Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
8840647 | Neuroscience | 2018 | 13 Pages |
Abstract
Wobbler mice are experimental models for amyotrophic lateral sclerosis. As such they show motoneuron degeneration, motor deficits, and astrogliosis and microgliosis of the spinal cord. Additionally, Wobbler mice show increased plasma, spinal cord and brain corticosterone levels and focal adrenocortical hyperplasia, suggesting a pathogenic role for glucocorticoids in this disorder. Considering this endocrine background, we examined whether the glucocorticoid receptor (GR) modulator CORT 113176 prevents spinal cord neuropathology of Wobblers. CORT 113176 shows high affinity for the GR, with low or null affinity for other steroid receptors. We employed five-month-old genotyped Wobbler mice that received s.c. vehicle or 30â¯mg/kg/day for 4â¯days of CORT 113176 dissolved in sesame oil. The mice were used on the 4th day, 2â¯h after the last dose of CORT 113176. Vehicle-treated Wobbler mice presented vacuolated motoneurons, increased glial fibrillary acidic protein (GFAP)+ astrocytes and decreased glutamine synthase (GS)+ cells. There was strong neuroinflammation, shown by increased staining for IBA1+ microglia and CD11b mRNA, enhanced expression of tumor necrosis factor-α, its cognate receptor TNFR1, toll-like receptor 4, the inducible nitric oxide synthase, NFkB and the high-mobility group box 1 protein (HMGB1). Treatment of Wobbler mice with CORT 113176 reversed the abnormalities of motoneurons and down-regulated proinflammatory mediators and glial reactivity. Expression of glutamate transporters GLT1 and GLAST mRNAs and GLT1 protein was significantly enhanced over untreated Wobblers. In summary, antagonism of GR with CORT 113176 prevented neuropathology and showed anti-inflammatory and anti-glutamatergic effects in the spinal cord of Wobbler mice.
Keywords
TNFαHMGB1IBA1SOD1CD11BTLR4NFRGLT-1GLASTNFkBtdp43iNOSGFAPnuclear factor kappa-light-chain enhancer of activated B cellsIL1βamyotrophic lateral sclerosisNeuroinflammationinterleukin 1 betaALSNeurodegenerationtumor necrosis factor alphaglutamate aspartate transporterinducible form of nitric oxide synthaseionized calcium-binding adaptor molecule 1Wobbler miceHPANitric oxideGlial fibrillary acidic proteinHigh-mobility group box 1 proteinglutamate transporter 1Glutamine synthaseToll-like receptor 4Mineralocorticoid receptorglucocorticoid receptor
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Authors
Maria Meyer, Agustina Lara, Hazel Hunt, Joseph Belanoff, E. Ronald de Kloet, Maria Claudia Gonzalez Deniselle, Alejandro F. De Nicola,