Efectos farmacológicos de la testosterona en un ratón que es modelo animal de una enfermedad de motoneurona

G. GARGIULO MONACHELLI; L GARAY; R GUENNOUN; DI GIORGIO NP; V LUX-LANTOS; DE NICOLA AF; LARA A; M MEYER; M SCHUMACHER; M. C. GONZALEZ-DENISELLE

Mar Del Plata

Congreso; LXI Reunión de la Sociedad Argentina de Investigación Clínica; 2016

Wobbler(WR) mouse, a useful model for human amyotrophic lateral sclerosis (ALS), showsmotoneuron degeneration with increased levels of intramitochondrial nitricoxide synthase (NOS) and astrogliosis in the spinal cord. Some steroids such asprogesterone favor mitochondrial function andneuroprotection, while others are deleterious. Here, we determined endogenoustestosterone (T) levels in male WRs and controls by radioimmunoassay and gaschromatography/mass spectrometry (GC/MS) at symptomatic stage. We demonstrateda strong decrease of T levels in serum, spinal cord and brain (p<0.05) inmale WRs vs male controls. Therefore, a silastic tube containing T crystals wasimplanted s.c. in WR mice at symptomatic stage for 2 months. We analyzed in cervicalspinal cord from male controls, WRs and WRs+T: 1) the % of vacuolated neurons,2) the number of glial fibrillary acidic protein (GFAP)+ astrocytes, 3) the numberof neurons and glial cells+  for NADPHd/NOSreaction, and 4) immunoreactivity (IR) for mitofusin-2 (Mfn2) and dynamin-like protein (DLP1), essential proteinsin mitochondrial biogenesis. T serum levels and seminal vesicles weight werehigher in WRs+T vs WRs (p<0.001) and vs controls (p<0.01), whilehypophysis mass, a parameter sensitive to aromatizable androgens, was notaffected by T. T reduced the % of vacuolated neurons in ventral horn (p<0.05vs WR), without changing GFAP+ astrogliosis. Hyperactivity of NADPH-d/NOS was reducedin glial cells from WRs+T vs WRs (p<0.01), but not in neurons. The IR for Mfn-2 and DLP1 was increased in the ventral horn of WR mice (p<0.001 and p<0.01),while T treatment only decreased DLP1 IR (p<0.05). In summary, supraphysiologicalT levels in WRs lessened neuronal vacuolation, NADPH-d/NOS activity in glialcells and DLP 1 but not Mfn2 IR. These effects may depend more on binding of Tto the androgen receptor rather than on T aromatization. Future studies areneeded to disclose the usefulness of T effects on WR mice.