Abstract
Background and Purpose-Intracerebral hemorrhage (ICH) is a subtype of stroke with highest mortality and morbidity. Pronounced inflammation plays a significant role in the development of the secondary brain injury after ICH. Recently, SIK- 2 (salt-inducible kinase-2) was identified as an important component controlling inflammatory response. Here we sought to investigate the role of SIK-2 in post-ICH inflammation and potential protective effects of SIK-2 inhibition after ICH. Methods-Two hundred and ninety-three male CD-1 mice were used. ICH was induced via injection of 30 μL of autologous blood. Recombinant SIK-2 was administrated 1 hour after ICH intracerebroventricularly. SIK-2 small interfering RNA was injected intracerebroventricularly 24 hours before ICH. Bosutinib, a clinically approved tyrosine kinase inhibitor with affinity to SIK-2, was given intranasally 1 hour or 6 hours after ICH. Effects of treatments were evaluated by neurological tests and brain water content calculation. Molecular pathways were investigated by Western blots and immunofluorescence studies. Results-Endogenous SIK-2 was expressed in microglia and neurons. SIK-2 expression was reduced after ICH. Exogenous SIK-2 aggravated post-ICH inflammation, leading to brain edema and the neurobehavioral deficits. SIK-2 inhibition attenuated post-ICH inflammation, reducing brain edema and ameliorating neurological dysfunctions. Bosutinib inhibited SIK-2-attenuating ICH-induced brain damage. Protective effects of Bosutinib were mediated, at least partly, by CRTC3 (cyclic amp-response element binding protein-regulated transcription coactivator 3)/cyclic amp-response element binding protein/NF-κB (nuclear factor-κB) pathway. Conclusions-SIK-2 participates in inflammation induction after ICH. SIK-2 inhibition via Bosutinib or small interfering RNA decreased inflammation, attenuating brain injury. SIK-2 effects are, at least partly, mediated by CRTC3-cyclic ampresponse element binding protein-NF-κB signaling pathway.
Original language | English |
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Pages (from-to) | 3108-3116 |
Number of pages | 9 |
Journal | Stroke |
Volume | 48 |
Issue number | 11 |
DOIs | |
State | Published - Nov 2017 |
ASJC Scopus Subject Areas
- Clinical Neurology
- Cardiology and Cardiovascular Medicine
- Advanced and Specialized Nursing
Keywords
- Bosutinib
- Intracerebral hemorrhage
- Microglia
- SIK-2 inhibition
- Salt-inducible kinases
- Aniline Compounds/pharmacology
- Neurons/enzymology
- Nitriles/pharmacology
- Male
- Signal Transduction/drug effects
- Quinolines/pharmacology
- Animals
- Transcription Factors/metabolism
- Gene Expression Regulation, Enzymologic/drug effects
- Cerebral Hemorrhage/drug therapy
- Inflammation/drug therapy
- Mice
- Protein Serine-Threonine Kinases/antagonists & inhibitors
- Disease Models, Animal
- Microglia/enzymology