2. Academic Validation
  3. The GHB analogue HOCPCA improves deficits in cognition and sensorimotor function after MCAO via CaMKIIα

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

  • J Cereb Blood Flow Metab. 2023 Aug;43(8):1419-1434. doi: 10.1177/0271678X231167920.
Nane Griem-Krey 1,  Anders B Klein 1 2,  Bettina H Clausen 3 4,  Mathias Rj Namini 1,  Pernille V Nielsen 3,  Mozammel Bhuiyan 5,  Raghavendra Y Nagaraja 5,  T Michael De Silva 6,  Christopher G Sobey 6,  Heung-Chin Cheng 7 8,  Cyrille Orset 9,  Denis Vivien 9,  Kate L Lambertsen 3 4,  Andrew N Clarkson 5 6,  Petrine Wellendorph 1
Affiliations

Affiliations

  • 1 Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, Denmark.
  • 2 Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
  • 3 Department of Neurobiology Research, Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark.
  • 4 Brain Research Inter-Disciplinary Guided Excellence (BRIDGE), Department of Clinical Research, University of Southern Denmark, Odense, Denmark.
  • 5 Department of Anatomy, Brain Health Research Centre and Brain Research New Zealand, University of Otago, Dunedin, New Zealand.
  • 6 Department of Microbiology, Anatomy, Physiology & Pharmacology and Centre for Cardiovascular Biology and Disease Research, School of Agriculture, Biomedicine & Environment, La Trobe University, Bundoora, Australia.
  • 7 Department of Biochemistry and Pharmacology, University of Melbourne, Parkville, Australia.
  • 8 Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, Australia.
  • 9 Physiopathology and Imaging of Neurological Disorders, University of Caen Normandy, Caen, France.
PMID: 37026450 DOI: 10.1177/0271678X231167920
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'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.

Keywords

CaMKII; HOCPCA; MCAO; excitotoxicity; functional recovery.

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