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Neurotoxic Effects (neurotoxic + effects)
Selected AbstractsNeurotoxic Effects of Three Fractions Isolated from Tityus serrulatus Scorpion VenomBASIC AND CLINICAL PHARMACOLOGY & TOXICOLOGY, Issue 4 2000Ana Leonor A. Nencioni Scorpion venoms contain low molecular weight basic polypeptides, neurotoxins, that are the principal toxic agents. These toxins act on ion channels, promoting a derangement that may result in an abnormal release of neurotransmitters. In the present study we investigated some of the effects of the F, H and J fractions isolated from Tityus serrulatus scorpion venom on the central nervous system of rodents. The venom was partially purified by gel filtration chromatography. The neurotoxic effect of these fractions was studied on convulsive activity after intravenous injection, and on electrographic activity and neuronal integrity of rat hippocampus when injected directly into this brain area. The results showed that intravenous injection of the F and H fractions induced convulsions, and intrahippocampal injection caused electrographic seizures in rats and neuronal damage in specific hippocampal areas. Fraction J injected intravenously reduced the general activity of mice in the open field but induced no changes when injected into the brain. These results suggest that scorpion toxins are able to act directly on the central nervous system promoting behavioural, electrographic and histological modifications. [source] Dose,time,response modeling of longitudinal measurements for neurotoxicity risk assessmentENVIRONMETRICS, Issue 6 2005Yiliang Zhu Abstract Neurotoxic effects are an important non-cancer endpoint in health risk assessment and environmental regulation. Neurotoxicity tests such as neurobehavioral screenings using a functional observational battery generate longitudinal dose,response data to profile neurological effects over time. Analyses of longitudinal neurotoxicological data have mostly relied on analysis of variance; explicit dose,time,response modeling has not been reported in the literature. As dose,response modeling has become an increasingly indispensible component in risk assessment as required by the use of benchmark doses, there are strong interests in and needs for appropriate dose,response models, effective model-fitting techniques, and computation methods for benchmark dose estimation. In this article we propose a family of dose,time,response models, illustrate statistical inference of these models in conjunction with random-effects to quantify inter-subject variation, and describe a procedure to profile benchmark dose across time. We illustrate the methods through a dataset from a US/EPA experiment involving the FOB tests on rats administered to a single dose of triethyl tin (TET). The results indicate that the existing functional observational battery data can be utilized for dose,response and benchmark dose analyses and the methods can be applied in general settings of neurotoxicity risk assessment. Copyright © 2005 John Wiley & Sons, Ltd. [source] Iron localization in superficial siderosis of the central nervous systemNEUROPATHOLOGY, Issue 2 2009Harry Kellermier Originally conceived as an uncommon disorder, with the advent of MRI, CNS superficial siderosis has been observed more frequently. We present histologic, histochemical, immunohistochemical, immunofluorescent and ultrastructural evaluation of a 56-year-old woman with superficial siderosis. Iron was concentrated in macrophages, superficial astrocytes and gray matter oligodendroglia deep within the cord. While spatially associated with dystrophic glial and neuronal spheroids, iron did not colocalize with mitochondria. Neurotoxic effects were observed despite selective iron localization only within a variety of non-neuronal cell types. [source] Neurotoxic effects of venoms from seven species of australasian black snakes (Pseudechis): Efficacy of black and tiger snake antivenomsCLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, Issue 1-2 2005Sharmaine Ramasamy SUMMARY 1.,Pseudechis species (black snakes) are among the most widespread venomous snakes in Australia. Despite this, very little is known about the potency of their venoms or the efficacy of the antivenoms used to treat systemic envenomation by these snakes. The present study investigated the in vitro neurotoxicity of venoms from seven Australasian Pseudechis species and determined the efficacy of black and tiger snake antivenoms against this activity. 2.,All venoms (10 µg/mL) significantly inhibited indirect twitches of the chick biventer cervicis nerve,muscle preparation and responses to exogenous acetylcholine (ACh; 1 mmol/L), but not to KCl (40 mmol/L), indicating activity at post-synaptic nicotinic receptors on the skeletal muscle. 3.,Prior administration of either black or tiger snake antivenom (5 U/mL) prevented the inhibitory effects of all Pseudechis venoms. 4.,Black snake antivenom (5 U/mL) added at t90 (i.e. the time-point at which the original twitch height was reduced by 90%) significantly reversed the effects of P. butleri (28 ± 5%), P. guttatus (25 ± 8%) and P. porphyriacus (28 ± 10%) venoms. Tiger snake antivenom (5 U/mL) added at the t90 time-point significantly reversed the neurotoxic effects of P. guttatus (51 ± 4%), P. papuanus (47 ± 5%) and P. porphyriacus (20 ± 7%) venoms. 