Nimodipine Reduces Dysfunction and Demyelination in Models of Multiple Sclerosis

• Published in: Annals of neurology Vol. 88; no. 1; pp. 123 - 136
• Main Authors: Desai, Roshni A., Davies, Andrew L., Del Rossi, Natalie, Tachrount, Mohamed, Dyson, Alex, Gustavson, Britta, Kaynezhad, Pardis, Mackenzie, Lewis, Putten, Marieke A., McElroy, Daniel, Schiza, Dimitra, Linington, Christopher, Singer, Mervyn, Harvey, Andrew R., Tachtsidis, Ilias, Golay, Xavier, Smith, Kenneth J.
• Format: Journal Article
• Language: English
• Published: Hoboken, USA John Wiley & Sons, Inc 01.07.2020; Wiley Subscription Services, Inc
• Subjects: Animals; Blood flow; Calcium Channel Blockers - therapeutic use; Central nervous system; Demyelination; Disease Progression; Encephalomyelitis, Autoimmune, Experimental - drug therapy; Encephalomyelitis, Autoimmune, Experimental - pathology; Experimental allergic encephalomyelitis; Female; Hypoxia; Inflammation; Lesions; Magnetic Resonance Imaging; Male; Mitochondria; Multiple sclerosis; Myelin Sheath - pathology; Nimodipine; Nimodipine - therapeutic use; Oxygen; Oxygenation; Perfusion; Rats; Rats, Sprague-Dawley; Recovery of function; Spinal cord; Spinal Cord - pathology; Steroids; Therapy; Tissues; Vasodilators
• ISSN: 0364-5134; 1531-8249
• DOI: 10.1002/ana.25749

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