Chronic mitochondrial inhibition induces selective motoneuron death in vitro: a new model for amyotrophic lateral sclerosis.
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TL;DR: An in vitro model of chronic motoneuron toxicity, based on malonate‐induced inhibition of complex II in the mitochondrial electron transport chain, shows that chronic mitochondrial inhibition leads to selective mot oneuron death, which is most likely apoptotic.
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Abstract: Evidence is increasing that mitochondrial dysfunction is involved in amyotrophic lateral sclerosis, a neurodegenerative disease characterized by selective motoneuron death. To study the role of mitochondrial dysfunction in the pathways leading to motoneuron death, we developed an in vitro model of chronic motoneuron toxicity, based on malonate-induced inhibition of complex II in the mitochondrial electron transport chain. Treatment with malonate resulted in a dose-dependent decrease in cellular ATP levels. We observed that motoneurons were significantly more vulnerable to mitochondrial inhibition than control neurons in the dorsal horn. We could reproduce this dose-dependent phenomenon with the complex IV inhibitor sodium azide. The free radical scavenger α-phenyl-N-tert-butylnitrone, the AMPA/kainate receptor blocker 6-cyano-7-nitroquinoxaline-2,3-dione, and riluzole, a drug that is currently used for the treatment of amyotrophic lateral sclerosis, were protective against malonate-induced motoneuron death. Furthermore, the caspase inhibitors N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone and z-Asp-Glu-Val-Asp-fluoromethyl ketone were both protective against malonate toxicity. Our model shows that chronic mitochondrial inhibition leads to selective motoneuron death, which is most likely apoptotic.
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TL;DR: In a rodent model of transient global cerebral ischemia, a complete suppression of the ischemIA-evoked surge in glutamic acid release has been observed and it is thought these effects may be partly due to inactivation of voltage-dependent sodium channels on glutamatergic nerve terminals.
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Mitochondrial dysfunction in neurodegenerative diseases
TL;DR: A potential pivotal role for mitochondrial dysfunction in neurodegenerative diseases is gaining increasing acceptance and therapeutic approaches include methods to buffer intracellular ATP and to scavenge free radicals.
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Chronic inhibition of glutamate uptake produces a model of slow neurotoxicity
TL;DR: Selective inhibition of glutamate transport produces a model of clinically relevant slow neurotoxicity and appears to be mediated by the action of non-N-methyl-D-aspartate receptors, which supports the hypothesis that the slow loss of motor neurons in amyotrophic lateral sclerosis could be due to defective glutamate transport.
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Increased 3-nitrotyrosine in both sporadic and familial amyotrophic lateral sclerosis.
M F Beal,Robert J. Ferrante,Susan E. Browne,Russell T. Matthews,Neil W. Kowall,Robert H. Brown +5 more
TL;DR: In this paper, biochemical measurements showed increased concentrations of 3-nitrotyrosine and 3nitro-4-hydroxyphenylacetic acid in the lumbar and thoracic spinal cord of ALS patients, indicating that peroxynitrite mediated oxidative damage may play a role in the pathogenesis of both sporadic and familial ALS.
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TL;DR: Electron microscopic analysis confirms that cells treated with PT inducers alone undergo apoptosis, whereas cells kept in identical conditions in the presence of Z-VAD.fmk die from necrosis, compatible with the hypothesis that PT would be a rate limiting step in both the apoptotic and the necrotic modes of cell death.
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