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A targeted covalent inhibitor of p97 with proteome-wide selectivity

Acta Pharmaceutica Sinica B 2022年第2期12卷 982-989页

作者： Zi Ye Ke Wang Lianguo Chen Xiaofeng Jin Hao Chen Guanghui Tang Shao Q.Yao Zhiqiang Feng Chong-Jing Zhang State Key Laboratory of Bioactive Substances and Functions of Natural Medicines and Beijing Key Laboratory of Active Substances Discovery and Drugability Evaluation Institute of Materia Medica Peking Union Medical College and Chinese Academy of Medical Sciences Department of Chemistry National University of Singapore

A resurging interest in targeted covalent inhibitors(TCIs)focus on compounds capable of irreversibly reacting with nucleophilic amino acids in a druggable target.p97 is an emerging protein target for cancer therapy,viral infections and neurodegenerative *** efforts were devoted to the development of p97 *** most promising inhibitor of p97 was in phase 1 clinical trials,but failed due to the off-target-induced toxicity,suggesting the selective inhibitors of p97 are highly *** report herein a new type of TCIs(i.e.,FL-18)that showed proteome-wide selectivity towards *** with a Michael acceptor and a basic imidazole,FL-18 showed potent inhibition towards U87 MG tumor cells,and in proteome-wide profiling,selectively modified endogenous p97 as confirmed by in situ fluorescence scanning,label-free quantitative proteomics and functional ***-18 selectively modified cysteine residues located within the D2 ATP site of *** covalent labeling of cysteine residue in p97 was verified by LC-MS/MS-based site-mapping and site-directed *** structure-activity relationship(SAR)studies with FL-18 analogs were ***,FL-18 is the first known small-molecule TCI capable of covalent engagement of p97 with proteome-wide selectivity,thus providing a promising scaffold for cancer therapy.

关键词： p97 Activity-based protein profiling Targeted covalent inhibitor Chemical proteomics

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Caffeic acid alleviates cerebral ischemic injury in rats by resisting ferroptosis via Nrf2 signaling pathway

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中国药理学报（英文版） 2024年第2期45卷 248-267页

作者： Xin-nan Li Nian-ying Shang Yu-ying Kang Ning Sheng Jia-qi Lan Jing-shu Tang Lei Wu Jin-lan Zhang Ying Peng State Key Laboratory of Bioactive Substances and Functions of Natural Medicines Institute of Materia MedicaChinese Academy of Medical Sciences & Peking Union Medical CollegeBeijing 100050China

There are few effective and safe neuroprotective agents for the treatment of ischemic stroke *** acid is a phenolic acid that widely exists in a number of plant *** studies show that caffeic acid ameliorates brain injury in rats after cerebral ischemia/*** this study we explored the protective mechanisms of caffeic acid against oxidative stress and ferroptosis in permanent cerebral *** stroke was induced on rats by permanent middle cerebral artery occlusion(pMCAO).Caffeic acid(0.4,2,10 mg·kg-1·d-1,i.g.)was administered to the rats for 3 consecutive days before or after the *** showed that either pre-pMCAO or post-pMCAO administration of caffeic acid(2 mg·kg-1·d-1)effectively reduced the infarct volume and improved neurological *** therapeutic time window could last to 2 h after *** found that caffeic acid administration significantly reduced oxidative damage as well as neuroinflammation,and enhanced antioxidant capacity in pMCAO rat *** further demonstrated that caffeic acid down-regulated TFR1 and ACSL4,and up-regulated glutathione production through Nrf2 signaling pathway to resist ferroptosis in pMCAO rat brain and in oxygen glucose deprivation/reoxygenation(OGD/R)-treated SK-N-SH cells in *** of ML385,an Nrf2 inhibitor,blocked the neuroprotective effects of caffeic acid in both in vivo and in vitro models,evidenced by excessive accumulation of iron ions and inactivation of the ferroptosis defense *** conclusion,caffeic acid inhibits oxidative stress-mediated neuronal death in pMCAO rat brain by regulating ferroptosis via Nrf2 signaling *** acid might serve as a potential treatment to relieve brain injury after cerebral ischemia.