5.,We show, for the first time, the presence of neurotoxins in the venom of these related snake species and that this activity is differentially affected by either black snake or tiger snake antivenoms. [source] Dissolved copper triggers cell death in the peripheral mechanosensory system of larval fishENVIRONMENTAL TOXICOLOGY & CHEMISTRY, Issue 2 2006Tiffany L. Linbo Abstract Dissolved copper is an increasingly common non,point source contaminant in urban and urbanizing watersheds. In the present study, we investigated the sublethal effects of dissolved copper on the peripheral mechanosensory system, or lateral line, of larval zebrafish (Danio rerio). Zebrafish larvae were exposed to copper (0,65 ,g/L), and the cytotoxic responses of individual lateral line receptor neurons were examined using a combination of in vivo fluorescence imaging, confocal microscopy, scanning electron microscopy, and conventional histology. Dissolved copper triggered a dose-dependent loss of neurons in identified lateral line neuromasts at concentrations ,20 ,g/L. The onset of cell death in the larval mechanosensory system was rapid (<1 h). When copper-exposed zebrafish were transferred to clean water, the lateral line regenerated over the course of 2 d. In contrast, the lateral line of larvae exposed continuously to dissolved copper (50 ,g/L) for 3 d did not recover. Collectively, these results show that peripheral mechanosensory neurons are vulnerable to the neurotoxic effects of copper. Consequently, dissolved copper in non-point source storm-water runoff has the potential to interfere with rheotaxis, schooling, predator avoidance, and other mechanosensory-mediated behaviors that are important for the migration and survival of fish. [source] Neurotoxicity of methylenedioxyamphetamines (MDMA; ecstasy) in humans: how strong is the evidence for persistent brain damage?ADDICTION, Issue 3 2006E. Gouzoulis-Mayfrank ABSTRACT Background The popular dance drug ecstasy (3,4-methylenedioxymethamphetamine: MDMA and some analogues) causes selective and persistent neurotoxic damage of central serotonergic neurones in laboratory animals. Serotonin plays a role in numerous functional systems in the central nervous system (CNS). Consequently, various abnormalities including psychiatric, vegetative, neuroendocrine and cognitive disorders could be expected in humans following MDMA-induced neurotoxic brain damage. Aims In recent years, the question of ecstasy-induced neurotoxicity and possible functional sequelae has been addressed in several studies with drug users. The aim of this paper was to review this literature and weigh the strength of the evidence for persistent brain damage in ecstasy users. Methods We used Medline to view all available publications on ,ecstasy' or ,MDMA'. All available studies dealing with ecstasy users entered this analysis. Findings and conclusions Despite large methodological problems the bulk of evidence suggests residual alterations of serotonergic transmission in MDMA users, although at least partial restitution may occur after long-term abstinence. However, functional sequelae may persist even after longer periods of abstinence. To date, the most consistent findings associate subtle cognitive, particularly memory, impairments with heavy ecstasy use. However, the evidence cannot be considered definite and the issues of possible pre-existing traits or the effects of polydrug use are not resolved. Recommendations Questions about the neurotoxic effects of ecstasy on the brain remain highly topical in light of its popularity among young people. More longitudinal and prospective studies are clearly needed in order to obtain a better understanding of the possible long-term sequelae of ecstasy use in humans. [source] Role of the pro-inflammatory cytokines TNF-, and IL-1, in HIV-associated dementiaEUROPEAN JOURNAL OF CLINICAL INVESTIGATION, Issue 7 2006N. A. C. H. Brabers Abstract Human immunodeficiency virus-1 (HIV-1)-infected and immune-activated macrophages and microglia secrete neurotoxins. Two of these neurotoxins are the pro-inflammatory cytokines tumour necrosis factor-, (TNF-,) and interleukin-1, (IL-1,), which are thought to play a major role in inducing neuronal death. Both TNF-, and IL-1, increase the permeability of the blood,brain barrier, through which subsequently HIV-infected monocytes can enter the brain. They both induce over-stimulation of the NMDA-receptor via several pathways, resulting in a lethal neuronal increase in Ca2+ levels. Additionally, TNF-, co-operates with several other proinflammatory mediators to enhance their toxic effects. Although most research has focused on the neurotoxic effects of TNF-, and IL-1, in HAD, there is also evidence that these cytokines can be neuroprotective. In this paper the effect of TNF-, and IL-1, on neuronal life and death in HAD is discussed. [source] PRECLINICAL STUDY: Ecstasy-induced oxidative stress to adolescent rat brain mitochondria in vivo: influence of monoamine oxidase type AADDICTION BIOLOGY, Issue 2 2009Ema Alves ABSTRACT The administration of a neurotoxic dose of 3,4-methylenedioxymethamphetamine (MDMA; ,ecstasy') to the rat results in mitochondrial oxidative damage in the central nervous system, namely lipid and protein oxidation and mitochondrial DNA deletions with subsequent impairment of the correspondent protein expression. Although these toxic effects were shown to be prevented by monoamine oxidase B inhibition, the role of monoamine oxidase A (MAO-A) in MDMA-mediated mitochondrial damage remains to be evaluated. Thus, the aim of the present study was to clarify the potential interference of a specific inhibition of MAO-A by clorgyline, on the deleterious effects produced by a binge administration of a neurotoxic dose of MDMA (10 mg MDMA/kg of body weight, intraperitoneally, every 2 hours in a total