TY - JOUR
T1 - Androgen Receptor Overexpression Is Neuroprotective in Experimental Stroke
AU - Ayala, Patricia
AU - Uchida, Masayoshi
AU - Akiyoshi, Kozaburo
AU - Cheng, Jian
AU - Hashimoto, Joel
AU - Jia, Taiping
AU - Ronnekleiv, Oline K.
AU - Murphy, Stephanie J.
AU - Wiren, Kristine M.
AU - Hurn, Patricia D.
N1 - Funding Information:
Acknowledgements We thank Ms. Kathy Gage for her outstanding editorial assistance. This research was funded by National Institute of Health grants NS 33668, NR 003521, and NS 49210.
PY - 2011/9
Y1 - 2011/9
N2 - 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 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.
AB - 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 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.
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U2 - 10.1007/s12975-011-0079-z
DO - 10.1007/s12975-011-0079-z
M3 - Review article
C2 - 24323653
AN - SCOPUS:80052278478
SN - 1868-4483
VL - 2
SP - 346
EP - 357
JO - Translational Stroke Research
JF - Translational Stroke Research
IS - 3
ER -