Pyruvate protects neurons against hydrogen peroxide-induced toxicity.
Hydrogen peroxide (H2O2) is suspected to be involved in numerous brain pathologies such as neurodegenerative diseases or in acute injury such as ischemia or trauma. In this study, we examined the ability of pyruvate to improve the survival of cultured striatal neurons exposed for 30 min to H2O2, as estimated 24 hr later by the 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazoliumbromide assay. Pyruvate strongly protected neurons against both H2O2 added to the external medium and H2O2 endogenously produced through the redox cycling of the experimental quinone menadione. The neuroprotective effect of pyruvate appeared to result rather from the ability of alpha-ketoacids to undergo nonenzymatic decarboxylation in the presence of H2O2 than from an improvement of energy metabolism. Indeed, several other alpha-ketoacids, including alpha-ketobutyrate, which is not an energy substrate, reproduced the neuroprotective effect of pyruvate. In contrast, lactate, a neuronal energy substrate, did not protect neurons from H2O2. Optimal neuroprotection was achieved with relatively low concentrations of pyruvate (</=1 mM), whereas at high concentration (10 mM) pyruvate was ineffective. This paradox could result from the cytosolic acidification induced by the cotransport of pyruvate and protons into neurons. Indeed, cytosolic acidification both enhanced the H2O2-induced neurotoxicity and decreased the rate of pyruvate decarboxylation by H2O2. Together, these results indicate that pyruvate efficiently protects neurons against both exogenous and endogenous H2O2. Its low toxicity and its capacity to cross the blood-brain barrier open a new therapeutic perspective in brain pathologies in which H2O2 is involved.
Desagher
S
S
Chaire de Neuropharmacologie, Institut National de la Santé et de la Recherche Médicale U114, Collège de France, 75 231 Paris Cedex 05, France.
Glowinski
J
J
Prémont
J
J
D000818:Animals; D002087:Butyrates / Q000494:pharmacology; D002478:Cells, Cultured; D003342:Corpus Striatum / Q000166:cytology*; D004734:Energy Metabolism / Q000187:drug effects; D006861:Hydrogen Peroxide / Q000633:toxicity*; D006863:Hydrogen-Ion Concentration; D007656:Ketoglutaric Acids / Q000494:pharmacology; D019344:Lactic Acid / Q000494:pharmacology; D051379:Mice; D009474:Neurons / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010071:Oxaloacetates / Q000494:pharmacology; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000187:drug effects; D019289:Pyruvic Acid / Q000494:pharmacology*; D014812:Vitamin K / Q000378:metabolism
D002087:Butyrates; D007656:Ketoglutaric Acids; D018696:Neuroprotective Agents; D010071:Oxaloacetates; D014812:Vitamin K; D019344:Lactic Acid; C005087:alpha-ketobutyric acid; D019289:Pyruvic Acid; D006861:Hydrogen Peroxide