Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
Department of Emergency Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
J Biol Chem. 2023 May;299(5):104693. doi: 10.1016/j.jbc.2023.104693. Epub 2023 Apr 8.
The Ca/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, 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 obtained with ≥500-fold 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 the 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, although 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（CaMKII）是学习和记忆的核心调节剂，这给其治疗靶点的确定带来了问题。事实上，我们的研究支持先前的结论，即长期干扰 CaMKII 信号会消除已形成的记忆。相比之下，用神经保护肽 tatCN19o 进行短期的 CaMKII 抑制仅轻度且短暂地干扰了小鼠的学习（不到 1 小时），并且根本没有逆转已形成的记忆。这些结果是在用 ≥500 倍于剂量下获得的，该剂量可在高度临床相关的短暂全脑缺血猪模型后保护海马神经元免于细胞死亡：心室颤动后进行高级生命支持和电除颤以诱导自主循环恢复。对于治疗开发而言，更为重要的是，我们在小鼠和猪中的初步心血管安全性研究并未表明急性 tatCN19o 注射存在任何问题。总之，尽管长时间干扰 CaMKII 信号会消除记忆，但用 tatCN19o 进行急性短期的 CaMKII 抑制不会引起逆行性遗忘，这不会对治疗构成禁忌。
