Rimal Nikesh, Khanal Shristi, Bohara Ganesh, Choi Dong-Young
College of Pharmacy, Yeungnam University, Gyeongsan, Gyeongbuk, 38541, Republic of Korea.
Neuropharmacology. 2025 Nov 15;279:110643. doi: 10.1016/j.neuropharm.2025.110643. Epub 2025 Aug 16.
Parkinson's disease (PD) is a neurodegenerative disease characterized by preferential loss of the dopaminergic neurons in the substantia nigra and consequent occurrence of typical symptoms including resting tremor, rigidity and bradykinesia. PD remains a significant challenge due to the lack of disease-modifying drugs despite extensive research efforts. Glucagon-like peptide-1 and its analogues have shown neuroprotective properties. However, its specific molecular mechanisms for the neuroprotection remains to elucidate. In this study, we explored the anti-inflammatory and neuroprotective effects of exendin-4 by employing BV2 microglial cells and the MPTP-induced mouse model for PD. Our study showed that exendin-4 significantly suppressed the production of pro-inflammatory cytokines, including TNF-α, IL-1β, and IL-6 in LPS-stimulated BV2 cells. Furthermore, exendin-4 increased AMPK phosphorylation and the activation of AMPK by exendin-4 played a crucial role in suppressing the production of proinflammatory cytokines, as addition of compound C, an inhibitor of AMPK diminished the effect. Additionally, exendin-4 demonstrated neuroprotective effects by attenuating SH-SY5Y cell death caused by conditioned media from BV2 cells exposed to LPS. Moreover, exendin-4 attenuated microglial and astroglial activation in the substantia nigra and striatum of MPTP-treated mice, which was accompanied by reduced proinflammatory cytokines. Exendin-4 also improved motor functions of MPTP-treated mice, as determined by beam test and rotarod test. In parallel with the anti-inflammatory effects, exendin-4 attenuated MPTP-mediated dopaminergic neurodegeneration as estimated by immunohistochemistry for tyrosine hydroxylase and HPLC analyses for the striatal dopamine and DOPAC. These results suggest that exendin-4 could be a promising therapeutic agent for PD, offering neuroprotection by modulating inflammatory pathways and preserving dopaminergic neurons.
帕金森病（PD）是一种神经退行性疾病，其特征是黑质中多巴胺能神经元选择性丧失，并随之出现包括静止性震颤、僵硬和运动迟缓等典型症状。尽管进行了广泛的研究，但由于缺乏疾病修饰药物，PD仍然是一个重大挑战。胰高血糖素样肽-1及其类似物已显示出神经保护特性。然而，其神经保护的具体分子机制仍有待阐明。在本研究中，我们通过使用BV2小胶质细胞和MPTP诱导的PD小鼠模型，探讨了艾塞那肽-4的抗炎和神经保护作用。我们的研究表明，艾塞那肽-4显著抑制了LPS刺激的BV2细胞中促炎细胞因子的产生，包括TNF-α、IL-1β和IL-6。此外，艾塞那肽-4增加了AMPK磷酸化，并且艾塞那肽-4对AMPK的激活在抑制促炎细胞因子的产生中起关键作用，因为添加AMPK抑制剂化合物C会减弱这种作用。此外，艾塞那肽-4通过减轻由暴露于LPS的BV2细胞的条件培养基引起的SH-SY5Y细胞死亡，表现出神经保护作用。此外，艾塞那肽-4减轻了MPTP处理小鼠黑质和纹状体中的小胶质细胞和星形胶质细胞激活，这伴随着促炎细胞因子的减少。艾塞那肽-4还改善了MPTP处理小鼠的运动功能，这通过光束试验和转棒试验确定。与抗炎作用并行，通过酪氨酸羟化酶免疫组织化学和纹状体多巴胺及DOPAC的HPLC分析估计，艾塞那肽-4减轻了MPTP介导的多巴胺能神经退行性变。这些结果表明，艾塞那肽-4可能是一种有前途的PD治疗药物，通过调节炎症途径和保护多巴胺能神经元提供神经保护。
