Effect of lactic acid on l-glutamate uptake in cultured astrocytes: mechanistic considerations

Elevated levels of lactic acid can be deleterious to CNS tissue. Lactic acid is known to cause astroglial swelling and since glial swelling has been shown to inhibit l-glutamate ( l-Glu) uptake, we examined whether one of the actions of lactic acid is to inhibit l-Glu uptake. Astrocyte cultures treated with lactic acid (25 mM; pH 6.1) showed an inhibition of l-Glu uptake by 65%. HCl (pH 6.1) also inhibited l-Glu uptake and this inhibition was potentiated by sodium lactate (25 mM). The inhibitory effect of lactic acid on l-Glu uptake was partially reversible and the reversibility was enhanced by hypothermia. Blocking glial swelling with d-mannitol, or treatment with antioxidants or hypothermia did not inhibit the effect of lactic acid on l-Glu uptake, indicating that swelling per se or free radicals, were not the factors in l-Glu uptake inhibition. Lactic acid induced a four-fold enhancement of l-Glu release and a seven-fold increase of K + release. Our results suggest that lactic acid, by direct effect on pH, brings about a stimulation of K + and l-Glu release which may be a factor in the inhibition of l-Glu uptake by lactic acid in astrocytes.