The selective glucocorticoid receptor modulator CORT 113176 reduces motoneuron degeneration and neuroinflammation in Wobbler mice spinal cord.

HAZEL HUNT; MEYER M; BELANOFF J.; GONZÁLEZ DENISELLE M. CLAUDIA; DE NICOLA A. F.; LIMA ANALÍA

Congreso; Reunión Anual Conjunta de las Sociedades de Biociencias; 2017

Wobbler (Wr) mice are experimental models for amyotrophiclateral sclerosis. As such they show motoneuron degeneration,motor deficits, and astrogliosis and microgliosis of the spinalcord. Additionally, Wr mice show increased plasma, spinal cordand brain corticosterone levels and focal adrenocortical hyperplasia,suggesting a pathogenic role for glucocorticoids in this disorder.Considering this endocrine background, we examined whetherthe glucocorticoid receptor (GR) modulator CORT113176 preventsspinal cord neuropathology of Wobblers. CORT113176 shows highaffinity for the GR, with low or null affinity for other steroid receptors.We employed five month old genotyped Wr mice that received s.c.vehicle or 30 mg / kg / day for 4 days of CORT113176 dissolvedin sesame oil. The mice were used on the 4th day, 2 hours afterthe last dose of CORT113176. Vehicle treated Wr mice presentedvacuolated motoneurons (p<0.001 vs. Control (Ctl)), increased glialfibrillary acidic protein (GFAP)+ astrocytes (p<0.001 vs. Ctl) and decreasedglutamine synthase (GS)+ cells (p<0.05). There was strongneuroinflammation, shown by increased staining for IBA1+ microglia(p<0.001 vs. Ctl) and CD11b mRNA (p<0.01 vs. Ctl), enhancedexpression of tumor necrosis factor-a (p<0.001 vs. Ctl), its cognatereceptor TNFR1 (p<0.05 vs. Ctl), toll-like receptor 4 (p<0.01 vs. Ctl),the inducible nitric oxide synthase (p<0.05 vs. Ctl), NFkB (p<0.05 vs.Ctl) and the high mobility group box 1 protein (HMGB1) (p<0.001 vs.Ctl). Treatment of Wr mice with CORT113176 reversed the abnormalitiesof motoneurons and down-regulated proinflammatory mediatorsand glial reactivity. Expression of glutamate transporters GLT1and GLAST mRNAs was significantly enhanced over control anduntreated Wobblers (p<0.01 Wr vs. Wr CORT113176). In summary,antagonism of GR with CORT113176 prevented neuropathologyand showed anti-inflammatory and anti-glutamatergic effects in thespinal cord of Wr mice.