Ningxia Key Laboratory of Cerebrocranial Disease, Incubation Base of National Key Laboratory, Ningxia Medical University, Yinchuan, Ningxia 750000, P.R. China.
Department of Neurosurgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310000, P.R. China.
Int J Mol Med. 2021 Dec;48(6). doi: 10.3892/ijmm.2021.5052. Epub 2021 Oct 22.
Epilepsy comorbidities and anti‑epileptic drugs (AEDs) are currently the main limitations of epilepsy treatment. Semaglutide is a glucagon like peptide‑1 analogue that has entered the market as a new once‑weekly drug for type II diabetes. The aim of the present study was to investigate the functions of semaglutide in epilepsy and inflammation models, in order to investigate its potential mechanism. , an inflammation model was established using lipopolysaccharide (LPS) and nigericin stimulation in BV2 cells. , chronic epilepsy model mice were generated using a pentylenetetrazole (PTZ) kindling method. BV2 cell proliferation was assessed using the Cell Counting Kit‑8. The effects of semaglutide on NLR family pyrin domain containing 3 (NLRP3) inflammasome activation and inflammatory cytokine secretion were determined using western blotting (WB) and ELISA. A lactate dehydrogenase (LDH) assay kit was used to detect the effect of semaglutide on LDH release. Electrocorticography and the modified Racine scale were used to assess seizure severity. Cognitive function was evaluated with behavioral assessment. Morphological changes in the hippocampus were observed with Nissl staining. Double immunofluorescence staining for NeuN and Iba‑1, WB and immunofluorescence analysis of apoptosis‑related proteins were used to evaluate neuronal apoptosis. The NLRP3 inflammasome was assessed by reverse transcription‑quantitative PCR, WB and immunofluorescence staining, and inflammatory cytokine release was evaluated by WB analysis in the hippocampus of C57/BL6J model mouse. Semaglutide attenuated the LPS‑ and nigericin‑induced inflammatory response and LDH release by blocking NLRP3 inflammasome activation in BV2 cells. Moreover, semaglutide decreased seizure severity, alleviated hippocampal neuronal apoptosis, ameliorated cognitive dysfunction, blocked NLRP3 inflammasome activation and decreased inflammatory cytokine secretion in PTZ‑kindled mice. These results indicated that semaglutide reduced seizure severity, exerted neuroprotective effects and ameliorated cognitive dysfunction, possibly via inhibition of NLRP3 inflammasome activation and inflammatory cytokine secretion. Semaglutide may therefore be a novel, promising adjuvant therapeutic for epilepsy and its associated comorbidities.
癫痫共病和抗癫痫药物（AEDs）目前是癫痫治疗的主要限制因素。司美格鲁肽是一种胰高血糖素样肽-1 类似物，已作为一种新型每周一次的 2 型糖尿病药物上市。本研究旨在探讨司美格鲁肽在癫痫和炎症模型中的作用，以研究其潜在机制。 ，使用脂多糖（LPS）和 Nigericin 刺激 BV2 细胞建立炎症模型。 ，使用戊四氮（PTZ）点燃法建立慢性癫痫模型小鼠。使用细胞计数试剂盒-8 评估 BV2 细胞增殖。使用 Western blot（WB）和 ELISA 测定司美格鲁肽对 NLR 家族含 pyrin 域蛋白 3（NLRP3）炎性小体激活和炎症细胞因子分泌的影响。使用乳酸脱氢酶（LDH）测定试剂盒检测司美格鲁肽对 LDH 释放的影响。使用脑电图和改良 Racine 量表评估癫痫发作严重程度。使用行为评估评估认知功能。通过尼氏染色观察海马形态变化。使用 NeuN 和 Iba-1 的双重免疫荧光染色、WB 和凋亡相关蛋白的免疫荧光分析评估神经元凋亡。通过逆转录-定量 PCR、WB 和免疫荧光染色评估 NLRP3 炎性小体，通过 WB 分析评估海马中炎症细胞因子的释放。司美格鲁肽通过阻断 NLRP3 炎性小体激活，减轻 LPS 和 Nigericin 诱导的炎症反应和 LDH 释放。此外，司美格鲁肽降低了癫痫发作严重程度，减轻了海马神经元凋亡，改善了认知功能障碍，阻断了 PTZ 点燃小鼠中 NLRP3 炎性小体的激活并减少了炎症细胞因子的分泌。这些结果表明，司美格鲁肽通过抑制 NLRP3 炎性小体激活和炎症细胞因子分泌，减轻癫痫发作严重程度，发挥神经保护作用并改善认知功能障碍。因此，司美格鲁肽可能成为癫痫及其相关共病的一种新的有前途的辅助治疗药物。
