PMID- 35985509 OWN - NLM STAT- MEDLINE DCOM- 20220915 LR - 20220915 IS - 1872-7972 (Electronic) IS - 0304-3940 (Linking) VI - 788 DP - 2022 Sep 25 TI - Soluble guanylate cyclase stimulator riociguat improves spatial memory in mice via peripheral mechanisms. PG - 136840 LID - S0304-3940(22)00401-3 [pii] LID - 10.1016/j.neulet.2022.136840 [doi] AB - Soluble guanylate cyclase (sGC) - cyclic guanosine monophosphate (cGMP) signalling is important for healthy memory function and a healthy vascular system. Targeting sGC-cGMP signalling can therefore be a potential strategy to enhance memory processes. sGC can be targeted by using agonists, such as sGC stimulator riociguat. Therefore, this study aimed to target sGC using riociguat to investigate its acute effects on memory function and neuronal plasticity in mice. The effects of riociguat on long-term memory and a biperiden-induced memory deficit model for assessing short-term memory were tested in the object location task, and working memory was tested in the Y-maze continuous alternation task. Pharmacokinetic measurements were performed within brain tissue of mice, and hippocampal plasticity measures were assessed using western blotting. Acute oral administration with a low dose of 0.03 mg/kg riociguat was able to enhance working-, short-, and long-term spatial memory. Under cerebral vasoconstriction higher doses of riociguat were still effective on memory. Pharmacokinetic measurements revealed poor brain penetration of riociguat and its metabolite M-1. Increased activation of VASP was found, while no effects were found on other memory-related hippocampal plasticity measures. Memory enhancing effects of riociguat are most likely regulated by vascular peripheral effects on cGMP signalling. Yet, further research is needed to investigate the possible contribution of hemodynamic or metabolic effects of sGC stimulators on memory performance. CI - Copyright (c) 2022 The Author(s). Published by Elsevier B.V. All rights reserved. FAU - Nelissen, Ellis AU - Nelissen E AD - Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience (MHeNS), Maastricht University, Universiteitssingel 50, 6229 ER Maastricht, the Netherlands. FAU - van Hagen, Britt T J AU - van Hagen BTJ AD - Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience (MHeNS), Maastricht University, Universiteitssingel 50, 6229 ER Maastricht, the Netherlands. FAU - Argyrousi, Elentina K AU - Argyrousi EK AD - Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience (MHeNS), Maastricht University, Universiteitssingel 50, 6229 ER Maastricht, the Netherlands. FAU - van Goethem, Nick P AU - van Goethem NP AD - Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience (MHeNS), Maastricht University, Universiteitssingel 50, 6229 ER Maastricht, the Netherlands. FAU - Heckman, Pim R A AU - Heckman PRA AD - Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience (MHeNS), Maastricht University, Universiteitssingel 50, 6229 ER Maastricht, the Netherlands. FAU - Paes, Dean AU - Paes D AD - Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience (MHeNS), Maastricht University, Universiteitssingel 50, 6229 ER Maastricht, the Netherlands. FAU - Mulder-Jongen, Danielle A J AU - Mulder-Jongen DAJ AD - Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience (MHeNS), Maastricht University, Universiteitssingel 50, 6229 ER Maastricht, the Netherlands. FAU - Ramaekers, Johannes G AU - Ramaekers JG AD - Department of Neuropsychology and Psychopharmacology, Faculty of Psychology and Neuroscience, Universiteitssingel 40, 6229 ER Maastricht University, Maastricht, the Netherlands. FAU - Blokland, Arjan AU - Blokland A AD - Department of Neuropsychology and Psychopharmacology, Faculty of Psychology and Neuroscience, Universiteitssingel 40, 6229 ER Maastricht University, Maastricht, the Netherlands. FAU - Schmidt, Harald H H W AU - Schmidt HHHW AD - Department of Pharmacology, Cardiovascular Research Institute Maastricht (CARIM), Faculty of Medicine, Health & Life Science, Universiteitssingel 50, 6229 ER, Maastricht University, Maastricht, the Netherlands. FAU - Prickaerts, Jos AU - Prickaerts J AD - Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience (MHeNS), Maastricht University, Universiteitssingel 50, 6229 ER Maastricht, the Netherlands. Electronic address: jos.prickaerts@maastrichtuniversity.nl. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20220817 PL - Ireland TA - Neurosci Lett JT - Neuroscience letters JID - 7600130 RN - 0 (Pyrazoles) RN - 0 (Pyrimidines) RN - 0 (Vasodilator Agents) RN - 31C4KY9ESH (Nitric Oxide) RN - EC 4.6.1.2 (Guanylate Cyclase) RN - EC 4.6.1.2 (Soluble Guanylyl Cyclase) RN - H2D2X058MU (Cyclic GMP) RN - RU3FE2Y4XI (riociguat) SB - IM MH - Animals MH - Cyclic GMP/metabolism MH - Guanylate Cyclase/metabolism MH - Mice MH - Nitric Oxide/metabolism MH - *Pyrazoles/pharmacology MH - Pyrimidines/pharmacology MH - Soluble Guanylyl Cyclase/metabolism MH - *Spatial Memory MH - Vasodilator Agents OTO - NOTNLM OT - Cognition OT - Guanosine monophosphate OT - Guanylyl cyclase OT - Pharmacokinetics OT - Spatial memory COIS- Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. EDAT- 2022/08/20 06:00 MHDA- 2022/09/16 06:00 CRDT- 2022/08/19 19:33 PHST- 2022/01/04 00:00 [received] PHST- 2022/07/10 00:00 [revised] PHST- 2022/08/11 00:00 [accepted] PHST- 2022/08/20 06:00 [pubmed] PHST- 2022/09/16 06:00 [medline] PHST- 2022/08/19 19:33 [entrez] AID - S0304-3940(22)00401-3 [pii] AID - 10.1016/j.neulet.2022.136840 [doi] PST - ppublish SO - Neurosci Lett. 2022 Sep 25;788:136840. doi: 10.1016/j.neulet.2022.136840. Epub 2022 Aug 17.