关键词： ischemic stroke caffeic acid oxidative stress neuroinflammation ferroptosis Nrf2

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Rg1 exerts protective effect in CPZ-induced demyelination mouse model via inhibiting CXCL10-mediated glial response

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中国药理学报（英文版） 2022年第3期43卷 563-576页

作者： Yi-xiao Dong Shi-feng Chu Sha-sha Wang Ya-juan Tian Wen-bin He Yu-sheng Du Zhen-zhen Wang Xu Yan Zhao Zhang Nai-hong Chen State Key Laboratory of Bioactive Substances and Functions of Natural Medicines Institute of Materia Medica&Neuroscience CenterChinese Academy of Medical SciencesPeking Union Medical CollegeBeijing 100050China Tianjin University of Traditional Chinese Medicine Tianjin 301617China State Key Laboratory of Bioactive Substances and Functions of Natural Medicines Institute of Materia Medica&Neuroscience CenterChinese Academy of Medical SciencesPeking Union Medical CollegeBeijing 100050China State Key Laboratory of Bioactive Substances and Functions of Natural Medicines Institute of Materia Medica&Neuroscience CenterChinese Academy of Medical SciencesPeking Union Medical CollegeBeijing 100050China Shanxi Key Laboratory of Chinese Medicine Encephalopathy Shanxi University of Chinese MedicineJinzhong 030619China Shanxi Key Laboratory of Chinese Medicine Encephalopathy Shanxi University of Chinese MedicineJinzhong 030619China State Key Laboratory of Bioactive Substances and Functions of Natural Medicines Institute of Materia Medica&Neuroscience CenterChinese Academy of Medical SciencesPeking Union Medical CollegeBeijing 100050China Tianjin University of Traditional Chinese Medicine Tianjin 301617China Shanxi Key Laboratory of Chinese Medicine Encephalopathy Shanxi University of Chinese MedicineJinzhong 030619China

Myelin damage and abnormal remyelination processes lead to central nervous system *** activation-induced microenvironment changes are characteristic features of the diseases with myelin *** previously showed that ginsenoside Rg1,a main component of ginseng,ameliorated MPTP-mediated myelin damage in mice,but the underlying mechanisms are *** this study we investigated the effects of Rg1 and mechanisms in cuprizone(CPZ)-induced demyelination mouse *** were treated with CPZ solution(300mg·kg-1·d-1,ig)for 5 weeks;from week 2,the mice received Rg1(5,10,and 20 mg·kg-1·d-1,ig)for 4 *** showed that Rg1 administration dose-dependently alleviated bradykinesia and improved CPZ-disrupted motor coordination ability in CPZ-treated ***,Rg1 administration significantly decreased demyelination and axonal injury in pathological *** further revealed that the neuroprotective effects of Rg1 were associated with inhibiting CXCL10-mediated modulation of glial response,which was mediated by NF-KB nuclear translocation and CXCL10 promoter *** microglial cell line BV-2,we demonstrated that the effects of Rg1 on pro-inflammatory and migratory phenotypes of microglia were related to CXCL10,while Rg1-induced phagocytosis of microglia was not directly related to *** CPZ-induced demyelination mouse model,injection of AAV-CXCL10 shRNA into mouse lateral ventricles 3 weeks prior CPZ treatment occluded the beneficial effects of Rg1 administration in behavioral and pathological *** conclusion,CXCL10 mediates the protective role of Rg1 in CPZ-induced demyelination mouse *** study provides new insight into potential disease-modifying therapies for myelin abnormalities.

