pO2, and FCD. This study showed that CLTZ demonstrated beneficial effect on the course of ANP in rats. Therefore, it may be used in the treatment of acute pancreatitis.

  19. 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

  20. Neurotoxicity induced by mephedrone: An up-to-date review.

    PubMed

    Pantano, Flaminia; Tittarelli, Roberta; Mannocchi, Giulio; Pacifici, Roberta; di Luca, Alessandro; Busardò, Francesco Paolo; Marinelli, Enrico

    2016-11-30

    Mephedrone is a β-ketoamphetamine belonging to the family of synthetic cathinones, an emerging class of designer drugs known for their hallucinogenic and psychostimulant properties as well as for their abuse potential. The aim of this review was to examine the emerging scientific literature on the possible mephedrone-induced neurotoxicity, yet not well defined due to the limited number of experimental studies, mainly carried on animal models. Relevant scientific articles were identified from international literature databases (Medline, Scopus, etc.) using the keywords: "Mephedrone", "4-MMC," "neurotoxicity," "neuropharmacology", "patents", "monoamine transporters" and "neurochemical effects". Of the 498 sources initially found, only 36 papers were suitable for the review. Neurotoxic effect of mephedrone on 5-HT and DA systems remains controversial. Although some studies in animal models reported no damage to DA nerve endings in the striatum and no significant changes in brain monoamine levels, some others suggested a rapid reduction in 5-HT and DA transporter function. Persistent serotonergic deficits were observed after binge like treatment in a warm environment and in both serotonergic and dopaminergic nerve endings at high ambient temperature. Oxidative stress cytotoxicity and an increase in frontal cortex lipid peroxidation were also reported. In vitro cytotoxic properties were also observed, suggesting that mephedrone may act as a reductant agent and can also determine changes in mitochondrial respiration. However, due to the differences in the design of the experiments, including temperature and animal model used, the results are difficult to compare. Further studies on toxicology and pharmacology of mephedrone are therefore necessary to establish an appropriate treatment for substance abuse and eventual consequences for public health.

  1. 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 dr