of four administrations) to an adolescent rat model. The parameters evaluated were mitochondrial lipid peroxidation, protein carbonylation and expression of the respiratory chain protein subunits II of reduced nicotinamide adenine dinucleotide dehydrogenase (NDII) and I of cytochrome oxidase (COXI). Considering that hyperthermia has been shown to contribute to the neurotoxic effects of MDMA, another objective of the present study was to evaluate the body temperature changes mediated by MDMA with a MAO-A selective inhibition by clorgyline. The obtained results demonstrated that the administration of a neurotoxic binge dose of MDMA to an adolescent rat model previously treated with the specific MAO-A inhibitor, clorgyline, resulted in synergistic effects on serotonin- (5-HT) mediated behaviour and body temperature, provoking high mortality. Inhibition of MAO-A by clorgyline administration had no protective effect on MDMA-induced alterations on brain mitochondria (increased lipid peroxidation, protein carbonylation and decrease in the expression of the respiratory chain subunits NDII and COXI), although it aggravated MDMA-induced decrease in the expression of COXI. These results reinforce the notion that the concomitant use of MAO-A inhibitors and MDMA is counter indicated because of the resulting severe synergic toxicity. [source] Role of the GLT-1 subtype of glutamate transporter in glutamate homeostasis: the GLT-1-preferring inhibitor WAY-855 produces marginal neurotoxicity in the rat hippocampusEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 12 2005Julie V. Selkirk Abstract Glutamate is the major excitatory neurotransmitter in the central nervous system and is tightly regulated by cell surface transporters to avoid increases in concentration and associated neurotoxicity. Selective blockers of glutamate transporter subtypes are sparse and so knock-out animals and antisense techniques have been used to study their specific roles. Here we used WAY-855, a GLT-1-preferring blocker, to assess the role of GLT-1 in rat hippocampus. GLT-1 was the most abundant transporter in the hippocampus at the mRNA level. According to [3H]- l -glutamate uptake data, GLT-1 was responsible for approximately 80% of the GLAST-, GLT-1-, and EAAC1-mediated uptake that occurs within dissociated hippocampal tissue, yet when this transporter was preferentially blocked for 120 h with WAY-855 (100 µm), no significant neurotoxicity was observed in hippocampal slices. This is in stark contrast to results obtained with TBOA, a broad-spectrum transport blocker, which, at concentrations that caused a similar inhibition of glutamate uptake (10 and 30 µm), caused substantial neuronal death when exposed to the slices for 24 h or longer. Likewise, WAY-855, did not significantly exacerbate neurotoxicity associated with simulated ischemia, whereas TBOA did. Finally, intrahippocampal microinjection of WAY-855 (200 and 300 nmol) in vivo resulted in marginal damage compared with TBOA (20 and 200 nmol), which killed the majority of both CA1,4 pyramidal cells and dentate gyrus granule cells. These results indicate that selective inhibition of GLT-1 is insufficient to provoke glutamate build-up, leading to NMDA receptor-mediated neurotoxic effects, and suggest a prominent role of GLAST and/or EAAC1 in extracellular glutamate maintenance. [source] Antisense oligodeoxynucleotide-induced suppression of basal forebrain NMDA-NR1 subunits selectively impairs visual attentional performance in ratsEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 1 2001Janita Turchi Abstract It is generally agreed that basal forebrain neuronal circuits contribute to the mediation of the ability to detect, select and discriminate signals, to suppress the processing of irrelevant information, and to allocate processing resources to competing tasks. Rats were trained in a task designed to assess sustained attention, or in a cued discrimination task that did not tax attentional processes. Animals were equipped with guide cannula to infuse bilaterally antisense oligodeoxynucleotides (ODNs) against the N -methyl- d -aspartate (NMDA) NR1 subunits, or missense ODNs, into the substantia innominata of the basal forebrain. Infusions of antisense or missense ODNs did not affect cued visual discrimination performance. Infusions of antisense ODNs dose-dependently impaired sustained attention performance by selectively decreasing the animals' ability to detect signals while their ability to reject nonsignal trials remained unchanged. The detrimental attentional effects of antisense infusions were maximal 24 h after the third and final infusion, and performance returned to baseline 24 h later. Missense infusions did not affect attentional performance. Separate experiments demonstrated extensive suppression of NR1 subunit immunoreactivity in the substantia innominata. Furthermore, infusions of antisense did not produce neurotoxic effects in that region as demonstrated by the Fluoro-Jade method. The present data support the hypothesis that NMDA receptor (NMDAR) stimulation in the basal forebrain, largely via glutamatergic inputs originating in the prefrontal cortex, represents a necessary mechanism to activate the basal forebrain corticopetal system for mediation of attentional performance. [source] Comprehensive studies of cognitive impairment of the elderly with type 2 diabetesGERIATRICS & GERONTOLOGY INTERNATIONAL, Issue 3 2006Takashi Sakurai Type 2 diabetes mellitus is associated with cognitive dysfunction and increases the risk of dementia for the elderly. The aim of the study presented here was to provide