Ovarian steroids reduce apoptosis induced by trophic insufficiency in nerve growth factor-differentiated PC12 cells and axotomized rat facial motoneurons.
Previous studies have demonstrated that ovarian steroids exert neuroprotective effects in a variety of in vitro and in vivo systems. The mechanisms underlying these effects remain poorly understood. In the present study, the neuroprotective effects of estradiol (E(2)) and progesterone (P) were examined in two models of apoptosis induced by growth factor insufficiency: partially nerve growth factor (NGF)-differentiated PC12 cells, after serum and NGF withdrawal; and axotomized immature rat facial motor motoneurons. E(2) and P both increased the survival of trophically withdrawn NGF-differentiated PC12 cells, at physiologically relevant concentrations. However, neither steroid had a significant effect on the survival of PC12 cells that had not been NGF treated. Exposure to NGF had no effect on the expression of estrogen receptor (ER)beta, but markedly increased the levels of ERalpha and altered the expression of the progesterone receptor (PR) from predominantly PR-B in NGF naive cells, to predominantly PR-A after NGF. The survival promoting effects of E(2) and P were blocked by the specific steroid receptor antagonists Faslodex (ICI 182780) and onapristone (ZK98299), respectively. Inhibitors of RNA (actinomycin D) or protein (cycloheximide) synthesis also abrogated the protective effects of both steroids. In immature rats, E(2) and P both significantly increased the numbers of surviving facial motor neurons at 21 days after axotomy. These data demonstrate significant protective effects of E(2) and P in two well-characterized models of apoptosis induced by trophic withdrawal and suggest that, at least in PC12 cells, the effects of the steroids are mediated via interaction with nuclear steroid receptor systems. The lack of steroid responsiveness in NGF-naive PC12 cells despite the presence of abundant ERbeta and PR-B are consistent with the view that ERalpha and PR-A may be particularly important as mediators of the neuroprotective effects of their corresponding hormonal ligands.
MacLusky
N J
NJ
Center for Reproductive Sciences, Department of Obstetrics and Gynecology, Columbia-Presbyterian Medical Center, 622 West 168th Street, New York, NY 10032-3702, USA. nm274@columbia.edu
Chalmers-Redman
R
R
Kay
G
G
Ju
W
W
Nethrapalli
I S
IS
Tatton
W G
WG
D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D019771:Axotomy; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002795:Choline O-Acetyltransferase / Q000378:metabolism; D016895:Culture Media, Serum-Free / Q000494:pharmacology; D004347:Drug Interactions / Q000502:physiology; D004958:Estradiol / Q000031:analogs & derivatives* / Q000494:pharmacology* / Q000627:therapeutic use; D047628:Estrogen Receptor alpha; D020220:Facial Nerve Injuries / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D000077267:Fulvestrant; D006067:Gonanes / Q000494:pharmacology; D020932:Nerve Growth Factor / Q000172:deficiency / Q000494:pharmacology; D018696:Neuroprotective Agents / Q000494:pharmacology* / Q000627:therapeutic use; D016716:PC12 Cells; D011374:Progesterone / Q000494:pharmacology* / Q000627:therapeutic use; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011960:Receptors, Estrogen / Q000037:antagonists & inhibitors / Q000378:metabolism; D011980:Receptors, Progesterone / Q000037:antagonists & inhibitors / Q000378:metabolism; D012183:Retrograde Degeneration / Q000188:drug therapy* / Q000378:metabolism / Q000517:prevention & control
D016895:Culture Media, Serum-Free; D047628:Estrogen Receptor alpha; D006067:Gonanes; D018696:Neuroprotective Agents; D011500:Protein Synthesis Inhibitors; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; C101118:progesterone receptor A; D000077267:Fulvestrant; D011374:Progesterone; D004958:Estradiol; D020932:Nerve Growth Factor; D002795:Choline O-Acetyltransferase; C053238:onapristone