Inhibition of chemokine-like factor 1 improves blood-brain barrier dysfunction in rats following focal cerebral ischemia.
Disruption of blood-brain barrier (BBB) and subsequent edema are major contributors to the pathogenesis of ischemic stroke, and the current clinical therapy remains unsatisfied. Chemokine-like factor 1 (CKLF1), as a novel C-C chemokine, plays important roles in immune response. The expression of CKLF1 increased after focal cerebral ischemia and inhibition of CKLF1 activity showed neuroprotective effect by alleviating infiltration of neutrophil and neuron apoptosis in cerebral ischemia. However, few studies have focused on the role of CKLF1 on BBB integrity. The objective of present study was to investigate the role of CKLF1 on BBB integrity by applying anti-CKLF1 antibodies in rat focal cerebral ischemia and reperfusion model. Brain water content, Evans blue leakage and the expression of aquaporin-4 (AQP-4), matrix metalloproteinase-9 (MMP-9), Zonula Occludens-1 (ZO-1) and Occludin were measured. After treatment with anti-CKLF1 antibody, brain water content and Evans blue leakage in ipsilateral hemisphere were decreased in a dose-dependent manner at 24h after reperfusion, but not changed in contralateral hemisphere. Anti-CKLF1 antibody reduced the expression of AQP-4 and MMP-9, and upregulated the expression of ZO-1 and Occludin. These results suggest that CKLF1 is involved in BBB disruption after reperfusion. Inhibition of CKLF1 protects against cerebral ischemia by maintaining BBB integrity, possibly via inhibiting the expression of AQP-4 and MMP-9, and increasing the expression of tight junction protein.
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, China; State key laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, China; Beijing Key Laboratory of Drug Targets Identification and Drug Screening, Centre for Pharmaceutical Screening, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, China.
Ling-Lei
LL
Kong
State key laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, China.
Zhi-Yuan
ZY
Wang
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, China.
Jin-Feng
JF
Hu
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, China.
Yu-He
YH
Yuan
State key laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, China. Electronic address: amms_hli@163.com.
Hua
H
Li
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, China. Electronic address: chennh0328@163.com.
Nai-Hong
NH
Chen
D000818:Animals; D000906:Antibodies / Q000008:administration & dosage; D051401:Aquaporin 4 / Q000378:metabolism; D001812:Blood-Brain Barrier / Q000378:metabolism* / Q000648:ultrastructure; D001929:Brain Edema / Q000150:complications / Q000378:metabolism / Q000517:prevention & control; D002545:Brain Ischemia / Q000150:complications / Q000378:metabolism* / Q000517:prevention & control*; D002199:Capillary Permeability; D018925:Chemokines / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism*; D062792:MARVEL Domain-Containing Proteins / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism*; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D062793:Occludin / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D062826:Zonula Occludens-1 Protein / Q000378:metabolism
D000906:Antibodies; C496032:Aqp4 protein, rat; D051401:Aquaporin 4; D018925:Chemokines; C486623:Cklf protein, rat; D062792:MARVEL Domain-Containing Proteins; D062793:Occludin; C568987:Ocln protein, rat; C569044:Tjp1 protein, rat; D062826:Zonula Occludens-1 Protein; D020780:Matrix Metalloproteinase 9
Aquaporin-4; Brain-blood barrier; Cerebral ischemia; Chemokine-like factor 1; Matrix metalloproteinase-9; Tight junction protein