ESTROGENS ATTENUATE NEURONAL INJURY DUE TO HEMOGLOBIN, CHEMICAL HYPOXIA, AND EXCITATORY AMINO-ACIDS IN MURINE CORTICAL CULTURES

A growing body of evidence supports the hypothesis that estrogens may be beneficial in Alzheimer's disease and other neurodegenerative proce sses. Less is known of their therapeutic potential in acute CNS insult s. In this study, we assessed the effect of estrogens in three injury paradigms that may be relevant to CNS hemorrhage, trauma, and ischemia . Supraphysiologic concentrations of 17 beta-estradiol, estrone, or eq uilin attenuated neuronal loss due to prolonged exposure to the pro-ox idant hemoglobin, with complete protection at 10 mu M. Most of this ef fect persisted despite concomitant treatment with the antiestrogen ICI 182,780 or the protein synthesis inhibitor cycloheximide. In contrast , the non-estrogenic steroid methylprednisolone, which is currently in clinical use in spinal cord injury, reduced neuronal loss by only abo ut 30%. High concentrations of equilin or estrone also attenuated the submaximal neuronal injury induced by 3.5-4.5 h exposure to the cytoch rome oxidase inhibitor sodium azide, with near complete protection at 30 mu M. Estrogens had a weaker and somewhat variable effect on pure e xcitotoxic injury, reducing neuronal loss due to 24 h kainate exposure by about half, and due to 24 h NMDA exposure by 15-65%; similar neuro protection was provided by the antioxidant 21-aminosteroid U74500A. Th ese results suggest that estrogens may be beneficial in acute CNS inju ries associated with oxidative and excitotoxic stress. Investigation o f high dose estro en therapy in in vivo models of CNS hemorrhage, trau ma, and ischemia is warranted. (C) 1997 Elsevier Science B.V.