Fas/FasL-mediated apoptosis in the arcuate nucleus and medial preoptic area of male ArKO mice is ameliorated by selective estrogen receptor alpha and estrogen receptor beta agonist treatment, respectively

The aromatase (ArKO) knockout mouse is estrogen deficient. Our previous analysis revealed apoptosis of dopaminergic neurons in the arcuate nucleus (Arc) and medial preoptic area (MPO) of 1-year-old male ArKO mice. We sought to determine which estrogen receptor (ER) is involved in the anti-apoptotic action of estrogen. Male ArKO (9.5-month-old) mice were treated with 16alpha-LE(2) (ERalpha-specific agonist) or 8beta-VE(2) (ERbeta-specific agonist). Daily injections (6 weeks) with 16alpha-LE(2) prevented dopaminergic cell death in the Arc of male ArKO mice, with no significant effect of 8beta-VE(2) treatment. In contrast, 8beta-VE(2) prevented dopaminergic cell death in the MPO, while 16alpha-LE(2) had no significant effect. Concomitant decreases in Fas and FasL protein levels were found upon 16alpha-LE(2) and 8beta-VE(2) treatment in the Arc and MPO, respectively. Our results indicate that anti-apoptotic effects of estrogen are ER mediated, and the specific ER subtype involved in regulating apoptosis depends on the particular brain nucleus in question.