Li Ma1, Anatol Manaenko1, Yi-Bo Ou1, An-Wen Shao1, Shu-Xu Yang1, John H Zhang2. 1. From the Department of Neurosurgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China (L.M., S.-X.Y.); Department of Basic Science, Loma Linda University, CA (Y.-B.O., A.-W.S., J.H.Z.); and Department of Neurology, University of Erlangen-Nuremberg, Germany (A.M.). 2. From the Department of Neurosurgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China (L.M., S.-X.Y.); Department of Basic Science, Loma Linda University, CA (Y.-B.O., A.-W.S., J.H.Z.); and Department of Neurology, University of Erlangen-Nuremberg, Germany (A.M.). johnzhang3910@yahoo.com martin735w@gmail.com martin735w@zju.edu.cn.
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 amp-response element binding protein-NF-κB signaling pathway.
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 amp-response element binding protein-NF-κB signaling pathway.
Authors: Qing-Hui Zhou; Ruben J Boado; Eric Ka-Wai Hui; Jeff Zhiqiang Lu; William M Pardridge Journal: Drug Metab Dispos Date: 2010-09-30 Impact factor: 3.922
Authors: Kirsty F MacKenzie; Kristopher Clark; Shaista Naqvi; Victoria A McGuire; Gesa Nöehren; Yosua Kristariyanto; Mirjam van den Bosch; Manikhandan Mudaliar; Pierre C McCarthy; Michael J Pattison; Patrick G A Pedrioli; Geoff J Barton; Rachel Toth; Alan Prescott; J Simon C Arthur Journal: J Immunol Date: 2012-12-14 Impact factor: 5.422
Authors: Beilei Lei; Hana N Dawson; Briana Roulhac-Wilson; Haichen Wang; Daniel T Laskowitz; Michael L James Journal: J Neuroinflammation Date: 2013-08-20 Impact factor: 8.322
Authors: Fernando L Pagan; Yasar Torres-Yaghi; Michaeline L Hebron; Barbara Wilmarth; R Scott Turner; Sara Matar; Dalila Ferrante; Jaeil Ahn; Charbel Moussa Journal: Alzheimers Dement (N Y) Date: 2022-06-01
Authors: Selasi Dankwa; Mary-Margaret Dols; Ling Wei; Elizabeth K K Glennon; Heather S Kain; Alexis Kaushansky; Joseph D Smith Journal: Cell Chem Biol Date: 2021-07-02 Impact factor: 8.116