Reversal of Global Ischemia-Induced Cognitive Dysfunction by Delayed Inhibition of TRPM2 Ion Channels

被引:21
作者
Dietz, Robert M. [1 ,2 ]
Cruz-Torres, Ivelisse [2 ,3 ]
Orfila, James E. [2 ,4 ]
Patsos, Olivia P. [2 ,4 ]
Shimizu, Kaori [2 ,4 ]
Chalmers, Nicholas [2 ,4 ]
Deng, Guiying [2 ,4 ]
Tiemeier, Erika [2 ,4 ]
Quillinan, Nidia [2 ,4 ]
Herson, Paco S. [2 ,3 ,4 ]
机构
[1] Univ Colorado, Dept Pediat, Sch Med, Aurora, CO USA
[2] Univ Colorado, Sch Med, Neuronal Injury & Plastic Program, Aurora, CO 80045 USA
[3] Univ Colorado, Dept Pharmacol, Sch Med, Aurora, CO 80045 USA
[4] Univ Colorado, Dept Anesthesiol, Sch Med, Aurora, CO 80045 USA
关键词
Neurorestoration; Synaptic plasticity; LTP; Cognitive impairment; Stroke; Cardiac arrest; CARDIAC-ARREST; CEREBRAL-ISCHEMIA; OXIDATIVE STRESS; INDUCED IMPAIRMENT; NEURONAL DEATH; ACTIVATION; BRAIN; RESUSCITATION; RECOVERY; STROKE;
D O I
10.1007/s12975-019-00712-z
中图分类号
R74 [神经病学与精神病学];
学科分类号
摘要
Hippocampal injury and cognitive impairments are common after cardiac arrest and stroke and do not have an effective intervention despite much effort. Therefore, we developed a new approach aimed at reversing synaptic dysfunction by targeting TRPM2 channels. Cardiac arrest/cardiopulmonary resuscitation (CA/CPR) in mice was used to investigate cognitive deficits and the role of the calcium-permeable ion channel transient receptor potential-M2 (TRPM2) in ischemia-induced synaptic dysfunction. Our data indicates that absence (TRPM2(-/-)) or acute inhibition of TRPM2 channels with tatM2NX reduced hippocampal cell death in males only, but prevented synaptic plasticity deficits in both sexes. Remarkably, administration of tatM2NX weeks after injury reversed hippocampal plasticity and memory deficits. Finally, TRPM2-dependent activation of calcineurin-GSK3 beta pathway contributes to synaptic plasticity impairments. These data suggest persistent TRPM2 activity following ischemia contributes to impairments of the surviving hippocampal network and that inhibition of TRPM2 channels at chronic time points may represent a novel strategy to improve functional recovery following cerebral ischemia that is independent of neuroprotection.
引用
收藏
页码:254 / 266
页数:13
相关论文
共 56 条
[1]   Modulation of NMDAR Subunit Expression by TRPM2 Channels Regulates Neuronal Vulnerability to Ischemic Cell Death [J].
Alim, Ishraq ;
Teves, Lucy ;
Li, Rongwen ;
Mori, Yasuo ;
Tymianski, Michael .
JOURNAL OF NEUROSCIENCE, 2013, 33 (44) :17264-17277
[2]   Cognitive function and quality of life after successful resuscitation from cardiac arrest [J].
Beesems, Stefanie G. ;
Wittebrood, Kim M. ;
de Haan, Rob J. ;
Koster, Rudolph W. .
RESUSCITATION, 2014, 85 (09) :1269-1274
[3]  
Benjamin EJ, 2019, CIRCULATION, V139, pE56, DOI [10.1161/CIR.0000000000000746, 10.1161/CIR.0000000000000659]
[4]   A pivotal role of GSK-3 in synaptic plasticity [J].
Bradley, Clarrisa A. ;
Peineau, Stephane ;
Taghibiglou, Changiz ;
Nicolas, Celine S. ;
Whitcomb, Daniel J. ;
Bortolotto, Zuner A. ;
Kaang, Bong-Kiun ;
Cho, Kwangwook ;
Wang, Yu Tian ;
Collingridge, Graham L. .
FRONTIERS IN MOLECULAR NEUROSCIENCE, 2012, 5
[5]   Brain Excitability in Stroke The Yin and Yang of Stroke Progression [J].
Carmichael, S. Thomas .
ARCHIVES OF NEUROLOGY, 2012, 69 (02) :161-167
[6]   Reducing excessive GABA-mediated tonic inhibition promotes functional recovery after stroke [J].
Clarkson, Andrew N. ;
Huang, Ben S. ;
MacIsaac, Sarah E. ;
Mody, Istvan ;
Carmichael, S. Thomas .
NATURE, 2010, 468 (7321) :305-U193
[7]   Long-term depression in the CNS [J].
Collingridge, Graham L. ;
Peineau, Stephane ;
Howland, John G. ;
Wang, Yu Tian .
NATURE REVIEWS NEUROSCIENCE, 2010, 11 (07) :459-473
[8]   Long-term neurological outcome after cardiac arrest and therapeutic hypothermia [J].
Cronberg, Tobias ;
Lilja, Gisela ;
Rundgren, Malin ;
Friberg, Hans ;
Widner, Hakan .
RESUSCITATION, 2009, 80 (10) :1119-1123
[9]   A novel mouse model of pediatric cardiac arrest and cardiopulmonary resuscitation reveals age-dependent neuronal sensitivities to ischemic injury [J].
Deng, G. ;
Yonchek, J. C. ;
Quillinan, N. ;
Strnad, F. A. ;
Exo, J. ;
Herson, P. S. ;
Traystman, R. J. .
JOURNAL OF NEUROSCIENCE METHODS, 2014, 222 :34-41
[10]   Autonomous CaMKII Activity as a Drug Target for Histological and Functional Neuroprotection after Resuscitation from Cardiac Arrest [J].
Deng, Guiying ;
Orfila, James E. ;
Dietz, Robert M. ;
Moreno-Garcia, Myriam ;
Rodgers, Krista M. ;
Coultrap, Steve J. ;
Quillinan, Nidia ;
Traystman, Richard J. ;
Bayer, K. Ulrich ;
Herson, Paco S. .
CELL REPORTS, 2017, 18 (05) :1109-1117