The sGC stimulator BAY-747 and activator runcaciguat can enhance memory in vivo via differential hippocampal plasticity mechanisms.
Journal
Scientific reports
ISSN: 2045-2322
Titre abrégé: Sci Rep
Pays: England
ID NLM: 101563288
Informations de publication
Date de publication:
04 03 2022
04 03 2022
Historique:
received:
04
10
2021
accepted:
10
02
2022
entrez:
5
3
2022
pubmed:
6
3
2022
medline:
15
4
2022
Statut:
epublish
Résumé
Soluble guanylate cyclase (sGC) requires a heme-group bound in order to produce cGMP, a second messenger involved in memory formation, while heme-free sGC is inactive. Two compound classes can increase sGC activity: sGC stimulators acting on heme-bound sGC, and sGC activators acting on heme-free sGC. In this rodent study, we investigated the potential of the novel brain-penetrant sGC stimulator BAY-747 and sGC activator runcaciguat to enhance long-term memory and attenuate short-term memory deficits induced by the NOS-inhibitor L-NAME. Furthermore, hippocampal plasticity mechanisms were investigated. In vivo, oral administration of BAY-747 and runcaciguat to male Wistar rats enhanced memory acquisition in the object location task (OLT), while only BAY-747 reversed L-NAME induced memory impairments in the OLT. Ex vivo, both BAY-747 and runcaciguat enhanced hippocampal GluA1-containing AMPA receptor (AMPAR) trafficking in a chemical LTP model for memory acquisition using acute mouse hippocampal slices. In vivo only runcaciguat acted on the glutamatergic AMPAR system in hippocampal memory acquisition processes, while for BAY-747 the effects on the neurotrophic system were more pronounced as measured in male mice using western blot. Altogether this study shows that sGC stimulators and activators have potential as cognition enhancers, while the underlying plasticity mechanisms may determine disease-specific effectiveness.
Identifiants
pubmed: 35246566
doi: 10.1038/s41598-022-07391-1
pii: 10.1038/s41598-022-07391-1
pmc: PMC8897390
doi:
Substances chimiques
Cyclic GMP
H2D2X058MU
Guanylate Cyclase
EC 4.6.1.2
Heme
42VZT0U6YR
NG-Nitroarginine Methyl Ester
V55S2QJN2X
Nitric Oxide
31C4KY9ESH
Soluble Guanylyl Cyclase
EC 4.6.1.2
Vasodilator Agents
0
2-(2-Chloro-4-(methylsulfonyl)-3-((2,2,2-trifluoroethoxy)methyl)benzoyl)-1,3-cyclohexanedione (BAY 747)
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
3589Informations de copyright
© 2022. The Author(s).
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