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
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.
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.
Cell Rep. 2017 Jan 31;18(5):1109-1117. doi: 10.1016/j.celrep.2017.01.011.
The Ca/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 Ca-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.
钙/钙调蛋白依赖性蛋白激酶II（CaMKII）是生理性谷氨酸信号传导的主要介质，但其在病理性谷氨酸信号传导（兴奋性毒性）中的作用仍不太清楚，有证据表明其具有神经毒性和神经保护功能。在此，利用我们的心脏骤停和心肺复苏（CA/CPR）小鼠模型评估了CaMKII在缺血性损伤中的作用。在临床相关时间点（复苏后30分钟）抑制CaMKII（使用tatCN21或tatCN19o）可大大减轻神经元损伤。重要的是，CaMKII抑制作用还可与当前的护理标准轻度低温联合使用。相关的药物靶点具体是由T286自身磷酸化产生的不依赖钙的“自主”CaMKII活性，这在自主性缺陷的T286A突变小鼠损伤大幅减少中得到了体现。除了减少细胞死亡外，tatCN19o还能保护存活的神经元免受功能可塑性损伤，并防止行为学习缺陷，即使在极低剂量（0.01mg/kg）下也是如此，这进一步凸显了我们研究结果的临床潜力。
