Rumian Nicole L, Brown Carolyn Nicole, Hendry-Hofer Tara B, Rossetti Thomas, Orfila James E, Tullis Jonathan E, Dwoskin Linda P, Buonarati Olivia R, Lisman John E, Quillinan Nidia, Herson Paco S, Bebarta Vikhyat S, Bayer K Ulrich
Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
Department of Emergency Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
bioRxiv. 2023 Jan 23:2023.01.23.523316. doi: 10.1101/2023.01.23.523316.
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 tatCN19o interfered with learning in mice only mildly and transiently (for less than 1 h) and did not at all reverse pre-formed memories. This was at ≥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 therapeutic development, 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（CaMKII）是学习和记忆的核心调节因子，这给以其为靶点进行治疗带来了难题。事实上，我们的研究支持了之前的结论，即长期干扰CaMKII信号传导会消除预先形成的记忆。相比之下，用tatCN19o进行短期药理学CaMKII抑制对小鼠学习的干扰仅轻微且短暂（不到1小时），并且完全不会逆转预先形成的记忆。这一剂量是在一个高度临床相关的短暂性全脑缺血猪模型（室颤后进行高级生命支持和电击除颤以诱导自主循环恢复）后保护海马神经元免于细胞死亡所需剂量的至少500倍。对治疗开发而言同样重要的是，在小鼠和猪身上进行的心血管安全性研究并未表明急性注射tatCN19o存在任何问题。综上所述，尽管长期干扰CaMKII信号传导会消除记忆，但用tatCN19o进行急性短期CaMKII抑制并不会导致会成为治疗禁忌症的逆行性失忆症。
