Abstract
Increasing evidence suggests a key role for tissue energy failure in the pathophysiology of multiple sclerosis (MS). Studies in experimental autoimmune encephalomyelitis (EAE), a commonly used model of MS, have been instrumental in illuminating the mechanisms that may be involved in compromising energy production. In this article, we review recent advances in EAE research focussing on factors that conspire to impair tissue energy metabolism, such as tissue hypoxia, mitochondrial dysfunction, production of reactive oxygen/nitrogen species, and sodium dysregulation, which are directly affected by energy insufficiency, and promote cellular damage. A greater understanding of how inflammation affects tissue energy balance may lead to novel and effective therapeutic strategies that ultimately will benefit not only people affected by MS but also people affected by the wide range of other neurological disorders in which neuroinflammation plays an important role.
Highlights
Multiple sclerosis (MS) is an immune-mediated disease of the central nervous system (CNS), characterised by multifocal, perivenous inflammation and focal destruction of myelin, typically resulting in a relapsing-remitting pattern of neurological deficit and leading to a progressive, neurodegenerative pathology
If used wisely, EAE can be a valuable tool for better understanding the pathophysiology of acute MS-like lesions and the mechanisms involved in dysfunction, damage and progression in MS in order to identify novel therapeutic targets
Important early studies were performed in optic nerve axons with energy failure due to imposed anoxia, but the recognition that nitric oxide (NO) both was a potent inhibitor of mitochondrial function[84,85] and was produced in abundance at sites of inflammation[93] suggested that sodium channels and raised internal sodium may be responsible for degeneration of axons in inflammatory lesions[55,94]
Summary
Multiple sclerosis (MS) is an immune-mediated disease of the central nervous system (CNS), characterised by multifocal, perivenous inflammation and focal destruction of myelin, typically resulting in a relapsing-remitting pattern of neurological deficit and leading to a progressive, neurodegenerative pathology. Important early studies were performed in optic nerve axons with energy failure due to imposed anoxia (for example, 92), but the recognition that NO both was a potent inhibitor of mitochondrial function[84,85] and was produced in abundance at sites of inflammation[93] suggested that sodium channels and raised internal sodium may be responsible for degeneration of axons in inflammatory lesions[55,94] This reasoning suggested that axons may be rendered vulnerable to degeneration by impulse conduction because this would promote sodium influx, and the combination of electrical activity and NO exposure was found to be a potent cause of degeneration[95]. It is noteworthy that Nav1.5 has been shown to play an important role in astrogliosis via reverse operation of the NCX and a subsequent robust calcium response in vitro[125]; targeting Nav1.5 may represent a therapeutic target for modulating reactive astrogliosis in MS and EAE
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