THE ROLE OF SIRTUIN-2 IN ISCHAEMIC STROKE-INDUCED NEURONAL CELL DEATH

Abstract

Sirtuin-2 (SIRT2) is a NAD+-dependant histone and protein deacetylase. SIRT2 mainly resides in the cytoplasm, and can transiently migrate to the nucleus to regulate multiple cellular processes. The inhibition of SIRT2 under ischaemic stroke conditions was hypothesized to reduce neuronal cell death. SIRT2 inhibition in vitro leads to marked decrease in cleaved caspase-3, bim and bad and significant increase in bcl-xL. The downregulation of FOXO3a, JNK MAPK and c-Jun pathways was identified to be responsible for reduced neuronal cell death. When tested in animals subjected to middle cerebral artery occlusion, AGK2 significantly reduced infarct area, improved neurological scores, and significantly reduced levels of pro-apoptotic proteins, FOXO3a and MAP kinases. A significant reduction of pro-inflammatory cytokines such as TNF-α and IL-1β was noted in OGD-treated microglia cell lines (BV2 and Sim-A9) in the presence of AGK2, which would be beneficial in the aftermath of an ischemic event.