A novel small-molecular CCR5 antagonist promotes neural repair after stroke.

Autor: Wu QL; Clinical Pharmacology Institute, Guangzhou University of Chinese Medicine, Guangzhou, 510405, China., Cui LY; State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Neuroscience Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China., Ma WY; Clinical Pharmacology Institute, Guangzhou University of Chinese Medicine, Guangzhou, 510405, China., Wang SS; Clinical Pharmacology Institute, Guangzhou University of Chinese Medicine, Guangzhou, 510405, China., Zhang Z; State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Neuroscience Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China., Feng ZP; Department of Physiology, Temerty Faculty of Medicine, University of Toronto, 1 King's College Circle, Toronto, ON, M5S 1A8, Canada., Sun HS; Department of Physiology, Temerty Faculty of Medicine, University of Toronto, 1 King's College Circle, Toronto, ON, M5S 1A8, Canada., Chu SF; State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Neuroscience Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China. chushifeng@imm.ac.cn., He WB; Shanxi Key Laboratory of Chinese Medicine Encephalopathy, Shanxi University of Chinese Medicine, Taiyuan, 030024, China. hewb@sxtcm.edu.cn.; National International Joint Research Center for Molecular Chinese Medicine, Shanxi University of Chinese Medicine, Taiyuan, 030024, China. hewb@sxtcm.edu.cn., Chen NH; Clinical Pharmacology Institute, Guangzhou University of Chinese Medicine, Guangzhou, 510405, China. chennh@imm.ac.cn.; State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Neuroscience Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China. chennh@imm.ac.cn.
Jazyk: angličtina
Zdroj: Acta pharmacologica Sinica [Acta Pharmacol Sin] 2023 Oct; Vol. 44 (10), pp. 1935-1947. Date of Electronic Publication: 2023 May 17.
DOI: 10.1038/s41401-023-01100-y
Abstrakt: Chemokine receptor 5 (CCR5) is one of the main co-receptors of HIV-1, and has been found to be a potential therapeutic target for stroke. Maraviroc is a classic CCR5 antagonist, which is undergoing clinical trials against stroke. As maraviroc shows poor blood-brain barrier (BBB) permeability, it is of interest to find novel CCR5 antagonists suitable for neurological medication. In this study we characterized the therapeutic potential of a novel CCR5 antagonist A14 in treating ischemic stroke mice. A14 was discovered in screening millions compounds in the Chemdiv library based on the molecular docking diagram of CCR5 and maraviroc. We found that A14 dose-dependently inhibited the CCR5 activity with an IC 50 value of 4.29 μM. Pharmacodynamic studies showed that A14 treatment exerted protective effects against neuronal ischemic injury both in vitro and vivo. In a SH-SY5Y cell line overexpressing CCR5, A14 (0.1, 1 μM) significantly alleviated OGD/R-induced cell injury. We found that the expression of CCR5 and its ligand CKLF1 was significantly upregulated during both acute and recovery period in focal cortical stroke mice; oral administration of A14 (20 mg·kg -1 ·d -1 , for 1 week) produced sustained protective effect against motor impairment. A14 treatment had earlier onset time, lower onset dosage and much better BBB permeability compared to maraviroc. MRI analysis also showed that A14 treatment significantly reduced the infarction volume after 1 week of treatment. We further revealed that A14 treatment blocked the protein-protein interaction between CCR5 and CKLF1, increasing the activity of CREB signaling pathway in neurons, thereby improving axonal sprouting and synaptic density after stroke. In addition, A14 treatment remarkably inhibited the reactive proliferation of glial cells after stroke and reduced the infiltration of peripheral immune cells. These results demonstrate that A14 is a promising novel CCR5 antagonist for promoting neuronal repair after ischemic stroke. A14 blocked the protein-protein interaction between CKLF1 and CCR5 after stroke by binding with CCR5 stably, improved the infarct area and promoted motor recovery through reversing the CREB/pCREB signaling which was inhibited by activated CCR5 Gαi pathway, and benefited to the dendritic spines and axons sprouting.
(© 2023. The Author(s), under exclusive licence to Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Chinese Pharmacological Society.)
Databáze: MEDLINE
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