Neuroprotective effect of ginkgetin in experimental cerebral ischemia/reperfusion via apoptosis inhibition and PI3K/Akt/mTOR signaling pathway activation.
Ginkgetin, extracted from Ginkgo biloba L leaves, has been demonstrated to have potential anti-inflammatory and immune-suppressive properties. But the neuroprotective effect and potential mechanisms of ginkgetin on cerebral ischemia/reperfusion (IR) injury remain unclear. In this research, we studied the neuroprotective effect of ginkgetin in the middle part of the middle cerebral artery occlusion/reperfusion rat model, by analyzing the apoptosis of brain tissues harvested from treatment groups and control groups using the terminal deoxynucleotidyl transferase dUTP nick-end labeling and apoptosis assays. In addition, we detected the association of the neuroprotective effect of ginkgetin with apoptosis inhibition via the activation of the phosphatidylinositol-3-kinase/Akt/mammalian target of rapamycin (PI3K/Akt/mTOR) signaling pathway using Western blot analysis. Our results showed that administration of ginkgetin remarkably reduced brain infarction volumes and neurologic deficits; in addition, reducing apoptotic cell numbers, downregulating the levels of cleaved caspase-3 and Bax, and upregulating the level of Bcl-2 in rats subjected to IR injury in a dose-dependent manner. Moreover, high-dose ginkgetin treatment (100 mg/kg) significantly increased the phosphorylations of Akt and mTOR. Blocking of PI3K by LY294002 clearly decreased its antiapoptotic effect and reduced both Akt and mTOR phosphorylation levels. Taken together, these results for the first time suggest that ginkgetin antagonizes cerebral IR-induced injury by inhibiting apoptosis in rats, and this effect was attenuated by the activation of PI3K/Akt/mTOR signaling pathway.