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

Nicole L. Rumian; Carolyn Nicole Brown; Tara B. Hendry-Hofer; Thomas Rossetti; James E. Orfila; Jonathan E. Tullis; Linda P. Dwoskin; Olivia R. Buonarati; John E. Lisman; Nidia Quillinan; Paco S. Herson; Vikhyat S. Bebarta; K. Ulrich Bayer

doi:10.1016/j.jbc.2023.104693

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

Nicole L. Rumian, Carolyn Nicole Brown, Tara B. Hendry-Hofer, Thomas Rossetti, James E. Orfila, Jonathan E. Tullis, Linda P. Dwoskin, Olivia R. Buonarati, John E. Lisman, Nidia Quillinan, Paco S. Herson, Vikhyat S. Bebarta, K. Ulrich Bayer

Research output: Contribution to journal › Article › peer-review

Abstract

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.

Original language	English
Article number	104693
Journal	Journal of Biological Chemistry
Volume	299
Issue number	5
DOIs	https://doi.org/10.1016/j.jbc.2023.104693
State	Published - May 2023

Bibliographical note

Funding Information:
This work was funded by National Institutes of Health grants T32 GM007635 (supporting C. N. B.), T32 AG000279 (supporting N. L. R.), F31 AG069458 (to N. L. R.), F31 NS129254 (to C. N. B.), F32 AG066536 (to O. R. B.), R01 AG067713 , R01 NS110383 , R01 NS081248 (to K. U. B.), and R01 NS118786 (to K. U. B. and P. S. H.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Publisher Copyright:
© 2023 The Authors

Keywords

Ca/calmodulin-dependent protein kinase II (CaMKII)
contextual fear conditioning
global cerebral ischemia
learning
memory
mouse
pig
ventricular fibrillation

ASJC Scopus subject areas

Biochemistry
Molecular Biology
Cell Biology

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10.1016/j.jbc.2023.104693

Cite this

Rumian, N. L., Brown, C. N., Hendry-Hofer, T. B., Rossetti, T., Orfila, J. E., Tullis, J. E., Dwoskin, L. P., Buonarati, O. R., Lisman, J. E., Quillinan, N., Herson, P. S., Bebarta, V. S., & Bayer, K. U. (2023). Short-term CaMKII inhibition with tatCN19o does not erase pre-formed memory in mice and is neuroprotective in pigs. Journal of Biological Chemistry, 299(5), Article 104693. https://doi.org/10.1016/j.jbc.2023.104693

@article{d21f4cb32bc34809b304f7dea85da611,

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

abstract = "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.",

keywords = "Ca/calmodulin-dependent protein kinase II (CaMKII), contextual fear conditioning, global cerebral ischemia, learning, memory, mouse, pig, ventricular fibrillation",

author = "Rumian, {Nicole L.} and Brown, {Carolyn Nicole} and Hendry-Hofer, {Tara B.} and Thomas Rossetti and Orfila, {James E.} and Tullis, {Jonathan E.} and Dwoskin, {Linda P.} and Buonarati, {Olivia R.} and Lisman, {John E.} and Nidia Quillinan and Herson, {Paco S.} and Bebarta, {Vikhyat S.} and Bayer, {K. Ulrich}",

note = "Funding Information: This work was funded by National Institutes of Health grants T32 GM007635 (supporting C. N. B.), T32 AG000279 (supporting N. L. R.), F31 AG069458 (to N. L. R.), F31 NS129254 (to C. N. B.), F32 AG066536 (to O. R. B.), R01 AG067713 , R01 NS110383 , R01 NS081248 (to K. U. B.), and R01 NS118786 (to K. U. B. and P. S. H.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Publisher Copyright: {\textcopyright} 2023 The Authors",

year = "2023",

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doi = "10.1016/j.jbc.2023.104693",

language = "English",

volume = "299",

number = "5",

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Rumian, NL, Brown, CN, Hendry-Hofer, TB, Rossetti, T, Orfila, JE, Tullis, JE, Dwoskin, LP, Buonarati, OR, Lisman, JE, Quillinan, N, Herson, PS, Bebarta, VS & Bayer, KU 2023, 'Short-term CaMKII inhibition with tatCN19o does not erase pre-formed memory in mice and is neuroprotective in pigs', Journal of Biological Chemistry, vol. 299, no. 5, 104693. https://doi.org/10.1016/j.jbc.2023.104693

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 - Funding Information: This work was funded by National Institutes of Health grants T32 GM007635 (supporting C. N. B.), T32 AG000279 (supporting N. L. R.), F31 AG069458 (to N. L. R.), F31 NS129254 (to C. N. B.), F32 AG066536 (to O. R. B.), R01 AG067713 , R01 NS110383 , R01 NS081248 (to K. U. B.), and R01 NS118786 (to K. U. B. and P. S. H.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. 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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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 -

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

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

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