title: A Novel CXCR4 Antagonist CX549 Induces Neuroprotection in Stroke Brain.
abstract: C-X-C chemokine receptor type 4 (CXCR4) is a receptor for a pleiotropic chemokine CXCL12. Previous studies have shown that the acute administration of the CXCR4 antagonist AMD3100 reduced neuroinflammation in stroke brain and mobilized bone marrow hematopoietic stem cells (HSCs). The purpose of this study was to characterize the neuroprotective and neurotrophic effect of a novel CXCR4 antagonist CX549. We demonstrated that CX549 had a higher affinity for CXCR4 and was more potent than AMD3100 to inhibit CXCL12-mediated chemotaxis in culture. CX549 effectively reduced the activation of microglia and improved neuronal survival after injury in neuron/microglia cocultures. Early poststroke treatment with CX549 significantly improved behavioral function, reduced brain infarction, and suppressed the expression of inflammatory markers. Compared to AMD3100, CX549 has a higher affinity for CXCR4, is more efficient to mobilize HSCs for transplantation, and induces behavioral improvement. Our data support that CX549 is a potent anti-inflammatory agent, is neuroprotective against ischemic brain injury, and may have clinical implications for the treatment of stroke.
authors.forename: Kuo-Jen
authors.initials: KJ
authors.lastname: Wu
authors.forename: Seong-Jin
authors.initials: SJ
authors.lastname: Yu
authors.forename: Kak-Shan
authors.initials: KS
authors.lastname: Shia
authors.forename: Chien-Huang
authors.initials: CH
authors.lastname: Wu
authors.forename: Jen-Shin
authors.initials: JS
authors.lastname: Song
authors.forename: Hsuan-Hao
authors.initials: HH
authors.lastname: Kuan
authors.forename: Kai-Chia
authors.initials: KC
authors.lastname: Yeh
authors.forename: Chiung-Tong
authors.initials: CT
authors.lastname: Chen
authors.forename: Eunkyune
authors.initials: E
authors.lastname: Bae
authors.forename: Yun
authors.initials: Y
authors.lastname: Wang
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology / Q000627:therapeutic use; D001522:Behavior, Animal / Q000187:drug effects; D001596:Benzylamines; D001921:Brain / Q000187:drug effects / Q000473:pathology*; D020520:Brain Infarction / Q000150:complications / Q000188:drug therapy / Q000473:pathology; D002633:Chemotaxis / Q000187:drug effects; D000080027:Cyclams; D057809:HEK293 Cells; D019650:Hematopoietic Stem Cell Mobilization; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects; D006571:Heterocyclic Compounds / Q000494:pharmacology; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000187:drug effects / Q000473:pathology; D000066829:Neuroprotection / Q000187:drug effects; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use*; D011799:Quinazolines / Q000494:pharmacology / Q000627:therapeutic use*; D017207:Rats, Sprague-Dawley; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D020521:Stroke / Q000150:complications / Q000188:drug therapy* / Q000473:pathology; D014230:Triazoles / Q000494:pharmacology / Q000627:therapeutic use*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; D001596:Benzylamines; C000617878:CX549 compound; D000080027:Cyclams; D006571:Heterocyclic Compounds; D015850:Interleukin-6; D018696:Neuroprotective Agents; D011799:Quinazolines; D019718:Receptors, CXCR4; D014230:Triazoles; D014409:Tumor Necrosis Factor-alpha; C088327:plerixafor