Vagus Nerve Stimulation Ameliorates Learning-Memory Deficits and Suppresses Neuronal Apoptosis via the ERK/CREB/BDNF Signaling Pathway in Epileptic Rats

This study aimed to evaluate the impact of vagus nerve stimulation （VNS） on learning, memory, and neuronal apoptosis in epileptic rats, and to investigate the involvement of the ERK/CREB/BDNF signaling pathway. Epilepsy was induced in rats via lithium chloride-pilocarpine. Then they were divided into four groups: epilepsy model, VNS-treated, and sodium valproate-treated (VPA), and sham groups (n = 6/group). VNS was administered at parameters of 1 mA, 30 Hz, 250 μs pulse width, for 30 min/12 h. Cognitive function was assessed by the Morris water maze. Hippocampal neuronal damage, apoptosis and pathology were evaluated via Nissl, TUNEL and H&E staining, respectively. Oxidative stress markers were quantified by ELISA, while ROS were detected using DCFH-DA probes. Western blotting analyzed expression levels of Bcl-2, Bax, ERK, p-ERK, CREB, p-CREB, and BDNF in the cerebral cortex. Healthy rats exhibited abundant, evenly distributed Nissl bodies and orderly arranged cortical neurons. The epilepsy group showed cytoplasmic hypochromia and disorganized neuronal arrangement. VNS restored neuronal morphology to an extent comparable with VPA treatment. Compared to sham group, the epilepsy group demonstrated increased seizure frequency, duration, Racine scores, and escape latency, alongside reduced target quadrant occupancy. Elevated MDA, TNF-α, and ROS levels were observed in the cerebral cortex, while SOD, IL-10, p-ERK/ERK, p-CREB/CREB, and BDNF levels were reduced. VNS significantly ameliorated these pathological changes. VNS enhances cognitive function in epileptic rats, potentially through activation of the ERK/CREB/BDNF pathway in the cerebral cortex, thereby attenuating oxidative stress and neuroinflammation.