The Selective Glucocorticoid Receptor Modulator CORT125329 Decreases Neuroinflammation and Gliosis and Enhances Myelination in the Wobbler Model of Amyotrophic Lateral Sclerosis

The Wobbler mouse is a genetic model of familial amyotrophic lateral sclerosis. Wobblers show spinal cord neurodegeneration associated with gliosis, neuroinflammation, and demyelination. Similar to human neurodegenerative diseases, Wobblers show high levels of corticosterone in blood and the nervous system. A role for glucocorticoids in neuropathology is suggested by the observation that pathological signs attenuate with treatment with glucocorticoid receptor (GR) antagonists/modulators. In the present study, we demonstrated in 5-month-old clinically afflicted Wobbler mice that the selective GR modulator CORT125329 decreased motoneuron degeneration, astro- and microgliosis, and levels of pro-inflammatory factors (HMGB1, toll-like receptor 4, tumor necrosis factorFα, and its receptor). In addition, CORT125329 increased the acetylcholine-producing enzyme choline acetyltransferase, the neurotrophin brain-derived neurotrophic factor, and their cellular colocalization. Furthermore, the increased oligodendrocyte number and a healthier myelin ultrastructure are consistent with the enhanced axonal myelination after CORT125329 treatment. Finally, the high expression of immunoreactive protein and mRNA levels of acquaporin4 in Wobblers was decreased by CORT125329 treatment, implying this water channel is a glucocorticoid target involved in neuropathology. The beneficial effects of CORT125329 correlated with enhanced motor behavioral performance and trophic changes of the forelimbs. In conclusion our results support further preclinical and clinical studies with GR modulators in sporadic amyotrophic lateral sclerosis.