Neuroprotective effects of estradiol in newborn female rat hippocampus.

Perinatal brain injury, consequent to hypoxic/ischemic events, is associated with the release of excess excitatory neurotransmitters, including glutamate. We have previously shown that administration of a glutamate receptor agonist, kainic acid (KA), to postnatal day 0 (PN0) and PN1 rats results in damage selective to the dentate gyrus of females. Pretreatment with the gonadal steroid estradiol prevents KA-induced damage to the female dentate gyrus. To begin to elucidate the cellular mechanism of the neuroprotective effects of estradiol in neonatal females, we have employed the estrogen receptor antagonists Tamoxifen and ICI 182,780 in vivo and in vitro, respectively. Peripheral administration of Tamoxifen, which crosses the blood-brain barrier, prevented estradiol-mediated neuroprotection against KA-induced damage in the dentate gyrus. The highly selective estrogen receptor antagonist ICI 182,780, which does not penetrate into the brain from the periphery, also prevented estradiol's protective effects on KA-induced cell death in cultured hippocampal neurons but only late in the time course of injury. The data suggest that the neuroprotection afforded by estradiol against KA-induced injury in the female is estrogen receptor mediated but may include an additional mechanism that is not antagonized at the receptor.