Topiramate Reverses Physiological and Behavioral Alterations by Postoperative Cognitive Dysfunction in Rat Model Through Inhibiting TNF Signaling Pathway

This study aimed to investigate the effects of topiramate (TPM) on rats with postoperative cognitive dysfunction (POCD) and elucidate the underlying mechanism. Differentially expressed genes in propofol-treated group and vehicle control group were filtered out and visualized in heatmap based on R program. POCD rat models were established for validation of TPM’s anti-inflammatory action and Morris water maze (MWM) test was employed for assessment of spatial learning and memory ability of rats. Hematoxylin and eosin (HE) staining was applied to detect the neurodegeneration, and the apoptosis status was detected using TUNEL assay. In vitro, hippocampal microglia was treated with lipopolysaccharide or TPM to validate the TPM’s anti-inflammatory action. Cell apoptosis was detected with flow cytometry. Inflammatory factors were detected by enzyme-linked immunosorbent assay, and factor-associated suicide (Fas), Fas-associated protein with death domain (FADD) expression were detected by western blot. As results, TPM administration improved the spatial learning and memory ability in POCD rat by decreasing the expression levels of Fas, FADD, and inflammatory factors (tumor necrosis factor-α, TNF-α; interleukin-1β, IL-1β; interleukin-6, IL-6) in POCD rats. In addition, TPM down-regulated cell apoptotic rate to suppress POCD by decreasing the expression of Caspase8, Bcl2-associated X (Bax), and poly ADP-ribose polymerase-1 (PARP1) yet enhancing B-cell lymphoma-2 (Bcl-2) expression. Besides, inhibition of Fas enhanced TPM-induced down-regulation of apoptosis of neuronal cell in hippocampus tissues of POCD rats. Our results revealed that treatment of POCD rats with TPM could suppress neuronal apoptosis in the hippocampus tissues, and the neuroprotective effects of TPM may relate with the regulation of tumor necrosis factor (TNF) signaling pathway.