The progesterone receptor agonist Nestorone holds back proinflammatory mediators and neuropathology in the wobbler mouse model of motoneuron degeneration
| Autor: | Regine Sitruk-Ware, Laura Garay, Rachida Guennoun, Maria Meyer, Michael Schumacher, M. C. Gonzalez Deniselle, A. F. De Nicola |
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| Rok vydání: | 2015 |
| Předmět: |
Agonist
Male medicine.medical_specialty CIENCIAS MÉDICAS Y DE LA SALUD medicine.drug_class Neuroimmunomodulation Anti-Inflammatory Agents Biology Microgliosis ASTROCYTES Neuroprotection Proinflammatory cytokine Internal medicine medicine WOBBLER Animals Gliosis Motor Neuron Disease Neuroinflammation Motor Neurons General Neuroscience PROGESTERONE Bioquímica y Biología Molecular medicine.disease Spinal cord Mice Mutant Strains GLIOSIS Astrogliosis Medicina Básica Disease Models Animal Endocrinology medicine.anatomical_structure Neuroprotective Agents Treatment Outcome Spinal Cord Astrocytes Immunology Microglia medicine.symptom Receptors Progesterone SPINAL CORD Norprogesterones |
| Zdroj: | Neuroscience. 308 |
| ISSN: | 1873-7544 |
| Popis: | Wobbler mutant mice suffer from progressive motoneuron degeneration and glial cell reactivity in the spinal cord. To prevent development of these abnormalities, we employed Nestorone, a high-affinity progesterone receptor agonist endowed with neuroprotective, promyelinating and anti-inflammatory activities in experimental brain ischemia, preventing neuroinflammation and chemical degeneration. Five-month-old Wobbler mice (wr-/wr-) received s.c. injections of 200μg/day/mouse of Nestorone in vegetable oil or vehicle for 10days. Control NFR/NFR mice (background strain for Wobbler) received vehicle only. Vehicle-treated Wobblers showed typical spinal cord abnormalities, such as vacuolated motoneurons, decreased immunoreactive choline-acetyltransferase, decreased expression of glutamine synthase (GS), increased glial fibrillary acidic protein-positive (GFAP) astrogliosis and curved digits in forelimbs. These cell-specific abnormalities were normalized in Nestorone-treated Wobblers. In addition, vehicle-treated Wobblers showed Iba1+ microgliosis, high expression of the microglial marker CD11b mRNA and up-regulation of the proinflammatory markers TNFα and iNOS mRNAs. In Nestorone-treated Wobblers, Iba1+ microgliosis subsided, whereas CD11b, TNFα and iNOS mRNAs were down-regulated. NFκB mRNA was increased in Wobbler spinal cord and decreased by Nestorone, whereas expression of its inhibitor IκBα was increased in Nestorone-treated Wobblers compared to control mice and vehicle-treated Wobblers. In conclusion, our results showed that Nestorone restraining effects on proinflammatory mediators, microgliosis and astrogliosis may support neurons in their resistance against degenerative processes 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: 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; Argentina Fil: Garay, Laura Ines. 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; Argentina Fil: Sitruk Ware, Regine. The Rockefeller University; Estados Unidos. Population Council; Estados Unidos Fil: Guennoun, Rachida. Inserm; Francia. Universite Paris Sud; Francia 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; Argentina |
| Databáze: | OpenAIRE |
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