Mechanisms of L-Cysteine Neurotoxicity

We review here the possible mechanisms of neuronal degeneration caused by L-cysteine, an odd excitotoxin. L-Cysteine lacks the omega carboxyl group required for excitotoxic actions via excitatory amino acid receptors, yet it evokes N-methyl-D-aspartate (NMDA) -like excitotoxic neuronal death and potentiates the Ca2+ influx evoked by NMDA. Both actions are prevented by NMDA antagonists. One target for cysteine effects is thus the NMDA receptor. The following mechanisms are discussed now: (1) possible increase in extracellular glutamate via release or inhibition of uptake/degradation, (2) generation of cysteine alpha-carbamate, a toxic analog of NMDA, (3) generation of toxic oxidized cysteine derivatives, (4) chelation of Zn2+ which blocks the NMDA receptor-ionophore, (5) direct interaction with the NMDA receptor redox site(s), (6) generation of free radicals, and (7) formation of S-nitrosocysteine. In addition to these, we describe another new alternative for cytotoxicity: (8) generation of the neurotoxic catecholamine derivative, 5-S-cysteinyl-3,4-dihydroxyphenylacetate (cysdopac).     

Neurotoxicity of depleted uranium

Depleted uranium (DU) is a byproduct of the enrichment process of uranium for its more radioactive isotopes to be used in nuclear energy. Because DU is pyrophoric and a dense metal with unique features when combined in alloys, it is used by the military in armor and ammunitions. There has been significant public concern regarding the use of DU by such armed forces, and it has been hypothesized to play a role in Gulf War syndrome. In light of experimental evidence from cell cultures, rats, and humans, there is justification for such concern. However, there are limited data on the neurotoxicity of DU. This review reports on uranium uses and its published health effects, with a major focus on in vitro and in vivo studies that escalate concerns that exposure to DU might be associated with neurotoxic health sequelae.     

Molecular Mechanisms of Lead Neurotoxicity

Epidemiological studies have shown a strong relationship between the level of lead in blood and bone as assessed by performance on IQ tests and other psychometric tests. Approximately 1 out of 10 children in the United States have blood lead levels above 10g/dl, which has been established as the level of concern. Studies on experimental animals exposed to lead after birth have shown learning deficits at similar blood lead levels. Since learning requires the remodeling of synapses in the brain, lead may specifically affect synaptic transmission. Although the molecular targets for lead are unknown, a vast amount of evidence accumulated over many years has shown that lead disrupts processes that are regulated by calcium. Our laboratory has been studying the effect of lead on protein kinase C, a family of isozymes some of which require calcium for activity. We and others have shown that picomolar concentrations of lead can replace micromolar concentrations of calcium in a protein kinase C enzyme assay. Furthermore, lead activates protein kinase C in intact cells and induces the expression of new genes by a mechanism dependent on protein kinase C. We propose that the learning deficits caused by lead are due to events regulated by protein kinase C that most likely occur at the synapse.     

两种PrP截短型多肽的神经毒性

PrP^106-126和PrP^118-135分别对应于人PrP^c序列中106～126残基和118～135残基,两个肽段在试验中具备prpsc的部分病理特症,因此PrP^106-126和PrP^118-135就成为了研究PrP^Sc神经细胞毒性致病机制的合适的模型。     

Neurotoxicity of methamphetamine and 3,4-methylenedioxymethamphetamine

Amphetamines are a class of psychostimulant drugs that are widely abused for their stimulant, euphoric, empathogenic and hallucinogenic properties. Many of these effects result from acute increases in dopamine and serotonin neurotransmission. Subsequent to these acute effects, methamphetamine and 3,4 methylenedioxymethamphetamine (MDMA) produce persistent damage to dopamine and serotonin nerve terminals. This review summarizes the numerous interdependent mechanisms including excitotoxicity, mitochondrial damage and oxidative stress that have been demonstrated to contribute to this damage. Emerging non-neuronal mechanisms by which the drugs may contribute to monoaminergic terminal damage, as well as the neuropsychiatric consequences of this terminal damage are also presented. Methamphetamine and 3,4-methylenedioxymethamphetamine (MDMA) have similar chemical structures and pharmacologic properties compared to other abused substances including cathinone (khat), as well as a relatively new class of novel synthetic amphetamines known as ‘bath salts’ that have gained popularity among drug abusers.     

