INHIBITION OF HYPOXIA INDUCIBLE FACTOR 1A BY SOY PHYTOESTROGENS: A POTENTIAL MECHANISM FOR NEUROPROTECTION IN STROKE

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2013-04-12

Authors

Namuduri, Anuradha

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Abstract

Purpose: Despite a multitude of endogenous mechanisms to compensate for transient decreases in glucose and oxygen delivery to the brain, ischemic stroke remains the third leading cause of death and the leading cause of long-term disability in the United States. Studies in animal models of cerebral ischemia have shown that both endogenous and exogenous estrogens improve histological and behavioral stroke outcomes. Similarly, phytoestrogens derived from soy and other plant products can reduce stroke injury in the lab. These compounds are structurally similar to estrogen and bind to and activate estrogen receptors. Our overall hypothesis is that soy phytoestrogens can induce adaptive responses in the brain to favor increased survival and cell repair. One early adaptive response to ischemia is activation of the oxygen homeostasis mediator hypoxia-inducible factor 1 alpha (HIF-1 alpha), a normally labile protein that is stable under conditions of low oxygen. Despite the importance of HIF-1 alpha in the adaptive response to hypoxia and ischemia, acute overactivation of this protein increases cerebral edema and cell death. The purpose of this research is to determine if soy phytoestrogens (genistein, daidzein, equol) inhibit acute ischemic injury by attenuating the detrimental actions of HIF-1 alpha. Methods: In vitro, HT22 hippocampal cells were treated with 0.1 or 1 micromolar genistein and exposed to oxygen and glucose deprivation to mimic conditions of ischemia within the brain. In vivo, ovariectomized female Sprague Dawley rats were fed a soy-free or high soy diet for 4 weeks followed by 90 minutes experimental stroke and 4-24 hours of recovery. HIF-1 alpha levels were determined by Western blotting for the HIF-1 alpha targets vascular endothelial growth factor (VEGF), endothelial nitric oxide synthase (eNOS), and BCL2/adenovirus E1B 19kDa interacting protein 3 (BNIP3). Results: In HT22 cells, genistein attenuated the HIF-1 alpha response to ischemia and increased degradation of HIF-1 alpha. Rats fed a high soy diet had significantly decreased levels of HIF-1 alpha and it's targets VEGF, eNOS, and BNIP3 in the ischemic hemisphere compared to rats on a soy-free diet. Conclusions: These results suggest that one mechanism of phytoestrogen neuroprotection is the attenuation of acute detrimental effects of HIF-1 alpha. These results further support the potential for dietary phytoestrogens as an effective prophylactic step in the prevention and management of ischemic strokes.

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