Universitas Indonesia Conferences, Asian Federation for Pharmaceutical Sciences (AFPS) 2019

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CXCR2 antagonism efficiently promotes oligodendrocyte precursor cell differentiation and enhances remyelination in a mouse model of multiple sclerosis

Last modified: 2019-06-15


Multiple sclerosis (MS) is a chronic autoimmune demyelinating disease characterized by the autoimmune attack of oligodendrocytes (OLs), leading to demyelination and progressive functional deficits. CXC chemokine receptor 2 (CXCR2) is a developmental molecule known to orchestrate the migration, proliferation and differentiation of oligodendrocyte precursor cells (OPCs) in the developing brain. CXCR2 increases in chronic demyelinating disease, marking it as a potential pharmacological target of MS. Here, we studied a brain penetrant CXCR2 antagonist for its therapeutic efficacy in multiple sclerosis and further investigated mechanisms involved in its remyelinating effect. The brain penetrant CXCR2 compound 2 significantly promoted OPCs proliferation and differentiation, as indicated by the decreased expression of platelet-derived growth factor receptor α (PDGFRα) and A2B5, and the increased expression of myelin basic protein (MBP). Further examination of CPZ-intoxicated mice suggested that compound 2 ameliorated neurological impairment and improved motor function. Additionally, in the demyelinated lesions of CPZ-intoxicated mice treated with compound 2, OPCs proliferation was more vigorous and myelin repair was more efficient compared with tissues from untreated mice. Subsequent investigation of the underlying mechanisms identified that upon the antagonism of CXCR2, compound 2 activated PI3K/AKT/mTOR signaling, thereby upregulating Ki67, transcription factor 2 (Olig2) and Caspr expression, ultimately promoting OPCs differentiation and enhancing remyelination in MS. In conclusion, our results demonstrated that the brain penetrant CXCR2 antagonist efficiently promoted OPC differentiation and thereby enhanced remyelination in CPZ-intoxicated mice, supporting CXCR2 as a promising therapeutic target for the treatment of chronic demyelinating diseases such as multiple sclerosis.