title: CXCR4 antagonist AMD3100 protects blood-brain barrier integrity and reduces inflammatory response after focal ischemia in mice.
abstract: OBJECTIVE
  Inflammatory response plays a critical role in propagating tissue damage after focal cerebral ischemia. CXCL12 is a key chemokine for leukocyte recruitment. However, the role of CXCL12 and its receptor CXCR4 in ischemia-induced inflammatory response is unclear. Here we use the pharmacological antagonist of CXCR4, AMD3100, to investigate the function of CXCL12/CXCR4 in regulating inflammatory response during acute ischemia.
  
  
  METHODS
  Adult male CD-1 mice (n=184) underwent permanent suture middle cerebral artery occlusion (MCAO). AMD3100 was injected for 3 days (1 mg/kg/day) after MCAO. Brain water content, infarct volume, neurological score, and myeloperoxidase (MPO) expression and activity were examined at 24, 48, and 72 hours after MCAO. Proinflammatory cytokine RNA and protein levels in brain tissue were measured by RT-PCR and enzyme linked immunosorbent assay.
  
  
  RESULTS
  Neurological score was greatly improved in AMD3100-treated mice compared with the control mice 3 days after MCAO (P<0.05). Brain edema-induced change of water content, IgG protein leakage, Evans blue extravasation, occludin, and ZO-1 expression in ipsilateral hemisphere were alleviated by acute treatment of AMD3100. MPO expression and activity revealed that AMD3100 profoundly reduced the number of MPO-positive cells in the ischemic region (P<0.05). It also attenuated proinflammatory cytokines including interleukin 6, tumor necrosis factor α, and interferon γ; their mRNA and protein levels changed accordingly compared with the controls (P<0.05).
  
  
  CONCLUSIONS
  CXCR4 antagonist AMD3100 significantly suppressed inflammatory response and reduced blood-brain barrier disruption after MCAO. AMD3100 attenuated ischemia-induced acute inflammation by suppressing leukocyte migration and infiltration, in addition to reducing proinflammatory cytokine expression in the ischemic region.
authors.affiliation: Neuroscience and Neuroengineering Research Center, Med-X Research Institute and School of Biomedical Engineering, Shanghai Jiao Tong University, 1954 Hua-shan Road, Shanghai 200030, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Huang
authors.forename: Yaning
authors.initials: Y
authors.lastname: Li
authors.forename: Yaohui
authors.initials: Y
authors.lastname: Tang
authors.forename: Guanghui
authors.initials: G
authors.lastname: Tang
authors.forename: Guo-Yuan
authors.initials: GY
authors.lastname: Yang
authors.forename: Yongting
authors.initials: Y
authors.lastname: Wang
mesh_terms: D000818:Animals; D001596:Benzylamines; D001812:Blood-Brain Barrier / Q000187:drug effects* / Q000473:pathology; D002545:Brain Ischemia / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000080027:Cyclams; D006571:Heterocyclic Compounds / Q000494:pharmacology / Q000627:therapeutic use*; D007249:Inflammation / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D008297:Male; D051379:Mice; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use*; D020556:Neutrophil Infiltration / Q000187:drug effects / Q000502:physiology; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors*
chemical_list: D001596:Benzylamines; C514936:CXCR4 protein, mouse; D000080027:Cyclams; D006571:Heterocyclic Compounds; D018696:Neuroprotective Agents; D019718:Receptors, CXCR4; C088327:plerixafor