Gynosaponin ameliorates sevoflurane anesthesia-induced cognitive dysfunction and neuronal apoptosis in rats through modulation of the phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin pathway.

Anesthetic sevoflurane (Sev) causes cognitive dysfunction and neuronal death when used as an anesthetic during surgical procedures. Gynosaponin (GpS) was studied for its effects on brain morphology and cognitive behaviors in Sevanesthetized rats. The present study investigated whether GpS has an effect on Sev anesthesia-induced abnormalities in brain morphology and cognitive behaviors, as well as on apoptosis and inflammation of neurons in rats, and delved into the molecular mechanisms. Male Sprague-Dawley rats were induced by 3% Sev anesthesia, and GpS was injected into the rats via the tail vein. The in vitro model of Sev anesthesia was constructed by treating primary rat hippocampal neurons with 4.1% Sev in the presence of GpS (5, 10, and 20 μM). The neuroprotective effects of GpS against Sev-induced cognitive deficits in rats were evaluated using the open field and Morris water maze tests. The apoptosis of hippocampal neurons was observed using hematoxylin-eosin (HE staining and TUNEL assay. Cleaved caspase-3 expression and reactive oxygen species production in rat hippocampal tissue were measured by immunofluorescence. Apoptosis-related proteins and the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) pathway were determined via Western blot. Pro-inflammatory factors tumor necrosis factor-α and interleukin-6 were measured via ELISA. Levels of malondialdehyde, superoxide dismutase and glutathione were assayed by commercial kits. Viability and apoptosis of hippocampal neurons were detected by Cell Counting Kit-8 and flow cytometry. Expression of cleaved caspase-3, B-cell leukemia/lymphoma 2 protein (Bcl-2) Bcl-2-associated protein (Bax) was determined by Western blot. GpS significantly reduced Sev-induced decline in short-term memory, learning and cognitive abilities, as well as neuronal degeneration apoptosis and inflammatory responses, GpS also lessened oxidative stress damage, and activated the PI3K/Akt/mTOR pathway (p<0.05). GpS therapy enhanced learning and memory abilities in rats suffering from Sev-induced cognitive deficits. The PI3K/Akt/mTOR pathway inhibitor LY294002 reversed the ameliorative effects of high-dose GpS on cognitive deficits and cell damage in primary hippocampal neurons in Sev anesthetized rats (p<0.05). We conclude that GpS ameliorates Sev-induced neurotoxicity and cognitive dysfunction by modulating the PI3K/Akt/mTOR pathway and alleviating neuronal apoptosis and oxidative stress.