PMID- 38445502 OWN - NLM STAT- MEDLINE DCOM- 20240327 LR - 20240327 IS - 1524-4628 (Electronic) IS - 0039-2499 (Linking) VI - 55 IP - 4 DP - 2024 Apr TI - Inhibition of Anaplastic Lymphoma Kinase Protects From Ischemic Stroke. PG - 1075-1085 LID - 10.1161/STROKEAHA.123.045991 [doi] AB - BACKGROUND: Ischemic stroke is often accompanied by oxidative stress and inflammatory response, both of which work synergistically to exacerbate the disruption of the blood-brain barrier and ischemic brain injury. ALK (anaplastic lymphoma kinase), a cancer-associated receptor tyrosine kinase, was found to play a role in oxidative stress and inflammation. In this study, we investigated the role of ALK inhibition in a murine model of ischemic stroke. METHODS: Focal cerebral ischemia was induced by temporary occlusion of the right middle cerebral artery in mice with a filament. The ALK inhibitor alectinib was administered following the stroke. ALOX15 (arachidonic acid 15-lipoxygenase) was overexpressed by adenovirus injection. The immunohistochemistry, Western blot, oxidative stress, inflammation, blood-brain barrier leakage, infarct volume, and functional outcomes were determined. RESULTS: We found that the expression of ALK was markedly increased in the neurovascular unit after cerebral ischemia. Treatment with the ALK inhibitor alectinib reduced the accumulation of reactive oxygen species, lipid peroxidation, and oxidative DNA, increased the vascular levels of antioxidant enzymes, inactivated the vascular NLRP3 (nucleotide-binding oligomerization domain-like receptor protein 3) inflammasome pathway, and reduced vascular inflammation (ICAM-1 [intercellular adhesion molecule-1] and MCP-1 [monocyte chemoattractant protein-1]) after ischemia. Moreover, alectinib reduced the loss of cerebrovascular integrity and blood-brain barrier damage, consequently decreasing brain infarction and neurological deficits. Furthermore, alectinib reduced stroke-evoked ALOX15 expression, whereas virus-mediated overexpression of ALOX15 abolished alectinib-dependent inhibition of oxidative stress and vascular inflammation, blood-brain barrier protection, and neuroprotection, suggesting the protective effects of alectinib for stroke may involve ALOX15. CONCLUSIONS: Our findings demonstrated that alectinib protects from stroke by regulating ischemic signaling cascades and suggest that ALK may be a novel therapeutic target for ischemic stroke. FAU - Hu, Yue AU - Hu Y AD - Department of Translational Neuroscience, Jing'an District Centre Hospital of Shanghai, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Fudan University, China (Y.H., L.C., Y.Z., X.G., Z.L., R.W., B.-Q.Z., W.F.). FAU - Chang, Luping AU - Chang L AD - Department of Translational Neuroscience, Jing'an District Centre Hospital of Shanghai, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Fudan University, China (Y.H., L.C., Y.Z., X.G., Z.L., R.W., B.-Q.Z., W.F.). FAU - Zhu, Yuanbo AU - Zhu Y AD - Department of Translational Neuroscience, Jing'an District Centre Hospital of Shanghai, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Fudan University, China (Y.H., L.C., Y.Z., X.G., Z.L., R.W., B.-Q.Z., W.F.). FAU - Geng, Xue AU - Geng X AD - Department of Translational Neuroscience, Jing'an District Centre Hospital of Shanghai, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Fudan University, China (Y.H., L.C., Y.Z., X.G., Z.L., R.W., B.-Q.Z., W.F.). FAU - Liu, Zhongwang AU - Liu Z AUID- ORCID: 0000-0003-2742-1326 AD - Department of Translational Neuroscience, Jing'an District Centre Hospital of Shanghai, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Fudan University, China (Y.H., L.C., Y.Z., X.G., Z.L., R.W., B.-Q.Z., W.F.). FAU - Wang, Ranran AU - Wang R AD - Department of Translational Neuroscience, Jing'an District Centre Hospital of Shanghai, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Fudan University, China (Y.H., L.C., Y.Z., X.G., Z.L., R.W., B.-Q.Z., W.F.). FAU - Wang, Yiheng AU - Wang Y AD - Institute of Neuroscience and Third Affiliated Hospital, Zhengzhou University, China (Y.W.). FAU - Zhao, Bing-Qiao AU - Zhao BQ AUID- ORCID: 0000-0002-6155-0618 AD - Department of Translational Neuroscience, Jing'an District Centre Hospital of Shanghai, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Fudan University, China (Y.H., L.C., Y.Z., X.G., Z.L., R.W., B.-Q.Z., W.F.). FAU - Fan, Wenying AU - Fan W AD - Department of Translational Neuroscience, Jing'an District Centre Hospital of Shanghai, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Fudan University, China (Y.H., L.C., Y.Z., X.G., Z.L., R.W., B.-Q.Z., W.F.). LA - eng PT - Journal Article DEP - 20240306 PL - United States TA - Stroke JT - Stroke JID - 0235266 RN - EC 2.7.10.1 (Anaplastic Lymphoma Kinase) RN - 0 (Protein Kinase Inhibitors) SB - IM MH - Animals MH - Mice MH - Anaplastic Lymphoma Kinase/metabolism MH - Blood-Brain Barrier/metabolism MH - *Brain Ischemia/pathology MH - Infarction, Middle Cerebral Artery/pathology MH - Inflammation/pathology MH - *Ischemic Stroke/complications MH - Protein Kinase Inhibitors/pharmacology MH - *Stroke OTO - NOTNLM OT - alectinib OT - anaplastic lymphoma kinase OT - blood-brain barrier OT - inflammation OT - ischemic stroke COIS- Disclosures None. EDAT- 2024/03/06 06:42 MHDA- 2024/03/27 06:44 CRDT- 2024/03/06 05:28 PHST- 2024/03/27 06:44 [medline] PHST- 2024/03/06 06:42 [pubmed] PHST- 2024/03/06 05:28 [entrez] AID - 10.1161/STROKEAHA.123.045991 [doi] PST - ppublish SO - Stroke. 2024 Apr;55(4):1075-1085. doi: 10.1161/STROKEAHA.123.045991. Epub 2024 Mar 6.