Ovarian hormones elicit phosphorylation of Akt and extracellular-signal regulated kinase in explants of the cerebral cortex.
Estradiol and progesterone both have been demonstrated to afford neuroprotection against various insults. In an attempt to identify potential mechanisms underlying these neuroprotective effects, two key elements within signal transduction pathways linked to neuroprotection were evaluated. In mouse cerebral cortical explants, both estradiol and progesterone elicited the phosphorylation of Akt, a downstream effector of the phosphoinositide-3 (PI-3) kinase pathway. Progesterone also elicited the phosphorylation of extracellular-signal regulated kinase (ERK), a component of the mitogen-activated protein kinase (MAPK) pathway. These effects were not inhibited by the progesterone receptor antagonist, RU486. However, inhibition of either MAPK/ERK kinase with PD98059 or PI-3 kinase with LY294002 successfully inhibited progesterone's actions on ERK and Akt, respectively. Collectively, the data offer novel mechanisms for both progesterone and estrogen action in the central nervous system, demonstrating the functional and mechanistic diversity of gonadal hormones and supporting their neuroprotective potential for such neurodegenerative disorders as Alzheimer disease.
Singh
M
M
Center for Reproductive Sciences and Department of Obstetrics and Gynecology, Columbia University, College of Physicians and Surgeons, New York, NY, USA. ms435@columbia.edu
D000818:Animals; D029681:Arabidopsis Proteins; D015153:Blotting, Western; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism*; D003720:Densitometry; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004958:Estradiol / Q000494:pharmacology*; D005260:Female; D005455:Fluorescent Antibody Technique; D006727:Hormone Antagonists / Q000494:pharmacology; D008297:Male; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009924:Organ Culture Techniques; D010053:Ovary / Q000502:physiology*; D010940:Plant Proteins / Q000378:metabolism*; D015221:Potassium Channels / Q000378:metabolism*; D011374:Progesterone / Q000037:antagonists & inhibitors / Q000494:pharmacology*
D029681:Arabidopsis Proteins; D004791:Enzyme Inhibitors; D006727:Hormone Antagonists; D010940:Plant Proteins; D015221:Potassium Channels; C074500:AKT1 protein, Arabidopsis; D011374:Progesterone; D004958:Estradiol; D020928:Mitogen-Activated Protein Kinases