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 language | English |
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Article number | 8134653 |
Pages (from-to) | 8134653 |
Journal | BioMed Research International |
Volume | 2017 |
DOIs | |
State | Published - 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