关键词： Biomedicine general Pharmacology/Toxicology Medical Microbiology Immunology Internal Medicine Vaccine

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Pyk2 inhibition attenuates hypoxic-ischemic brain injury in neonatal mice

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中国药理学报（英文版） 2022年第4期43卷 797-810页

作者： Jie Zhu Shi-feng Chu Ye Peng Dan-dan Liu Chen Chen Wen-xuan Jian Hong-shuo Sun Zhong-ping Feng Zhao Zhang Nai-hong Chen State Key Laboratory of Bioactive Substances and Functions of Natural Medicines Institute of Materia Medica&Neuroscience CenterChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100050China State Key Laboratory of Bioactive Substances and Functions of Natural Medicines Institute of Materia Medica&Neuroscience CenterChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100050China College of Pharmacy Hunan University of Chinese MedicineChangsha 410208China State Key Laboratory of Bioactive Substances and Functions of Natural Medicines Institute of Materia Medica&Neuroscience CenterChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100050China Institute of Clinical Pharmacology Guangzhou University of Chinese MedicineGuangzhou 510720China Department of Physiology Faculty of MedicineUniversity of TorontoTorontoONCanada State Key Laboratory of Bioactive Substances and Functions of Natural Medicines Institute of Materia Medica&Neuroscience CenterChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100050China College of Pharmacy Hunan University of Chinese MedicineChangsha 410208China Institute of Clinical Pharmacology Guangzhou University of Chinese MedicineGuangzhou 510720China

Newborns suffering from hypoxia-ischemia(HI)brain injury still lack effective ***-rich tyrosine kinase 2(Pyk2)is a non-receptor tyrosine kinase,which is highly correlated with transient ischemic brain injury in *** this study,we investigated the role of Pyk2 in neonatal HI brain *** was induced in postnatal day 7 mouse pups by unilateral common carotid artery ligation followed by hypoxic ***2 interference lentivirus(LV-Pyk2 shRNA)was constructed and injected into unilateral cerebral ventricle of neonatal mice before *** volume,pathological changes,and neurological behaviors were assessed on postnatal day *** showed that the phosphorylation level of Pyk2 was significantly increased in neonatal brain after HI,whereas LV-Pyk2 shRNA injection significantly attenuated acute HI brain damage and improved neurobehavioral *** oxygen-glucose deprivation-treated cultured cortical neurons,Pyk2 inhibition significantly alleviated NMDA receptor-mediated excitotoxicity;similar results were also observed in neonatal HI brain *** demonstrated that Pyk2 inhibition contributes to the long-term cerebrovascular recovery assessed by laser speckle contrast imaging,but cognitive function was not obviously improved as evaluated in Morris water maze and novel object recognition ***,we constructed lentiviral LV-HIF-Pyk2 shRNA,through which HIF-1 α promoter-mediated interference of Pyk2 would occur during the anoxic *** injection of LV-HIF-Pyk2 shRNA significantly improved long-term recovery of cognitive function in HI-treated neonatal *** conclusion,this study demonstrates that Pyk2 interference protects neonatal brain from hypoxic-ischemic ***-1 α promoter-mediated hypoxia conditional control is a useful tool to distinguish between hypoxic period and normal ***2 is a promising drug target for potential treatment of neonatal HI brain injury.

关键词： neonatal mice hypoxic-ischemic brain injury Pyk2 NMDA receptor excitotoxicity HIF-1α

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Long non-coding RNAs: From disease code to drug role

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Acta Pharmaceutica Sinica B 2021年第2期11卷 340-354页

作者： Yuanyuan Chen Zhaojun Li Xiaoguang Chen Sen Zhang State Key Laboratory of Bioactive Substances and Functions of Natural Medicines Institute of Materia MedicaChinese Academy of Medical SciencesPeking Union Medical CollegeBeijing 100050China

Enormous studies have corroborated that long non-codig RNAs(LncRNAs)extensively participate in crucial physiological processes such as metabolism and immunity,and are closely related to the occurrence and development of tumors,cardiovascular diseases,nervous system disorders,nephropathy,and other *** application of lncRNAs as biomarkers or intervention targets can provide new insights into the diagnosis and treatment of *** paper has focused on the emerging research into lncRNAs as pharmacological targets and has reviewed the transition of IncRNAs from the role of disease coding to acting as drug candidates,including the current status and progress in preclinical ***-edge strategies for lncRNA modulation have been summarized,including the sources of LncRNA-related drugs,such as genetic technology and small-molecule compounds,and related delivery *** current progress of clinical trials of lncRNA-targeting drugs is also *** information will form a latest updated reference for research and development of lncRNA-based drugs.

