Sirtuin 2 (
SIRT2) is a family member of
nicotinamide adenine dinucleotide (
NAD+)-dependent deacetylases which appears to have detrimental roles in an array of
neurological disorders such as
Parkinson's disease (PD) and
Huntington's disease (HD). In light of the recently emerging roles of
sirtuins in normal physiology and pathological conditions such as
ischemic stroke, we investigated the role of
SIRT2 in
ischemic stroke-induced neuronal cell death. Primary cortical neurons were subjected to
oxygen-
glucose deprivation (OGD) under in vitro ischemic conditions, and subsequently tested for the efficacy of
SIRT2 inhibitors AK1 and AGK2 in attenuating apoptotic cell death caused by OGD. We have also evaluated the effect of
SIRT2 inhibition in C57BL/6 mice subjected to 1 h
middle cerebral artery occlusion (MCAO) followed by 24 h reperfusion, which is a model for ischemic
reperfusion injury in vivo. Significant reductions in apoptotic cell death were noted in neurons treated with AK1 or AGK2, as evidenced by reduced cleaved
caspase-3 and other apoptotic markers such as Bim and Bad. In addition, downregulation of phosphorylated-AKT and FOXO3a
proteins of the AKT/FOXO3a pathway, as well as a marked reduction of JNK activity and its downstream target c-Jun, were also observed. When tested in animals subjected to MCAO, the
neuroprotective effects of AGK2 in vivo were evidenced by a substantial reduction in ipsilateral
infarct area and a significant improvement in neurological outcomes. A similar reduction in the levels of
pro-apoptotic proteins in the
infarct tissue, as well as downregulation of AKT/FOXO3a and JNK pathway, were also noted. In summary, the current study demonstrated the
neuroprotective effects of
SIRT2 inhibition in
ischemic stroke, and identified the downregulation of AKT/FOXO3a and MAPK pathways as intermediary mechanisms which may contribute to the reduction in apoptotic cell death by
SIRT2 inhibition.