Estrogen exerts neuroprotective effects via membrane estrogen receptors and rapid Akt/NOS activation.
The neuroprotective role of estrogen (E2) is supported by a multitude of experimental and epidemiological data, although its mode of action is not fully understood. The present work was conducted to study the underlying mechanisms of its neuroprotective action, using the rat cell line PC12, an established model for neuronal cell apoptosis and survival. Our results show that E2 (but not androgens or progestins) prevent growth inhibition and apoptosis of PC12 cells, induced by serum deprivation. Several mechanisms of action were investigated: 1) intracellular estrogen receptors (ERs) have been identified but do not appear to mediate the protective effect of E2. 2) The antioxidant properties of E2 cannot explain their protective actions at the concentrations used (10(-12)-10(-6) M). 3) Finally, membrane sites for E2 have been identified, and the underlying initial signaling cascade (2-30 min after E2) has been tested, showing Ca(2+) mobilization-->PI3K activation-->Akt phosporylation-->NOS activation. Inhibition of PI3K or NOS completely reversed the anti-apoptotic effect of E2. These results suggest a new mechanism of neuroprotective action of estrogen.
Alexaki
Vasilia-Ismini
VI
Laboratory of Experimental Endocrinology, University of Crete, School of Medicine, Heraklion, Greece.
Charalampopoulos
Ioannis
I
Kampa
Marilena
M
Vassalou
Helen
H
Theodoropoulos
Panayiotis
P
Stathopoulos
Efstathios N
EN
Hatzoglou
Anastassia
A
Gravanis
Achille
A
Castanas
Elias
E
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002462:Cell Membrane / Q000378:metabolism*; D016895:Culture Media, Serum-Free / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D004967:Estrogens / Q000494:pharmacology*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D019001:Nitric Oxide Synthase / Q000378:metabolism*; D016716:PC12 Cells; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D051381:Rats; D011960:Receptors, Estrogen / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
D016895:Culture Media, Serum-Free; D004967:Estrogens; D018696:Neuroprotective Agents; D011518:Proto-Oncogene Proteins; D011960:Receptors, Estrogen; D019001:Nitric Oxide Synthase; C494920:Akt1 protein, rat; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt