A derivative of honokiol HM568 has an anti-neuroinflammatory effect in Parkinson's disease.
Autor: | Zhong C; 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., Wang C; 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., Li W; 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., Li W; 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., Chen X; Criminal Science and Technology Research Institute of Huizhou Public Security Bureau, Huizhou, 516000, PR China., Guo J; 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., Feng Y; 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. Electronic address: yffeng@gdpu.edu.cn., Wu X; 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. Electronic address: wxiaxia@gdpu.edu.cn. |
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Jazyk: | angličtina |
Zdroj: | Chemico-biological interactions [Chem Biol Interact] 2024 Nov 01; Vol. 403, pp. 111212. Date of Electronic Publication: 2024 Sep 04. |
DOI: | 10.1016/j.cbi.2024.111212 |
Abstrakt: | 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. Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Xia Wu reports financial support was provided by National Natural Science Foundation of China-Guangdong Joint Fund. Xia Wu reports financial support was provided by Guangdong Medical Science and Technology Research Fund Project. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. (Copyright © 2024 Elsevier B.V. All rights reserved.) |
Databáze: | MEDLINE |
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