Estrogen activates protein kinase C in neurons: role in neuroprotection.
It has been previously demonstrated that estrogen can protect neurons from a variety of insults, including beta-amyloid (Abeta). Recent studies have shown that estrogen can rapidly modulate intracellular signaling pathways involved in cell survival. In particular, estrogen activates protein kinase C (PKC) in a variety of cell types. This enzyme plays a key role in many cellular events, including regulation of apoptosis. In this study, we show that 17beta-estradiol (E2) rapidly increases PKC activity in primary cultures of rat cerebrocortical neurons. A 1 h pre-treatment with E2 or phorbol-12-myristate-13-acetate (PMA), a potent activator of PKC, protects neurons against Abeta toxicity. Protection afforded by both PMA and E2 is blocked by pharmacological inhibitors of PKC. Further, depletion of PKC levels resulting from prolonged PMA exposure prevents subsequent E2 or PMA protection. Our results indicate that E2 activates PKC in neurons, and that PKC activation is an important step in estrogen protection against Abeta. These data provide new understanding into the mechanism(s) underlying estrogen neuroprotection, an action with therapeutic relevance to Alzheimer's disease and other age-related neurodegenerative disorders.
Cordey
Myriam
M
Neuroscience Graduate Program, Keck School of Medicine, Department of Cell and Neurobiology, Andrus Gerontology Center, University of Southern California, Los Angeles, California 90089-0191, USA.
Gundimeda
Usha
U
Gopalakrishna
Rayudu
R
Pike
Christian J
CJ
D016229:Amyloid beta-Peptides / Q000494:pharmacology; D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D019610:Cytoprotection / Q000187:drug effects / Q000502:physiology; D004789:Enzyme Activation / Q000187:drug effects; D020536:Enzyme Activators / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004958:Estradiol / Q000494:pharmacology; D004967:Estrogens / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010446:Peptide Fragments / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
D016229:Amyloid beta-Peptides; D020536:Enzyme Activators; D004791:Enzyme Inhibitors; D004967:Estrogens; D018696:Neuroprotective Agents; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D004958:Estradiol; D011493:Protein Kinase C; D013755:Tetradecanoylphorbol Acetate