17 beta-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 neu rones in the cerebral cortex against pathological conditions, An in vivo mo del of glutamate excitotoxicity in which glutamate is applied to the cortex of rats through a microdialysis probe has been used to investigate the neu roprotective processes initiated by 17 beta -estradiol. Rats were pre-treat ed with 17 beta -estradiol (i.v.) before local application of 100 mM glutam ate into the cortex through a microdialysis probe. Pre-treatment with 17 be ta -estradiol significantly reduced the size of the glutamate-induced corti cal lesion. In the cortical microdialysates collected from the probe, a pea k of lactate was observed immediately after glutamare application. After 17 beta -estradiol pre-treatment this peak of lactate was significantly highe r with estradiol than without 120 min after glutamate application, reaching 700% basal level at the end of measurement. The level of extracellular glu cose was markedly decreased with and without 17 beta -estradiol pre-treatme nt. Local blockage of neuronal lactate transporters with alpha -cyano-4-hyd roxycinnamate (4-CIN) completely abolished the neuroprotective effect of 17 beta -estradiol and induced a larger cortical lesion. An accumulation of e xtracellular lactate was observed after inhibition of the lactate transport ers suggesting that transport of lactate into neurones is necessary for the neuroprotective effect of 17 beta -estradiol. The anti-estrogen tamoxifen also abolished the neuroprotective effect of 17 beta -estradiol on the lesi on size and inhibited the production of lactate. These results suggest a ne w neuroprotective mechanism of 17 beta -estradiol by activating glutamate-s timulated lactate production, which is estrogen receptor-dependent. (C) 200 1 Elsevier Science B.V. All rights reserved.