Abstract |
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.
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Authors | M Meyer, M C Gonzalez Deniselle, L Garay, R Sitruk-Ware, R Guennoun, M Schumacher, A F De Nicola |
Journal | Neuroscience
(Neuroscience)
Vol. 308
Pg. 51-63
(Nov 12 2015)
ISSN: 1873-7544 [Electronic] United States |
PMID | 26349009
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Copyright | Copyright © 2015 IBRO. Published by Elsevier Ltd. All rights reserved. |
Chemical References |
- Anti-Inflammatory Agents
- Neuroprotective Agents
- Norprogesterones
- Receptors, Progesterone
- ST 1435
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Topics |
- Animals
- Anti-Inflammatory Agents
(pharmacology)
- Astrocytes
(drug effects, metabolism, pathology)
- Disease Models, Animal
- Gliosis
(drug therapy, pathology, physiopathology)
- Male
- Mice, Mutant Strains
- Microglia
(drug effects, metabolism, pathology)
- Motor Neuron Disease
(drug therapy, pathology, physiopathology)
- Motor Neurons
(drug effects, metabolism, pathology)
- Neuroimmunomodulation
(drug effects, physiology)
- Neuroprotective Agents
(pharmacology)
- Norprogesterones
(pharmacology)
- Receptors, Progesterone
(agonists, metabolism)
- Spinal Cord
(drug effects, metabolism, pathology)
- Treatment Outcome
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