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 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 , 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.