a brief review of how disturbance of glucose and metabolic homeostasis may be implicated in the cognitive decline of patients with type 2 diabetes. Several risk factors such as nutrition, cerebrovascular disorders and the neurotoxic effects of hyperglycemia may combine for the formation of mechanisms of cognitive decline in the diabetic elderly. It should be noted that cognitive deficits of diabetes are accompanied by neuroradiological changes in the brain, so that cognitive dysfunction both with and without brain structural changes may overlap during cognitive decline of the diabetic elderly. Recently, we conducted two studies to explore, by means of brain imaging, hierarchical relationships among clinical profiles of diabetes, cognitive function, white matter hyperintensity and brain atrophy. The results suggested that subcortical brain atrophy and hyperintensity constitute predictors of the rate of progression of cognitive dysfunction in the diabetic elderly, while cortical atrophy is associated with high diastolic blood pressure and lower HbA1c. These hypotheses may explain in part the underlying mechanisms of cognitive impairment in the diabetic elderly. Prospective intervention studies are needed, however, to clarify the mechanism of cognitive dysfunction of the diabetic elderly and what the targets are for preventive measures. [source] Trisialoganglioside GT1b induces in vivo degeneration of nigral dopaminergic neurons: Role of microgliaGLIA, Issue 1 2002Jae K. Ryu Abstract We recently showed that trisialoganglioside (GT1b) induces cell death of dopaminergic neurons in rat mesencephalic cultures (Chung et al., Neuroreport 12:611,614, 2001). The present study examines the in vivo neurotoxic effects of GT1b on dopaminergic neurons in the substantia nigra (SN) of Sprague-Dawley rats. Seven days after GT1b injection into the SN, immunocytochemical staining of SN tissue revealed death of nigral neurons, including dopaminergic neurons. Additional immunostaining using OX-42 and OX-6 antibodies showed that GT1b-activated microglia were present in the SN where degeneration of nigral neurons was found. Western blot analysis and double-labeled immunohistochemistry showed that inducible nitric oxide synthase (iNOS) was expressed in the SN, where its levels were maximal at 8 h post-GT1b injection, and that iNOS was localized exclusively within microglia. GT1b-induced loss of dopaminergic neurons in the SN was partially inhibited by NG -nitro-L-arginine methyl ester hydrochloride, an NOS inhibitor. Our results indicate that in vivo neurotoxicity of GT1b against nigral dopaminergic neurons is at least in part mediated by nitric oxide released from activated microglia. Because GT1b exists abundantly in central nervous system neuronal membranes, our data support the hypothesis that immune-mediated events triggered by endogenous compounds such as GT1b could contribute to the initiation and/or the progression of dopaminergic neuronal cell death that occurs in Parkinson's disease. GLIA 38:15,23, 2002. © 2002 Wiley-Liss, Inc. [source] Investigating the potential neurotoxicity of Ecstasy (MDMA): an imaging approachHUMAN PSYCHOPHARMACOLOGY: CLINICAL AND EXPERIMENTAL, Issue 8 2001Liesbeth Reneman Abstract Human users of 3,4-methylenedioxymethamphetamine (MDMA, ,Ecstasy') users may be at risk of developing MDMA-induced neuronal injury. Previously, no methods were available for directly evaluating the neurotoxic effects of MDMA in the living human brain. However, development of in vivo neuroimaging tools has begun to provide insights into the effects of MDMA in the human brain. In this review, contributions of brain imaging studies on the potential neurotoxic effects of MDMA and functional consequences are highlighted. An overview is given of PET, SPECT and MR spectroscopy studies, most of which show evidence of neuronal injury in MDMA users. Different neuroimaging tools are discussed that have investigated potential functional consequences of MDMA-induced 5-HT neurotoxic lesions. Finally, the contribution of brain imaging in future studies is discussed, emphasising the crucial role it will play in our understanding of MDMA's short- and long-term effects in the human brain. Copyright © 2001 John Wiley & Sons, Ltd. [source] Inhibition of A, aggregation and neurotoxicity by the 39-kDa receptor-associated proteinJOURNAL OF NEUROCHEMISTRY, Issue 5 2010Megan L. Kerr J. Neurochem. (2010) 112, 1199,1209. Abstract Aggregation of ,-amyloid protein (A,) to form oligomers is considered to be a key step in generating neurotoxicity in the Alzheimer's disease brain. Agents that bind to A, and inhibit oligomerization have been proposed as Alzheimer's disease therapeutics. In this study, we investigated the binding of fluorescein-labeled A,1,42 (FluoA,1,42) to SH-SY5Y neuroblastoma cells and examined the effect of the 39-kDa receptor-associated protein (RAP), on the A, cell interaction. FluoA,1,42 bound to the cells in a punctate pattern. Surprisingly, when RAP was added to the incubations, FluoA,1,42 and RAP were found to be co-localized on the cell surface, suggesting that RAP and A, may bind to each other. Experiments using the purified proteins confirmed that a RAP,A, complex was stable and resistant to sodium dodecyl sulfate. RAP also inhibited A, oligomerization. We next examined whether RAP could inhibit the neurotoxic effects of A,. Addition of A,1,42 to SH-SY5Y cells caused an increase in intracellular Ca2+ that was inhibited by treatment of the A, peptide with RAP. RAP also blocked an A,-induced inhibition of long-term memory consolidation in 1-day-old