Targeting Mitochondrial Redox Signaling Promotes Neuroregeneration and Functional Recovery in a Multiple Sclerosis Model.

Abstract

Neurodegenerative diseases, including multiple sclerosis (MS), are characterized by progressive neuronal loss and limited regenerative capacity. To stimulate in vivo neurogenesis and oligodendrogenesis by harnessing the untapped regenerative potential of endogenous neural progenitor cells (NPCs) that are upregulated in the CNS under disease conditions, we developed a novel compound that targets Notch signaling, a pathway known to suppress neuronal differentiation of NPCs. Furapyrrodole, which was identified by screening a natural product-like synthetic chemical library, binds to and activates the mitochondrial reductase CYB5R3, which naturally downregulates Notch signaling downstream of γ-secretase. The in vivo efficacy of furapyrrodole was evaluated in mice with experimental autoimmune encephalomyelitis (EAE), a mouse model of MS. Furapyrrodole treatment after the peak of EAE disease significantly improved motor function and promoted recovery of motor neurons and myelination by stimulating endogenous NPC-derived neurogenesis and oligodendrogenesis. In addition, furapyrrodole supresses neuroinflammation in the CNS. Collectively, these findings indicate furapyrrodole is a promising therapeutic candidate for MS by harnessing endogenously upregulated NPCs and inducing anti-inflammation. Our study demonstrates for the first time that modulation of mitochondrial redox signaling promotes neuroregeneration and remyelination without causing severe adverse effects.