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

Ellis Nelissen,Elentina K Argyrousi,Gayathri Swaminath,Joerg Hueser,Jos Prickaerts,Catherine D G Hines,Peter Sandner,Fuqiang Zhao,Michael Gerisch,Nick P Van Goethem

doi:10.3390/biomedicines9081047

Ellis Nelissen, Elentina K Argyrousi + Show 8 more

Open Access

https://doi.org/10.3390/biomedicines9081047

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Abstract

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.

Highlights

Vascular cognitive impairment (VCI) is a broad term that covers a large group of neurological and neurodegenerative disorders that are all characterized by cognitive alterations caused by a vascular component [1]
A one-way ANOVA revealed no differences between exploration times in T1
Since the PK measurements indicated little to no brain penetration for vericiguat, the effects of vericiguat were measured ex vivo by means of an acquisition-like chemical LTP (cLTP) model to determine the hippocampal plasticity effects in the absence of blood–brain barrier (BBB) limitations

Summary

Introduction

Vascular cognitive impairment (VCI) is a broad term that covers a large group of neurological and neurodegenerative disorders that are all characterized by cognitive alterations caused by a vascular component [1]. Nitric oxide (NO) is one of the key regulators of most of these processes. NO regulates CBF, for example by controlling the tone of vascular smooth muscle cells (VSMCs). In this process, NO produced by endothelial nitric oxide synthase (eNOS) diffuses to VSMCs and can stimulate the enzyme soluble guanylate cyclase (sGC) to produce cGMP. NO produced by endothelial nitric oxide synthase (eNOS) diffuses to VSMCs and can stimulate the enzyme soluble guanylate cyclase (sGC) to produce cGMP This NO-sGC-cGMP cascade can trigger intracellular processes in VSMCs to eventually induce VMSC relaxation

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