Shin Nakayama1, Noriko Taguchi2, Yumi Isaka3, Takako Nakamura3, Makoto Tanaka4. 1. Department of Anesthesiology, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, Japan. snakayama@md.tsukuba.ac.jp. 2. Department of Anesthesiology, Tsukuba University Hospital Mito Clinical Education and Training Center, Mito Kyodo General Hospital, University of Tsukuba, Ibaraki, Japan. 3. Technical Service Office for Medical Sciences, University of Tsukuba, Ibaraki, Japan. 4. Department of Anesthesiology, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, Japan.
Abstract
BACKGROUND: Cerebral edema is one of the major causes of mortality following cardiac arrest (CA) and cardiopulmonary resuscitation (CPR). A subunit of the sulfonylurea receptor 1-transient receptor potential M4 (Sur1-TRPM4) channel has been implicated in the pathogenesis of ischemia-evoked cerebral edema. In this study, we examined whether glibenclamide (GBC), a Sur1-TRPM4 channel inhibitor, attenuates cerebral edema following CA/CPR and further examined the efficacy of GBC combined with therapeutic hypothermia. METHODS: Isoflurane-anesthetized adult male wild-type C57Bl/6 mice subjected to 7-min CA/CPR were randomized into five groups: sham operation, control with normothermia, GBC with normothermia, control with hypothermia, and GBC with hypothermia. The primary outcome was to evaluate regional brain water content; the secondary outcome was to measure blood glucose level, Sur1-TRPM4 expression, and pro-inflammatory factor expression. RESULTS: Compared with normothermia, GBC treatment or hypothermia significantly attenuated brain water content in mice subjected to CA/CPR. GBC combined with hypothermia had no additional effects on attenuating cerebral edema. Pro-inflammatory factor messenger RNA expression (TNF-α and IL-6), NFκβ activation, and SUR1-TRPM4 levels were upregulated after CA/CPR. Compared with normothermia, hypothermia, but not GBC, partly suppressed these factors' expression. CONCLUSIONS: GBC attenuated cerebral edema following CA/CPR by blocking Sur1-TRPM4 channels upregulated by CA insult. The effect of GBC was comparable with that of therapeutic hypothermia alone. These results suggest that GBC is an alternative approach for treating CA-evoked cerebral edema.
BACKGROUND:Cerebral edema is one of the major causes of mortality following cardiac arrest (CA) and cardiopulmonary resuscitation (CPR). A subunit of the sulfonylurea receptor 1-transient receptor potential M4 (Sur1-TRPM4) channel has been implicated in the pathogenesis of ischemia-evoked cerebral edema. In this study, we examined whether glibenclamide (GBC), a Sur1-TRPM4 channel inhibitor, attenuates cerebral edema following CA/CPR and further examined the efficacy of GBC combined with therapeutic hypothermia. METHODS:Isoflurane-anesthetized adult male wild-type C57Bl/6 mice subjected to 7-min CA/CPR were randomized into five groups: sham operation, control with normothermia, GBC with normothermia, control with hypothermia, and GBC with hypothermia. The primary outcome was to evaluate regional brain water content; the secondary outcome was to measure blood glucose level, Sur1-TRPM4 expression, and pro-inflammatory factor expression. RESULTS: Compared with normothermia, GBC treatment or hypothermia significantly attenuated brain water content in mice subjected to CA/CPR. GBC combined with hypothermia had no additional effects on attenuating cerebral edema. Pro-inflammatory factor messenger RNA expression (TNF-α and IL-6), NFκβ activation, and SUR1-TRPM4 levels were upregulated after CA/CPR. Compared with normothermia, hypothermia, but not GBC, partly suppressed these factors' expression. CONCLUSIONS:GBCattenuated cerebral edema following CA/CPR by blocking Sur1-TRPM4 channels upregulated by CA insult. The effect of GBC was comparable with that of therapeutic hypothermia alone. These results suggest that GBC is an alternative approach for treating CA-evoked cerebral edema.
Authors: Feng Xiao; Shu Zhang; Thomas C Arnold; J Steven Alexander; Jian Huang; Donna L Carden; Steven A Conrad Journal: Acad Emerg Med Date: 2002-02 Impact factor: 3.451
Authors: Clifton W Callaway; Michael W Donnino; Ericka L Fink; Romergryko G Geocadin; Eyal Golan; Karl B Kern; Marion Leary; William J Meurer; Mary Ann Peberdy; Trevonne M Thompson; Janice L Zimmerman Journal: Circulation Date: 2015-11-03 Impact factor: 29.690
Authors: K Zweckberger; K Hackenberg; C S Jung; D N Hertle; K L Kiening; A W Unterberg; O W Sakowitz Journal: Neuroscience Date: 2014-04-30 Impact factor: 3.590
Authors: J Marc Simard; Mingkui Chen; Kirill V Tarasov; Sergei Bhatta; Svetlana Ivanova; Ludmila Melnitchenko; Natalya Tsymbalyuk; G Alexander West; Volodymyr Gerzanich Journal: Nat Med Date: 2006-03-19 Impact factor: 53.440
Authors: Melika Hosseini; Robert H Wilson; Christian Crouzet; Arya Amirhekmat; Kevin S Wei; Yama Akbari Journal: Neurotherapeutics Date: 2020-04 Impact factor: 7.620
Authors: Ruchira M Jha; Anupama Rani; Shashvat M Desai; Sudhanshu Raikwar; Sandra Mihaljevic; Amanda Munoz-Casabella; Patrick M Kochanek; Joshua Catapano; Ethan Winkler; Giuseppe Citerio; J Claude Hemphill; W Taylor Kimberly; Raj Narayan; Juan Sahuquillo; Kevin N Sheth; J Marc Simard Journal: Int J Mol Sci Date: 2021-11-02 Impact factor: 5.923
Authors: Melissa Pergakis; Neeraj Badjatia; Seemant Chaturvedi; Carolyn A Cronin; W Taylor Kimberly; Kevin N Sheth; J Marc Simard Journal: Expert Opin Investig Drugs Date: 2019-10-24 Impact factor: 6.206