The role of the GLP-1/GLP-1R signaling pathway in regulating seizure susceptibility in rats.

OBJECTIVE

This study aimed to investigate the role of glucagon-like peptide-1 (GLP-1)/GLP-1 receptor(R) signaling in the regulation of seizure susceptibility and to explore the potential mechanism in rats.

METHODS

Hyperthermia-induced seizures in SD rats were generated using hot bath methods, and seizure severity was measured according to Racine scores and electroencephalogram (EEG). Protein levels of GLP-1 and GLP-1R in the brain tissues of rats were evaluated through ELISA, western blot analysis, and immunohistochemistry to explore the possible roles of each in FS. Neuronal excitability, spontaneous inhibitory postsynaptic currents (sIPSCs) and transient receptor potential cation channel subfamily V member 1(TRPV1) currents were tested using the patch-clamp method in cultured hippocampal neurons.

RESULTS

Significant decreases in the levels of GLP-1 and GLP-1R were observed in the hippocampi of rats compared to those in the control group. Furthermore, treatment with the GLP-1R pharmacological inhibitor exendin9-39 increased hyperthermia- induced seizure severity in rats and promoted neuronal firing activity in cultured neurons. Importantly, exendin9-39 and GLP-1R knockdown decreased the amplitude and frequency of sIPSCs in cultured neurons. In addition, GLP-1R knockdown elevated downstream TRPV1 expression and promoted capsaicin-induced TRPV1 function, which may regulate inhibitory neurotransmission to affect seizure susceptibility.

CONCLUSIONS

The present study suggests that inhibition of GLP-1R signaling promotes seizure activity, which plays a key role in the pathogenesis of FS.