Activation of Kir4.1 Channels by 2-D08 Promotes Myelin Repair in Multiple Sclerosis

Multiple sclerosis (MS) is a chronic inflammatory disease that leads to myelin loss and neurological dysfunction. Clinical studies show increased anti-Kir4.1 antibody levels in MS patients' serum, indicating its diagnostic potential. However, the specific mechanism has remained elusive. In a mouse model of experimental autoimmune encephalomyelitis (EAE), it is found that impaired Kir4.1 channels in oligodendrocyte precursor cells (OPCs) hindered myelin repair in the spinal cord. Using a thermal shift assay (TSA), the small molecule 2-D08 is identified, which effectively activated Kir4.1 channels and reduced demyelination in both EAE mice and marmosets. The neuroprotective effects are mainly due to enhanced phosphorylation of FYN tyrosine kinase, promoting OPCs differentiation. The findings highlight the critical role of Kir4.1 channels in MS pathogenesis and suggest that pharmacological activation of these channels by 2-D08 can be a promising therapeutic strategy for enhancing brain recovery in demyelinating diseases.