CaMKII in global cerebral ischemia: mechanisms and therapeutic intervention

项目总结/摘要 Ca 2 +/钙调蛋白依赖性蛋白激酶II（CaMKII）是两种相反形式的NMDA的中心介体。 受体（NMDAR）依赖性突触可塑性：长时程增强（LTP）和抑制（LTD）。 脑缺血期间NMDAR的病理性过度刺激引起兴奋性毒性神经元细胞死亡， 我们最近已经表明CaMK Ⅱ也介导了全脑缺血（GCI）后的神经元损伤。 重要的是，体内注射我们优化的CaMKII抑制剂（tatCN 19 〇）提供了显著的神经保护作用。 在GCI模型之后，这些模型最接近地模拟了最相关的人类条件：心肺复苏（CPR） 在小鼠心脏骤停后或在猪心室纤颤后（未发表）。CaMKII抑制（i）在 这些条件的高度临床相关的时间点（CPR后30分钟）;（ii）也有效， 用当前的护理标准（治疗性低温）;和（iii）不仅保护免于神经元细胞死亡， 也是因为存活神经元中的LTP长期功能受损。 在这里，三个相互联系但独立的目标将直接促进我们对CaMKII的机械理解- 介导的调节神经元细胞死亡和LTP损伤。具体而言，该项目将调查（1） 在介导缺血诱导的神经元损伤中，CaMKII自主机制的串扰，（2）可能的 CaMKII在神经元细胞死亡与存活中的双重作用，以及（3）CaMKII- 缺血后存活的神经元的依赖性长期LTP损伤。这一切的结果 这项研究将大大推进我们对缺血性神经元损伤的分子机制的理解， 细胞死亡此外，它们将为人类治疗的未来发展提供信息。

Project Summary/Abstract The Ca2+/calmodulin-dependent protein kinase II (CaMKII) is a central mediator of two opposing forms of NMDA- receptor (NMDAR)-dependent synaptic plasticity: long-term potentiation (LTP) and depression (LTD). Pathological overstimulation of NMDARs during cerebral ischemia causes excitotoxic neuronal cell death, and we have recently shown that CaMKII mediates also the neuronal damage after global cerebral ischemia (GCI). Importantly, in vivo injection of our optimized CaMKII inhibitor (tatCN19o) provided significant neuroprotection after GCI models that closely mimic the most relevant human conditions: cardiopulmonary resuscitation (CPR) after cardiac arrest in mice or after ventricular fibrillations in pig (unpublished). CaMKII inhibition (i) was done at a highly clinically relevant timepoint for these conditions (30 min after CPR); (ii) was effective also in conjunction with current standard of care (therapeutic hypothermia); and (iii) protected not only from neuronal cell death but also from the long-lasting functional impairments in LTP that are seen in the surviving neurons. Here, three connected but independent aims will directly promote, our mechanistic understanding of CaMKII- mediated regulation of neuronal cell death and LTP impairment. Specifically, the project will investigate (1) the cross-talk of CaMKII autonomy mechanisms in mediating ischemia-induced neuronal damage, (2) a possible dual role of CaMKII in neuronal cell death versus survival, and (3) mechanisms that underly the CaMKII- dependent long-term LTP impairment of the neurons that survive after ischemia. Together, the results of this study will significantly advance our understanding of the molecular mechanisms underlying ischemic neuronal cell death. Additionally, they will inform future development of a therapy in humans.