Long-term effects of the glucocorticoid receptor modulator CORT113176 in murine motoneuron degeneration
| Autor: | Maria Claudia Gonzalez Deniselle, Joseph K. Belanoff, Alejandro F. De Nicola, Paulina Roig, Maria Meyer, Hazel Hunt, Laura Garay, Analia Lima, E. Ronald de Kloet, Maria Sol Kruse |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Male medicine.medical_specialty Glucocorticoid receptor antagonist Cell Survival Excitotoxicity Glutamic Acid medicine.disease_cause 03 medical and health sciences chemistry.chemical_compound Mice 0302 clinical medicine Glucocorticoid receptor Receptors Glucocorticoid Neuroinflammation Corticosterone Internal medicine Motor behavior medicine Animals Receptor Molecular Biology Motor Neurons Cell Death business.industry General Neuroscience Glutamate receptor Isoquinolines Amyotrophic lateral sclerosis 030104 developmental biology Endocrinology medicine.anatomical_structure chemistry Spinal Cord Astrocytes Encephalitis Pyrazoles Interleukin 18 Female Neurology (clinical) Microglia business Wobbler mouse 030217 neurology & neurosurgery Developmental Biology Astrocyte |
| Zdroj: | Brain Research, 1727. ELSEVIER |
| Popis: | The Wobbler mouse spinal cord shows vacuolated motoneurons, glial reaction, inflammation and abnormal glutamatergic parameters. Wobblers also show deficits of motor performance. These conditions resemble amyotrophic lateral sclerosis (ALS). Wobbler mice also show high levels of corticosterone in blood, adrenals and brain plus adrenal hypertrophy, suggesting that chronically elevated glucocorticoids prime spinal cord neuroinflammation. Therefore, we analyzed if treatment of Wobbler mice with the glucocorticoid receptor (GR) antagonist CORT113176 mitigated the mentioned abnormalities. 30 mg/kg CORT113176 given daily for 3 weeks reduced motoneuron vacuolation, decreased astro and microgliosis, lowered the inflammatory mediators high mobility group box 1 protein (HMGB1), toll-like receptor 4, myeloid differentiation primary response 88 (MyD88), p50 subunit of nuclear factor kappa B (NFκB), tumor necrosis factor (TNF) receptor, and interleukin 18 (IL18) compared to untreated Wobblers. CORT113176 increased the survival signal pAKT (serine-threonine kinase) and decreased the death signal phosphorylated Junk-N-terminal kinase (pJNK), symptomatic of antiapoptosis. There was a moderate positive effect on glutamine synthase and astrocyte glutamate transporters, suggesting decreased glutamate excitotoxicity. In this pre-clinical study, Wobblers receiving CORT113176 showed enhanced resistance to fatigue in the rota rod test and lower forelimb atrophy at weeks 2–3. Therefore, long-term treatment with CORT113176 attenuated degeneration and inflammation, increased motor performance and decreased paw deformity. Antagonism of the GR may be of potential therapeutic value for neurodegenerative diseases. |
| Databáze: | OpenAIRE |
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