chicks. This study demonstrates that RAP binds to A, and is an inhibitor of the neurotoxic effects of A,. [source] Protection from MPTP-induced neurotoxicity in differentiating mouse N2a neuroblastoma cellsJOURNAL OF NEUROCHEMISTRY, Issue 3 2001Luigi A. De Girolamo 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 µm) 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 µm) 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 osidase (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. [source] Astroglia growth retardation and increased microglia proliferation by lithium and ornithine decarboxylase inhibitor in rat cerebellar cultures: Cytotoxicity by combined lithium and polyamine inhibition,JOURNAL OF NEUROSCIENCE RESEARCH, Issue 3 2007Gad M. Gilad Abstract Lithium, the most prevalent treatment for manic-depressive illness, might have a neuroprotective effect after brain injury. In culture, lithium can exert neurotoxic effects associated with reduction in polyamine synthesis but neuroprotective effects as cultured neurons mature. Cumulative evidence suggests that lithium may exert some of its effects on neurons indirectly, by initially acting on glial cells. We used rat cerebellar cultures to ascertain the effects of lithium on ornithine decarboxylase (ODC) activity, the enzyme catalyzing the first step in polyamine synthesis, and to compare effects of lithium with those of the ODC inhibitor ,-difluoromethylornithine (DFMO) on neuron survival and glial growth. Switching cultures from high (25 mM) to low (5 mM) KCl concentrations served as the traumatic neuronal insult. The results indicate the following. 1) Whereas high depolarizing KCl concentration enhances neuron survival, it inhibits astroglial growth. 2) Lithium (LiCl; 1,5 mM) enhances neuronal survival but inhibits astroglial growth. 3) Lithium treatment leads to reduced ODC activity. 4) DFMO enhances neuron survival but inhibits astroglial growth. 5) Lithium and DFMO lead to transformation of astroglia from epithelioid (flat) to process-bearing morphology and to increased numbers of microglia. 6) Combined lithium plus DFMO treatment is cytolethal to both neurons and glia in culture. In conclusion, lithium treatment results in growth retardation and altered cell morphology of cultured astroglia and increased microglia proliferation, and these effects may be associated with inhibition of polyamine synthesis. This implies that direct effects on astrocytes and microglia may contribute to the effects of lithium on neurons. © 2006 Wiley-Liss, Inc. [source] Preconditioning with thrombin can be protective or worsen damage after endothelin-1-induced focal ischemia in ratsJOURNAL OF NEUROSCIENCE RESEARCH, Issue 3 2006Petra Henrich-Noack Abstract The serine protease thrombin has shown direct neuroprotective and neurotoxic effects on brain tissue in cerebral ischemia. Previous data suggested that thrombin-induced protection in vivo can be achieved by preconditioning rather than by acute treatment. In the current work, we used a model of mild ischemia to investigate the effects of preischemic intracerebral thrombin injection on neural damage. By intracerebral injection of endothelin-1 in freely moving animals, we achieved middle cerebral artery occlusion (MCAO), and 7 days postischemia we performed histological quantification of the infarct areas. Thrombin was injected as a preconditioning stimulus intracerebrally 7 days or 2 and 3 days before ischemia. For acute treatment, thrombin was injected 20 min before MCAO. Thrombin induced significant neuroprotection when given 7 days before endothelin-1-induced MCAO but was deleterious when given 2 and 3 days before the insult. The deleterious effect was not seen when thrombin was given acutely before ischemia. Our data demonstrate that preconditioning with thrombin can protect against damage or worsen ischemic damage. Its effect depended on the time interval between thrombin injection and insult. A low dose of thrombin did not induce a major deleterious effect in the acute phase of the infarct development after mild transient ischemia. © 2006 Wiley-Liss, Inc. [source] ,-glutamylcysteine ethyl ester-induced up-regulation of glutathione protects neurons against A,(1,42)-mediated oxidative stress and neurotoxicity: Implications for Alzheimer's diseaseJOURNAL OF NEUROSCIENCE RESEARCH, Issue 5 2005Debra Boyd-Kimball Abstract Glutathione (GSH) is an important endogenous antioxidant found in millimolar concentrations in the brain. GSH levels have been shown to decrease with aging. Alzheimer's disease (AD) is a neurodegenerative disorder associated with aging and oxidative stress. A,(1,42) has been shown to induce oxidative stress and has been proposed to play a central role in the oxidative damage detected in AD brain. It has been shown that administration of ,-glutamylcysteine ethyl ester (GCEE) increases cellular levels of GSH, circumventing the regulation of GSH biosynthesis by providing the limiting substrate. In this study, we evaluated the protective role of up-regulation of GSH by GCEE against the oxidative and neurotoxic effects of A,(1,42) in primary neuronal culture. Addition of GCEE to neurons led to an elevated mean cellular GSH level compared with untreated control. Inhibition of ,-glutamylcysteine synthetase by buthionine sulfoximine (BSO) led to a 98% decrease in total cellular GSH compared with control, which was returned to control levels by addition of GCEE. Taken together, these results suggest that GCEE up-regulates cellular GSH levels which, in turn, protects neurons against protein oxidation, loss of mitochondrial