Journal
NEUROBIOLOGY OF DISEASE
Volume 96, Issue -, Pages 248-260Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.nbd.2016.09.013
Keywords
Stroke; Hypothermia; Neurotensin receptor agonist; HPI-201; Inflammation; M1/M2 polarization; Microglia migration; Functional recovery
Categories
Funding
- NIH [NS073378, NS075338, NS085568, NS091585]
- VA National Merit grant [RX000666]
- American Heart Association Postdoctoral Fellowship [14P0ST20130024, 15POST25680013, 15POST25710112]
- NIH S10 grant [1S10 RR025679 01]
- O. Wayne Rollins Endowed Chair fund
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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 degrees C for 6 h) 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 30 min after stroke. The TH treatment decreased the expression of M1 type reactive factors including tumor necrosis factor-alpha (TNF-alpha), interleukin-1 beta (IL-1 beta, 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-1 alpha(MIP-1 alpha), two key chemokines in the regulation of microglia activation and infiltration. Consistently, physical cooling during OGD significantly decreased microglia migration 16 h after OGD. Finally, TH improved functional recovery at 1, 3, and 7 days 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. (C) 2016 Elsevier Inc. All rights reserved.
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