The GHB analogue HOCPCA improves deficits in cognition and sensorimotor function after MCAO via CaMKIIα

Research output: Contribution to journal › Journal article › Research › peer-review

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The GHB analogue HOCPCA improves deficits in cognition and sensorimotor function after MCAO via CaMKIIα. / Griem-Krey, Nane; Klein, Anders B.; Clausen, Bettina H.; Namini, Mathias R.J.; Nielsen, Pernille V.; Bhuiyan, Mozammel; Nagaraja, Raghavendra Y.; De Silva, T. Michael; Sobey, Christopher G.; Cheng, Heung Chin; Orset, Cyrille; Vivien, Denis; Lambertsen, Kate L.; Clarkson, Andrew N.; Wellendorph, Petrine.

In: Journal of Cerebral Blood Flow and Metabolism, Vol. 43, No. 8, 2023, p. 1419-1434.

Research output: Contribution to journal › Journal article › Research › peer-review

Harvard

Griem-Krey, N, Klein, AB, Clausen, BH, Namini, MRJ, Nielsen, PV, Bhuiyan, M, Nagaraja, RY, De Silva, TM, Sobey, CG, Cheng, HC, Orset, C, Vivien, D, Lambertsen, KL, Clarkson, AN & Wellendorph, P 2023, 'The GHB analogue HOCPCA improves deficits in cognition and sensorimotor function after MCAO via CaMKIIα', Journal of Cerebral Blood Flow and Metabolism, vol. 43, no. 8, pp. 1419-1434. https://doi.org/10.1177/0271678X231167920

APA

Griem-Krey, N., Klein, A. B., Clausen, B. H., Namini, M. R. J., Nielsen, P. V., Bhuiyan, M., Nagaraja, R. Y., De Silva, T. M., Sobey, C. G., Cheng, H. C., Orset, C., Vivien, D., Lambertsen, K. L., Clarkson, A. N., & Wellendorph, P. (2023). The GHB analogue HOCPCA improves deficits in cognition and sensorimotor function after MCAO via CaMKIIα. Journal of Cerebral Blood Flow and Metabolism, 43(8), 1419-1434. https://doi.org/10.1177/0271678X231167920

Vancouver

Griem-Krey N, Klein AB, Clausen BH, Namini MRJ, Nielsen PV, Bhuiyan M et al. The GHB analogue HOCPCA improves deficits in cognition and sensorimotor function after MCAO via CaMKIIα. Journal of Cerebral Blood Flow and Metabolism. 2023;43(8):1419-1434. https://doi.org/10.1177/0271678X231167920

Author

Griem-Krey, Nane ; Klein, Anders B. ; Clausen, Bettina H. ; Namini, Mathias R.J. ; Nielsen, Pernille V. ; Bhuiyan, Mozammel ; Nagaraja, Raghavendra Y. ; De Silva, T. Michael ; Sobey, Christopher G. ; Cheng, Heung Chin ; Orset, Cyrille ; Vivien, Denis ; Lambertsen, Kate L. ; Clarkson, Andrew N. ; Wellendorph, Petrine. / The GHB analogue HOCPCA improves deficits in cognition and sensorimotor function after MCAO via CaMKIIα. In: Journal of Cerebral Blood Flow and Metabolism. 2023 ; Vol. 43, No. 8. pp. 1419-1434.

Bibtex

@article{a269d60e571b44b6906d6a71738e3867,
title = "The GHB analogue HOCPCA improves deficits in cognition and sensorimotor function after MCAO via CaMKIIα",
abstract = "Ca2+/calmodulin-dependent protein kinase II alpha (CaMKIIα) is a major contributor to physiological and pathological glutamate-mediated Ca2+ signals, and its involvement in various critical cellular pathways demands specific pharmacological strategies. We recently presented γ-hydroxybutyrate (GHB) ligands as the first small molecules selectively targeting and stabilizing the CaMKIIα hub domain. Here, we report that the cyclic GHB analogue 3-hydroxycyclopent-1-enecarboxylic acid (HOCPCA), improves sensorimotor function after experimental stroke in mice when administered at a clinically relevant time and in combination with alteplase. Further, we observed improved hippocampal neuronal activity and working memory after stroke. On the biochemical level, we observed that hub modulation by HOCPCA results in differential effects on distinct CaMKII pools, ultimately alleviating aberrant CaMKII signalling after cerebral ischemia. As such, HOCPCA normalised cytosolic Thr286 autophosphorylation after ischemia in mice and downregulated ischemia-specific expression of a constitutively active CaMKII kinase proteolytic fragment. Previous studies suggest holoenzyme stabilisation as a potential mechanism, yet a causal link to in vivo findings requires further studies. Similarly, HOCPCA{\textquoteright}s effects on dampening inflammatory changes require further investigation as an underlying protective mechanism. HOCPCA{\textquoteright}s selectivity and absence of effects on physiological CaMKII signalling highlight pharmacological modulation of the CaMKIIα hub domain as an attractive neuroprotective strategy.",
keywords = "CaMKII, excitotoxicity, functional recovery, HOCPCA, MCAO",
author = "Nane Griem-Krey and Klein, {Anders B.} and Clausen, {Bettina H.} and Namini, {Mathias R.J.} and Nielsen, {Pernille V.} and Mozammel Bhuiyan and Nagaraja, {Raghavendra Y.} and {De Silva}, {T. Michael} and Sobey, {Christopher G.} and Cheng, {Heung Chin} and Cyrille Orset and Denis Vivien and Lambertsen, {Kate L.} and Clarkson, {Andrew N.} and Petrine Wellendorph",
note = "Publisher Copyright: {\textcopyright} The Author(s) 2023.",
year = "2023",
doi = "10.1177/0271678X231167920",
language = "English",
volume = "43",
pages = "1419--1434",
journal = "Journal of Cerebral Blood Flow and Metabolism",
issn = "0271-678X",
publisher = "SAGE Publications",
number = "8",