关键词： LncRNAs Targeted drug Gene therapy Small molecules Delivery ASncmtRNA Translational medicine Clinical trials

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Baicalein attenuates rotenone-induced SH-SY5Y cell apoptosis through binding to SUR1 and activating ATP-sensitive potassium channels

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中国药理学报（英文版） 2024年第3期45卷 480-489页

作者： De-wen Kong Li-da Du Run-zhe Liu Tian-yi Yuan Shou-bao Wang Yue-hua Wang Yang Lu Lian-hua Fang Guan-hua Du State Key Laboratory of Bioactive Substances and Functions of Natural Medicines Institute of Materia MedicaChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100050China Beijing Key Laboratory of Drug Targets Identification and Drug Screening National Center for Pharmaceutical ScreeningInstitute of Materia MedicaChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100050China Shandong Soteria Pharmaceutical Co Ltd. Jinan 250022China State Key Laboratory of Bioactive Substances and Functions of Natural Medicines Institute of Materia MedicaChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100050China Beijing Key Laboratory of Drug Targets Identification and Drug Screening National Center for Pharmaceutical ScreeningInstitute of Materia MedicaChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100050China Beijing Key Laboratory of Polymorphic Drugs Institute of Materia MedicaChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100050China

Dopaminergic neurons in the substantia nigra(SN)expressing SUR1/Kir6.2 type ATP-sensitive potassium channels(K-ATP)are more vulnerable to rotenone or metabolic stress,which may be an important reason for the selective degeneration of neurons in Parkinson's disease(PD).Baicalein has shown neuroprotective effects in PD animal *** this study,we investigated the effect of baicalein on K-ATP channels and the underlying mechanisms in rotenone-induced apoptosis of SH-SY5Y cells.K-ATP currents were recorded from SH-SY5Y cells using whole-cell voltage-clamp *** dissolved in the external solution at the final concentration were directly pipetted onto the *** showed that rotenone and baicalein opened K-ATP channels and increased the current amplitudes with EC50 values of 0.438 μM and 6.159 μM,respectively.K-ATP channel blockers glibenclamide(50 μM)or 5-hydroxydecanoate(5-HD,250 μM)attenuated the protective effects of baicalein in reducing reactive oxygen species(ROS)content and increasing mitochondrial membrane potential and ATP levels in rotenone-injured SH-SY5Y cells,suggesting that baicalein protected against the apoptosis of SH-SY5Y cells by regulating the effect of rotenone on opening K-ATP *** of baicalein(150,300 mg·kg-1·d-1,i.g.)significantly inhibited rotenone-induced overexpression of SUR1 in SN and striatum of *** conducted surface plasmon resonance assay and molecular docking,and found that baicalein had a higher affinity with SUR1 protein(KD=10.39μM)than glibenclamide(KD=24.32 μM),thus reducing the sensitivity of K-ATP channels to *** of SUR1 subunit reduced rotenone-induced apoptosis and damage of SH-SY5Y cells,confirming that SURI was an important target for slowing dopaminergic neuronal degeneration in *** together,we demonstrate for the first time that baicalein attenuates rotenone-induced SH-SY5Y cell apoptosis through binding to SUR1 and activating K-ATP channels.

关键词： Parkinson’s disease baicalein SH-SY5Y cells K-ATP channels SUR1 subunit rotenone

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Dynamic gut microbiome-metabolome in cationic bovine serum albumin induced experimental immune-complex glomerulonephritis and effect of losartan and mycophenolate mofetil on microbiota modulation

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Journal of Pharmaceutical Analysis 2024年第4期14卷 562-577页

