TY - JOUR
T1 - Short-term CaMKII inhibition with tatCN19o does not erase pre-formed memory in mice and is neuroprotective in pigs
AU - Rumian, Nicole L.
AU - Brown, Carolyn Nicole
AU - Hendry-Hofer, Tara B.
AU - Rossetti, Thomas
AU - Orfila, James E.
AU - Tullis, Jonathan E.
AU - Dwoskin, Linda P.
AU - Buonarati, Olivia R.
AU - Lisman, John E.
AU - Quillinan, Nidia
AU - Herson, Paco S.
AU - Bebarta, Vikhyat S.
AU - Bayer, K. Ulrich
N1 - Publisher Copyright:
© 2023 The Authors
PY - 2023/5
Y1 - 2023/5
N2 - 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, 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.
AB - 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, 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.
KW - Ca/calmodulin-dependent protein kinase II (CaMKII)
KW - contextual fear conditioning
KW - global cerebral ischemia
KW - learning
KW - memory
KW - mouse
KW - pig
KW - ventricular fibrillation
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UR - http://www.scopus.com/inward/citedby.url?scp=85156155633&partnerID=8YFLogxK
U2 - 10.1016/j.jbc.2023.104693
DO - 10.1016/j.jbc.2023.104693
M3 - Article
C2 - 37037305
AN - SCOPUS:85156155633
SN - 0021-9258
VL - 299
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 5
M1 - 104693
ER -