Dose-dependent effects of androgens on outcome after focal cerebral ischemia in adult male mice.
Males exhibit greater histologic and behavioral impairment after stroke than do age-matched females. However, the contribution of androgens to stroke outcome remains unclear. We compared outcomes from middle cerebral artery occlusion (MCAO) in castrated mice with those in testosterone- or dihydrotestosterone (DHT)-replaced castrated mice. Castrates treated with 1.5 mg testosterone or 0.5 mg DHT before MCAO showed smaller infarct volumes (hemisphere: 27 or 26%) at 24 h after 90 mins MCAO than did untreated castrates (37%), whereas 5 mg testosterone or 1.5 mg DHT exacerbated infarcts (53 or 51%). These outcomes were blocked by the androgen receptor antagonist, flutamide, suggesting that androgen receptors mediate these responses to ischemia. We further evaluated long-term outcomes with a milder 60-min MCAO in castrates treated with the protective 1.5 mg testosterone dose. Consistent with data obtained at 24 h reperfusion, the infarct volume was decreased at 9 days reperfusion. Neurobehavioral analysis showed that motor functional recovery was improved during the first 3 days of reperfusion, but not improved at 7 days. We conclude that testosterone exhibits dose-dependent and time-sensitive effects after ischemia and that testosterone is likely to be an important factor in sex-linked differences in cerebrovascular disease.
Department of Anesthesiology and Peri-Operative Medicine, Oregon Health & Science University, Portland, Oregon 97239-3098, USA.
Masayoshi
M
Uchida
Julie M
JM
Palmateer
Paco S
PS
Herson
A Courtney
AC
DeVries
Jian
J
Cheng
Patricia D
PD
Hurn
D000726:Androgen Antagonists / Q000494:pharmacology; D059002:Androgen Receptor Antagonists; D000728:Androgens / Q000378:metabolism* / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D002545:Brain Ischemia / Q000209:etiology / Q000378:metabolism* / Q000517:prevention & control*; D002369:Castration; D013196:Dihydrotestosterone / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D020244:Infarction, Middle Cerebral Artery / Q000150:complications; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011944:Receptors, Androgen / Q000378:metabolism*; D012727:Sex Characteristics; D013739:Testosterone / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use
D000726:Androgen Antagonists; D059002:Androgen Receptor Antagonists; D000728:Androgens; D011944:Receptors, Androgen; D013196:Dihydrotestosterone; D013739:Testosterone