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

Qing-lin Wu1, Li-yuan Cui2, Wen-yu Ma1, Sha-sha Wang1, Zhao Zhang2, Zhong-ping Feng3, Hong-shuo Sun3, Shi-feng Chu2, Wen-bin He4,5, Nai-hong Chen1,2
1 Clinical Pharmacology Institute, Guangzhou University of Chinese Medicine, Guangzhou 510405, China
2 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
3 Department of Physiology, Temerty Faculty of Medicine, University of Toronto, 1 King’s College Circle, Toronto, ON M5S 1A8, Canada
4 Shanxi Key Laboratory of Chinese Medicine Encephalopathy, Shanxi University of Chinese Medicine, Taiyuan 030024, China
5 National International Joint Research Center for Molecular Chinese Medicine, Shanxi University of Chinese Medicine, Taiyuan 030024, China
Correspondence to: Shi-feng Chu: chushifeng@imm.ac.cn, Wen-bin He: hewb@sxtcm.edu.cn, Nai-hong Chen: chennh@imm.ac.cn,
DOI: 10.1038/s41401-023-01100-y
Received: 12 September 2022
Accepted: 25 April 2023
Advance online: 17 May 2023

Abstract

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 IC50 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.

Keywords: ischemic stroke; neural repair; chemokine receptor 5; CKLF1; CCR5 antagonist; CREB signaling

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