Pyruvate Protects Neurons against Hydrogen Peroxide-Induced Toxicity

Abstract

Hydrogen peroxide (H 2 O 2) 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 H 2 O 2, as estimated 24 hr later by the 3-[4,5-dimethylthiazol-2-yl]−2,5-diphenyltetrazoliumbromide assay. Pyruvate strongly protected neurons against both H 2 O 2 added to the external medium and H 2 O 2 endogenously produced through the redox cycling of the experimental quinone menadione. The neuroprotective effect of pyruvate appeared to result rather from the ability of α-ketoacids to undergo nonenzymatic decarboxylation in the presence of H 2 O 2 than from an improvement of energy metabolism. Indeed, several other α-ketoacids, including α-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 H 2 O 2. Optimal neuroprotection was achieved with relatively low concentrations of pyruvate (≤1 m m), whereas at high concentration (10 m m) 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 H 2 O 2-induced neurotoxicity and decreased the rate of pyruvate decarboxylation by H 2 O 2. Together, these results indicate that pyruvate efficiently protects neurons against both exogenous and endogenous H 2 O 2. Its low toxicity and its capacity to cross the blood–brain barrier open a new therapeutic perspective in brain pathologies in which H 2 O 2 is involved.