Salicin is a major natural compound of
willow bark and displays diverse beneficial biological properties, such as
antioxidant activity. However, little information available for the neuroprotective potential of
salicin against ischemic
brain injury has been reported. Thus, this study was performed to investigate the neuroprotective potential of
salicin against
ischemia and reperfusion (IR) injury and its mechanisms in the hippocampus using a gerbil model of 5-min transient
ischemia (TI) in the forebrain, in which a massive loss (death) of pyramidal neurons cells occurred in the subfield Cornu Ammonis 1 (CA1) among the hippocampal subregions (CA1-3) at 5 days after TI. To examine neuroprotection by
salicin, gerbils were pretreated with
salicin alone or together with
LY294002, which is a
phosphatidylinositol 3-kinase (PI3K) inhibitor, once daily for 3 days before TI. Treatment with 20 mg/kg of
salicin significantly protected CA1 pyramidal neurons against the ischemic injury. Treatment with 20 mg/kg of
salicin significantly reduced the TI-induced increase in
superoxide anion generation and lipid peroxidation in the CA1 pyramidal neurons after TI. The treatment also reinstated the TI-induced decrease in
superoxide dismutases (SOD1 and SOD2),
catalase, and
glutathione peroxidase in the CA1 pyramidal cells after TI. Moreover,
salicin treatment significantly elevated the levels of phosphorylation of Akt and
glycogen synthase kinase-3β (GSK3β), which is a major downstream target of PI3K, in the ischemic CA1. Notably, the
neuroprotective effect of
salicin was abolished by
LY294002. Taken together, these findings clearly indicate that
salicin protects against ischemic
brain injury by attenuating oxidative stress and activating the PI3K/Akt/GSK3β pathway.