Abstract:
Epilepsy is a chronic neurological disorder. Drug-resistant epilepsy (DRE) accounts for about one-third of epilepsy patients worldwide. Peimine, a main active component of Fritillaria, has been reported to show anti-inflammatory effects. However, its potential therapeutic role in DRE is not yet fully understood. In this work, a DRE rat model was established by injecting 1 μg kainic acid (KA), followed by a 250 mg/kg administration of valproic acid (VPA) from day 4-31. Rats were treated with different doses of peimine (2.5 mg/kg, 5 mg/kg and 10 mg/kg) daily from day 32-62. In vitro, BV-2 microglia were exposed to different doses of peimine (7.5 μg/ml, 15 μg/ml, and 30 μg/ml) in presence of LPS. The aim of this study was to investigate the potential therapeutic effects of peimine on DRE. The results showed that peimine efficiently suppressed the KA-induced epileptic behaviors of rats in a dose-dependent manner, as recorded by electroencephalography. Furthermore, peimine ameliorated hippocampal neuron injury in DRE rats, and promoted an M1-to-M2 microglial phenotype shift in a dose-dependent manner. Mechanistically, peimine inhibited the TLR4/NF-κB/HIF-1α signaling pathway both in vivo and in vitro. Additionally, peimine suppressed the apoptosis of primary neurons induced by LPS-treated microglia. In conclusion, peimine augments the microglial polarization towards an M2 phenotype by inhibiting the TLR4/NF-κB/HIF-1α signaling pathway, thereby attenuating DRE.
摘要:
癫痫是一种慢性神经系统疾病。耐药性癫痫(DRE)约占全球癫痫患者的三分之一。Peimine,贝母的主要活性成分,据报道显示抗炎作用。然而,其在DRE中的潜在治疗作用尚未完全了解.在这项工作中,通过注射1μg海藻酸(KA)建立DRE大鼠模型,然后从第4-31天给予250mg/kg丙戊酸(VPA)。大鼠用不同剂量的贝亚胺(2.5mg/kg,从第32-62天每天5mg/kg和10mg/kg)。体外,BV-2小胶质细胞暴露于不同剂量的PEIMine(7.5μg/ml,15μg/ml,和30μg/ml)在LPS存在下。这项研究的目的是研究培美明对DRE的潜在治疗作用。结果表明,培美素能有效抑制KA诱导的大鼠癫痫行为,并呈剂量依赖性,通过脑电图记录。此外,培美素改善DRE大鼠海马神经元损伤,并以剂量依赖性方式促进M1-M2小胶质细胞表型转变。机械上,在体内和体外都能抑制TLR4/NF-κB/HIF-1α信号通路。此外,peimine抑制LPS处理的小胶质细胞诱导的原代神经元凋亡。总之,peimine通过抑制TLR4/NF-κB/HIF-1α信号通路增强小胶质细胞向M2表型的极化,从而衰减DRE。