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 suc h as ischemia or trauma. In this study, we examined the ability of pyr uvate to improve the survival of cultured striatal neurons exposed for 30 min to H2O2, as estimated 24 hr later by the methylthiazol-2-yl]-2 ,5-diphenyltetrazoliumbromide assay. Pyruvate strongly protected neuro ns against both H2O2 added to the external medium and H2O2 endogenousl y produced through the redox cycling of the experimental quinone menad ione. The neuroprotective effect of pyruvate appeared to result rather from the ability of alpha-ketoacids to undergo nonenzymatic decarboxy lation in the presence of H2O2 than from an improvement of energy meta bolism. Indeed, several other alpha-ketoacids, including alpha-ketobut yrate, which is not an energy substrate, reproduced the neuroprotectiv e effect of pyruvate. In contrast, lactate, a neuronal energy substrat e, did not protect neurons from H2O2. Optimal neuroprotection was achi eved with relatively low concentrations of pyruvate(less than or equal to 1 mM), whereas at high concentration (10 mM) pyruvate was ineffect ive. This paradox could result from the cytosolic acidification induce d by the cotransport of pyruvate and protons into neurons. Indeed, cyt osolic acidification both enhanced the H2O2-induced neurotoxicity and decreased the rate of pyruvate decarboxylation by H2O2. Together, thes e 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.