Potential effects of gender disparity in downregulation of AKT after post-cerebral ischemia and reperfusion

Research Article

Received February 22, 2018; Accepted July 10, 2018; Published August 12, 2018
http://dx.doi.org/10.18081/2333-5106/015-10/619-630

John M. Morrison^a, Claire B. Gibson, Zhan Wang, Daniel H. Klionsky

Author Affiliations

a Department of Neurology, School of Medicine, University of Bristol, Medical Sciences Building, Bristol, BS8 1TD, United Kingdom.

Abstract

Sex-dependent differences exist in stroke susceptibility, prevalence, severity, and response to treatment in humans. It is well documented that age, sex, and hormonal fluctuations alter not only the course of acute brain insult but also the inflammatory responses during the recovery phase. However, the underlying molecular mechanisms of sex differences following exogenous stimulation remain unclear, particularly in males and females. It is worth mentioning that activation of the protein kinase B AKT pathway followed by experimental brain ischemia/reperfusion injury (tMCAO/R) is attenuated to a greater extent in females than in males and is blocked by estrogen depletion in females. Conclusion: We have shown beyond doubt that there are gender differences in the responses of the phosphatidylinositol 3-kinase PI3K/AKT pathway after tMCAO/R. Disruption of endogenous testosterone synthesis worsens tMCAO/R outcomes in males and causes exogenously administered estrogens to lose their protective effects. Our findings suggest that there may be an ATP-protective therapeutic window in the early hours after a stroke in both men and women. Based on the length of the gap in response to ischemia/reperfusion in humans and the findings in the DoTS, we predict that treatment of men early after a stroke with synthetic S-equol will be beneficial in terms of outcome. These findings suggest that women are delayed in their response to ischemia/reperfusion injury and that early treatment with synthetic S-equol is beneficial in men, but older women should adjust their traditional dose of neuroprotective medications and men should consider delaying their onset of treatment in women.

Keywords: Cerebral stroke; Akt pathway; Bcl-2/Bax; Ischemia/Reperfusion

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