The progesterone receptor agonist Nestorone holds back proinflammatory mediators and neuropathology in the wobbler mouse model of motoneuron degeneration.
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.
Laboratory of Neuroendocrine Biochemistry, Instituto de Biologia y Medicina Experimental, Obligado 2490, 1428 Buenos Aires, Argentina.
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Meyer
Laboratory of Neuroendocrine Biochemistry, Instituto de Biologia y Medicina Experimental, Obligado 2490, 1428 Buenos Aires, Argentina; Dept. of Physiology, Faculty of Medicine, University of Buenos Aires, Paraguay 2155, 1425 Buenos Aires, Argentina.
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Gonzalez Deniselle
Laboratory of Neuroendocrine Biochemistry, Instituto de Biologia y Medicina Experimental, Obligado 2490, 1428 Buenos Aires, Argentina; Dept. of Human Biochemistry, Faculty of Medicine, University of Buenos Aires, Paraguay 2155, 1425 Buenos Aires, Argentina.
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Garay
The Population Council and Rockefeller University, 1230 York Avenue, New York, NY 10065, USA.
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Sitruk-Ware
U1195 Inserm and Université Paris-Sud, 80 rue du Général Leclerc, 94276 Le Kremlin-Bicêtre Cedex, France.
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Guennoun
U1195 Inserm and Université Paris-Sud, 80 rue du Général Leclerc, 94276 Le Kremlin-Bicêtre Cedex, France.
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Schumacher
Laboratory of Neuroendocrine Biochemistry, Instituto de Biologia y Medicina Experimental, Obligado 2490, 1428 Buenos Aires, Argentina; Dept. of Human Biochemistry, Faculty of Medicine, University of Buenos Aires, Paraguay 2155, 1425 Buenos Aires, Argentina. Electronic address: alejandrodenicola@gmail.com.
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De Nicola
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D005911:Gliosis / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology; D008297:Male; D008817:Mice, Mutant Strains; D017628:Microglia / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D016472:Motor Neuron Disease / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D009046:Motor Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D015213:Neuroimmunomodulation / Q000187:drug effects / Q000502:physiology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009653:Norprogesterones / Q000494:pharmacology*; D011980:Receptors, Progesterone / Q000819:agonists* / Q000378:metabolism; D013116:Spinal Cord / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D016896:Treatment Outcome
D000893:Anti-Inflammatory Agents; D018696:Neuroprotective Agents; D009653:Norprogesterones; D011980:Receptors, Progesterone; C029167:ST 1435
Wobbler mouse; microglia; nestorone; neuroinflammation; neuroprotection; proinflammatory factors