The GHB analogue HOCPCA improves deficits in cognition and sensorimotor function after MCAO via CaMKIIα.
J Cereb Blood Flow Metab
; 43(8): 1419-1434, 2023 08.
Article
en En
| MEDLINE
| ID: mdl-37026450
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.
Palabras clave
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Oxibato de Sodio
/
Accidente Cerebrovascular
Límite:
Animals
Idioma:
En
Revista:
J Cereb Blood Flow Metab
Año:
2023
Tipo del documento:
Article
País de afiliación:
Dinamarca