title: Regulation of therapeutic hypothermia on inflammatory cytokines, microglia polarization, migration and functional recovery after ischemic stroke in mice.
abstract: Stroke is a leading threat to human life and health in the US and around the globe, while very few effective treatments are available for stroke patients. Preclinical and clinical studies have shown that therapeutic hypothermia (TH) is a potential treatment for stroke. Using novel neurotensin receptor 1 (NTR1) agonists, we have demonstrated pharmacologically induced hypothermia and protective effects against brain damages after ischemic stroke, hemorrhage stroke, and traumatic brain injury (TBI) in rodent models. To further characterize the mechanism of TH-induced brain protection, we examined the effect of TH (at ±33°C for 6h) induced by the NTR1 agonist HPI-201 or physical (ice/cold air) cooling on inflammatory responses after ischemic stroke in mice and oxygen glucose deprivation (OGD) in cortical neuronal cultures. Seven days after focal cortical ischemia, microglia activation in the penumbra reached a peak level, which was significantly attenuated by TH treatments commenced 30min after stroke. The TH treatment decreased the expression of M1 type reactive factors including tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), IL-12, IL-23, and inducible nitric oxide synthase (iNOS) measured by RT-PCR and Western blot analyses. Meanwhile, TH treatments increased the expression of M2 type reactive factors including IL-10, Fizz1, Ym1, and arginase-1. In the ischemic brain and in cortical neuronal/BV2 microglia cultures subjected to OGD, TH attenuated the expression of monocyte chemoattractant protein-1 (MCP-1) and macrophage inflammatory protein-1α (MIP-1α), two key chemokines in the regulation of microglia activation and infiltration. Consistently, physical cooling during OGD significantly decreased microglia migration 16h after OGD. Finally, TH improved functional recovery at 1, 3, and 7days after stroke. This study reveals the first evidence for hypothermia mediated regulation on inflammatory factor expression, microglia polarization, migration and indicates that the anti-inflammatory effect is an important mechanism underlying the brain protective effects of a TH therapy.
authors.affiliation: Department of Anesthesiology, Emory University School of Medicine, Atlanta, GA 30322, United States; Center for Visual and Neurocognitive Rehabilitation, Atlanta Veterans Affairs Medical Center, Decatur, GA 30033, United States.
authors.forename: Jin Hwan
authors.initials: JH
authors.lastname: Lee
authors.affiliation: Department of Anesthesiology, Emory University School of Medicine, Atlanta, GA 30322, United States; Center for Visual and Neurocognitive Rehabilitation, Atlanta Veterans Affairs Medical Center, Decatur, GA 30033, United States.
authors.forename: Zheng Z
authors.initials: ZZ
authors.lastname: Wei
authors.affiliation: Department of Anesthesiology, Emory University School of Medicine, Atlanta, GA 30322, United States.
authors.forename: Wenyuan
authors.initials: W
authors.lastname: Cao
authors.affiliation: Department of Anesthesiology, Emory University School of Medicine, Atlanta, GA 30322, United States.
authors.forename: Soonmi
authors.initials: S
authors.lastname: Won
authors.affiliation: Department of Anesthesiology, Emory University School of Medicine, Atlanta, GA 30322, United States; Center for Visual and Neurocognitive Rehabilitation, Atlanta Veterans Affairs Medical Center, Decatur, GA 30033, United States.
authors.forename: Xiaohuan
authors.initials: X
authors.lastname: Gu
authors.affiliation: Department of Anesthesiology, Emory University School of Medicine, Atlanta, GA 30322, United States.
authors.forename: Megan
authors.initials: M
authors.lastname: Winter
authors.affiliation: JT Pharmaceuticals, Mt. Pleasant, SC 29464, United States; Department of Drug Discovery and Biomedical Sciences, Medical University of South Carolina, Charleston, SC 29401, United States.
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Dix
authors.affiliation: Department of Anesthesiology, Emory University School of Medicine, Atlanta, GA 30322, United States; Department of Neurology, Emory University School of Medicine, Atlanta, GA 30322, United States.
authors.forename: Ling
authors.initials: L
authors.lastname: Wei
authors.affiliation: Department of Anesthesiology, Emory University School of Medicine, Atlanta, GA 30322, United States; Center for Visual and Neurocognitive Rehabilitation, Atlanta Veterans Affairs Medical Center, Decatur, GA 30033, United States. Electronic address: spyu@emory.edu.
authors.forename: Shan Ping
authors.initials: SP
authors.lastname: Yu
mesh_terms: D000818:Animals; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism; D002465:Cell Movement / Q000502:physiology*; D016764:Cell Polarity / Q000502:physiology*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D016207:Cytokines / Q000378:metabolism*; D004195:Disease Models, Animal; D004622:Embryo, Mammalian; D005947:Glucose / Q000172:deficiency; D007036:Hypothermia, Induced / Q000379:methods*; D000860:Hypoxia; D020244:Infarction, Middle Cerebral Artery / Q000473:pathology / Q000503:physiopathology / Q000628:therapy*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism; D017628:Microglia / Q000502:physiology*; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D009842:Oligopeptides / Q000627:therapeutic use; D010100:Oxygen; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D020127:Recovery of Function / Q000502:physiology*
chemical_list: C575024:ABS-201; C491049:Aif1 protein, mouse; D002135:Calcium-Binding Proteins; D016207:Cytokines; D008840:Microfilament Proteins; D009842:Oligopeptides; D010751:Phosphopyruvate Hydratase; D005947:Glucose; D010100:Oxygen
keywords: Functional recovery; HPI-201; Hypothermia; Inflammation; M1/M2 polarization; Microglia migration; Neurotensin receptor agonist; Stroke