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

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2018
Author
Cerveró Cebrià, Clàudia
Blasco Carmona, Alba
Tarabal Mostazo, Olga
Casanovas i Llorens, Anna
Piedrafita Llorens, Lídia
Navarro, X. (Xavier)
Esquerda Colell, Josep
Calderó i Pardo, Jordi
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Cerveró Cebrià, Clàudia; Blasco Carmona, Alba; Tarabal Mostazo, Olga; Casanovas i Llorens, Anna; Piedrafita Llorens, Lídia; Navarro, X. (Xavier); ... Calderó i Pardo, Jordi. (2018) . 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, 2018, vol. 77, num. 7, p. 577-597. https://doi.org/10.1093/jnen/nly033.
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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 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.
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http://hdl.handle.net/10459.1/67781
DOI
https://doi.org/10.1093/jnen/nly033
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Journal of Neuropathology and Experimental Neurology, 2018, vol. 77, num. 7, p. 577-597
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