The effects of extracellular acidosis on neurons and glia in vitro

Cerebral lactic acid, a product of ischemic anaerobic glycolysis, may directly contribute to ischemic brain damage in vivo. In this study we evaluated the effects of extracellular acid exposure on 7-day-old cultures of embryonic rat forebrain. Mixed neuronal and glial cultures were exposed to either lactic or hydrochloric acid to compare the toxicities of relatively permeable and impermeable acids. Neurons were relatively resistant to extra-cellular HCl acidosis, often surviving 10-min exposures to pH 3.8. In the same cultures, immunochemically defined astrocytes survived 10-min HCl exposures to a maximum acidity of pH 4.2. Similarly, axonal bundles defasciculated in HCl-titrated media below pH 4.4, although their constituent fibers often survived pH 3.8. Cell death occurred at higher pH in cultures subjected to lactic acidosis than in those exposed to HCl. Over half of forebrain neurons and glia subjected for 10 min to lactic acidification failed to survive exposure to pH 4.9. Longer 1-h lactic acid incubations resulted in cell death below pH 5.2. The potent cytotoxicity of lactic acid may be a direct result of the relatively rapid transfer of its neutral protonated form across cell membranes. This process would rapidly deplete intracellular buffer stores, resulting in unchecked cytosolic acidification. Neuronal and glial death from extracellular acidosis may therefore be a function of both the degree and the rapidity of intracellular acidification.