function, and DNA fragmentation induced by A,(1,42). These results are consistent with the notion that up-regulation of GSH by GCEE may play a viable protective role in the oxidative and neurotoxicity induced by A,(1,42) in AD brain. © 2005 Wiley-Liss, Inc. [source] Histamine-3 receptor antagonists reduce superoxide anion generation and lipid peroxidation in rat brain homogenatesJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 6 2005H. E. Badenhorst Using a cyanide model to induce neurotoxic effects in rat brain homogenates, we examined the neuroprotective properties of three H3 antagonists, namely clobenpropit, thioperamide and impentamine, and compared them to aspirin, a known neuroprotective agent. Superoxide anion levels and malondialdehyde concentration were assessed using the nitroblue tetrazolium and lipid peroxidation assays. Clobenpropit and thioperamide significantly reduced superoxide anion generation and lipid peroxidation. Impentamine reduced lipid peroxidation at all concentrations used, but only reduced superoxide anion generation at a concentration of 1 mM. In the lipid peroxidation assay, all the drugs compared favourably to aspirin. This study demonstrates the potential of these agents to be neuroprotective by exerting antioxidant effects. [source] Loud noise enhances nigrostriatal dopamine toxicity induced by MDMA in miceMICROSCOPY RESEARCH AND TECHNIQUE, Issue 4 2004Marco Gesi Abstract The neurotoxicity of 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) has been intensely investigated due to the widespread abuse of this drug and its neurotoxic effects. In mice, MDMA neurotoxicity has been demonstrated for striatal dopamine (DA) terminals. However, the current literature has reported great variability in the effects induced by MDMA; this is partially due to changes in environmental conditions. For instance, elevated temperature and a crowded noisy environment markedly increase the neurotoxic effects induced by MDMA. The environmental factor loud noise is often present during ecstasy intake; however, only a few studies have analysed the consequence of a concomitant exposure to loud noise and ecstasy intake. In the present experimental work, we investigated whether nigrostriatal DA toxicity occurring after MDMA administration was potentiated in the presence of loud noise (100 dBA). We administered MDMA to C57/Black mice using a "binging" pattern for two durations of white noise exposure. We found a marked enhancement of MDMA toxicity (7.5 mg/Kg ×4, 2 hours apart, i.p.) in the presence of white noise exposure lasting for at least 6 hours. The striatal damage was assessed by assaying DA levels as well as the loss of tyrosine hydroxylase (TH) and the increase in striatal glial fibrillary acidic protein (GFAP) immunohistochemistry. Since loud noise often accompanies ecstasy intake, the present findings call for more in-depth studies aimed at disclosing the fine mechanisms underlying this enhancement. Microsc. Res. Tech. 64:297,303, 2004. © 2004 Wiley-Liss, Inc. [source] High dose levodopa therapy is not toxic in multiple system atrophy: Experimental evidenceMOVEMENT DISORDERS, Issue 7 2007Nadia Stefanova MD Abstract Levodopa is generally regarded the first choice therapy for parkinsonism associated with multiple system atrophy (MSA-P). However, MSA-P patients often show a poor or unsustained levodopa response which inflicts high dose therapy. This is generally attributed to progressive striatal degeneration with loss of dopamine receptors. Experimental evidence suggests that dopaminergic stimulation may accelerate the striatal disease process in MSA, possibly by pro-oxidative mechanisms. Intact nigrostriatal dopamine release augments striatal lesion size in the unilateral nigral and striatal double lesion rat model of MSA-P. Further, neuronal vulnerability to exogenous oxidative stress is increased in a transgenic MSA mouse model with oligodendroglial ,-synuclein inclusions. The aim of the present study was to analyze whether high dose levodopa delivery in the transgenic MSA model is associated with neurotoxicity exacerbated by the presence of oligodendroglial ,-synuclein inclusion pathology. Control and transgenic MSA mice underwent pulsatile treatment with either vehicle, low or high dose levodopa for a period of 1 month. Behavioral and neuropathological indices failed to show evidence for neurotoxic effects of high-dose levodopa in this ,-synuclein transgenic MSA model. These findings support the idea that high dose levodopa therapy in MSA is not detrimental to the underlying neuropathological process. © 2007 Movement Disorder Society [source] Neurotoxic effect of occupational exposure to mixed organic solvents in Korea: Posturographic studyAMERICAN JOURNAL OF INDUSTRIAL MEDICINE, Issue 5 2009Jae-Beom Park MD Abstract Background This study used static posturography to investigate the neurotoxic effects on workers exposed to mixed organic solvents at low concentrations under the levels of the threshold limit values (TLV). Methods Forty-one workers from four plants exposed to mixed solvents and 90 non-exposed referents were examined. The lifetime cumulative biological exposure (CE) was estimated according to subject's occupational history and biological monitoring results. Static posturography and questionnaire were the basis of data collection. Results The mean exposure index of mixed organic solvents of four plants was 0.47 (SD: 0.33, range: 0.08,1.39). The exposed group showed a larger sway area and length under the eye open condition than did the non-exposed group. In a multiple linear regression, a significant