Journal
BRAIN BEHAVIOR AND IMMUNITY
Volume 48, Issue -, Pages 115-122Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.bbi.2015.03.005
Keywords
TLR4; Ischemia; Neurotoxicity; M2 microglia; M2 macrophages; HIF1 alpha; HIF2 alpha
Categories
Funding
- University of Colorado Boulder Innovative Seed Grant Program
- NIH Intramural Research Programs of the National Institute on Drug Abuse (NIDA)
- National Institute of Alcohol Abuse and Alcoholism (NIAAA)
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Despite dramatic improvement in cardiopulmonary resuscitation (CPR) and other techniques for cardiac arrest (CA), the majority of survivors continue to show signs of decreased memory or executive cognitive function. Such memory impairment may be due to hippocampal CA1 neuronal death, which is delayed by several days after CA/CPR. Classical microgliosis in the CA1 region may contribute to neuronal death, yet the role of a key activation receptor Toll Like Receptor 4 (TLR4) has not been previously investigated for such neuronal death after CA/CPR. We show that (+)-naltrexone was neuroprotective after CA/CPR. TLR4 blockade was associated with decreased expression of markers for microglial/macrophage activation and T cell and B cell infiltration, as well as decreased pro-inflammatory cytokine levels. Notably, IL-10 expression was elevated in response to CA/CPR, but was not attenuated by (+)-naltrexone, suggesting that the local monocyte/microglial phenotype had shifted towards alternative activation. This was confirmed by elevated expression of Arginase-1, and decreased expression of NF kappa B p65 subunit. Thus, (+)-naltrexone and other TLR4 antagonists may represent a novel therapeutic strategy to alleviate the substantial burden of memory or executive cognitive function impairment after CA/CPR. (C) 2015 Elsevier Inc. All rights reserved.
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