}

RIS

TY - JOUR

T1 - The GHB analogue HOCPCA improves deficits in cognition and sensorimotor function after MCAO via CaMKIIα

AU - Griem-Krey, Nane

AU - Klein, Anders B.

AU - Clausen, Bettina H.

AU - Namini, Mathias R.J.

AU - Nielsen, Pernille V.

AU - Bhuiyan, Mozammel

AU - Nagaraja, Raghavendra Y.

AU - De Silva, T. Michael

AU - Sobey, Christopher G.

AU - Cheng, Heung Chin

AU - Orset, Cyrille

AU - Vivien, Denis

AU - Lambertsen, Kate L.

AU - Clarkson, Andrew N.

AU - Wellendorph, Petrine

N1 - Publisher Copyright: © The Author(s) 2023.

PY - 2023

Y1 - 2023

N2 - Ca2+/calmodulin-dependent protein kinase II alpha (CaMKIIα) is a major contributor to physiological and pathological glutamate-mediated Ca2+ signals, and its involvement in various critical cellular pathways demands specific pharmacological strategies. We recently presented γ-hydroxybutyrate (GHB) ligands as the first small molecules selectively targeting and stabilizing the CaMKIIα hub domain. Here, we report that the cyclic GHB analogue 3-hydroxycyclopent-1-enecarboxylic acid (HOCPCA), improves sensorimotor function after experimental stroke in mice when administered at a clinically relevant time and in combination with alteplase. Further, we observed improved hippocampal neuronal activity and working memory after stroke. On the biochemical level, we observed that hub modulation by HOCPCA results in differential effects on distinct CaMKII pools, ultimately alleviating aberrant CaMKII signalling after cerebral ischemia. As such, HOCPCA normalised cytosolic Thr286 autophosphorylation after ischemia in mice and downregulated ischemia-specific expression of a constitutively active CaMKII kinase proteolytic fragment. Previous studies suggest holoenzyme stabilisation as a potential mechanism, yet a causal link to in vivo findings requires further studies. Similarly, HOCPCA’s effects on dampening inflammatory changes require further investigation as an underlying protective mechanism. HOCPCA’s selectivity and absence of effects on physiological CaMKII signalling highlight pharmacological modulation of the CaMKIIα hub domain as an attractive neuroprotective strategy.

AB - Ca2+/calmodulin-dependent protein kinase II alpha (CaMKIIα) is a major contributor to physiological and pathological glutamate-mediated Ca2+ signals, and its involvement in various critical cellular pathways demands specific pharmacological strategies. We recently presented γ-hydroxybutyrate (GHB) ligands as the first small molecules selectively targeting and stabilizing the CaMKIIα hub domain. Here, we report that the cyclic GHB analogue 3-hydroxycyclopent-1-enecarboxylic acid (HOCPCA), improves sensorimotor function after experimental stroke in mice when administered at a clinically relevant time and in combination with alteplase. Further, we observed improved hippocampal neuronal activity and working memory after stroke. On the biochemical level, we observed that hub modulation by HOCPCA results in differential effects on distinct CaMKII pools, ultimately alleviating aberrant CaMKII signalling after cerebral ischemia. As such, HOCPCA normalised cytosolic Thr286 autophosphorylation after ischemia in mice and downregulated ischemia-specific expression of a constitutively active CaMKII kinase proteolytic fragment. Previous studies suggest holoenzyme stabilisation as a potential mechanism, yet a causal link to in vivo findings requires further studies. Similarly, HOCPCA’s effects on dampening inflammatory changes require further investigation as an underlying protective mechanism. HOCPCA’s selectivity and absence of effects on physiological CaMKII signalling highlight pharmacological modulation of the CaMKIIα hub domain as an attractive neuroprotective strategy.

KW - CaMKII

KW - excitotoxicity

KW - functional recovery

KW - HOCPCA

KW - MCAO

U2 - 10.1177/0271678X231167920

DO - 10.1177/0271678X231167920

M3 - Journal article

C2 - 37026450

AN - SCOPUS:85152299314

VL - 43

SP - 1419

EP - 1434

JO - Journal of Cerebral Blood Flow and Metabolism

JF - Journal of Cerebral Blood Flow and Metabolism

SN - 0271-678X

IS - 8

ER -

ID: 344435251