Osteopontin attenuates inflammation via JAK2/STAT1 pathway in hyperglycemic rats after intracerebral hemorrhage

Lei Gong, Anatol Manaenko, Ruiming Fan, Lei Huang, Budbazar Enkhjargal, Devin W. McBride, Yan Ding, Jiping Tang, Xiaoqiu Xiao, John H. Zhang

Research output: Contribution to journalArticlepeer-review

Abstract

Acute intracerebral hemorrhage (ICH) complicated by hyperglycemia is associated with aggravation of post-stroke inflammation, leading to exacerbation of brain edema and predicting poor neurological outcomes and higher mortality of patients. Osteopontin (OPN) is a neuroprotective glycoprotein, which is able to attenuate brain injury induced by hemorrhagic stroke. In the current study we investigated whether OPN will decrease the inflammatory post-ICH response as well as attenuate brain edema and neurological deficits in hyperglycemic rats. We employed a collagenase model of ICH on male Sprague-Dawley rats (n = 148) rats and 50% of Dextrose was injected intraperitoneally (i.p) 3 h after ICH (ICH + HG). Intranasal administration of recombinant OPN (rOPN) was performed 1 h after ICH. The development of brain injury was evaluated by brain water content (BWC) and neurological deficits, western blot and immunohistochemistry study. Small interfering ribonucleic acid (siRNA) for integrin-β1 receptor and a JAK2 agonist, Coumermycin A1 (C-A1), were used for detailed investigation of the molecular pathway. The administration of OPN (3 μg) significantly improved neurobehavior and increased expression of OPN and integrin-β1 receptor in the brain followed with decrease of neutrophil infiltration, JAK2, STAT1, TNF-a, IL-1b, MMP-9 and brain edema in the ICH + HG + OPN rats compared with ICH + HG rats. The effects of OPN were reversed by the intervention of intergrin-β1 siRNA and C-A1. In conclusion, rOPN attenuated ICH-induced brain inflammation in hyperglycemic rats, leading to attenuation of brain edema and improving neurological functions. Effects of rOPN were mediated at least partly by integrin-β1 induced inhibition of JAK2/STAT1 pathway.

Original languageEnglish
Pages (from-to)160-169
Number of pages10
JournalNeuropharmacology
Volume138
DOIs
StatePublished - Aug 2018

ASJC Scopus Subject Areas

  • Pharmacology
  • Cellular and Molecular Neuroscience

Keywords

  • Brain edema
  • Hyperglycemia
  • ICH
  • Inflammation
  • Osteopontin
  • STAT1 Transcription Factor/metabolism
  • Integrin beta1/metabolism
  • Male
  • Brain Edema/drug therapy
  • Glucose
  • Random Allocation
  • Neuroprotective Agents/pharmacology
  • Osteopontin/pharmacology
  • Rats, Sprague-Dawley
  • Signal Transduction/drug effects
  • Brain/drug effects
  • Collagenases
  • Animals
  • Encephalitis/drug therapy
  • Hyperglycemia/drug therapy
  • Cerebral Hemorrhage/drug therapy
  • Janus Kinase 2/metabolism
  • Disease Models, Animal

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