Cerebroprotective Effect of 17β-Estradiol Replacement Therapy in Ovariectomy-Induced Post-Menopausal Rats Subjected to Ischemic Stroke: Role of MAPK/ERK1/2 Pathway and PI3K-Independent Akt Activation
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Updated: Jul 15, 2025
Ovariectomy and 17β-estradiol Replacement in Rats and Mice: A Visual Demonstration
Published on: June 7, 2012
María C Burguete1,2, Teresa Jover-Mengual1,2, María Castelló-Ruiz1,3
1Unidad Mixta de Investigación Cerebrovascular, Instituto de Investigación Sanitaria La Fe, Universitat de València, 46100 Burjassot, Spain.
Abstract:
Despite the overwhelming advances in the understanding of the pathogenesis of stroke, a devastating disease affecting millions of people worldwide, currently there are only a limited number of effective treatments available. Preclinical and clinical studies show that stroke is a sexually dimorphic disorder, affecting males and females differently. Strong experimental evidence indicates that estrogen may play a role in this difference and that exogenous 17β-estradiol (E2) is neuroprotective against stroke in both male and female rodents. However, the molecular mechanisms by which E2 intervenes in ischemia-induced cell death, revealing these sex differences, remain unclear. The present study was aimed to determine, in female rats, the molecular mechanisms of two well-known pro-survival signaling pathways, MAPK/ERK1/2 and PI3K/Akt, that mediate E2 neuroprotection in response to acute ischemic stroke. E2 pretreatment reduced brain damage and attenuated apoptotic cell death in ovariectomized female rats after an ischemic insult. Moreover, E2 decreased phosphorylation of ERK1/2 and prevented ischemia/reperfusion-induced dephosphorylation of both Akt and the pro-apoptotic protein, BAD. However, MAPK/ERK1/2 inhibitor PD98059, but not the PI3K inhibitor LY294002, attenuated E2 neuroprotection. Thus, these results suggested that E2 pretreatment in ovariectomized female rats modulates MAPK/ERK1/2 and activates Akt independently of PI3K to promote cerebroprotection in ischemic stroke. A better understanding of the mechanisms and the influence of E2 in the female sex paves the way for the design of future successful hormone replacement therapies.
Insights
Estrogen (17β-estradiol) protects female rats from stroke by modulating the MAPK/ERK1/2 pathway and activating Akt. This research clarifies estrogen
Area of Science:
- Neuroscience
- Endocrinology
- Cell Signaling
Background:
- Stroke is a leading cause of death and disability worldwide, with limited effective treatments.
- Stroke exhibits sexual dimorphism, with estrogen implicated in neuroprotection.
- The precise molecular mechanisms of estrogen's neuroprotective effects in stroke remain unclear.
Purpose of the Study:
- To elucidate the molecular mechanisms of 17β-estradiol (E2) neuroprotection in female rats following ischemic stroke.
- To investigate the roles of MAPK/ERK1/2 and PI3K/Akt signaling pathways in E2-mediated cerebroprotection.
- To understand the sex-specific mechanisms of estrogen's influence on stroke outcomes.
Main Methods:
- Ovariectomized female rats were pretreated with 17β-estradiol (E2) before inducing ischemic stroke.
- Brain damage and apoptotic cell death were assessed.
- Levels of phosphorylated MAPK/ERK1/2, Akt, and BAD were measured.
- Specific inhibitors (PD98059 for MAPK/ERK1/2, LY294002 for PI3K) were used to probe signaling pathways.
Main Results:
- E2 pretreatment significantly reduced brain damage and attenuated apoptosis in female rats post-stroke.
- E2 decreased MAPK/ERK1/2 phosphorylation and prevented ischemia/reperfusion-induced dephosphorylation of Akt and BAD.
- Inhibition of MAPK/ERK1/2 (but not PI3K) attenuated E2's neuroprotective effects.
- E2 activated Akt independently of the PI3K pathway.
Conclusions:
- 17β-estradiol (E2) exerts neuroprotection in female rats against ischemic stroke.
- E2 modulates the MAPK/ERK1/2 pathway and activates Akt independently of PI3K to confer cerebroprotection.
- Understanding these mechanisms can inform future hormone replacement therapies for stroke prevention and treatment in women.
