17beta-Estradiol reduces cortical lesion size in the glutamate excitotoxicity model by enhancing extracellular lactate: a new neuroprotective pathway.

Estrogens play an important role in neuronal function and in protecting neurones in the cerebral cortex against pathological conditions. An in vivo model of glutamate excitotoxicity in which glutamate is applied to the cortex of rats through a microdialysis probe has been used to investigate the neuroprotective processes initiated by 17beta-estradiol. Rats were pre-treated with 17beta-estradiol (i.v.) before local application of 100 mM glutamate into the cortex through a microdialysis probe. Pre-treatment with 17beta-estradiol significantly reduced the size of the glutamate-induced cortical lesion. In the cortical microdialysates collected from the probe, a peak of lactate was observed immediately after glutamate application. After 17beta-estradiol pre-treatment this peak of lactate was significantly higher with estradiol than without 120 min after glutamate application, reaching 700% basal level at the end of measurement. The level of extracellular glucose was markedly decreased with and without 17beta-estradiol pre-treatment. Local blockage of neuronal lactate transporters with alpha-cyano-4-hydroxycinnamate (4-CIN) completely abolished the neuroprotective effect of 17beta-estradiol and induced a larger cortical lesion. An accumulation of extracellular lactate was observed after inhibition of the lactate transporters suggesting that transport of lactate into neurones is necessary for the neuroprotective effect of 17beta-estradiol. The anti-estrogen tamoxifen also abolished the neuroprotective effect of 17beta-estradiol on the lesion size and inhibited the production of lactate. These results suggest a new neuroprotective mechanism of 17beta-estradiol by activating glutamate-stimulated lactate production, which is estrogen receptor-dependent.