作者： Wenying Shi Zhaojun Li Weida Wang Xikun Liu Haijie Wu Xiaoguang Chen Xunrong Zhou Sen Zhang State Key Laboratory of Bioactive Substances and Functions of Natural Medicines Institute of Materia MedicaChinese Academy of Medical Sciences&Peking Union Medical CollegeBeijing100050China State Key Laboratory of Functions and Applications of Medicinal Plants College of PharmacyGuizhou Provincial Engineering Technology Research Center for Chemical Drug R&DGuizhou Medical UniversityGuiyang550004China Department of Medicine Solna Center for Molecular MedicineKarolinska University Hospital and Karolinska InstituteStockholm17176Sweden Department of Pharmacy The Second Affiliated Hospital of Guizhou University of Traditional Chinese MedicineGuiyang550001China

Dynamic changes in gut dysbiosis and metabolomic dysregulation are associated with immune-complex glomerulonephritis(ICGN).However,an in-depth study on this topic is currently ***,we report an ICGN model to address this *** was induced via the intravenous injection of cationized bovine serum albumin(c-BSA)into Sprague-Dawley(SD)rats for two weeks,after which mycophenolate mofetil(MMF)and losartan were administered *** and six weeks after ICGN establishment,fecal samples were collected and 16S ribosomal DNA(rDNA)sequencing and untargeted metabolomic were *** microbiota transplantation(FMT)was conducted to determine whether gut normali-zation caused by MMF and losartan contributed to their renal protective effects.A gradual decline in microbial diversity and richness was accompanied by a loss of renal *** 18 genera were found to have significantly different relative abundances between the early and later stages,and Marvinbryantia and Allobaculum were markedly upregulated in both *** metabolomics indicated that the tryptophan metabolism was enhanced in ICGN,characterized by the overproduction of indole and kynurenic acid,while the serotonin pathway was *** of losartan and MMF ameliorated microbial dysbiosis and reduced the accumulation of indoxyl conjugates in *** using feces from animals administered MMF and losartan improved gut dysbiosis by decreasing the Firmicutes/Bacteroidetes(F/B)ratio but did not improve renal *** findings indicate that ICGN induces serous gut dysbiosis,wherein an altered tryptophan metabolism may contribute to its *** and losartan significantly reversed the gut microbial and metabolomic dysbiosis,which partially contributed to their renoprotective effects.

关键词： Immune-complex glomerulonephritis Gut microbiome Metabolomics Fecal microbiota transplant Tryptophan metabolism

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Connexin 43:insights into candidate pathological mechanisms of depression and its implications in antidepressant therapy

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中国药理学报（英文版） 2022年第10期43卷 2448-2461页

作者： Ning-ning Zhang Yi Zhang Zhen-zhen Wang Nai-hong Chen State Key Laboratory of Bioactive Substances and Functions of Natural Medicines Institute of Materia Medica&Neuroscience CenterChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100050China Department of Anatomy School of Chinese MedicineBeijing University of Chinese MedicineBeijing 102488China

Major depressive disorder(MDD),a chronic and recurrent disease characterized by anhedonia,pessimism or even suicidal thought,remains a major chronic mental concern *** 43(Cx43)is the most abundant connexin expressed in astrocytes and forms the gap junction channels(GJCs)between astrocytes,the most abundant and functional glial cells in the *** regulate neurons'synaptic strength and function by expressing receptors and regulating various *** dysfunction causes synaptic abnormalities,which are related to various mood disorders,e.g.,*** evidence suggests a crucial role of Cx43 in the pathogenesis of *** down-regulates Cx43 expression in humans and rats,and dysfunction of Cx43 also induces depressive behaviors in rats and *** Cx43 has received considerable critical attention and is highly implicated in the onset of ***,the pathological mechanisms of depression-like behavior associated with Cx43 still remain *** this review we summarize the recent progress regarding the underlying mechanisms of Cx43 in the etiology of depression-like behaviors including gliotransmission,metabolic disorders,and *** also discuss the effects of antidepressants(monoamine antidepressants and ketamine)on *** clarity of the candidate pathological mechanisms of depression-like behaviors associated with Cx43 and its potential pharmacological roles for antidepressants will benefit the exploration of a novel antidepressant target.

