title: Neuroendocrine mechanism for tolerance to cerebral ischemia-reperfusion injury in male rats.
abstract: Testosterone has been shown to exacerbate cerebral ischemia-reperfusion injury, which suggests that the well-known stress-induced testosterone reduction could be a protective response. We hypothesized that stress-induced testosterone reduction contributes to ischemia tolerance in cerebral ischemia-reperfusion injury in male rats. In intact male rats, stress was induced by brief anesthesia at 6 h before transient middle cerebral artery occlusion (MCAO). Testosterone levels were significantly decreased 6 h after stress. Testosterone reduction was associated with a 50% reduction in cerebral lesion volume in the stressed animals. Further, the stress-induced cerebral ischemia tolerance was eliminated by testosterone replacement in castrated males. Immunohistochemical staining showed that androgen receptors were up-regulated after cerebral ischemia-reperfusion injury and partially colocalized with terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) positive cells in the parietal cortex and extensively colocalized in the caudate putamen. Heat shock protein 70 (Hsp70) and 90 (Hsp90) are involved in ischemia tolerance, and were not colocalized with TUNEL in the immunohistochemical staining, suggesting an antiapoptotic role of Hsp's. To determine the effect of testosterone on MCAO-induced Hsp70 and -90 expression, a testosterone replacement or withdrawal paradigm was used. Testosterone-replaced animals exhibited a decrease in Hsp expression, whereas testosterone withdrawal (mimicking the stress-induced testosterone suppression) normalized this deficit. In summary, stress-induced testosterone reduction contributes to ischemia tolerance in cerebral ischemia-reperfusion injury in males, which could be related to the loss of inhibition by testosterone of Hsp70 and -90 expression.
authors.affiliation: Department of Pharmacology and Neuroscience, Health Science Center at Fort Worth, University of North Texas, Fort Worth, Texas 76107, USA.
authors.forename: Shao-Hua
authors.initials: SH
authors.lastname: Yang
authors.forename: Ran
authors.initials: R
authors.lastname: Liu
authors.forename: Yi
authors.initials: Y
authors.lastname: Wen
authors.forename: Evelyn
authors.initials: E
authors.lastname: Perez
authors.forename: Jason
authors.initials: J
authors.lastname: Cutright
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Brun-Zinkernagel
authors.forename: Meharvan
authors.initials: M
authors.lastname: Singh
authors.forename: Arthur L
authors.initials: AL
authors.lastname: Day
authors.forename: James W
authors.initials: JW
authors.lastname: Simpkins
mesh_terms: D000818:Animals; D002545:Brain Ischemia / Q000209:etiology / Q000378:metabolism*; D016923:Cell Death; D004195:Disease Models, Animal; D007839:Functional Laterality; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism; D015151:Immunoblotting / Q000379:methods; D020287:In Situ Nick-End Labeling / Q000379:methods; D020244:Infarction, Middle Cerebral Artery / Q000150:complications / Q000378:metabolism; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D011944:Receptors, Androgen / Q000378:metabolism; D015427:Reperfusion Injury / Q000209:etiology / Q000378:metabolism*; D013312:Stress, Physiological / Q000097:blood*; D013739:Testosterone / Q000378:metabolism*; D013997:Time Factors
chemical_list: D018840:HSP70 Heat-Shock Proteins; D018841:HSP90 Heat-Shock Proteins; D011944:Receptors, Androgen; D013739:Testosterone