Metabolism and effects of testosterone in the spinal cord from Wobbler-ALS mice after treatment with exogenous testosterone

LARA A; A LIMA; CLAUDIA GONZALEZ DENISELLE; M MEYER; P ROIG; A. F. DE NICOLA; ESPERANTE I; LIERE P; GUENNOUN R

Congreso; Reunion de la sociedad Argentina de Investigacion Clinica; 2020

Amyotrophic lateral sclerosis(ALS) patients present motoneuron degeneration leading to muscle atrophy,dysphagia and dysarthria. The Wobbler (WR)-ALS mice, a recognized model of thisdisease, shows a selective loss of motoneurons, astrocytosis andmicrogliosis in cervical spinal cord (CSC). The incidence of ALS isgreater in men; however it increases in women after menopause, suggesting arole of sex steroids in ALS. Testosterone is a complex steroid that exerts its effects directly via androgen (AR)and indirectly via estrogen receptors (ER) after aromatization into estradiol. Its reduced-metabolite 5a-dihydrotestosterone acts via AR. This study analyzed the metabolism oftestosterone in the spinal cord and studied testosterone effects on myelinbasic protein (MBP) and rotarod performance in male symptomatic WRs. Controlsor WRs received empty or testosterone-filled silastic tubes for 2 months. The CSC from testosterone-treatedWRs showed: 1) similar androgenlevels to untreated control, and 2) increased levels of testosterone(p<0.05), and its 5a-reduced metabolites, 5a-dihydrotestosterone (p<0.01) and 3b-androstanediol(p<0.001), but 3) undetectablelevels of estradiol compared to untreated WRs. Testosterone-treatedcontrols showed comparable steroid concentrations to untreated controls. CSCfrom WRs showed low number of oligodendrocyte CC1+cells (p<0.05) and highimmunoreactivity for MBP (p<0.05) vs. controls.  Intestosterone-treated WRs, we showed increased number of CC1+cells (p<0.01) associatedto high % of immunoreactive area for MBP (p<0.05) vs. WRs. Clinically, testosteronetreatment in WRs improved rotarod performance (p<0.05). Collectively, our findings indicate a promyelinating effect of testosterone in the CSC ofWobbler-ALS mice. These results coincided with a high concentration ofandrogen-reduced derivatives after testosterone treatment suggesting that the profile of steroid metabolites mayhave a beneficial role on disease progression.