Autonomous CaMKII Activity as a Drug Target for Histological and Functional Neuroprotection after Resuscitation from Cardiac Arrest.
The Ca2+/calmodulin-dependent protein kinase II (CaMKII) is a major mediator of physiological glutamate signaling, but its role in pathological glutamate signaling (excitotoxicity) remains less clear, with indications for both neuro-toxic and neuro-protective functions. Here, the role of CaMKII in ischemic injury is assessed utilizing our mouse model of cardiac arrest and cardiopulmonary resuscitation (CA/CPR). CaMKII inhibition (with tatCN21 or tatCN19o) at clinically relevant time points (30 min after resuscitation) greatly reduces neuronal injury. Importantly, CaMKII inhibition also works in combination with mild hypothermia, the current standard of care. The relevant drug target is specifically Ca2+-independent "autonomous" CaMKII activity generated by T286 autophosphorylation, as indicated by substantial reduction in injury in autonomy-incompetent T286A mutant mice. In addition to reducing cell death, tatCN19o also protects the surviving neurons from functional plasticity impairments and prevents behavioral learning deficits, even at extremely low doses (0.01 mg/kg), further highlighting the clinical potential of our findings.
Department of Anesthesiology, University of Colorado School of Medicine, Aurora, CO 80045, USA; Neuronal Injury Program, University of Colorado School of Medicine, Aurora, CO 80045, USA.
Guiying
G
Deng
Department of Anesthesiology, University of Colorado School of Medicine, Aurora, CO 80045, USA; Neuronal Injury Program, University of Colorado School of Medicine, Aurora, CO 80045, USA.
James E
JE
Orfila
Neuronal Injury Program, University of Colorado School of Medicine, Aurora, CO 80045, USA; Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO 80045, USA.
Robert M
RM
Dietz
Department of Anesthesiology, University of Colorado School of Medicine, Aurora, CO 80045, USA; Neuronal Injury Program, University of Colorado School of Medicine, Aurora, CO 80045, USA.
Myriam
M
Moreno-Garcia
Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO 80045, USA; Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO 80045, USA.
Krista M
KM
Rodgers
Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO 80045, USA.
Steve J
SJ
Coultrap
Department of Anesthesiology, University of Colorado School of Medicine, Aurora, CO 80045, USA; Neuronal Injury Program, University of Colorado School of Medicine, Aurora, CO 80045, USA.
Nidia
N
Quillinan
Department of Anesthesiology, University of Colorado School of Medicine, Aurora, CO 80045, USA; Neuronal Injury Program, University of Colorado School of Medicine, Aurora, CO 80045, USA; Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO 80045, USA.
Richard J
RJ
Traystman
Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO 80045, USA. Electronic address: ulli.bayer@ucdenver.edu.
K Ulrich
KU
Bayer
Department of Anesthesiology, University of Colorado School of Medicine, Aurora, CO 80045, USA; Neuronal Injury Program, University of Colorado School of Medicine, Aurora, CO 80045, USA; Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO 80045, USA. Electronic address: paco.herson@ucdenver.edu.
Paco S
PS
Herson
D000818:Animals; D002118:Calcium / Q000378:metabolism; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism*; D016923:Cell Death / Q000502:physiology; D006323:Heart Arrest / Q000378:metabolism* / Q000503:physiopathology*; D006624:Hippocampus / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000378:metabolism / Q000502:physiology; D000066829:Neuroprotection / Q000502:physiology*; D010766:Phosphorylation / Q000502:physiology
D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D002118:Calcium
CaMKII; LTP; cardiac arrest; ischemia; neuroprotection; tatCN19o