Lim Hye-Sun, Park Jinyoung, Kim Eunjeong, Lee Wonhwa, Yun Hwi-Yeol, Lee Seung Hoon, Park Gunhyuk
Herbal Medicine Resources Research Center, Korea Institute of Oriental Medicine, 111 Geonjae-Ro, Naju-Si, Jeollanam-Do, 58245, Republic of Korea.
Department of Chemistry, Sungkyunkwan University, Suwon, 16419, Republic of Korea.
J Neuroinflammation. 2025 May 17;22(1):132. doi: 10.1186/s12974-025-03461-z.
Parkinson's disease (PD) is characterized by dopaminergic neuron loss, neuroinflammation, and motor dysfunction. PD is a multifactorial disease, with neuroinflammation driven by NLRP3 inflammasome activation representing an important component of its pathological progression. Therefore, we aimed to evaluate the therapeutic potential of rebamipide (Mucosta®), a clinically approved anti-inflammatory agent, in PD by targeting the NLRP3 inflammasome. Specifically, we examined the effects of rebamipide on neuroinflammation, dopaminergic neuron preservation, and motor deficits using BV2 microglia cells and a 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP)-induced mouse model.
Rebamipide alleviated microglial activation and downstream neuroinflammation by suppressing the NLRP3-NEK7 interaction, resulting in dopaminergic neuron protection in the MPTP-induced PD model. Rebamipide downregulated IL-1β levels in BV2 microglia cells treated with α-synuclein and MPP. Molecular docking analysis revealed a high binding affinity between rebamipide and the NLRP3-NEK7 interaction interface. Surface plasmon resonance analysis confirmed the direct binding of rebamipide to NLRP3, with notable kinetic affinity, supporting its role as a novel NLRP3 inflammasome inhibitor. Rebamipide significantly downregulated IL-1β levels, microglial activation, and dopaminergic neuron loss in the MPTP mouse model by disrupting inflammasome activation. Rebamipide preserved dopamine levels in the striatum and improved motor deficits, including bradykinesia and motor coordination. The neuroprotective effects of rebamipide were neutralized in NLRP3 knockout mice, confirming the dependency of its action on NLRP3.
Considering its established clinical use, this study supports repurposing rebamipide for treating PD and other NLRP3 inflammasome-driven neuroinflammatory diseases.
帕金森病（PD）的特征是多巴胺能神经元丢失、神经炎症和运动功能障碍。PD是一种多因素疾病，由NLRP3炎性小体激活驱动的神经炎症是其病理进展的重要组成部分。因此，我们旨在通过靶向NLRP3炎性小体来评估临床批准的抗炎药物瑞巴派特（膜固思达®）在PD中的治疗潜力。具体而言，我们使用BV2小胶质细胞和1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）诱导的小鼠模型，研究了瑞巴派特对神经炎症、多巴胺能神经元保护和运动缺陷的影响。
瑞巴派特通过抑制NLRP3-NEK7相互作用减轻小胶质细胞活化和下游神经炎症，从而在MPTP诱导的PD模型中保护多巴胺能神经元。瑞巴派特下调了用α-突触核蛋白和MPP处理的BV2小胶质细胞中IL-1β的水平。分子对接分析显示瑞巴派特与NLRP3-NEK7相互作用界面之间具有高结合亲和力。表面等离子体共振分析证实瑞巴派特与NLRP3直接结合，具有显著的动力学亲和力，支持其作为新型NLRP3炎性小体抑制剂的作用。瑞巴派特通过破坏炎性小体激活，显著下调MPTP小鼠模型中IL-1β水平、小胶质细胞活化和多巴胺能神经元丢失。瑞巴派特维持纹状体中的多巴胺水平并改善运动缺陷，包括运动迟缓及运动协调性。瑞巴派特的神经保护作用在NLRP3基因敲除小鼠中被中和，证实了其作用对NLRP3的依赖性。
考虑到其已确立的临床应用，本研究支持将瑞巴派特重新用于治疗PD和其他由NLRP3炎性小体驱动的神经炎症性疾病。
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