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

Journal of Neuropathology and Experimental Neurology
Clàudia CerveróJordi Calderó

Abstract

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 glios...Continue Reading

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Citations

Jul 22, 2020·Journal of Cachexia, Sarcopenia and Muscle·Alba BlascoJordi Calderó
Aug 8, 2020·British Journal of Pharmacology·Mireia Herrando-GrabulosaXavier Navarro
Nov 3, 2020·Investigative Ophthalmology & Visual Science·Jing WangSylvia B Smith
Apr 16, 2020·Neurobiology of Disease·Elena AbatiStefania Corti
Jul 16, 2020·The International Journal of Biochemistry & Cell Biology·Zeinab Y MotaweJerome W Breslin
Jul 3, 2021·International Journal of Molecular Sciences·Núria Gaja-CapdevilaMireia Herrando-Grabulosa

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