Adoptive Autophagy Activation: a Much-Needed Remedy Against Chemical Induced Neurotoxicity/Developmental Neurotoxicity

The profound significance of autophagy as a cell survival mechanism under conditions of metabolic stress is a well-proven fact. Nearly a decade-long research in this area has led scientists to unearth various roles played by autophagy other than just being an auto cell death mechanism. It is implicated as a vital cell survival pathway for clearance of all the aberrant cellular materials in case of cellular injury, metastasis, disease states, cellular stress, neurodegeneration and so on. In this review, we emphasise the critical role of autophagy in the environmental stressors-induced neurotoxicity and its therapeutic implications for the same. We also attempt to shed some light on the possible protective role of autophagy in developmental neurotoxicity (DNT) which is a rapidly growing health issue of the human population at large and hence a point of rising concern amongst researchers. The intimate association between DNT and neurodegenerative disorders strongly indicates towards adopting autophagy activation as a much-needed remedy for DNT.     

Neurotoxicity of macrophages infected by HIV1

Conclusion Neuronal astrocytes and perhaps oligodendrocytic lesions occur during the course of HIVinfection of CNS cells. Most of the results suggest that these lesions are indirectlyinduced by infected macrophages, probably monocytes, present in the brain. Twomechanisms of neurotoxicity have been studied to date, one testing soluble factors presentin supernatant of infected monocytes and the other the direct effect of adhering HIV-infected monocytes to neurons and astrocytes. These two mechanisms are not mutually exclusive. They both indicate a major role for monocytes in the induction of brain lesionsand the crucial importance of the neurotoxic approach in the study of HIV inducedencephalopathy.     

THC Prevents MDMA Neurotoxicity in Mice

The majority of MDMA (ecstasy) recreational users also consume cannabis. Despite the rewarding effects that both drugs have, they induce several opposite pharmacological responses. MDMA causes hyperthermia, oxidative stress and neuronal damage, especially at warm ambient temperature. However, THC, the main psychoactive compound of cannabis, produces hypothermic, anti-inflammatory and antioxidant effects. Therefore, THC may have a neuroprotective effect against MDMA-induced neurotoxicity. Mice receiving a neurotoxic regimen of MDMA (20 mg/kg ×4) were pretreated with THC (3 mg/kg ×4) at room (21°C) and at warm (26°C) temperature, and body temperature, striatal glial activation and DA terminal loss were assessed. To find out the mechanisms by which THC may prevent MDMA hyperthermia and neurotoxicity, the same procedure was carried out in animals pretreated with the CB₁ receptor antagonist AM251 and the CB₂ receptor antagonist AM630, as well as in CB₁, CB₂ and CB₁/CB₂ deficient mice. THC prevented MDMA-induced-hyperthermia and glial activation in animals housed at both room and warm temperature. Surprisingly, MDMA-induced DA terminal loss was only observed in animals housed at warm but not at room temperature, and this neurotoxic effect was reversed by THC administration. However, THC did not prevent MDMA-induced hyperthermia, glial activation, and DA terminal loss in animals treated with the CB₁ receptor antagonist AM251, neither in CB₁ and CB₁/CB₂ knockout mice. On the other hand, THC prevented MDMA-induced hyperthermia and DA terminal loss, but only partially suppressed glial activation in animals treated with the CB₂ cannabinoid antagonist and in CB₂ knockout animals. Our results indicate that THC protects against MDMA neurotoxicity, and suggest that these neuroprotective actions are primarily mediated by the reduction of hyperthermia through the activation of CB₁ receptor, although CB₂ receptors may also contribute to attenuate neuroinflammation in this process.     

