Androgen Receptor Overexpression Is Neuroprotective in Experimental Stroke
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REVIEW
Androgen Receptor Overexpression Is Neuroprotective in Experimental Stroke Patricia Ayala & Masayoshi Uchida & Kozaburo Akiyoshi & Jian Cheng & Joel Hashimoto & Taiping Jia & Oline K. Ronnekleiv & Stephanie J. Murphy & Kristine M. Wiren & Patricia D. Hurn
Received: 25 February 2011 / Revised: 31 March 2011 / Accepted: 4 April 2011 / Published online: 15 April 2011 # Springer Science+Business Media, LLC 2011
Abstract Male sex is a known risk factor in human stroke. However, the role of the cognate receptor for androgens— the androgen receptor (AR)—in stroke outcome remains unclear. Here, we found that AR mRNA is downregulated in the peri-infarct tissue of gonadally intact male mice subjected to middle cerebral artery occlusion (MCAO) and 6 h reperfusion. We then used genetically engineered mice overexpressing AR in brain (AR-Tg) to compare outcomes from MCAO in intact or castrated males and to evaluate the neuroprotective role of dihydrotestosterone (DHT) replacement in AR-Tg castrates. A further evaluation of AR overexpression in ischemic paradigms was performed using rat PC12 cells transfected with human AR and treated with oxidative and apoptotic stressors. We then studied the role of DHT in cultures overexpressing AR. Our results show (1) ischemia alters the expression of AR by decreasing AR mRNA levels, (2) AR overexpression is protective in vivo
Section Disease-Related Neuroscience P. Ayala (*) : M. Uchida : K. Akiyoshi : J. Cheng : S. J. Murphy : K. M. Wiren : P. D. Hurn Department of Anesthesiology and Perioperative Medicine, Oregon Health & Science University, 3181 SW Sam Jackson Park Rd, Portland, OR 97239-3098, USA e-mail: [email protected] O. K. Ronnekleiv : P. D. Hurn Department of Physiology and Pharmacology, Oregon Health & Science University, Portland, OR 97239-3098, USA J. Hashimoto : T. Jia : K. M. Wiren Department of Behavioral Neuroscience, Oregon Health & Science University; Research Service, Portland Veterans Affairs Medical Center P3-R&D39, Portland, OR 97239, USA
against MCAO in intact and castrated AR-Tg mice and in vitro against oxidative and apoptotic stressors in AR-PC12 cells, and (3) DHT does not enhance the protection triggered by AR overexpression in AR-Tg castrated mice nor in AR-PC12 cells. Keywords Cerebral ischemia . Stroke . Androgen receptor . DHT . Transgenic mice . PC12
Introduction Sexual dimorphism in human stroke outcome has been well documented. Although male sex is a known risk factor [1], the role of androgens in male cerebral ischemia has been under-investigated. Low testosterone levels are associated with poor outcome after acute ischemia in men [2], yet findings from the few studies on the effect of androgens in rodent stroke are inconsistent. For instance, testosterone and dihydrotestosterone (DHT) have been shown to either protect against or exacerbate damage and dysfunction after cerebral ischemia [3–5]. Such variable results may have emerged from the use of different androgen doses or animals in different stages of life [1, 6]. To elucidate this apparent
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