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.
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Acknowledgements
This work was supported by the National Key R&D Program of China (2022YFC3500300), National Natural Science Foundation of China (U2202214, 82074044, 82130109, U21A20410), CAMS Innovation Fund for Medical Sciences (CIFMS) (2021-I2M-1-020), and Key R&D Program of Shanxi Province (201803D421006, 201903D421018).
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QLW, SFC, WBH and NHC designed the research. QLW, LYC, WYM, SSW and ZZ performed the experiments and drafted the paper. WBH, SFC and NHC participated in data analysis. ZPF and HSS were involved in the discussion of the experiments. SFC and NHC revised the paper. All authors read and approved the final paper.
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Wu, Ql., Cui, Ly., Ma, Wy. et al. A novel small-molecular CCR5 antagonist promotes neural repair after stroke. Acta Pharmacol Sin 44, 1935–1947 (2023). https://doi.org/10.1038/s41401-023-01100-y
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DOI: https://doi.org/10.1038/s41401-023-01100-y