title: (+)-Naltrexone is neuroprotective and promotes alternative activation in the mouse hippocampus after cardiac arrest/cardiopulmonary resuscitation.
abstract: 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 NFκB 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.
authors.affiliation: Department of Psychology and The Center for Neuroscience, University of Colorado Boulder, Boulder, CO, USA.
authors.forename: Peter M
authors.initials: PM
authors.lastname: Grace
authors.affiliation: Department of Anesthesiology, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA.
authors.forename: Kaori
authors.initials: K
authors.lastname: Shimizu
authors.affiliation: Department of Psychology and The Center for Neuroscience, University of Colorado Boulder, Boulder, CO, USA.
authors.forename: Keith A
authors.initials: KA
authors.lastname: Strand
authors.affiliation: Chemical Biology Research Branch, National Institute on Drug Abuse and National Institute on Alcohol Abuse and Alcoholism, Rockville, MD, USA.
authors.forename: Kenner C
authors.initials: KC
authors.lastname: Rice
authors.affiliation: Department of Pharmacology, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA.
authors.forename: Guiying
authors.initials: G
authors.lastname: Deng
authors.affiliation: Department of Psychology and The Center for Neuroscience, University of Colorado Boulder, Boulder, CO, USA.
authors.forename: Linda R
authors.initials: LR
authors.lastname: Watkins
authors.affiliation: Department of Anesthesiology, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA; Department of Pharmacology, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA. Electronic address: paco.herson@ucdenver.edu.
authors.forename: Paco S
authors.initials: PS
authors.lastname: Herson
mesh_terms: D000818:Animals; D016887:Cardiopulmonary Resuscitation; D016923:Cell Death / Q000187:drug effects*; D006323:Heart Arrest / Q000378:metabolism / Q000473:pathology*; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D016753:Interleukin-10 / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009271:Naltrexone / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology*
chemical_list: D018696:Neuroprotective Agents; D016753:Interleukin-10; D009271:Naltrexone
keywords: HIF1α; HIF2α; Ischemia; M2 macrophages; M2 microglia; Neurotoxicity; TLR4