5-Hydroxytryptamine 6 Receptor Antagonism Ameliorates Depression-Like Behaviors in Temporal Lobe Epilepsy Rats with Potential Involvement of the MEF2C/NF-κB Pathway

This study aimed to investigate whether 5-HT6 receptor (5-HT6R) antagonism could ameliorate epilepsy-associated emotional and behavioral disturbances in rats with temporal lobe epilepsy (TLE) and to explore its potential association with the MEF2C/NF-κB pathway. Thirty rats were randomly divided into normal control (NC) group, Model group and 5-HT6R group. The TLE model was established using lithium chloride-pilocarpine. The rats in 5-HT6R group were treated with 5-HT6R antagonist SB271046. Behavioral tests were conducted to evaluate anxiety- and depression-like behaviors associated with epilepsy. Levels of inflammatory factors, 5-HT and KYN in hippocampal tissues were detected by enzyme-linked immunosorbent assay. Neuronal cell death in brain tissues was assessed by TUNEL staining, and the protein expressions of MEF2C and NF-κB p65 were measured by Western blotting. Molecular docking between SB271046 and MEF2C/NF-κB p65 was performed using AutoDock 4. In addition, JASPAR database was used to analyze the putative binding of CREB1 to MEF2C promoter. Rats in the Model group exhibited significant epilepsy-associated anxiety- and depression-like behaviors, accompanied by aggravated inflammation, decreased MEF2C protein expression and increased NF-κB p65 protein expression. Treatment with SB271046 significantly ameliorated these behavioral abnormalities and inflammatory responses, and was associated with upregulated MEF2C protein expression and downregulated NF-κB p65 protein expression. KEGG enrichment analysis suggested the involvement of NF-κB pathway in TLE. Molecular docking revealed potential interactions between SB271046 and MEF2C/NF-κB p65. 5-HT6R antagonist SB271046 may alleviate epilepsy-associated emotional and cognitive disturbances, potentially through neurostabilizing and anti-inflammatory effects linked to modulation of the MEF2C/NF-κB pathway. These mechanistic associations remain preliminary and warrant further validation using targeted gain- or loss-of-function approaches.