Neuroprotective Effects of Gabapentin Against Cerebral Ischemia Reperfusion-Induced Neuronal Autophagic Injury via Regulation of the PI3K/Akt/mTOR Signaling Pathways.

Gabapentin (GBP), an analgesic, adjunct antiepileptic, and migraine prophylactic drug, reduces neuronal injury induced by cerebral ischemia reperfusion (IR). However, the underlying biological molecular mechanism of GBP neuroprotection is not clear. In this study, we confirmed that dose-dependent (75 and 150mg/kg) GBP treatment could significantly reduce IR-induced neuronal death. IR-induced neuronal death was inhibited by pretreatment with 150mg/kg GBP in a middle cerebral artery occlusion rat model. In addition, 150mg/kg GBP treatment remarkably promoted the levels of antioxidants and reduced the autophagy of neurons in the infarct penumbra. Moreover, the phosphoinositide-3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) signaling pathway was activated by pretreatment with 150mg/kg GBP, as detected by Western blot analyses. In vitro, pretreatment of PC12 cells with 450 mu M GBP significantly reduced cell death induced by oxygen-glucose deprivation, increased antioxidant function, and reduced the levels of autophagy and reactive oxygen species via activation of the PI3K/Akt/mTOR pathway. This neuroprotection by GBP was inhibited significantly by 10 mu M LY294002. In summary, dose-dependent pretreatment with GBP protected against cerebral IR injury via activation of the PI3K/Akt/mTOR pathway, which provided a neuroprotective function to inhibit oxidative stress-related neuronal autophagy.