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Published on: June 7, 2012
Neuroprotective effects of estradiol in newborn female rat hippocampus
Genell D Hilton1, Adanma N Ndubuizu, Margaret M McCarthy
1Department of Physiology, University of Maryland, 655 W. Baltimore St., Room 5-014, Baltimore, MD 21201, USA. Ghilt001@umaryland.edu
Insights
Estradiol protects the female brain from glutamate-induced injury by activating estrogen receptors. This neuroprotection against kainic acid (KA) damage in neonatal rats involves receptor-mediated pathways, potentially with additional mechanisms.
Area of Science:
- Neuroscience
- Developmental Neuroscience
- Neuroprotection
Background:
- Perinatal brain injury from hypoxia/ischemia involves excessive glutamate release.
- Estradiol prevents glutamate-induced damage in the female neonatal rat dentate gyrus.
- Understanding estradiol's neuroprotective mechanism is crucial for treating neonatal brain injury.
Purpose of the Study:
- To investigate the cellular mechanisms underlying estradiol's neuroprotective effects.
- To determine the role of estrogen receptors in estradiol-mediated neuroprotection.
- To differentiate between direct and indirect receptor-mediated effects.
Main Methods:
- Utilized kainic acid (KA) to induce excitotoxic injury in neonatal rats and cultured hippocampal neurons.
- Administered estrogen receptor antagonists Tamoxifen (in vivo) and ICI 182,780 (in vitro).
- Assessed the impact of antagonists on estradiol's ability to prevent KA-induced neurotoxicity.
Main Results:
- Tamoxifen blocked estradiol's neuroprotection against KA-induced damage in vivo.
- ICI 182,780 inhibited estradiol's protective effects in cultured neurons, particularly later in the injury timeline.
- Estradiol's neuroprotection is estrogen receptor-dependent but may involve additional pathways.
Conclusions:
- Estradiol confers neuroprotection against excitotoxic injury via estrogen receptors.
- The protective mechanism involves both central and potentially peripheral estrogen receptor signaling.
- Additional non-estrogen receptor-mediated pathways may contribute to estradiol's neuroprotective effects in the neonatal female brain.
Abstract:
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.
