Nimodipine reduces dysfunction and demyelination in models of multiple sclerosis

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

Research output: Contribution to journalArticlepeer-review

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 central nervous system (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 2 MS models.

Methods
A variety of methods have been used 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 of the early MS lesion, seem 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. ANN NEUROL 2020 ANN NEUROL 2020;88:123–136
Original languageEnglish
Pages (from-to)123-136
Number of pages14
JournalAnnals of Neurology
Volume88
Issue number1
Early online date15 Apr 2020
DOIs
Publication statusPublished - 31 Jul 2020

Keywords

  • nimodipine
  • dysfunction
  • demyelination
  • multiple sclerosis (MS)
  • hypoxia

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