Hippocampal responsiveness to 17β-estradiol and equol after long-term ovariectomy: implication for a therapeutic window of opportunity.
A 'critical window of opportunity' has been proposed for the efficacy of ovarian hormone intervention in peri- and post-menopausal women. We sought to address this hypothesis using a long-term ovariectomized non-human primate (NHP) model, the cynomolgus macaque (Macaca fascicularis). In these studies, we assessed the ability of 17β-estradiol and equol to regulate markers of hippocampal bioenergetic capacity. Results indicated that 17β-estradiol treatment significantly increased expression of mitochondrial respiratory chain proteins complex-I and -III in the hippocampus when compared to non-hormone-treated animals. Expression of the TCA cycle protein succinate dehydrogenase α was decreased in animals treated with equol compared to those treated with 17β-estradiol. There were no significant effects of either 17β-estradiol or equol treatment on glycolytic protein expression in the hippocampus, nor were there significant effects of treatment on expression levels of antioxidant enzymes. Similarly, 17β-estradiol and equol treatment had no effect on mitochondrial fission and fusion protein expression. In summary, findings indicate that while 17β-estradiol induced a significant increase in several proteins, the overall profile of bioenergetic system proteins was neutral to slightly positively responsive. The profile of responses with the ERβ-preferring molecule equol was consistent with overall nonresponsiveness. Collectively, the data indicate that long-term ovariectomy is associated with a decline in response to estrogens and estrogen-like compounds. By extension, the data are consistent with a primary tenet of the critical window hypothesis, i.e., that the brains of post-menopausal women ultimately lose their ability to respond positively to estrogenic stimulation.
Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA 90089, USA.
Ryan T
RT
Hamilton
Jamaica R
JR
Rettberg
Zisu
Z
Mao
Jimmy
J
To
Liqin
L
Zhao
Susan E
SE
Appt
Thomas C
TC
Register
Jay R
JR
Kaplan
Roberta Diaz
RD
Brinton
D000367:Age Factors; D000818:Animals; D004334:Drug Administration Schedule; D060754:Equol / Q000494:pharmacology* / Q000627:therapeutic use; D004958:Estradiol / Q000494:pharmacology* / Q000627:therapeutic use; D005260:Female; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism*; D008252:Macaca fascicularis; D010052:Ovariectomy; D013997:Time Factors
D004958:Estradiol; D060754:Equol
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