Lactacidosis modulates glutathione metabolism and oxidative glutamate toxicity

Lactate and acidosis increase infarct size in humans and in animal models of cerebral ischemia but the mechanisms by which they exert their neurotoxic effects are poorly understood. Oxidative glutamate toxicity is a form of nerve cell death, wherein glutamate inhibits cystine uptake via the cystine/glutamate antiporter system x(c) leading to glutathione depletion, accumulation of reactive oxygen species and, ultimately, programmed cell death. Using the hippocampal cell line, HT22, we show that lactate and acidosis exacerbate oxidative glutamate toxicity and further decrease glutathione levels. Acidosis but not lactate inhibits system x(c)(-), whereas both acidosis and lactate inhibit the enzymatic steps of glutathione synthesis downstream of cystine uptake. In contrast, when glutathione synthesis is completely inhibited by cystine-free medium, acidosis partially protects against glutathione depletion and cell death. Both effects of acidosis are also present in primary neuronal and astrocyte cultures. Furthermore, we show that some neuroprotective compounds are much less effective in the presence of lactacidosis. Our findings indicate that lactacidosis modulates glutathione metabolism and neuronal cell death. Furthermore, lactacidosis may interfere with the action of some neuroprotective drugs rendering these less likely to be therapeutically effective in cerebral ischemia.