Testosterone amplifies excitotoxic damage of cultured oligodendrocytes

Abstract

An overactivation of a-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA)/kainate receptors has been implicated in the pathophysiology of oligodendrocyte damage in demyelinating disorders of the CNS. We decided to examine the effect of testosterone on excitotoxic death of oligodendrocytes because a gender difference exists in the incidence and disease course of multiple sclerosis. Short-term pure cultures of oligodendrocytes (4 days in vitro) were exposed to a brief pulse with kainate or AMPA + cyclothiazide for the induction of excitotoxicity. Exposure to testosterone enantate was slightly toxic per se and amplified both AMPA and kainate toxicity. Testosterone treatment induced all gene targets of p53, and amplified the induction of these genes induced by kainate. The effect of testosterone was mediated by the activation of androgen receptors and was resistant to the aromatase inhibitors, DL-aminoglutethimide and 4-hydroxyandrost-4-ene-3,17-dione. Testosterone treatment also potentiated the stimulation of 45 Ca 2+ influx induced by AMPA + cyclothiazide or kainate without changing the expression of the glutamate receptor (GluR) 1, -2/3, and -4 subunits of AMPA receptors or the GluR6/7 subunits of kainate receptors. We conclude that testosterone amplifies excitotoxic damage of oligodendrocytes acting at an early step of the death cascade triggered by AMPA/kainate receptors.

Diabetic neuropathic pain: a role for testosterone metabolites

“…These results indicate that testosterone metabolites are valuable candidates for the treatment of diabetic neuropathic pain, at least in male individuals. However, since androgens may have adverse effects, including the induction of neuronal apoptosis (Yang et al 2002, Caruso et al 2004, Estrada et al 2006, Gatson & Singh 2007, further studies are necessary to exclude undesirable effects of the treatments before envisaging a possible clinical application of the present findings.…”

Non-genomic actions of androgens

“…For example, T was shown to exacerbate the size of a lesion resulting from middle cerebral artery occlusion in male rats [166; 167]. Furthermore, T treatment increased kainic acid-induced cell death of cultured oligodendrocytes [168]. Thus, androgens can be protective or damage promoting, but the mechanism underlying this duality is still unclear.…”

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

“…Alternatively, other data show that testosterone can induce cell death. For example, superphysiological levels of testosterone have been shown to induce neuronal and glial cell death and to amplify excitotoxicity in vitro (Caruso et al, 2004;Gatson and Singh, 2007;Orlando et al, 2007). Furthermore, colleagues (2002, 2005) have demonstrated that chronic testosterone replacement increased lesion volume in a middle cerebral artery occlusion model in male rats, and that gonadectomy or administration of 17b-estradiol reduced lesion volume, which suggests that testosterone may be deleterious in CNS injury.…”