Pranav Gadangi

Introduction. Multiple sclerosis (MS) is a chronic, autoimmune disease of the central nervous system that leads to demyelination and neurodegeneration in nearly 200 patients per week¹. The condition starts in a relapsing-remitting form for the first 10-15 years followed by a severe, progressive form that decreases life expectancy by 7 years^2-3. Current treatments are limited to forms of interferon beta that slow disease progression without addressing previously incurred neural damage³. The body attempts to repair this damage with myelinating oligodendrocytes. As humans age, early oligodendrocyte progenitor cells (OPCs) become non-myelinating adult OPCs, which show similar morphology, but different function⁴. Activating a metabolic pathway of AMP activated protein kinase (AMPK) has been shown to suppress the mammalian target of rapamycin complex 1, mTORC1. Both AMPK and mTORC1 have been implicated in the differentiation of early OPCs to adult OPCs^5-8. As metabolic syndromes are comorbidities seen in 31.1% of MS cases, it is hypothesized that caloric restriction (CR) and metformin administration promote therapeutic myelination in MS patients through activating AMPK⁹. Methods. mTORC1 association with aging OPCs was determined by levels of pS6K in young and aged mice⁵. mTORC1 influence on myelination was assessed by administering rapamycin to a group of mice lacking tuberous sclerosis complex 2⁶. The effect of CR on AMPK activation was determined by phosphorylation of AMPK (pAMPK) in intestinal cells of mice⁸. The effects of CR and metformin administration on myelination were compared in mice exposed to an ethidium bromide induced demyelination injury. The role of the AMPK pathway in mediating CR-induced myelin formation was determined by the effect of dorsomorphin and the expression of myelin basic protein (MBP) in metformin-treated mice⁵. Results. Aged mice showed increased mTORC1 activity indicated by increased pS6K levels⁵. Inhibition of mTORC1 activity with rapamycin resulted in improved myelination⁶. Mice under CR showed 3 times greater pAMPK than those fed traditionally⁸. Improved myelination and decreased pS6K levels were also seen in both CR- and metformin-treated mice. Mice subject to both dorsomorphin and metformin showed reduced MBP and pAMPK compared to mice treated with metformin alone⁵. Conclusion. The aging and differentiation of OPCs into a non-myelinating form is associated with increased mTORC1. This activity was shown to be suppressed through AMPK activation. AMPK activation, through CR or metformin administration, can promote myelin formation as a means to repair previously incurred loss of myelin. These studies suggest that CR is a potential treatment for multiple sclerosis.

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