Soluble Guanylate Cyclase Stimulator Vericiguat Enhances Long-Term Memory in Rats without Altering Cerebral Blood Volume

Biomedicines

Joerg Hueser¹  Michael Gerisch¹  Peter Sandner¹  Elentina K. Argyrousi²  Jos Prickaerts²  Nick P. Van Goethem²  Ellis Nelissen²  Catherine D. G. Hines³  Fuqiang Zhao³  Gayathri Swaminath⁴ 

[1] Bayer AG, Pharmaceuticals R&D, Pharma Research Center, 42113 Wuppertal, Germany;Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience (MHeNS), Maastricht University, Universiteitssingel 50, 6229 ER Maastricht, The Netherlands;Merck & Co., Inc., Kenilworth, NJ 07033, USA;Merck & Co., Inc., South San Francisco, CA 94080, USA;

关键词: soluble guanylate cyclase;    cGMP;    AMPA;    acquisition;    memory;   

DOI  :  10.3390/biomedicines9081047

来源: DOAJ

【 摘 要 】

Vascular cognitive impairment (VCI) is characterized by impairments in cerebral blood flow (CBF), endothelial function and blood–brain barrier (BBB) integrity. These processes are all physiologically regulated by the nitric oxide (NO)-soluble guanylate cyclase (sGC)-cGMP signaling pathway. Additionally, cGMP signaling plays an important role in long-term potentiation (LTP) underlying memory formation. Therefore, targeting the NO-sGC-cGMP pathway may be a therapeutic strategy for treating VCI. Hence, in this study we investigated whether sGC stimulator vericiguat has potential as a cognitive enhancer. The effects of vericiguat on long-term memory were measured in rats using an object location task. Due to the low brain-penetrance of vericiguat found in this study, it was investigated whether in the absence of BBB limitations, vericiguat enhanced hippocampal plasticity using an ex vivo memory acquisition-like chemical LTP model. Finally, peripheral effects were measured by means of blood pressure and cerebral blood volume. Vericiguat successfully enhanced long-term memory and increased hippocampal plasticity via enhanced translocation of α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors to the cell membrane, while blood pressure and cerebral blood volume were unaltered. Although the memory enhancing effects in this study are likely due to peripheral effects on the cerebral microvasculature, sGC stimulation may provide a new therapeutic strategy for treating VCI, especially when BBB integrity is reduced.

【 授权许可】

Unknown