Sodium channel blockers for neuroprotection in multiple sclerosis

Yang, Chunsong; Zhang, Lingli; Zeng, Hao; Zeng, Linan; Wen, Jin

doi:10.1002/14651858.cd010422

Cited by 2 publications

(1 citation statement)

References 38 publications

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“…Multiple factors including cytokines, complement, free radicals, nitric oxide, proteases, excess glutamate and calcium contribute to a harmful environment for vulnerable demyelinated axons in MS (Trapp et al ., 1998a; Yong et al ., 2007; Gonsette, 2008). Similarly neuronal damage in MS is triggered by numerous intracellular molecular cascades (Yang et al ., 2015). Interventions aimed at individual molecular targets may offer only partial neuroprotection and targeting programs of gene expression represents a viable strategy for the development of neuroprotective agents (Yong et al ., 2007; Gonsette, 2008).…”

Section: Introductionmentioning

confidence: 99%

MicroRNA-223 protects neurons from degeneration in Experimental Autoimmune Encephalomyelitis

Morquette

Juźwik

Drake

et al. 2018

Preprint

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Multiple sclerosis (MS) is an autoimmune disease characterized by demyelination and neurodegeneration in the brain, spinal cord and optic nerve. Neuronal degeneration and death underlie progressive forms of MS and cognitive dysfunction. Neuronal damage is triggered by numerous harmful factors in the brain that engage diverse signalling cascades in neurons thus therapeutic approaches to protect neurons will need to focus on agents that can target broad biological processes. To target the broad spectrum of signaling events that mediate neurodegeneration in MS we have focused on non-coding small microRNAs (miRNAs). microRNAs are epigenetic regulators of protein expression, targeting messenger RNAs (mRNAs) and inhibiting their translation. Dysregulation of miRNAs has been described in many neurodegenerative diseases including MS. In this study we identified two miRNAs, miR-223-3p and miR-27a-3p, that were upregulated in neurons in the experimental autoimmune encephalomyelitis (EAE) mouse model of CNS inflammation and in active MS lesions. Overexpression of miR-27a-3p or miR-223-3p protected dissociated cortical neurons from degeneration in response to peripheral blood mononuclear cell conditioned media (PBMC-CM). Introduction of miR-223-3p in vivo in mouse retinal ganglion cells (RGCs) protected RGC axons from degeneration in the EAE model. By in silico analysis we found that mRNAs in the glutamate receptor (GluR) pathway are enriched in miR-27a-3p and miR-223-3p targets. Antagonism of the GluR pathway protected neurons from PBMC-CM-dependent degeneration. Our results suggest that miR-223-3p and miR-27a-3p are upregulated in response to inflammation to mediate a compensatory neuroprotective gene expression program that desensitizes neurons to glutamate by downregulating mRNAs involved in GluR signalling.

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