Approaches to Prevent Dopamine Quinone-Induced Neurotoxicity

Dopamine (DA) and its metabolites containing two hydroxyl residues exert cytotoxicity in dopaminergic neuronal cells, primarily due to the generation of highly reactive DA and DOPA quinones. Quinone formation is closely linked to other representative hypotheses such as mitochondrial dysfunction, inflammation, oxidative stress, and dysfunction of the ubiquitin-proteasome system, in the pathogenesis of neurodegenerative diseases such as Parkinson’s disease and methamphetamine-induced neurotoxicity. Therefore, pathogenic effects of the DA quinone have focused on dopaminergic neuron-specific oxidative stress. Recently, various studies have demonstrated that some intrinsic molecules and several drugs exert protective effects against DA quinone-induced damage of dopaminergic neurons. In this article, we review recent studies on some neuroprotective approaches against DA quinone-induced dysfunction and/or degeneration of dopaminergic neurons. Special issue article in honor of Dr. Akitane Mori.     

Neurotoxicity of Glucocorticoids in the Primate Brain

Severe and prolonged physical and psychological stress is known to cause brain damage; long-term torture victims in prison bare later developed psychiatric disorders and cerebral cortical atrophy observed in CT scans (Jensen, Genefke, Hyldebrandt, Pedersen, Petersen, and Weile. 1982). In nonhuman primates, we observed degeneration and depletion of the hippocampal neurons in African green monkeys that had been severely abused by cagemates and died with complications of multiple gastric ulcers and adrenal cortical hyperplasia (Uno, Tarara, Else, Suleman and Sapolsky, 1989). In our previous studies the administration of dexamethasone (DEX) (5 mg/kg) to pregnant rhesus monkeys at 132 to 133 days of gestation induced degeneration and depletion of the hippocampal pyramidal and dentate granular neurons in the brains of 135-gestation-day fetuses, and these changes were retained in the brains of fetuses at near term, 165 days of gestation (Uno, Lohmiller, Thieme, Kemnitz, Engle, Roecker, and Farrell, 1990). We also found that implantation of a cortisol pellet in the vicinity of the hippocampus in adult vervet monkeys induced degeneration of the CA3 pyramidal neurons and their dendritic branches (Sapolsky, Uno, Rebert, and Finch, 1990). Thus, hippocampal pyramidal neurons containing a high concentration of glucocorticoid receptors appear to be highly vulnerable to either hypercortisolemia caused by severe stress or to exposure to exogenous glucocorticoids. To study the long-term postnatal sequelae of prenatal brain damage, eight rhesus monkeys were treated with either DEX (5 mg/kg), 5 animals, or vehicle, 3 animals, at 132 to 133 days of gestation. After natural birth, all animals lived with their mothers for 1 year. At 9 months of age, we found that DEX-treated animals had significantly high plasma cortisol at both base and post stress (isolation) levels compared to age-matched vehicle-treated animals. Magnetic resonance images (MRI) of the brain at 20 months of age showed an approximately 30% reduction in size and segmental volumes of the hippocampus in DEX-treated compared to vehicle-treated animals. Measurements of whole brain volume by MRI showed no significant differences between DEX and vehicle groups. Prenatal administration of a potent glucocorticoid (DEX) induced an irreversible deficiency of the hippocampal neurons and high plasma cortisol at the circadian baseline and post-stress levels in juvenile rhesus monkeys. These results suggest that the hippocampus mediates negative feedback of cortisol release; a lack or deficiency of the hippocampal neurons attenuates this feedback resulting in hypercortisolemia. The hippocampal deficiency in rhesus monkeys induced by prenatal administration of DEX appears to be a good model for neuroendocrinological dysfunctions and hippocampal development in human juveniles whose mothers were exposed to severe stress or received a high dose of glucocorticosteroids during pregnancy.     

