The Selective Glucocorticoid Receptor Modulator Cort 113176 Reduces Neurodegeneration and Neuroinflammation in Wobbler Mice Spinal Cord

Autor: Agustina Lara, Maria Meyer, Hazel Hunt, Alejandro F. De Nicola, E. Ronald de Kloet, Maria Claudia Gonzalez Deniselle, Joseph K. Belanoff
Rok vydání: 2018
Předmět:
0301 basic medicine
medicine.medical_specialty
CIENCIAS MÉDICAS Y DE LA SALUD
Neurociencias
GLUCOCORTICOID RECEPTOR ANTAGONISM
NEUROINFLAMMATION
Mice
Mice
Neurologic Mutants
03 medical and health sciences
chemistry.chemical_compound
Receptors
Glucocorticoid
0302 clinical medicine
Glucocorticoid receptor
Corticosterone
Internal medicine
Glial Fibrillary Acidic Protein
medicine
Animals
Receptor
Neuroinflammation
Inflammation
Glial fibrillary acidic protein
biology
General Neuroscience
Amyotrophic Lateral Sclerosis
Neurodegeneration
NEURODEGENERATION
Isoquinolines
medicine.disease
Spinal cord
Astrogliosis
Medicina Básica
Disease Models
Animal
WOBBLER MICE
Neuroprotective Agents
Treatment Outcome
030104 developmental biology
Endocrinology
medicine.anatomical_structure
Spinal Cord
chemistry
Astrocytes
Nerve Degeneration
biology.protein
Pyrazoles
030217 neurology & neurosurgery
Zdroj: Neuroscience. 384:384-396
ISSN: 0306-4522
DOI: 10.1016/j.neuroscience.2018.05.042
Popis: 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 30 mg/kg/day for 4 days of CORT 113176 dissolved in sesame oil. The mice were used on the 4th day, 2 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. Fil: Meyer, Maria. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina Fil: Lara, Agustina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina Fil: Hunt, Hazel. CORCEPT Therapeutic; Estados Unidos Fil: Belanoff, Joseph. CORCEPT Therapeutic; Estados Unidos Fil: de Kloe, Ronald E.. Leiden University; Países Bajos Fil: Gonzalez Deniselle, Maria Claudia. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Bioquímica Humana; Argentina Fil: de Nicola, Alejandro Federico. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Bioquímica Humana; Argentina
Databáze: OpenAIRE
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