Metabolic and Hypoxic Disturbances of CNS in MS

The use of T1-weighted MRI with gadolinium contrast as a diagnostic tool for MS relapse suggests that BBB disruption is a key feature of MS and causes leakage of the contrast agent at perivascular cuffs in the brain. The effectiveness of MS therapies and whether they improve BBB function can be seen by whether they relieve lesions since the number, size, and intensity of these lesions reflect BBB failure and disease severity. White matter lesions in MS are characterized by oligodendro- gliopathy (apoptosis and regression of oligodendrocytes) and can be exacerbated by metabolic disturbances [54]. For example, ischemic stress can also intensify the injury that results from the proinflammatory cytokines present in MS. This stress may be especially important in MS etiology because BECs are sensitive not only to metabolic stress but also to ischemic stress that disrupt barrier function, promote microparticle (MP) release [55], and induce endothelial cell adhesion molecule (ECAM) expression. MS involves intense neuroinflammation; this inflammation can cause vasoconstriction, limited perfusion resulting from edema, thrombosis, and activation of macrophages or glial cells, ultimately leading to tissue hypoxia. In addition, ischemic stress can occur even in the presence of adequate oxygen: toxic metabolite accumulation can interfere with mitochondrial ATP production, leading to ischemic stress despite oxygenation [54]. Such metabolites include glutamate, oxidants, and peroxynitrite, which can cause excitotoxic- ity in CNS neurons. Excitotoxicity and oxidative stress mediate neuronal loss characteristic of neurodegenerative diseases including MS [56]. Glutamate can indirectly contribute to oxidant generation as well, which is suggested to cause barrier disturbances in stroke and possibly in MS [57, 58]. Glutamate-dependent stress is exacerbated in MS due to glutamate accumulation that results from increased levels of proinflammatory cytokines in the CNS that impair glial clearance of glutamate [59].

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