sitagliptin-phosphate and Seizures--Febrile

Dipeptidyl peptidase-IV (DPP4) is a cell surface serine peptidase widely expressed in the brain. Recent studies suggest that DPP4 contributes to the development of febrile seizures (FS); however, the underlying mechanism is still unclear. Thus, we investigated the role of DPP4 in the progression of FS at the molecular and electrophysiological levels using FS models in vivo and in vitro. Herein, we found that both the mRNA and protein levels of DPP4 were upregulated in the FS model. Administration of the pharmacological DPP4 inhibitor sitagliptin suppressed the hyperthermia-induced neuronal excitability as determined via whole-cell patch-clamp recordings in vitro. Interestingly, sitagliptin administration activated the glucagon-like peptide-1 (GLP-1)/GLP-1 receptor (GLP-1R) pathway by increasing the expression of GLP-1 and GLP-1R in a rat model of FS. Moreover, administration of the GLP-1R inhibitor exendin9-39 increased seizure severity, and sitagliptin reversed the effect, as shown in the electroencephalogram (EEG) and patch-clamp results in a rat model of FS. Furthermore, the GLP-1R-mediated reduction in GABAergic transmission was enhanced by sitagliptin and DPP4 knockdown through increasing miniature inhibitory post-synaptic currents (mIPSCs) in vitro accompanied by increased synaptic release of GABA in vivo. Taken together, our results demonstrate a role of DPP4 in regulating GABAergic transmission via the GLP-1/GLP-1R pathway. These findings indicated that DPP4 may represent a novel therapeutic strategy and target for FS.

Topics: Animals; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Female; Gene Expression Regulation; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Hippocampus; Male; Neurturin; Rats; Rats, Sprague-Dawley; RNA Interference; Seizures, Febrile; Signal Transduction; Sitagliptin Phosphate

Febrile seizures (FS) are the most common seizure disorders in children aged 6 months to 5 years. Children suffering from complex FS have a high risk of developing subsequent temporal lobe epilepsy (TLE). Neuroinflammation is involved in the pathogenesis of FS although the mechanism remains unknown. Our previous study using the Whole Rat Genome Oligo Microarray determined that Dipeptidyl peptidase IV (DPP4) is potentially a related gene in FS rats. In this study, we demonstrated that DPP4 expression was significantly increased at both the protein and mRNA levels after hyperthermia induction. Sitagliptin, a specific enzyme inhibitor of DPP4, remarkably attenuated the severity of seizures in FS rats, and hyperthermia-induced astrocytosis was suppressed after DPP4 inhibition. Furthermore, sitagliptin significantly decreased the levels of the inflammatory cytokines IL-1β, TNF-α, and IL-6 but not IL-10. In addition, sitagliptin prevented NF-κB activation by decreasing phosphorylation of the p65 subunit. Taken together, our findings demonstrate that DPP4 functions as a critical regulator of neuroinflammation in hyperthermia-induced seizures and the DPP4 inhibitor may be a viable option for FS therapeutics.

Topics: Animals; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Disease Models, Animal; Hyperthermia, Induced; Inflammation; NF-kappa B; Rats; Rats, Sprague-Dawley; Seizures, Febrile; Sitagliptin Phosphate; Up-Regulation

Febrile seizures (FS) are the most common type of convulsive events in infants and young children, but the precise underlying genetic mechanism remains to be explored. To investigate the underlying pathogenic factors in FS and subsequent epilepsy, alterations in gene expression between the two new strains of rats (hyperthermia-prone [HP] vs hyperthermia-resistant [HR]), were investigated by using the Whole Rat Genome Oligo Microarray. This process identified 1,140 differentially expressed genes (DEGs; 602 upregulated and 538 downregulated), which were analyzed to determine significant Gene Ontology (GO) categories, signaling pathways and gene networks. Based on the GO analyses, the modified genes are closely related to various FS pathogenesis factors, including immune and inflammatory responses and ion transport. Certain DEGs identified have not been previously examined in relation to FS pathogenesis. Among these genes is dipeptidyl peptidase 4 (DPP4), a gene closely linked to interleukin 6 (IL-6), which played a key role in the gene network analysis. Furthermore, sitagliptin, a DPP4 inhibitor significantly decreased epileptic discharge in rats, observed via electroencephalogram, suggesting an important role for DPP4 in FS. The effectiveness of sitagliptin in reducing seizure activity may occur through a mechanism that stabilizes cellular Ca2+ homeostasis. In addition, DPP4 expression may be regulated by DNA methylation. The hippocampal gene expression profiles in novel rat models of FS provides a large database of candidate genes and pathways, which will be useful for researchers interested in disorders of neuronal excitability.

Topics: Animals; Cell Line, Tumor; Dipeptidyl-Peptidase IV Inhibitors; Disease Models, Animal; Gene Expression Profiling; Gene Ontology; Gene Regulatory Networks; Hippocampus; Pyrazines; Rats; Rats, Sprague-Dawley; Seizures, Febrile; Sitagliptin Phosphate; Triazoles