The Possible Role of Metformin and Fibroblast Growth Factor-21 in Multiple Sclerosis Neuropathology: Birds of a Feather Flock Together

Multiple sclerosis (MS) is a progressive demyelinating disease of the CNS, characterized by inflammation, the formation of CNS plaques, and damage to the neuronal myelin sheath (Graphical abstract). Fibroblast growth factor 21 (FGF21) is involved in various metabolic disorders and neurodegenerative diseases. FGF21 and its co-receptor beta-Kloth are essential in the remyelination process of MS. Metformin, an insulin-sensitizing drug that is the first-line treatment for type 2 diabetes mellitus (T2DM), may have a potential neuroprotective impact by up-regulating the production of FGF21, which may prevent the onset of neurodegenerative diseases including MS. The purpose of this review is to clarify how metformin affects MS neuropathology mechanistically via modifying FGF21. Metformin increases the expression of FGF21. Metformin also increases the expression of beta-Klotho, modulates oxidative stress, reduces glutamate-induced excitotoxicity, and regulates platelet function and coagulation cascades. In conclusion, metformin can enhance the functional activity of FGF21 in counteracting the development and progression of MS. Preclinical and clinical studies are warranted in this regard.