Protective Effects of Zonisamide Against Rotenone-Induced Neurotoxicity

Zonisamide (ZNS), an antiepileptic drug having beneficial effects also against Parkinson’s disease symptoms, has proven to display an antioxidant effects in different experimental models. In the present study, the effects of ZNS on rotenone-induced cell injury were investigated in human neuroblastoma SH-SY5Y cells differentiated towards a neuronal phenotype. Cell cultures were exposed for 24 h to 500 nM rotenone with or without pre-treatment with 10–100 μM ZNS. Then, the following parameters were analyzed: (a) cell viability; (b) intracellular reactive oxygen species production; (c) mitochondrial transmembrane potential; (d) cell necrosis and apoptosis; (e) caspase-3 activity. ZNS dose-dependently suppressed rotenone-induced cell damage through a decrease in intracellular ROS production, and restoring mitochondrial membrane potential. Similarly to ZNS effects, the treatment with N-acetyl-cysteine (100 μM) displayed significant protective effects against rotenone-induced ROS production and Δψ_m at 4 and 12 h respectively, reaching the maximal extent at 24 h. Additionally, ZNS displayed antiapoptotic effects, as demonstrated by flow cytometric analysis of annexin V/propidium iodide double staining, and significant attenuated rotenone-increased caspase 3 activity. On the whole, these findings suggest that ZNS preserves mitochondrial functions and counteracts apoptotic signalling mechanisms mainly by an antioxidant action. Thus, ZNS might have beneficial effect against neuronal cell degeneration in different experimental models involving mitochondrial dysfunction.     

Role of Astrocytes in Manganese Neurotoxicity Revisited

Neurochemical Research - Manganese (Mn) overexposure is a public health concern due to its widespread industrial usage and the risk for environmental contamination. The clinical symptoms of Mn...     

Nerve Excitability Assessment in Chemotherapy-induced Neurotoxicity

Chemotherapy-induced neurotoxicity is a serious consequence of cancer treatment, which occurs with some of the most commonly used chemotherapies^1,2. Chemotherapy-induced peripheral neuropathy produces symptoms of numbness and paraesthesia in the limbs and may progress to difficulties with fine motor skills and walking, leading to functional impairment. In addition to producing troubling symptoms, chemotherapy-induced neuropathy may limit treatment success leading to dose reduction or early cessation of treatment. Neuropathic symptoms may persist long-term, leaving permanent nerve damage in patients with an otherwise good prognosis³. As chemotherapy is utilised more often as a preventative measure, and survival rates increase, the importance of long-lasting and significant neurotoxicity will increase.There are no established neuroprotective or treatment options and a lack of sensitive assessment methods. Appropriate assessment of neurotoxicity will be critical as a prognostic factor and as suitable endpoints for future trials of neuroprotective agents. Current methods to assess the severity of chemotherapy-induced neuropathy utilise clinician-based grading scales which have been demonstrated to lack sensitivity to change and inter-observer objectivity⁴. Conventional nerve conduction studies provide information about compound action potential amplitude and conduction velocity, which are relatively non-specific measures and do not provide insight into ion channel function or resting membrane potential. Accordingly, prior studies have demonstrated that conventional nerve conduction studies are not sensitive to early change in chemotherapy-induced neurotoxicity^4-6. In comparison, nerve excitability studies utilize threshold tracking techniques which have been developed to enable assessment of ion channels, pumps and exchangers in vivo in large myelinated human axons^7-9.Nerve excitability techniques have been established as a tool to examine the development and severity of chemotherapy-induced neurotoxicity^10-13. Comprising a number of excitability parameters, nerve excitability studies can be used to assess acute neurotoxicity arising immediately following infusion and the development of chronic, cumulative neurotoxicity. Nerve excitability techniques are feasible in the clinical setting, with each test requiring only 5 -10 minutes to complete. Nerve excitability equipment is readily commercially available, and a portable system has been devised so that patients can be tested in situ in the infusion centre setting. In addition, these techniques can be adapted for use in multiple chemotherapies.In patients treated with the chemotherapy oxaliplatin, primarily utilised for colorectal cancer, nerve excitability techniques provide a method to identify patients at-risk for neurotoxicity prior to the onset of chronic neuropathy. Nerve excitability studies have revealed the development of an acute Na⁺ channelopathy in motor and sensory axons^10-13. Importantly, patients who demonstrated changes in excitability in early treatment were subsequently more likely to develop moderate to severe neurotoxicity¹¹. However, across treatment, striking longitudinal changes were identified only in sensory axons which were able to predict clinical neurological outcome in 80% of patients¹⁰. These changes demonstrated a different pattern to those seen acutely following oxaliplatin infusion, and most likely reflect the development of significant axonal damage and membrane potential change in sensory nerves which develops longitudinally during oxaliplatin treatment¹⁰. Significant abnormalities developed during early treatment, prior to any reduction in conventional measures of nerve function, suggesting that excitability parameters may provide a sensitive biomarker.     

