New Drug Research and Development Center, Guangdong Pharmaceutical University, Guangzhou, 510006, PR China; Guangdong Provincial Key Laboratory of Advanced Drug Delivery, Guangdong Provincial Engineering Center of Topical Precise Drug Delivery System, Guangdong Pharmaceutical University, 510006 Guangzhou, PR China.
Guangdong Provincial Key Laboratory of Advanced Drug Delivery, Guangdong Provincial Engineering Center of Topical Precise Drug Delivery System, Guangdong Pharmaceutical University, 510006 Guangzhou, PR China.
Chem Biol Interact. 2024 Nov 1;403:111212. doi: 10.1016/j.cbi.2024.111212. Epub 2024 Sep 4.
Parkinson's disease (PD) is the fastest growing neurodegenerative disease in the world at present. Neuroinflammation plays an important role in Parkinson's disease. In our study, we initially screened magnolol/honokiol derivatives synthesized by our group for their potential anti-neuroinflammatory properties. This was done using LPS-activated BV-2 microglial cell and MPP + -induced PC-12 cell models. Most of derivatives had increased anti-inflammatory activities and decreased toxicities compared to raw materials. Then, compounds were scored with inflammatory factors IL-1β, TNF-α and IL-6 by molecular docking in silico. Our studies revealed the strongest binding compound HM568 which binds with honokiol and metformin. Furthermore, HM568 showed no acute toxicity in mice through acute toxicity. And it is stable under high temperature, high humidity and strong light irradiation. Combining cell experiments and computer results, HM568 was considered for further in vivo pharmacological validations. Intraperitoneal injection administration of MPTP into C57BL/6 mice was utilized as Parkinson's animal model. Results showed that administration of HM568 for 14 days in MPTP-PD mice led to a significant alleviation in weight loss and movement disorders. Further HM568 could significantly down-regulate the expression levels of inflammatory factors IL-1β, IL-6 and TNF-α in brain tissue of the mouse model, reduce the level of caspase-3 and the ratio of Bcl-2/Bax, and up-regulate the level of transforming factor TGF-β, thus producing anti-apoptosis and anti-neuroinflammatory effects on neuronal cells. In terms of pathological features, HM568 could reduce the infiltration of neuronal cells and alleviate the development of lesions, promote the transformation of microglia from M1 negative phenotype to M2 type, and reverse the reduction of TH-positive immune cells in mouse neurons induced by MPTP. The administration of HM568 could reduce the abnormal accumulation of α-syn, and thus produce neuroprotective effect on MPTP-PD mice. Cell experiments, molecular docking and animal experiments thus depict HM568 as a promising agent to delay neuronal degeneration in PD, and its mechanism is related to anti-neuroinflammation.
帕金森病（PD）是目前世界上增长最快的神经退行性疾病。神经炎症在帕金森病中起着重要作用。在我们的研究中，我们最初筛选了我们小组合成的厚朴酚/和厚朴酚衍生物，以研究它们潜在的抗炎特性。这是通过 LPS 激活的 BV-2 小胶质细胞和 MPP+诱导的 PC-12 细胞模型来完成的。与原料相比，大多数衍生物具有更强的抗炎活性和更低的毒性。然后，通过分子对接计算机模拟，用炎症因子 IL-1β、TNF-α 和 IL-6 对化合物进行评分。我们的研究揭示了结合最强的结合物 HM568，它与和厚朴酚和二甲双胍结合。此外，HM568 在小鼠中通过急性毒性试验没有表现出急性毒性。而且它在高温、高湿度和强光照射下稳定。结合细胞实验和计算机结果，考虑进一步对 HM568 进行体内药理学验证。将 MPTP 腹腔注射到 C57BL/6 小鼠中作为帕金森病动物模型。结果表明，在 MPTP-PD 小鼠中连续 14 天给予 HM568 治疗可显著缓解体重减轻和运动障碍。进一步的 HM568 可以显著下调脑组织中炎症因子 IL-1β、IL-6 和 TNF-α 的表达水平，降低 caspase-3 水平和 Bcl-2/Bax 比值，上调转化因子 TGF-β水平，从而对神经元细胞产生抗凋亡和抗炎作用。在病理特征方面，HM568 可减少神经元细胞浸润，减轻病变发展，促进小胶质细胞从 M1 阴性表型向 M2 型转化，并逆转 MPTP 诱导的小鼠神经元中 TH 阳性免疫细胞的减少。HM568 的给药可以减少α-syn 的异常积累，从而对 MPTP-PD 小鼠产生神经保护作用。细胞实验、分子对接和动物实验表明，HM568 是一种有前途的药物，可以延缓 PD 中的神经元变性，其机制与抗炎有关。
