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.

Sex-dependent Effect of BAG1 in Ameliorating Motor Deficits of Huntington Disease Transgenic Mice

“…Recent studies also demonstrate gender differences in both basal and inducible levels of various chaperones (41)(42)(43)(44) and that such gender-specific differences can be modulated by sex steroids (45,46). For example, estradiol increases chaperone expression in brain tissue (47), whereas testosterone inhibits the up-regulation of Hsp70 and Hsp90 in brain tissue following ischemia/reperfusion in rats (48). It should be noted that the neuroprotective effects of BAG1 on stroke were observed in male mice (10).…”

Greater stress protein expression enhanced by combined prostaglan-din A1and lithium in a rat model of focal ischemia

“…They are involved in the conformational maturation of signal transduction molecules (for example, nuclear hormone receptors and kinases) and in the cellular stress response [18] . The finding that HSP90 is induced in response to diverse apoptotic stimuli, such as UV, sodium arsenite and cerebral ischemia, has supported its involvement in cell survival [35][36][37] . Recently, it was reported that HSP90 could form a cytosolic complex with Apaf-1 and inhibit cytochrome c-mediated oligomerization of Apaf-1 and the activation of procaspase-9 [20] .…”

Effect of Endogenous Androgens on 17β-Estradiol-Mediated Protection after Spinal Cord Injury in Male Rats

“…Since testosterone can be aromatized to estrogen (Azcoitia et al, 2001), we hypothesized that endogenous testosterone would increase estrogen-mediated protection. However, previous work has shown that endogenous or exogenous testosterone increases excitotoxicity and lesion volume in a MCAO rodent model of ischemia (Yang et al, 2002(Yang et al, , 2005. Thus we evaluated the effect of endogenous, testicularderived testosterone on estrogen-mediated protection and outcome after SCI.…”