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Type: Artigo de periódico
Title: Diazoxide protects against methylmalonate-induced neuronal toxicity
Author: Kowaltowski, AJ
Maciel, EN
Fornazari, M
Castilho, RF
Abstract: Methylmalonic acidemia is an inherited metabolic disorder that leads to brain damage associated to the accumulation of methylmalonic acid (MMA) and impairment of energy metabolism. We demonstrate here that treatment with diazoxide, an agonist of mitochondrial ATP-sensitive K+ channels (mitoK(ATP)), can prevent death promoted by treatment with MMA in PC12 cells and freshly prepared rat brain slices. This diazoxide effect was reversed by 5-hydroxydecanoate, a mitoK(ATP) antagonist, confirming it occurs due to the activity of this channel. Diazoxide was not capable of preventing inner membrane potential loss promoted by MMA and Ca2+ in isolated mitochondria, indicating it does not directly prevent mitochondrial damage. Furthermore, diazoxide did not prevent respiratory inhibition in cells treated with MMA. Interestingly, we found that the mitochondrial inner membrane potential within intact cells treated with MMA was maintained in part by the reverse activity of ATP synthase (ATP hydrolysis) and that diazoxide prevented the formation of the membrane potential in the presence of MMA, in a manner sensitive to 5-hydroxydecanoate. Furthermore, the effects of diazoxide on cell survival after treatment with MMA were similar to those of ATP synthase inhibitor oligomycin and adenine nucleotide translocator inhibitor atractyloside. These results indicate that diazoxide prevents PC12 cell death promoted by MMA by decreasing mitochondrial ATP hydrolysis. These results uncover new potential neuroprotective effects of mitoK(ATP) agonists under situations in which oxidative phosphorylation is inhibited. (c) 2006 Elsevier Inc. All rights reserved.
Subject: ATP-sensitive K+ channels
cell death
electron transport chain
energy metabolism
metabolic disease
Country: EUA
Editor: Academic Press Inc Elsevier Science
Rights: fechado
Identifier DOI: 10.1016/j.expneurol.2006.04.004
Date Issue: 2006
Appears in Collections:Unicamp - Artigos e Outros Documentos

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