Prosaposin Overexpression following Kainic Acid-Induced Neurotoxicity

Because excessive glutamate release is believed to play a pivotal role in numerous neuropathological disorders, such as ischemia or seizure, we aimed to investigate whether intrinsic prosaposin (PS), a neuroprotective factor when supplied exogenously in vivo or in vitro, is up-regulated after the excitotoxicity induced by kainic acid (KA), a glutamate analog. In the present study, PS immunoreactivity and its mRNA expression in the hippocampal and cortical neurons showed significant increases on day 3 after KA injection, and high PS levels were maintained even after 3 weeks. The increase in PS, but not saposins, detected by immunoblot analysis suggests that the increase in PS-like immunoreactivity after KA injection was not due to an increase in saposins as lysosomal enzymes after neuronal damage, but rather to an increase in PS as a neurotrophic factor to improve neuronal survival. Furthermore, several neurons with slender nuclei inside/outside of the pyramidal layer showed more intense PS mRNA expression than other pyramidal neurons. Based on the results from double immunostaining using anti-PS and anti-GABA antibodies, these neurons were shown to be GABAergic interneurons in the extra- and intra-pyramidal layers. In the cerebral cortex, several large neurons in the V layer showed very intense PS mRNA expression 3 days after KA injection. The choroid plexus showed intense PS mRNA expression even in the normal rat, and the intensity increased significantly after KA injection. The present study indicates that inhibitory interneurons as well as stimulated hippocampal pyramidal and cortical neurons synthesize PS for neuronal survival, and the choroid plexus is highly activated to synthesize PS, which may prevent neurons from excitotoxic neuronal damage. To the best of our knowledge, this is the first study that demonstrates axonal transport and increased production of neurotrophic factor PS after KA injection.     

Neurotoxicity of Human Amylin in Rat Primary Hippocampal Cultures: Similarity to Alzheimer's Disease Amyloid-β Neurotoxicity

Amylin, a 37-amino-acid amyloidogenic peptide, bears biophysical similarities to the amyloid-β peptide (Aβ) deposited in Alzheimer's disease. Using embryonic rat hippocampal cultures we tested whether amylin induces neurotoxicity similar to that previously observed with Aβ(1–40). Treatment with human amylin (1–37) resulted in prominent toxicity as assessed by phasecontrast microscopy and quantification of lactate dehydrogenase in the medium. Amylin-induced neurotoxicity was morphologically similar to that induced by Aβ(1–40). In contrast, the nonamyloidogenic rat amylin showed negligible neurotoxicity despite having 95% sequence similarity to human amylin. Only full-length human amylin was toxic; various amylin peptide fragments including amino acid residues 20–29 were nontoxic at similar concentrations. These studies suggest that unrelated amyloidogenic peptides like human amylin and Aβ can adopt a similar neurotoxic conformation in vitro. Similar conformation-dependent neurotoxicity may drive the prominent neurite degeneration around compacted but not diffuse deposits of Aβ in Alzheimer's disease.