Reparixin attenuates neuronal injury in experimental Klebsiella pneumoniae meningoencephalitis through dual effects on neuroprotection and neuroinflammation

Chien-Tsai Chiu, Li-Li Wen, Hsin-Ping Pao, Ling-Yu Yang, Ya-Ni Huang, Jia-Yi Wang

Research output: Contribution to journalArticle

Abstract

Aims: 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 2h following experimental Klebsiella pneumoniae meningoencephalitis. Methods: 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. Results: Levels of chemokine (C-X-C motif) ligand (CXCL)2 in CSF time-dependently increased markedly as early as 2h, and peaked at 8h 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 24h. 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. Conclusions: Reparixin not only reduces amplified inflammation, but also provides direct neuroprotective effects in K.pneumoniae meningoencephalitis.

Original languageEnglish
Pages (from-to)326-343
Number of pages18
JournalNeuropathology and Applied Neurobiology
Volume42
Issue number4
DOIs
Publication statusPublished - Jun 1 2016

Keywords

  • Brain cytokine and chemokine networks
  • Meningoencephalitis
  • Neuroinflammation
  • Neutrophils
  • Reparixin

ASJC Scopus subject areas

  • Clinical Neurology
  • Pathology and Forensic Medicine
  • Neurology
  • Histology
  • Physiology (medical)

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