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Reparixin attenuates neuronal injury in experimental K lebsiella pneumoniae meningoencephalitis through dual effects on neuroprotection and neuroinflammation
Author(s) -
Chiu ChienTsai,
Wen LiLi,
Pao HsinPing,
Yang LingYu,
Huang YaNi,
Wang JiaYi
Publication year - 2016
Publication title -
neuropathology and applied neurobiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.538
H-Index - 95
eISSN - 1365-2990
pISSN - 0305-1846
DOI - 10.1111/nan.12261
Subject(s) - chemokine , proinflammatory cytokine , meningoencephalitis , immunology , chemokine receptor , microglia , biology , neuroprotection , inflammation , pharmacology
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 2 h following experimental K lebsiella pneumoniae meningoencephalitis. Methods We used a previously established meningoencephalitis animal model in which S prague‐ D awley 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 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 [ CXCL 1, CXCL 2, chemokine ( C ‐ C motif) ligand ( CCL )2 and CCL 5] 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.