Glial Activation and Central Synapse Loss, but Not Motoneuron Degeneration, Are Prevented by the Sigma-1 Receptor Agonist PRE-084 in the Smn2B/− Mouse Model of Spinal Muscular Atrophy
| Autor: | Josep E. Esquerda, Olga Tarabal, Xavier Navarro, Alba Blasco, Lídia Piedrafita, Jordi Calderó, Clàudia Cerveró, Anna Casanovas |
|---|---|
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Sigma-1 receptor Synapse Mice 0302 clinical medicine Gliosis Axon Motor Neurons Behavior Animal General Medicine SMA Muscle Denervation Motoneuron Motoneuron synaptic afferents Survival of Motor Neuron 2 Protein medicine.anatomical_structure Neurology Microglia medicine.symptom Neuroglia Agonist medicine.medical_specialty Sensory Receptor Cells Smn2B/- mouse medicine.drug_class Morpholines Neuromuscular Junction Pathology and Forensic Medicine Muscular Atrophy Spinal 03 medical and health sciences Cellular and Molecular Neuroscience Internal medicine medicine Animals Receptors sigma PRE-084 business.industry Spinal muscular atrophy Macrophage Activation medicine.disease Axons Mice Inbred C57BL C-boutons 030104 developmental biology Endocrinology SMNΔ7 mouse Nerve Degeneration Synapses Cholinergic Neurology (clinical) business 030217 neurology & neurosurgery |
| Zdroj: | Repositorio Abierto de la UdL Universitad de Lleida Recercat. Dipósit de la Recerca de Catalunya instname |
| ISSN: | 1554-6578 0022-3069 |
| DOI: | 10.1093/jnen/nly033 |
| Popis: | Spinal muscular atrophy (SMA) is characterized by the loss of α-motoneurons (MNs) with concomitant muscle denervation. MN excitability and vulnerability to disease are particularly regulated by cholinergic synaptic afferents (C-boutons), in which Sigma-1 receptor (Sig1R) is concentrated. Alterations in Sig1R have been associated with MN degeneration. Here, we investigated whether a chronic treatment with the Sig1R agonist PRE-084 was able to exert beneficial effects on SMA. We used a model of intermediate SMA, the Smn2B/− mouse, in which we performed a detailed characterization of the histopathological changes that occur throughout the disease. We report that Smn2B/− mice exhibited qualitative differences in major alterations found in mouse models of severe SMA: Smn2B/− animals showed more prominent MN degeneration, early motor axon alterations, marked changes in sensory neurons, and later MN deafferentation that correlated with conspicuous reactive gliosis and altered neuroinflammatory M1/M2 microglial balance. PRE-084 attenuated reactive gliosis, mitigated M1/M2 imbalance, and prevented MN deafferentation in Smn2B/− mice. These effects were also observed in a severe SMA model, the SMNΔ7 mouse. However, the prevention of gliosis and MN deafferentation promoted by PRE-084 were not accompanied by any improvements in clinical outcome or other major pathological changes found in SMA mice. This work was supported by grants from the Ministerio de Economía y Competitividad co-financed by FEDER (SAF2015-70801). |
| Databáze: | OpenAIRE |
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