positive association was demonstrated between postural sway area and CE. Conclusions This study results suggest that the exposure to organic solvents under TLV levels may cause disturbance in postural stability. Am. J. Ind. Med. 52:429,437, 2009. © 2009 Wiley-Liss, Inc. [source] Electrospray ionisation with selected reaction monitoring for the determination of Mn-citrate, Fe-citrate, Cu-citrate and Zn-citrateRAPID COMMUNICATIONS IN MASS SPECTROMETRY, Issue 15 2009Volker Nischwitz Citrate complexes of Mn and Fe, and potentially those of Cu and Zn, are considered as important low molecular mass species in human serum and cerebrospinal fluid (CSF). For example, Mn is supposed to enter the brain under excess exposure as Mn-citrate leading to neurotoxic effects. Mn-citrate has been characterised in human CSF using chromatography and electrophoresis online with inductively coupled plasma mass spectrometry, but not yet with molecular mass spectrometry. Therefore, this study explores the potential of electrospray ionisation (ESI) with selected reaction monitoring (SRM) for the detection of metal-citrate complexes, in particular Mn-citrate. The collision-induced dissociation of precursor ions with various metal:citrate stoichiometries was studied for Mn-citrate, Fe-citrate, Cu-citrate and Zn-citrate. High selectivity was achieved for Mn(II)-citrate even in respect to Fe(III)-citrate which forms isobaric precursor ions. The limit of detection for Mn-citrate was estimated to be around 250,µg,L,1 (referring to the total Mn content in the standard) using flow injection. The sensitivity was sufficient for the determination of Mn-citrate in standard solutions and in an extract of an Mn-citrate-containing supplement. An improved ESI source design is expected to reduce the limits of detection significantly. The developed ESI-SRM method has the potential to provide complementary data for the quality control of current separation methods for metal citrates using element-selective detection, with application to biomedical samples and further matrices. Copyright © 2009 John Wiley & Sons, Ltd. [source] Effect of Maternal Lead Exposure on Craniofacial Ossification in Rat Fetuses and the Role of Antioxidant TherapyANATOMIA, HISTOLOGIA, EMBRYOLOGIA, Issue 5 2009H. A. Saleh Summary Lead exposure during intrauterine life was found to result in reduced birth weight, impaired skeletal development and post-natal neurotoxic effects. In this study, the effect of pre-natal exposure to different doses of lead on the development of craniofacial skeleton in rat fetuses was investigated. Vitamin E was tested as a concomitant treatment, aiming to improve the fetotoxic effects of lead. Positively pregnant female rats were randomly divided into four groups; groups I and II (L250 and L500), exposed to lead acetate in doses of 250 and 500 mg/l respectively, group III (L500 + E), exposed to lead acetate (500 mg/l) wit concomitant vitamin E and group IV (Control) which was given sodium acetate only. All the treatments started from the first day of gestation till the 20th day, where all rats were sacrificed and the fetuses were recovered. Fetuses were processed to alizarin red staining for ossified components. Twenty-seven bones of the craniofacial skeleton were studied in each fetus where the ossification was scored as being complete, delayed or absent. In all studied fetuses from all groups, changes were found only in eight bones while the remaining craniofacial bones were normally ossified. In affected bones there was a significant decrease in the number of completely ossified bones; associated with a significant increase of both partially ossified and absent bones in L250 and L500 treated groups when compared to the control group. These differences were more significant in the L500 treated group. Giving vitamin E improved the percentage of completely ossified craniofacial bones and decreased the percentage of both partially ossified and absent bones. The most affected bone was presphenoid, then to a lesser extent supraoccipital, squamosal, parietal, interparietal and frontal bone respectively. In conclusion, lead exposure to rats during pregnancy led to varying degrees of fetal growth retardation as well as delayed ossification of some craniofacial bones which were dose dependent and the concomitant supplementation with vitamin E greatly improved the deleterious effect of lead. [source] Impaired Energy Metabolism after Co-Exposure to Leadand EthanolBASIC AND CLINICAL PHARMACOLOGY & TOXICOLOGY, Issue 6 2005Suresh Kumar Verma One such factor, ethanol, might affect the neurotoxicity of lead by regulating its absorption and distribution. However, there is little information regarding the possible biochemical mechanism by which ethanol might be affecting the state of neuronal functions in lead-exposed individuals. Therefore, the present investigation involved the effect of alcohol (3 g/kg body weight, intragastrically, for 8 weeks) on lead-induced (50 mg/kg body weight, intragastrically, for 8 weeks) mitochondrial dysfunction in adult rat brain. Ethanol was found to enhance the toxic effects of lead in terms of decreased cellular energy reserves (ATP levels). Co-exposure to lead and ethanol caused marked decline in the rate of mitochondrial respiration as compared to lead alone. Further the activies of various components of the electron transport chain, viz. NADH dehydrogenase, succinate dehydrogenase and cytochrome oxidase depicted a significant decrease in the lead and ethanol co-exposed rats as compared to the lead-treated group. The results of the present study reflect