In this study, we investigate the effects of treatment with oxygen in two models of MS, namely both active and passive EAE. Convincingly, the hypoxia and resulting disability are promptly and significantly reduced by simple therapy to promote perfusion and oxygen delivery, using the vasodilating drug nimodipine, or promoting oxygenation by breathing raised oxygen.
Mitochondrial function is also compromised apparently leading to an energy crisis that depolarises neurons/axons, preventing neurological signalling. The suspicion that hypoperfusion and hypoxia may be the link between inflammation and disability has been considerably strengthened by findings in a common animal model of MS, namely, experimental autoimmune encephalomyelitis (EAE), where hypoperfusion and tissue hypoxia correlate spatially, temporally and quantitatively with the expression of disability. Most directly, using frequency domain near‐infrared spectroscopy to measure microvascular haemoglobin oxygen saturation in the brains of awake MS patients, Yang and Dunn have found a significant relationship between haemoglobin oxygen saturation and clinical disability, with 42% of saturation values more than twice the standard deviation lower than the control mean. Hypoperfusion is likely to result in tissue hypoxia, and there is substantial evidence that the MS brain is actually hypoxic, including the expression of hypoxia‐related antigens, the upregulation of genes induced by ischaemic preconditioning and the presence of lesions characterised by hypoxia‐like demyelination. Some studies have considered whether the reduction in cerebral blood flow is likely to be just a secondary consequence of reduced demand and cerebral atrophy, or whether it is a primary cause of damage, and the clear conclusion is that the reduction is a primary event probably causing pathology and thereby disability. Certainly, hypoperfusion in MS has been recognised for over 70 years, and as methods to measure perfusion have become more sophisticated, the overwhelming finding is of very significant hypoperfusion in both relapsing–remitting (RRMS) and primary and secondary progressive MS (PPMS and SPMS) that significantly correlates with disability. The deficits can be caused by neuroinflammation in the absence of demyelination, and increasing evidence from animal models suggests that in this case, the mechanism is a reduction in neuronal function due to tissue hypoxia arising from hypoperfusion. Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS), which causes debilitating neurological deficits in young adults.
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