A Specific glucocorticoid receptor (GR) antagonist (CORT113176) prevents inflammation and neurodegeneration in the Wobbler mouse model of Amyotrophic Lateral Sclerosis

GONZALEZ DENISELLE MC; BELANOFF J.; MEYER M; HAZEL HUNT; LIMA A; DE NICOLA A. F.

Congreso; LXI Reunión Anual de la Sociedad Argentina de Investigación Clínica (SAIC).; 2016

Sociedad Argentina de Investigación Clínica (SAIC).

Wobbler (WR) mice show motoneuron degeneration, astrogliosis and microgliosis of the spinal cord. Additionally, increased plasma and brain corticosterone and focal adrenocortical hypertrophy suggest a role of hyperadrenocorticism in the WR disease. In the presents work we evaluated if antagonizing the GR with CORT113176 prevents development of spinal cord abnormalities. CORT113176 shows high affinity towards GR without binding to progestin, androgen or estrogen receptors. Five month old genotyped WR mice received s.c. vehicle or 30 mg / kg / day for 4 days of CORT113176 dissolved in sesame oil. The mice were used the 4th. day, 2 hours after the last dose of CORT113176. Antagonist-naïve WR showed several abnormalities of the spinal cord, such as vacuolated motoneurons, increased glial fibrillary acidic protein (GFAP) + astrocytes, decrease glutamine synthetase (GS) + cells, increased number of IBA1+ microglia and decreased number of cells + for the calcium-binding protein B (S100B). Treatment of WR with CORT113176 normalized these altered parameters. Furthermore untreated WR expressed high levels of mRNA for CD11b (microglia marker) (p