Journal
STEROIDS
Volume 78, Issue 6, Pages 624-632Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.steroids.2012.11.004
Keywords
Estrogen; Dkk1; Hippocampus; Long-term estrogen deprivation; Menopause; Neuroprotection
Funding
- American Heart Association [12PRE11530009, 10SDG2560092]
- NINDS, National Institutes of Health [NS050730]
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Surgically menopausal women incur a 2- to 5-fold increased risk for dementia and mortality from neurological diseases, but the mechanisms underlying these increased risks remain unclear. Previously, we demonstrated that after global cerebral ischemia (GC), 17 beta-estradiol (E2 or estrogen) suppresses hippocampal elevation of the Wnt antagonist Dickkopf-1 (Dkk1), a neurodegenerative factor. We, thus, hypothesized that prolonged loss of E2 may lead to dysregulation of neural Dkk1 and Wnt/beta-Catenin signaling, which could contribute to an increased risk of neurodegeneration. To test this hypothesis, we examined the effect of short-term (1 week - STED) and long-term E2 deprivation (10 weeks - LTED) via ovariectomy upon basal and E2-regulated Dkk1 levels and Wnt/beta-Catenin signaling in the hippocampal CA1 region following GCI. In STED rats, E2 exerted robust neuroprotection against GCI, suppressed post-ischemic elevation of Dkk1, and enhanced pro-survival Wnt/beta-Catenin signaling, effects that were lost in LTED rats. Intriguingly, LTED rats displayed modest basal changes in Dkk1 and survivin expression. Further work showed that c-Jun N-terminal Kinase (JNK) mediated GCI-induced changes in Dkk1 and survivin, and JNK inhibition afforded neuroprotection in LTED rats. Finally, we extended our findings to natural aging, as 24-month-old, reproductively senescent female rats also displayed a modest increase in basal Dkk1 in the CA1, which consistently co-localized with the apoptotic marker TUNEL after GCI and coincided with a loss of E2 neuroprotection. As a whole, this study supports the critical period hypothesis and further suggests that perimenopausal estradiol replacement may prevent neurodegenerative changes in the hippocampus by maintaining favorable Wnt/beta-Catenin signaling. (C) 2012 Elsevier Inc. All rights reserved.
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