17alpha-Estradiol is neuroprotective in male and female rats in a model of early brain injury.
One of the most critical times in the human lifespan is the late embryonic/early postnatal period, due to the careful orchestration of numerous events leading to normal brain development. This period is also characterized by a heightened incidence of harmful events that act via the GABAergic system, including hypoxia-ischemia, seizures and drug exposure from maternal circulation (e.g., alcohol, barbiturates). Unfortunately, there are few effective means of attenuating damage in the immature brain. In the current investigation, we documented the effect of 17alpha-estradiol, a natural epimer of 17beta-estradiol that has potent estrogen receptor-independent actions, on excessive GABA(A) receptor-induced damage to the neonatal brain. We observed that treatment with 17alpha-estradiol significantly attenuates the GABA(A) receptor-induced reduction in hippocampal volume and impaired hippocampal-dependent performance on the Morris water maze and radial arm maze. 17alpha-Estradiol-mediated neuroprotection is hypothesized to be achieved by attenuating GABA(A) receptor-induced cell loss, assessed in primary hippocampal cultures using both the lactate dehydrogenase assay and TUNEL, with equivalent prevention of cell loss in the presence or absence of the estrogen receptor antagonist, ICI-182,780. These data highlight one of the initial investigations of the neuroprotective potential of 17alpha-estradiol in an in vivo model of injury to the immature brain.
McClean
Jacob
J
Neuroscience Program and Department of Psychology, Michigan State University, East Lansing, MI 48824, USA.
Nuñez
Joseph L
JL
D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D001522:Behavior, Animal / Q000187:drug effects; D001930:Brain Injuries / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004958:Estradiol / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use*; D004965:Estrogen Antagonists / Q000494:pharmacology; D005260:Female; D000077267:Fulvestrant; D018755:GABA Agonists / Q000494:pharmacology; D006624:Hippocampus / Q000166:cytology; D020287:In Situ Nick-End Labeling; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D009118:Muscimol / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012737:Sex Factors; D013997:Time Factors
D004965:Estrogen Antagonists; D018755:GABA Agonists; D018696:Neuroprotective Agents; D000077267:Fulvestrant; D009118:Muscimol; D004958:Estradiol; D007770:L-Lactate Dehydrogenase