关键词： depression Connexin 43 astrocyte prefrontal cortex hippocampus Ca2+ wave ATP antidepressant target

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Ginsenoside Rg1 exerts neuroprotective effects in 3-nitropronpionic acid-induced mouse model of Huntington's disease via suppressing MAPKs and NF-κB pathways in the striatum

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中国药理学报（英文版） 2021年第9期42卷 1409-1421页

作者： Xiong Yang Shi-feng Chu Zhen-zhen Wang Fang-fang Li Yu-he Yuan Nai-hong Chen State Key Laboratory of Bioactive Substances and Functions of Natural Medicines Institute of Materia Medica & Neuroscience CenterChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100050China

Huntington's disease (HD) is one of main neurodegenerative diseases,characterized by striatal atrophy,involuntary movements,and motor *** Rg1 (Rg1),an active ingredient in ginseng,possesses a variety of neuroprotective effects with low toxicity and side *** this study,we investigated the potential therapeutic effects of Rg1 in a mouse model of HD and explored the underlying *** was induced in mice by injection of 3-nitropropionic acid (3-NP,i.p.) for 4 *** the first day of 3-NP injection,the mice were administered Rg1 (10,20,40 mg·kg-1,p.o.) for 5 *** showed that oral pretreatment with Rg1 alleviated 3-NP-induced body weight loss and behavioral ***,pretreatment with Rg1 ameliorated 3-NP-induced neuronal loss and ultrastructural morphological damage in the ***,pretreatment with Rg1 reduced 3-NP-induced apoptosis and inhibited the activation of microglia,inflammatory mediators in the *** revealed that Rg1 exerted neuroprotective effects by suppressing 3-NP-induced activation of the MAPKs and NF-KB signaling pathways in the ***,our results suggest that Rg1 exerts therapeutic effects on 3-NP-induced HD mouse model via suppressing MAPKs and NF-KB signaling ***1 may be served as a novel therapeutic option for HD.

关键词： Huntington’s disease ginsenoside Rg1 3-nitropropionic acid striatum neuroprotective effects MAPKs NF-κB

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

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中国药理学报（英文版） 2023年第10期44卷 1935-1947页

作者： Qing-lin Wu Li-yuan Cui Wen-yu Ma Sha-sha Wang Zhao Zhang Zhong-ping Feng Hong-shuo Sun Shi-feng Chu Wen-bin He Nai-hong Chen Clinical Pharmacology Institute Guangzhou University of Chinese MedicineGuangzhou 510405China State Key Laboratory of Bioactive Substances and Functions of Natural Medicines Institute of Materia MedicaNeuroscience CenterChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100050China Department of Physiology Temerty Faculty of MedicineUniversity of Toronto1 King's College CircleTorontoON M5S 1A8Canada Shanxi Key Laboratory of Chinese Medicine Encephalopathy Shanxi University of Chinese MedicineTaiyuan 030024China National International Joint Research Center for Molecular Chinese Medicine Shanxi University of Chinese MedicineTaiyuan 030024China Clinical Pharmacology Institute Guangzhou University of Chinese MedicineGuangzhou 510405China State Key Laboratory of Bioactive Substances and Functions of Natural Medicines Institute of Materia MedicaNeuroscience CenterChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100050China

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 *** is a classic CCR5 antagonist,which is undergoing clinical trials against *** maraviroc shows poor blood-brain barrier(BBB)permeability,it is of interest to find novel CCR5 antagonists suitable for neurological *** 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 *** found that A14 dose-dependently inhibited the CCR5 activity with an IC50 value of 4.29 μ*** studies showed that A14 treatment exerted protective effects against neuronal ischemic injury both in vitro and *** a SH-SY5Y cell line overexpressing CCR5,A14(0.1,1 μM)significantly alleviated OGD/R-induced cell *** 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 *** analysis also showed that A14 treatment significantly reduced the infarction volume after 1 week of *** 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 *** addition,A14 treatment remarkably inhibited the reactive proliferation of glial cells after stroke and reduced the infiltration of peripheral immune *** results demonstrate that A14 is a promising novel CCR5 antagonist for promoting neuronal repair after ischemic stroke.

关键词： CCR5 antagonist chemokine receptor 5 CKLF1 CREB signaling ischemic stroke neural repair

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