that ethanol makes adult rat brain more vulnerable to the neurotoxic effects of lead in terms of altered mitochondrial energy metabolism. [source] Neurocognitive function in patients with small cell lung cancer,CANCER, Issue 3 2008Effect of prophylactic cranial irradiation Abstract BACKGROUND. The use of prophylactic cranial irradiation (PCI) in patients with small cell lung cancer (SCLC) has been tempered by fears of detrimental effects on cognitive function. Neuropsychologic testing was prospectively conducted before and after PCI to evaluate its effects on cognitive function in patients with SCLC. METHODS. Ninety-six patients who completely or partially responded to initial therapy underwent formal neurocognitive testing before PCI. Three patients who had central nervous system metastasis were excluded. Of the remaining patients, 69 received PCI (mean dose, 25 grays [Gy] in 10 fractions). Repeat testing was performed on 37 patients (median follow-up, 23 months; range, 6,120 months). RESULTS. Baseline impairment was defined as ,1.5 standard deviations below the normative mean. Before undergoing PCI, 47% of patients had evidence of impaired cognitive function. After PCI, univariate analysis revealed significant transient declines in executive function (pre-PCI mean, 15.6 ± 11.5; post-PCI, 27.1 ± 17.6 [P = .008]) and language (pre-PCI mean, 33.8 ± 9.9; post-PCI, 31.0 ± 9.0 [P = .049]) at early timepoints. Controlling for noncentral nervous system disease progression the deficit in executive function was no longer significant. Moreover, these deficits were not sustained, and significant improvements in language and motor coordination were recorded. On multivariate analysis, no significant differences before and after PCI were found. CONCLUSIONS. Neurocognitive testing demonstrated that a substantial portion of patients with SCLC had impaired brain functioning at baseline. Persistent declines in cognitive function were not observed after cranial irradiation. These data do not favor the omission of PCI on the basis of fears of neurotoxic effects. Cancer 2008. © 2007 American Cancer Society. [source] Neurotoxic effects of venoms from seven species of australasian black snakes (Pseudechis): Efficacy of black and tiger snake antivenomsCLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, Issue 1-2 2005Sharmaine Ramasamy SUMMARY 1.,Pseudechis species (black snakes) are among the most widespread venomous snakes in Australia. Despite this, very little is known about the potency of their venoms or the efficacy of the antivenoms used to treat systemic envenomation by these snakes. The present study investigated the in vitro neurotoxicity of venoms from seven Australasian Pseudechis species and determined the efficacy of black and tiger snake antivenoms against this activity. 2.,All venoms (10 µg/mL) significantly inhibited indirect twitches of the chick biventer cervicis nerve,muscle preparation and responses to exogenous acetylcholine (ACh; 1 mmol/L), but not to KCl (40 mmol/L), indicating activity at post-synaptic nicotinic receptors on the skeletal muscle. 3.,Prior administration of either black or tiger snake antivenom (5 U/mL) prevented the inhibitory effects of all Pseudechis venoms. 4.,Black snake antivenom (5 U/mL) added at t90 (i.e. the time-point at which the original twitch height was reduced by 90%) significantly reversed the effects of P. butleri (28 ± 5%), P. guttatus (25 ± 8%) and P. porphyriacus (28 ± 10%) venoms. Tiger snake antivenom (5 U/mL) added at the t90 time-point significantly reversed the neurotoxic effects of P. guttatus (51 ± 4%), P. papuanus (47 ± 5%) and P. porphyriacus (20 ± 7%) venoms. 5.,We show, for the first time, the presence of neurotoxins in the venom of these related snake species and that this activity is differentially affected by either black snake or tiger snake antivenoms. [source] Comparison of the in vitro neuromuscular activity of venom from three australian snakes (Hoplocephalus stephensi, Austrelaps superbus and Notechis scutatus): Efficacy of tiger snake antivenomCLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, Issue 3 2003Wayne C Hodgson Summary 1.,Tiger snake antivenom, raised against Notechis scutatus venom, is indicated not only for the treatment of envenomation by this snake, but also that of the copperhead (Austrelaps superbus) and Stephen's banded snake (Hoplocephalus stephensi). The present study compared the neuromuscular pharmacology of venom from these snakes and the in vitro efficacy of tiger snake antivenom. 2.,In chick biventer cervicis muscle and mouse phrenic nerve diaphragm preparations, all venoms (3,10 µg/mL) produced inhibition of indirect twitches. In the biventer muscle, venoms (10 µg/mL) inhibited responses to acetylcholine (1 mmol/L) and carbachol (20 µmol/L), but not KCl (40 mmol/L). The prior (10 min) administration of 1 unit/mL antivenom markedly attenuated the neurotoxic effects of A. superbus and N. scutatus venoms (10 µg/mL), but was less effective against H. stephensi venom (10 µg/mL); 5 units/mL antivenom attenuated the neurotoxic activity of all venoms. 3.,Administration of 5 units/mL antivenom at t90 partially reversed, over a period of 3 h, the inhibition of twitches produced by N. scutatus (10 µg/mL; 41% recovery), A. superbus (10 µg/mL; 25% recovery) and H. stephensi (10 µg/mL; 50% recovery) venoms. All venoms (10,100 µg/mL) also displayed signs of in vitro myotoxicity. 4.,The results of the present study indicate that all three venoms contain neurotoxic activity that is effectively attenuated by tiger snake antivenom. [source] | ||||||||||||||||