BETA-ESTRADIOL PROTECTS HIPPOCAMPAL CA1 NEURONS AGAINST TRANSIENT FOREBRAIN ISCHEMIA IN GERBIL

beta-Estradiol has been considered to be a neurotrophic agent, but its in vivo effect on gerbils with transient forebrain ischemia has not y et been demonstrated. In the first set of the present experiments, we infused beta-estradiol at a dose of 0.05 or 0.25 mu g/day for 7 days i nto the lateral ventricles of normothermic gerbils starting 2 h before 3-min forebrain ischemia. beta-estradiol infusion at a dose of 0.25 m u g/day prevented significantly the ischemia-induced reduction of resp onse latency time as revealed by a step-down passive avoidance task. S ubsequent light and electron microscopic examinations showed that pyra midal neurons in the hippocampal CAI region as well as synapses within the strata moleculare, radiatum and oriens of the region were signifi cantly more numerous in gerbils infused with beta-estradiol than in th ose receiving saline infusion. beta-Estradiol at a dose of 1.25 mu g/d ay was ineffective and occasionally increased the mortality of experim ental animals. Since the total brain content of exogenous beta-estradi ol at 12 h after forebrain ischemia was estimated to be less than 145 ng, the second set of experiments focused on the neurotrophic action o f beta-estradiol at concentrations around 100 ng/ml in vitro. beta-est radiol at concentrations of 1-100 ng/ml facilitated the survival and p rocess extension of cultured hippocampal neurons, but it did not exhib it any significant radical-scavenging effects al the concentration ran ge. On the other hand: 100 mu g/ml of beta-estradiol, even though fail ing to support hippocampal neurons in vitro, effectively scavenged fre e radicals in subsequent in vitro studies, as demonstrated elsewhere. These findings suggest that beta-estradiol at a dose of 0.25 mu g/day prevents ischemia-induced learning disability and neuronal loss al ear ly stages after transient forebrain ischemia, possibly via a receptor- mediated pathway without attenuating free radical neurotoxicity. (C) 1 997 Elsevier Science Ireland Ltd.