title: Sirtuin-2 mediates male specific neuronal injury following experimental cardiac arrest through activation of TRPM2 ion channels.
abstract: OBJECTIVE
  Sirtuins (Sirt) are a class of deacetylase enzymes that play an important role in cell proliferation. Sirt2 activation produces O-acetylated-ADPribose (OAADPr) which can act as a ligand for transient receptor potential cation channel, M2 (TRPM2). We tested the hypothesis that Sirt2 is activated following global cerebral ischemia and contributes to neuronal injury through activation of TRPM2.
  
  
  METHODS
  Adult male and female mice (8-12 weeks old) C57Bl/6 and TRPM2 knock-out mice were subjected to 8 min of cardiac arrest followed by cardiopulmonary resuscitation (CA/CPR). The Sirt2 inhibitor AGK-2 was administered intravenously 30 min after resuscitation. Hippocampal CA1 injury was analyzed at 3 days after CA/CPR. Acute Sirt2 activity was analyzed at 3 and 24 h after CA/CPR. Long-term hippocampal function was assessed using slice electrophysiology 7 days after CA/CPR.
  
  
  RESULTS
  AGK-2 significantly reduced CA1 injury in WT but not TRPM2 knock-out males and had no effect on CA1 injury in females. Elevated Sirt2 activity was observed in hippocampal tissue from males at 24 h after cardiac arrest and was reduced by AGK-2. In contrast, Sirt2 activity in females was increased at 3 but not 24 h. Finally, we observed long-term benefit of AGK-2 on hippocampal function, with a protection of long-term potentiation at CA1 synapses at 7 and 30 days after ischemia.
  
  
  CONCLUSIONS
  In summary, we observed a male specific activation of Sirt2 that contributes to neuronal injury and functional deficits after ischemia specifically in males. These results are consistent with a role of Sirt2 in activating TRPM2 following global ischemia in a sex specific manner. These results support the growing body of literature showing that oxidative stress mechanisms predominate in males and converge on TRPM2 activation as a mediator of cell death.
authors.affiliation: Department of Anesthesiology, University of Colorado, School of Medicine, Aurora, CO 80045, United States.
authors.forename: Kaori
authors.initials: K
authors.lastname: Shimizu
authors.affiliation: Department of Anesthesiology, University of Colorado, School of Medicine, Aurora, CO 80045, United States. Electronic address: nidia.quillinan@ucdenver.edu.
authors.forename: Nidia
authors.initials: N
authors.lastname: Quillinan
authors.affiliation: Department of Anesthesiology, University of Colorado, School of Medicine, Aurora, CO 80045, United States.
authors.forename: James E
authors.initials: JE
authors.lastname: Orfila
authors.affiliation: Department of Anesthesiology, University of Colorado, School of Medicine, Aurora, CO 80045, United States; Department of Pharmacology, University of Colorado, School of Medicine, Aurora, CO 80045, United States.
authors.forename: Paco S
authors.initials: PS
authors.lastname: Herson
mesh_terms: D000818:Animals; D016887:Cardiopulmonary Resuscitation; D005260:Female; D005663:Furans / Q000494:pharmacology; D006323:Heart Arrest / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D011804:Quinolines / Q000494:pharmacology; D012737:Sex Factors; D056565:Sirtuin 2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D013569:Synapses / Q000378:metabolism; D050053:TRPM Cation Channels / Q000235:genetics / Q000378:metabolism*
chemical_list: C521855:AGK2 compound; D005663:Furans; D011804:Quinolines; D050053:TRPM Cation Channels; C544443:TRPM2 protein, mouse; D056565:Sirtuin 2
keywords: Cardiac arrest; Cerebral ischemia; Sirtuin; TRPM2