Testosterone protects cerebellar granule cells from oxidative stress-induced cell death through a receptor mediated mechanism

It is known that steroid hormones can affect neuronal susceptibility to dif ferent types of insults, including oxidative stress. Using an in vitro/ex v ivo model, we have previously shown that cerebellar granule cells prepared from neonatal rats treated with a single dose of testosterone are less vuln erable to oxidative stress-induced cell death, via a mechanism involving an upregulation of the cellular antioxidant defenses. Whether the testosteron e protective action on cerebellar granule cells was direct or indirect rema ined to be clarified. Therefore, in this study we have investigated the eff ects of in vitro testosterone treatment, to see whether it also protects ce rebellar granule cells from oxidative stress-induced damage. Cerebellar gra nule cells treated with 10(-6) M testosterone for 48 h were found less susc eptible to damage induced by 50 muM hydrogen peroxide. as shown by a 30% de crease in the number of cells with apoptotic morphology. The addition of th e androgen receptor antagonist flutamide abolished the protective effect of testosterone, suggesting an androgen receptor-mediated mechanism. This hyp othesis was further supported by the presence of the androgen receptor in c ultured cerebellar granule cells. The activity of the antioxidant enzyme ca talase was also measured, and a 2-fold increase was detected in the testost erone treated cells, but not in the cells co-treated with flutamide. The pr esent results demonstrate that cerebellar granule cells treated in vitro wi th testosterone are protected from oxidative stress via a mechanism mediate d by the androgen receptor. Similarly to what we observed after in vivo adm inistration of testosterone, the potentiation of the antioxidant defences s eems to play a major role in the protection afforded by testosterone. (C) 2 001 Elsevier Science B.V. All rights reserved.