SPHINGOSINE KINASE INHIBITION AMELIORATES CHRONIC HYPOPERFUSION-INDUCED WHITE MATTER LESIONS

Abstract

WHITE MATTER LESIONS (WML) ARE THOUGHT TO CONTRIBUTE TO VASCULAR COGNITIVE IMPAIRMENT IN ELDERLY PATIENTS. GROWING EVIDENCE SHOW DISRUPTION OF OLIGODENDROCYTE PROGENITOR CELL (OPC) DIFFERENTIATION IS A CAUSE OF CHRONIC VASCULAR WHITE MATTER DAMAGE. IN THIS STUDY, WE INDICATED THAT BILATERAL CAROTID ARTERY STENOSIS (BCAS) INDUCED HYPOPERFUSION AND ALTERED THE AMOUNT AND COMPOSITION OF PHOSPHOLIPID AND SPHINGOLIPID IN CEREBRAL WM IN MOUSE, AND INDUCED HYPOXIA INDUCIBLE FACTOR (HIF)-1A, SPHK2, S1P, AND NG2 UP-REGULATION TOGETHER WITH ACCUMULATION OF WML. IN ADDITION, SPHK INHIBITOR SKI-II SHOWED PARTIAL REVERSAL OF SPHK2, S1P AND NG2 ELEVATION AND AMELIORATION OF WML. IN AN IN VITRO MODEL OF HYPOXIA, SKI-II REVERSED THE SUPPRESSION OF OPC DIFFERENTIATION.. THIS STUDY SUGGESTS A MECHANISM FOR HYPOPERFUSION-ASSOCIATED WML INVOLVING LIPID ALTERATIONS AND HIF-1A-SPHK2-S1P PATHWAY- MEDIATED DISRUPTION OF OPC DIFFERENTIATION, AND PROPOSES THE SPHK SIGNALING PATHWAY AS A POTENTIAL THERAPEUTI