Abstract: Objective   To explore the effect of vagus nerve stimulation (VNS) on cognitive function in rats with intractable epilepsy and its possible mechanism.    Methods   The intractable epilepsy rat model was established by intraperitoneal injection of lithium chloride pilocarpine. The rats were randomly divided into a model group (18 rats), a VNS group (15 rats) and a control group (20 rats). The vagus nerve was separated and the stimulator was implanted, but no stimulation for the rats in the control group and model group, while the rats in the VNS group underwent vagus nerve stimulation for 4 weeks. The seizure of rats was detected. Morris water mate test was used to detect the cognitive function of rats. The pathological morphology of hippocampus was observed by Nissl staining. The expression levels of TNF-ɑ, IL-6 and IL-10 in the hippocampus were detected by ELISA. The relative expressions of iNOS, Arg1 were detected by immunofluorescence staining and Western blot, respectively.   Results    ①The seizure grade and duration were significantly higher in the model group than those in the control group (P<0.05). After continuous intervention with VNS for 4 weeks, the seizure grade and duration in the model group were significantly  decreased (P<0.05). ②The escape latency time of rats in the model group was significantly longer than that in the control group, and the times of crossing platform was significantly less than that in the control group (P<0.05). After continuous intervention with VNS for 4 weeks, the escape latency time of epileptic rats was significantly reduced, and the times of crossing platform increased (P<0.05). ③The morphology of hippocampal neurons was normal in the control group. The hippocampal neurons in the model group were severely damaged, and the number of neurons was decreased (P<0.05). Compared with the model group, the damage of hippocampal neurons in the VNS group was significantly reduced, and the number of neurons was increased (P<0.05). ④The relative expression of TNF-ɑ and IL-6 in the hippocampus of model group were significantly higher than those in the control group, the relative expression of IL-10 was significantly decreased (P<0.05). After continuous intervention with VNS for 4 weeks, the relative expression of TNF-ɑ and IL-6 in the hippocampus of epileptic rats were significantly decreased, the relative expression of IL-10 was significantly increased (P<0.05). ⑤ Compared with the control group, the relative expression of iNOS in the hippocampus of the model group was significantly increased , while the relative expression of Arg1 was decreased significantly(P<0.05). Compared with the model group, the relative expression of iNOS in the hippocampus of the VNS group was significantly decreased, while the relative expression of Arg1 was significantly increased (P<0.05).   Conclusions   VNS can significantly improve the cognitive dysfunction of rats with intractable epilepsy, and its mechanism may be through promoting the polarization of M2 microglia to reduce the inflammatory reaction of central nervous system, and protect hippocampal neurons.

Key words: Vagus nerve stimulation; ,  ,  Intractable epilepsy, 　M1/M2 microglia, 　Cognitive function