α 7 Nicotinic Acetylcholine Receptor Stimulation Attenuates Neuroinflammation through JAK2-STAT3 Activation in Murine Models of Intracerebral Hemorrhage

Paul R. Krafft, Devin McBride, William B. Rolland, Tim Lekic, Jerry J. Flores, John H. Zhang

Research output: Contribution to journalArticlepeer-review

Abstract

Accounting for high mortality and morbidity rates, intracerebral hemorrhage (ICH) remains one of the most detrimental stroke subtypes lacking a specific therapy. Neuroinflammation contributes to ICH-induced brain injury and is associated with unfavorable outcomes. This study aimed to evaluate whether α7 nicotinic acetylcholine receptor (α7nAChR) stimulation ameliorates neuroinflammation after ICH. Male CD-1 mice and Sprague-Dawley were subjected to intracerebral injection of autologous blood or bacterial collagenase. ICH animals received either α7nAChR agonist PHA-543613 alone or combined with α7nAChR antagonist methyllycaconitine (MLA) or Janus kinase 2 (JAK2) antagonist AG490. Neurobehavioral deficits were evaluated at 24 hours, 72 hours, and 10 weeks after ICH induction. Perihematomal expressions of JAK2, signal transducer and activator of transcription 3 (STAT3), tumor necrosis factor-α (TNF-α), and myeloperoxidase (MPO) were quantified via Western blot. Histologic volumetric analysis of brain tissues was conducted after 10 weeks following ICH induction. PHA-543613 improved short-term neurobehavioral (sensorimotor) deficits and increased activated perihematomal JAK2 and STAT3 expressions while decreasing TNF-α and MPO expressions after ICH. MLA reversed these treatment effects. PHA-543613 also improved long-term neurobehavioral (sensorimotor, learning, and memory) deficits and ameliorated brain atrophy after ICH. These treatment effects were reduced by AG490. α7nAChR stimulation reduced neuroinflammation via activation of the JAK2-STAT3 pathway, thereby ameliorating the short- and long-term sequelae after ICH.

Original languageEnglish
Article number8134653
Pages (from-to)8134653
JournalBioMed Research International
Volume2017
DOIs
StatePublished - Apr 16 2017

ASJC Scopus Subject Areas

  • General Biochemistry,Genetics and Molecular Biology
  • General Immunology and Microbiology

Keywords

  • Blood Transfusion, Autologous/methods
  • Humans
  • STAT3 Transcription Factor/genetics
  • Rats
  • Collagenases/administration & dosage
  • Neurons/drug effects
  • Tumor Necrosis Factor-alpha/genetics
  • Bridged Bicyclo Compounds, Heterocyclic/administration & dosage
  • Cerebral Hemorrhage/complications
  • Janus Kinase 2/genetics
  • Animals
  • Brain Injuries/drug therapy
  • Peroxidase/genetics
  • Tyrphostins/administration & dosage
  • alpha7 Nicotinic Acetylcholine Receptor/agonists
  • Inflammation/complications
  • Mice
  • Quinuclidines/administration & dosage
  • Disease Models, Animal

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