Nimodipine reduces dysfunction and demyelination in models of multiple sclerosis

Desai, Roshni A.; Davies, Andrew L.; Del Rossi, Natalie; Tachrount, Mohamed; Dyson, Alex; Gustavson, Britta; Kaynezhad, Pardis; MacKenzie, Lewis; van der Putten, Marieke A.; McElroy, Daniel; Schiza, Dimitra; Linington, Christopher; Singer, Mervyn; Harvey, Andrew R.; Tachtsidis, Ilias; Golay, Xavier; Smith, Kenneth J.

Abstract

Objective: Treatment of relapses in multiple sclerosis (MS) has not advanced beyond steroid use, which reduces acute loss of function, but has little effect on residual disability. Acute loss of function in an MS model (experimental autoimmune encephalomyelitis; EAE) is partly due to CNS hypoxia, and function can promptly improve upon breathing oxygen. Here we investigate the cause of the hypoxia and whether it is due to a deficit in oxygen supply arising from impaired vascular perfusion. We also explore whether the CNS‐selective vasodilating agent, nimodipine, may provide a therapy to restore function, and protect from demyelination in two MS models. Methods: A variety of methods have been employed to measure basic cardiovascular physiology, spinal oxygenation, mitochondrial function and tissue perfusion in EAE. Results: We report that the tissue hypoxia in EAE is associated with a profound hypoperfusion of the inflamed spinal cord. Treatment with nimodipine restores spinal oxygenation and can rapidly improve function. Nimodipine therapy also reduces demyelination in both EAE, and a model of the early MS lesion. Interpretation: Loss of function in EAE, and demyelination in EAE and the model early MS lesion, appear to be due, at least in part, to tissue hypoxia due to local spinal hypoperfusion. Therapy to improve blood flow not only protects neurological function, but also reduces demyelination. We conclude that nimodipine could be repurposed to offer substantial clinical benefit in MS.

Citation

Desai, R. A., Davies, A. L., Del Rossi, N., Tachrount, M., Dyson, A., Gustavson, B., …Smith, K. J. (2020). Nimodipine reduces dysfunction and demyelination in models of multiple sclerosis. Annals of Neurology, 88(1), 123-136. https://doi.org/10.1002/ana.25749

• Journal Article Type: Article
• Acceptance Date: Apr 13, 2020
• Online Publication Date: May 6, 2020
• Publication Date: 2020-07
• Deposit Date: Apr 20, 2020
• Publicly Available Date: May 20, 2020
• Journal: Annals of Neurology
• Publisher: Wiley
• Peer Reviewed: Peer Reviewed
• Volume: 88
• Issue: 1
• Pages: 123-136
• DOI: https://doi.org/10.1002/ana.25749