Objective To investigate mechanism of levetiracetam (LEV) on rats with febrile seizures (FS) based on the dipeptidyl peptidase-4 (DPP4)/glucagon-like peptide-1 (GLP-1)/glucagon-like peptide-1 receptor(GLP-1R) signaling axis.
Methods SD juvenile rats were randomly divided into blank control group, model group, low-dose LEV group, medium-dose LEV group and high-dose LEV group, with 10 rats in each group. The behavioral indicators of seizures in rats were observed. Hematoxylin-eosin(HE) staining was used to detect histopathological damage in the hippocampus. Nissl staining was employed to observe the number of Nissl bodies in hippocampal neurons. Enzyme-linked immunosorbent assay (ELISA) was utilized to measure the levels of tumor necrosis factor-α(TNF-α), interleukin-1β(IL-1β), interleukin-6(IL-6), glutamate(Glu) and γ-aminobutyric acid (GABA) in the hippocampus. Western blot was applied to detect the protein expressions of glial fibrillary acidic protein (GFAP), inducible nitric oxide synthase(iNOS), CD86, arginase 1 (Arg1), CD206, brain-derived neurotrophic factor (BDNF), DPP4, GLP-1 and GLP-1R in the hippocampus.
Results Compared with the blank control group, the model group showed histopathological changes in the hippocampus, with a decreased number of Nissl bodies. The relative protein expressions of GFAP, BDNF, iNOS, CD86 and DPP4, as well as the levels of TNF-α, IL-1β, IL-6 and Glu in the hippocampus were increased, while the relative protein expressions of Arg1, CD206, GLP-1 and GLP-1R, and the level of GABA were decreased, with statistically significant differences (P < 0.05). Compared with the model group, the seizure latency in the low-dose, medium-dose and high-dose LEV groups was prolonged in a dose-dependent manner, and the incidence of grade 3 to 5 seizures was reduced in a dose-dependent manner. The histopathological damage in the hippocampus was alleviated, the number of Nissl bodies increased in a dose-dependent manner, the relative protein expressions of GFAP, BDNF, iNOS, CD86 and DPP4, and the levels of TNF-α, IL-1β, IL-6 and Glu were decreased in a dose-dependent manner, while the relative protein expressions of Arg1, CD206, GLP-1 and GLP-1R, and the level of GABA were increased in a dose-dependent manner, with statistically significant differences (P < 0.05).
Conclusion LEV can effectively alleviate seizure attacks and histopathological damage in the hippocampus of FS rats, and reduce hippocampal inflammatory responses and neurotransmitter imbalance. Its mechanism may be related to the inhibition of DPP4 signaling and the activation of the GLP-1/GLP-1R signaling pathway.
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