Short-term CaMKII inhibition with tatCN19o does not erase pre-formed memory in mice and is neuroprotective in pigs

The Ca2+/calmodulin-dependent protein kinase II (CaMKII) is a central regulator of learning and memory, which poses a problem for targeting it therapeutically. Indeed, our study supports prior conclusions that long-term interference with CaMKII signaling can erase pre-formed memories. By contrast, we demonstrate here that short-term pharmacological CaMKII inhibition with the neuroprotective peptide tatCN19o interfered with learning in mice only mildly and transiently (for less than 1 h) and did not at all reverse pre-formed memories. These results were determined with ≥500fold of the dose that protected hippocampal neurons from cell death after a highly clinically relevant pig model of transient global cerebral ischemia: ventricular fibrillation followed by advanced life support and electrical defibrillation to induce return of spontaneous circulation. Of additional importance for therapy development, our preliminary cardiovascular safety studies in mice and pig did not indicate any concerns with acute tatCN19o injection. Taken together, even though prolonged interference with CaMKII signaling can erase memory, acute short-term CaMKII inhibition with tatCN19o did not cause such retrograde amnesia that would pose a contraindication for therapy.钙/钙调蛋白依赖性蛋白激酶II（Ca2+/calmodulin-dependent protein kinase II, CaMKII）是学习与记忆的核心调控因子，这使其成为治疗靶点时面临诸多挑战。本研究验证了此前的结论：长期干扰CaMKII信号通路可清除已形成的记忆。与之形成鲜明对比的是，本研究证实，使用神经保护肽tatCN19o进行短期药理学CaMKII抑制，仅会对小鼠的学习产生轻度且短暂（不足1小时）的干扰，且完全不会逆转已形成的记忆。 本研究结果基于≥500倍于可在临床相关性极高的短暂性全脑缺血猪模型中保护海马神经元免于死亡的剂量获得；该造模模型通过心室颤动（ventricular fibrillation）、后续高级生命支持（advanced life support）与电除颤（electrical defibrillation）诱导自主循环恢复（return of spontaneous circulation）。 此外，本研究在小鼠与猪体内开展的初步心血管安全性试验未发现急性注射tatCN19o存在任何安全隐患，这对治疗开发具有重要参考价值。 综上，尽管长期干扰CaMKII信号通路可清除记忆，但使用tatCN19o进行急性短期CaMKII抑制并不会引发此类逆行性遗忘（retrograde amnesia），因此不会成为治疗应用的禁忌症（contraindication）。