Nimodipine Reduces Dysfunction and Demyelination in Models of Multiple Sclerosis

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

Cerebral blood flow decrease as an early pathological mechanism in Alzheimer's disease

“…Similarly, a mutation in the microglial TREM2 receptor (an AD susceptibility gene) that increases the production of inflammatory mediators also leads to a decrease of CBF [85]. The neuroinflammation occurring in multiple sclerosis can also be associated with hypoperfusion that is correctable by blocking ET A receptors or voltage-gated calcium channels [33,34]. Schematic diagram showing how the amyloid beta and tau cascades can be initiated from two entry points (red boxes): (i) a decrease of cerebral blood flow (CBF) which lowers brain O 2 and glucose and thus upregulates the enzyme (BACE1) that makes Aβ or (ii) an increase in Aβ level due to more production or less clearance of Aβ.…”

“…Similarly, a mutation in the microglial TREM2 receptor (an AD susceptibility gene) that increases the production of inflammatory mediators also leads to a decrease of CBF [ 85 ]. The neuroinflammation occurring in multiple sclerosis can also be associated with hypoperfusion that is correctable by blocking ET A receptors or voltage-gated calcium channels [ 33 , 34 ].…”

Optical Coherence Tomography Angiography (OCTA) in Multiple Sclerosis and Neuromyelitis Optica Spectrum Disorder

“…Investigations indicated that the hypoxia was caused by insufficient perfusion of the CNS, creating a shortage of oxygen delivery in the inflamed area ( 54 ). Accordingly, it was found that therapeutic approaches aimed at alleviating hypoxia, with inspired oxygen, or alleviating hypoperfusion, with vasodilating agents, were related to improved neurologic outcome and reduced later stage demyelination in the affected animals ( 17 ). These findings suggest that hypoxia and hypoperfusion may render nerve cells inexcitable through depolarization, causing disability in the acute stage, but also damage oligodendrocytes, causing subsequent demyelination.…”

“…However, if vascular density loss occurs after thinning of retinal layers, this suggests that vascular supply may be reduced due to lower local metabolic demand. This is an important question, given the potential therapeutic possibilities that may reduce MS disability accrual by alleviating hypoperfusion, that OCTA might help answer ( 17 ).…”

“…Even though immune mediated mechanisms are considered the most important drivers of neuroinflammatory disease, accumulating evidence indicates that CNS tissue energy failure, caused by hypoperfusion and hypoxia, is present in MS patients. This energy crisis may render neurons ineffective during an acute relapse and cause damage to oligodendrocytes which sets in action insidious processes of chronic demyelination and atrophy ( 1 , 17 ). Neuropathologic studies of NMOSD affected tissue show that CNS lesions have a clear predilection for forming in perivascular locations ( 18 ).…”