title: Reparixin attenuates neuronal injury in experimental Klebsiella pneumoniae meningoencephalitis through dual effects on neuroprotection and neuroinflammation.
abstract: Bacterial meningitis causes high mortality and brain damage. The host immune response is associated with brain injury. Chemokine (C-X-C motif) (CXC) chemokines are neutrophil chemoattractants. This study focused on the beneficial effects of intracerebroventricular administration of reparixin, an inhibitor of chemokine (C-X-C motif) receptor (CXCR)1/2, to rats at 2 h following experimental Klebsiella pneumoniae meningoencephalitis.
  
  
  
  We used a previously established meningoencephalitis animal model in which Sprague-Dawley rats were infected by K. pneumoniae. Sham and infected animals were treated with vehicle or reparixin and sacrificed at various time points. Leukocyte infiltration into cerebrospinal fluid (CSF) and brain as well as gene and protein expression of chemokines and receptors, and neuronal apoptosis were examined. Primary cultures of neuron/glia were infected with K. pneumoniae as an in vitro model of meningoencephalitis.
  
  
  
  Levels of chemokine (C-X-C motif) ligand (CXCL)2 in CSF time-dependently increased markedly as early as 2 h, and peaked at 8 h following infection and were much higher than those in serum collected simultaneously. Reparixin significantly reduced leukocyte infiltration into CSF and brain tissues, clinical illness, and brain cell apoptosis at 24 h. Reparixin reduced the elevated CSF concentrations of chemokines [CXCL1, CXCL2, chemokine (C-C motif) ligand (CCL)2 and CCL5] and proinflammatory cytokines. Reparixin also reduced the expression of mRNA of various chemokines, chemokine receptors and proinflammatory cytokines in infected brain tissues. Using primary cultures that are devoid of leukocytes, we further observed that reparixin attenuated the neuronal, but not microglial cell death after infection.
  
  
  
  Reparixin not only reduces amplified inflammation, but also provides direct neuroprotective effects in K. pneumoniae meningoencephalitis.
authors.affiliation: Department of Neurological Surgery, Tri-service General Hospital, National Defense Medical Center, Taipei, Taiwan.|Department of Neurosurgery, En Chu Kong Hospital, New Taipei City, Taiwan.
authors.forename: Chien-Tsai
authors.initials: CT
authors.lastname: Chiu
authors.affiliation: Clinical Laboratory, En Chu Kong Hospital, New Taipei City, Taiwan.
authors.forename: Li-Li
authors.initials: LL
authors.lastname: Wen
authors.affiliation: Graduate Institute of Medical Sciences and Department of Physiology, College of Medicine, Taipei Medical University, Taipei, Taiwan.
authors.forename: Hsin-Ping
authors.initials: HP
authors.lastname: Pao
authors.affiliation: Graduate Institute of Medical Sciences and Department of Physiology, College of Medicine, Taipei Medical University, Taipei, Taiwan.
authors.forename: Ling-Yu
authors.initials: LY
authors.lastname: Yang
authors.affiliation: Department of Nursing, Hsin Sheng College of Medical Care and Management, Taoyuan, Taiwan.
authors.forename: Ya-Ni
authors.initials: YN
authors.lastname: Huang
authors.affiliation: Graduate Institute of Medical Sciences and Department of Physiology, College of Medicine, Taipei Medical University, Taipei, Taiwan.
authors.forename: Jia-Yi
authors.initials: JY
authors.lastname: Wang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000473:pathology; D054426:Chemokine CXCL2 / Q000134:cerebrospinal fluid; D004195:Disease Models, Animal; D018836:Inflammation Mediators / Q000134:cerebrospinal fluid; D007710:Klebsiella Infections / Q000150:complications / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D008590:Meningoencephalitis / Q000150:complications / Q000382:microbiology* / Q000473:pathology / Q000517:prevention & control*; D018696:Neuroprotective Agents / Q000008:administration & dosage*; D020556:Neutrophil Infiltration; D012333:RNA, Messenger / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D013449:Sulfonamides / Q000008:administration & dosage*
chemical_list: D054426:Chemokine CXCL2; C513296:Cxcl2 protein, rat; D018836:Inflammation Mediators; D018696:Neuroprotective Agents; D012333:RNA, Messenger; D013449:Sulfonamides; C490707:reparixin
keywords: brain cytokine and chemokine networks; meningoencephalitis; neuroinflammation; neutrophils; reparixin