Isoflurane preconditioning neuroprotection in experimental focal stroke is androgen-dependent in male mice

• Published in: Neuroscience Vol. 169; no. 2; pp. 758 - 769
• Main Authors: Zhu, W, Wang, L, Zhang, L, Palmateer, J.M, Libal, N.L, Hurn, P.D, Herson, P.S, Murphy, S.J
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ltd 25-08-2010; Elsevier
• Subjects: androgen receptor; Androgen receptors; androgens; Androgens - blood; Androgens - pharmacology; Androgens - physiology; Anesthetics, Inhalation - therapeutic use; Animals; Aromatase - genetics; Aromatase Inhibitors - pharmacology; Biological and medical sciences; Brain - metabolism; Brain - pathology; dihydrotestosterone; Dihydrotestosterone - blood; Dihydrotestosterone - pharmacology; Estradiol - blood; Exploratory Behavior - drug effects; Fundamental and applied biological sciences. Psychology; Infarction, Middle Cerebral Artery - pathology; Infarction, Middle Cerebral Artery - prevention & control; Infarction, Middle Cerebral Artery - psychology; Ischemic Attack, Transient - pathology; Ischemic Attack, Transient - prevention & control; Ischemic Attack, Transient - psychology; Isoflurane - therapeutic use; Male; Medical sciences; Mice; Mice, Inbred C57BL; Mice, Knockout; Motor Activity - drug effects; Neurology; neuroprotection; Neuroprotective Agents - therapeutic use; Orchiectomy; preconditioning; Receptors, Androgen - physiology; Recognition (Psychology) - drug effects; testosterone; Testosterone - blood; Testosterone - pharmacology; Vascular diseases and vascular malformations of the nervous system; Vertebrates: nervous system and sense organs; P aO 2; androgens; dihydrotestosterone; aromatase wild-type; P aCO 2; partial arterial pressure oxygen; preconditioning; LDF; partial arterial pressure carbon dioxide; DHT; androgen receptor; analysis of variance; ANOVA; polymerase chain reaction; MCAO; testosterone; aromatase knockout; ArKO; laser Doppler flowmetry; AR; ArWT; neuroprotection; SEM; standard error of the mean; middle cerebral artery occlusion; PCR; Neuroprotection; Nervous system diseases; Stroke; Androgen; Rodentia; Cardiovascular disease; Male; Isoflurane; Cerebral disorder; Vascular disease; Testosterone; Vertebrata; Dihydrotestosterone; Mammalia; Anesthetic; Mouse; Animal; Central nervous system disease; Androgen receptor; Testicular hormone; Sex steroid hormone; Preconditioning; Cerebrovascular disease
• ISSN: 0306-4522; 1873-7544
• DOI: 10.1016/j.neuroscience.2010.05.038

Abstract Isoflurane preconditioning neuroprotection in experimental stroke is male-specific. The role of androgens in the ischemic sensitivity of isoflurane preconditioned male brain and whether androgen effects are androgen receptor dependent were assessed. Male C57BL/6 mice were implanted with flutamide (androgen receptor antagonist), or castrated and implanted with testosterone, dihydrotestosterone, flutamide, letrozole (aromatase inhibitor), or vehicle 7–13 days before preconditioning. P450 estrogen aromatase wild-type and knockout mice were also evaluated. All mice were preconditioned for 4 h with 0% (sham preconditioning) or 1% isoflurane (isoflurane preconditioning) and recovered for 24 h. Mice then underwent 2 h of middle cerebral artery occlusion and were evaluated 22 h later for infarct volume. For neurobehavioral outcomes, sham and isoflurane preconditioned castrated male±dihydrotestosterone groups underwent 1 h of middle cerebral artery occlusion followed by 9 days of reperfusion. Isoflurane preconditioning neuroprotection relative to infarct volume outcomes were testosterone and dihydrotestosterone dose-specific and androgen receptor-dependent. Relative to long-term neurobehavioral outcomes, front paw sensorimotor function improved in isoflurane preconditioned mice regardless of androgen status while androgen replacement independently improved sensorimotor function. In contrast, isoflurane preconditioning improved cognitive function in castrates lacking endogenous androgens, but this improvement was absent in androgen replaced mice. Our findings suggest that androgen availability during isoflurane preconditioning may influence infarct volume and neurobehavioral outcomes in male mice following experimental stroke.