sitagliptin-phosphate and Epilepsy

Accumulating evidence suggests that disease-associated microglia (DAM), a recently discovered subset of microglia, plays a protective role in neurological diseases. Targeting DAM phenotypic transformation may provide new therapeutic options. However, the relationship between DAM and epilepsy remains unknown.. Analysis of public RNA-sequencing data revealed predisposing factors (such as dipeptidyl peptidase IV; DPP4) for epilepsy related to DAM conversion. Anti-epileptic effect was assessed by electroencephalogram recordings and immunohistochemistry in a kainic acid (KA)-induced mouse model of epilepsy. The phenotype, morphology and function of microglia were assessed by qPCR, western blotting and microscopic imaging.. Our results demonstrated that DPP4 participated in DAM conversion and epilepsy. The treatment of sitagliptin (a DPP4 inhibitor) attenuated KA-induced epilepsy and promoted the expression of DAM markers (Itgax and Axl) in both mouse epilepsy model in vivo and microglial inflammatory model in vitro. With sitagliptin treatment, microglial cells did not display an inflammatory activation state (enlarged cell bodies). Furthermore, these microglia exhibited complicated intersections, longer processes and wider coverage of parenchyma. In addition, sitagliptin reduced the activation of NF-κB signaling pathway and inhibited the expression of iNOS, IL-1β, IL-6 and the proinflammatory DAM subset gene CD44.. The present results highlight that the DPP4 inhibitor sitagliptin can attenuate epilepsy and promote DAM phenotypic transformation. These DAM exhibit unique morphological features, greater migration ability and better surveillance capability. The possible underlying mechanism is that sitagliptin can reduce the activation of NF-κB signaling pathway and suppress the inflammatory response mediated by microglia. Thus, we propose DPP4 may act as an attractive direction for DAM research and a potential therapeutic target for epilepsy.

Topics: Animals; Cell Differentiation; Dipeptidyl-Peptidase IV Inhibitors; Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; Epilepsy; Male; Mice; Mice, Inbred C57BL; Microglia; Phenotype; Sitagliptin Phosphate

The current investigation aimed at studying the anti-epileptogenic effect of sitagliptin. The possible effect of the drug in combination with pregabalin in pentylenetetrazole (PTZ)- induced seizures was studied. In addition, the postulated mechanisms that could mediate such effect were explored namely, suppression of oxidative stress and neuro-inflammatory markers, autophagy and apoptosis. Seven days prior to PTZ (60 mg/kg, sc) injection, mice were treated with sitagliptin (5, 15, and 60 mg/kg, twice daily, orally) or pregabalin (30 mg/kg, once daily, orally) or their combination. At the end of the experiment, several parameters were assessed including: oxidative/nitro-oxidative stress such as superoxide dismutase (SOD), reduced glutathione (GSH), glutathione peroxidase (GP-x) catalase (CAT), and lipid peroxidation assessed as malondialdehyde (MDA), nitrate/nitrite (NOx), 3-nitrotyrosine (3-NT). Seizure latency was evaluated. Neuronal damage was also assessed by performing tissue staining by hematoxylin and eosin, estimating hippocampus level of glutamate, gamma-aminobutyric acid (GABA), glial fibrillary acidic protein (GFAP) and brain-derived neurotrophic factor (BDNF). Also, markers for inflammation, autophagy and apoptosis were measured, nuclear factor erythroid-derived 2- like 2 (Nrf2), nuclear factor kappa-B (NF-κB), phosphatidylethanolamine-conjugated form of microtubule-associated protein light chain-3 (LC3-II), casapase-3, Bcl-2-like protein 4 (BAX) and glucagon like peptide-1 (GLP-1) activity. Sitagliptin significantly suppressed epileptogenesis in PTZ-induced seizures. Sitagliptin counteracted neuronal damage and all biochemical, and histo-chemical alteration induced by PTZ. Also, a more significant protective effect was observed after combination with pregabalin. This study is indicative for the antiepileptogenic potential of sitagliptin with or without pregabalin in the PTZ model of epilepsy which is likely to be through its effect on antioxidant, anti-apoptotic and autophagic pathways.

Topics: Animals; Antioxidants; Autophagy; Epilepsy; Hippocampus; Kindling, Neurologic; Lipid Peroxidation; Male; Mice; Neurons; Neuroprotective Agents; Oxidative Stress; Pentylenetetrazole; Pregabalin; Sitagliptin Phosphate