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Neurotoxic Mechanisms (neurotoxic + mechanism)
Selected AbstractsNeurotoxic mechanisms of 2,9-dimethyl-,-carbolinium ion in primary dopaminergic cultureJOURNAL OF NEUROCHEMISTRY, Issue 4 2006Juliane Hamann Abstract ,-Carbolines are potential endogenous and exogenous neurotoxicants that may contribute to the pathogenesis of Parkinson's disease. The 2,9-dimethyl-,-carbolinium ion (either 2,9-dimethyl-,-norharmanium or 2,9-Me2NH+) was found to be neurotoxic in primary mesencephalic cultures and to be a potent inhibitor of mitochondrial complex I. However, the precise mechanisms of cell death remained obscure. Here, we investigated the mechanism of cell death in primary dopaminergic cultures of the mouse mesencephalon mediated by 2,9-Me2NH+. The ,-carboline caused preferential death of dopaminergic neurones, which could not be attributed to cellular uptake via the dopamine transporter. Transient incubation with 2,9-Me2NH+ for 48 h caused a progressive deterioration in the morphology of dopaminergic neurones during a 5-day recovery period and persistent damage to the overall culture. An increase in free radical production and caspase-3 activity, as well as a decrease of respiratory activity, mitochondrial membrane potential and ATP content, contributed to toxicity and pointed to an apoptotic mode of cell death, although a significant quantity of cells dying via necrosis were present simultaneously. These data underline the preferential susceptibility of dopaminergic neurones to 2,9-Me2NH+ as a potent, oxidative stress generating neurotoxin. [source] Intrastriatal administration of human immunodeficiency virus-1 glycoprotein 120 reduces glial cell-line derived neurotrophic factor levels and causes apoptosis in the substantia nigraDEVELOPMENTAL NEUROBIOLOGY, Issue 12 2006Rachel L. Nosheny Abstract Uninfected neurons of the substantia nigra (SN) degenerate in human immunodeficiency virus (HIV)-positive patients through an unknown etiology. The HIV envelope glycoprotein 120 (gp120) causes apoptotic neuronal cell death in the rodent striatum, but its primary neurotoxic mechanism is still under investigation. Previous studies have shown that gp120 causes neurotoxicity in the rat striatum by reducing brain-derived neurotrophic factor (BDNF). Because glial cell line-derived neurotrophic factor (GDNF) and BDNF are neurotrophic factors crucial for the survival of dopaminergic neurons of the SN, we investigated whether gp120 reduces GDNF and BDNF levels concomitantly to induce apoptosis. Rats received a microinjection of gp120 or vehicle into the striatum and were sacrificed at various time intervals. GDNF but not BDNF immunoreactivity was decreased in the SN by 4 days in gp120-treated rats. In these animals, a significant increase in the number of caspase-3- positive neurons, both tyrosine hydroxylase (TH)-positive and -negative, was observed. Analysis of TH immunoreactivity revealed fewer TH-positive neurons and fibers in a medial and lateral portion of cell group A9 of the SN, an area that projects to the striatum, suggesting that gp120 induces retrograde degeneration of nigrostriatal neurons. We propose that dysfunction of the nigrostriatal dopaminergic system associated with HIV may be caused by a reduction of neurotrophic factor expression by gp120. © 2006 Wiley Periodicals, Inc. J Neurobiol, 2006 [source] Expression of mutant SOD1G93A in astrocytes induces functional deficits in motoneuron mitochondriaJOURNAL OF NEUROCHEMISTRY, Issue 5 2008Lynsey G. Bilsland Abstract Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by motoneuron degeneration resulting in paralysis and eventual death. ALS is regarded as a motoneuron-specific disorder but increasing evidence indicates non-neuronal cells play a significant role in disease pathogenesis. Although the precise aetiology of ALS remains unclear, mutations in the superoxide dismutase (SOD1) gene are known to account for approximately 20% of familial ALS. We examined the influence of SOD1G93A expression in astrocytes on mitochondrial homeostasis in motoneurons in a primary astrocyte : motoneuron co-culture model. SOD1G93A expression in astrocytes induced changes in mitochondrial function of both SOD1G93A and wild-type motoneurons. In the presence of SOD1G93A astrocytes, mitochondrial redox state of both wild-type and SOD1G93A motoneurons was more reduced and mitochondrial membrane potential decreased. While intra-mitochondrial calcium levels [Ca2+]m were elevated in SOD1G93A motoneurons, changes in mitochondrial function did not correlate with [Ca2+]m. Thus, expression of SOD1G93A in astrocytes directly alters mitochondrial function even in embryonic motoneurons, irrespective of genotype. These early deficits in mitochondrial function induced by surrounding astrocytes may increase the vulnerability of motoneurons to other neurotoxic mechanisms involved in ALS pathogenesis. [source] Neurotoxicity by microglia: Mechanisms and potential therapeutic strategyCLINICAL AND EXPERIMENTAL NEUROIMMUNOLOGY, Issue 1 2010Hideyuki Takeuchi Abstract Microgliosis (accumulation of activated microglia) around degenerative neurons is a common pathological feature of various neurological disorders. Glutamate released by activated microglia induces excito-neurotoxicity and most likely contributes to neurodegeneration in numerous neurological diseases including ischemia, inflammation, epilepsy and neurodegenerative diseases. Although both blockade of glutamate receptors and inhibition of microglial activation are the therapeutic candidates for activated microglia-mediated neurodegenerative diseases, clinical trials have been failed because of adverse effects. In the present review, the neurotoxic factors from activated microglia are examined, and how these factors disturb neuronal functions is discussed. The efforts to suppress neurotoxic mechanisms by microglia are also introduced. (Clin. Exp. Neuroimmunol. doi: 10.1111/j.1759-1961.2009.00001.x, January 2010) [source] | ||||||||||