The effects of the soluble guanylate cyclase stimulator riociguat on memory performance in healthy volunteers with a biperiden-induced memory impairment

Borghans, Laura; Sambeth, Anke; Prickaerts, Jos; Ramaekers, Johannes G.; Blokland, Arjan

doi:10.1007/s00213-018-4938-0

Cited by 12 publications

(7 citation statements)

References 33 publications

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“…Most of the significant effects were observed after 4 mg biperiden. The PD effects were consistent with literature, especially the effects on the adaptive tracking test, 11 verbal memory, 11 , 12 , 14 , 15 , 40 n‐back test reaction time, 11 , 40 , 41 and the pupil/iris ratio. 40 , 42 The consistency with literature demonstrating the repeatability of the PD effects and the low variability of the PD effects is required for a reliable challenge model.…”

Section: Discussionsupporting

confidence: 89%

Biperiden Challenge Model in Healthy Elderly as Proof‐of‐Pharmacology Tool: A Randomized, Placebo‐Controlled Trial

Bakker

Esdonk

Stuurman

et al. 2021

The Journal of Clinical Pharma

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Selective M 1 muscarinic acetylcholine receptor (mAChR) agonists are being developed as symptomatic treatment for neurodegenerative and neuropsychiatric disorders that lead to cognitive dysfunction. Demonstrating cognition enhancing effects in early phase clinical development in healthy subjects is difficult. A challenge with the M 1 mAChR antagonist biperiden could be used to demonstrate procognitive and pharmacological effects of selective M 1 mAChR agonists. The aim of this study was to develop such a model. To this end, twelve healthy elderly subjects participated in a randomized, placebo controlled, three-way crossover study investigating tolerability, pharmacokinetic (PK) and pharmacodynamic (PD) effects of 2 and 4 mg biperiden. Repeated PD assessments were performed using neurocognitive tasks and electrophysiological measurements. A population PK-PD model was developed. Four mg biperiden showed significant impairment of sustained attention (-2.1% point in adaptive tracking (95% CI [-3.043; -1.148])), verbal memory (2-3 words fewer recalled (95% CI [-5.9; -0.2])), and working memory (up to 50 ms increase in the n-back task reaction time (95% CI [21.854; 77.882])) compared with placebo. The PK data was best fitted by a 2-compartment model and showed a high inter-occasion and inter-subject variability. Population PK-PD analysis quantified significant concentration-effect relationships for the n-back reaction times, n-back accuracies and adaptive tracking. In conclusion, biperiden caused M 1 mAChR related doseand concentration-dependent temporary declines in cognitive functioning. Therefore a biperiden pharmacological challenge model can be used for proof-of-pharmacology studies and to demonstrate cognition enhancing effects of new cholinergic compounds that are being developed.

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Section: Discussionsupporting

confidence: 89%

Biperiden Challenge Model in Healthy Elderly as Proof‐of‐Pharmacology Tool: A Randomized, Placebo‐Controlled Trial

Bakker

Esdonk

Stuurman

et al. 2021

The Journal of Clinical Pharma

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“…Yet the memory enhancing effects could most likely be attributed to effects on the cerebromicrovasculature, since both riociguat and vericiguat show very limited to no brain penetration and riociguat particularly attenuated the memory impairment effects of the cerebral vasoconstrictor sumatriptan 12 . Riociguat did not enhance memory in a clinical study 14 , yet the effective dose could have been missed in this study due to the narrow therapeutic window of riociguat. Recently, a study in mice was performed with CY6463, a novel sGC stimulator capable of crossing the blood–brain barrier, and the results indicated central effects of CY6463 (e.g.…”

Section: Introductionmentioning

confidence: 67%

The sGC stimulator BAY-747 and activator runcaciguat can enhance memory in vivo via differential hippocampal plasticity mechanisms

Nelissen

Possemis

Goethem

et al. 2022

Sci Rep

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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.

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“…Riociguat, a direct activator of sGC approved for the treatment of pulmonary hypertension, has been trialed on cognition in 20 healthy volunteers in a double-blind, placebo-controlled study using the cholinergic muscarinic antagonist biperiden (0.5 and 1 mg) to induce memory deficits [ 55 ]. Riociguat was not effective in any of the tests used to assess different types of memory (episodic, working, spatial), as well as in tasks evaluating attention and psychomotor activity.…”

Section: Clinical Studies On Cgmp-enhancersmentioning

confidence: 99%

Memory Enhancers for Alzheimer’s Dementia: Focus on cGMP

Fedele

Ricciarelli

2021

Pharmaceuticals

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Cyclic guanosine-3′,5′-monophosphate, better known as cyclic-GMP or cGMP, is a classical second messenger involved in a variety of intracellular pathways ultimately controlling different physiological functions. The family of guanylyl cyclases that includes soluble and particulate enzymes, each of which comprises several isoforms with different mechanisms of activation, synthesizes cGMP. cGMP signaling is mainly executed by the activation of protein kinase G and cyclic nucleotide gated channels, whereas it is terminated by its hydrolysis to GMP operated by both specific and dual-substrate phosphodiesterases. In the central nervous system, cGMP has attracted the attention of neuroscientists especially for its key role in the synaptic plasticity phenomenon of long-term potentiation that is instrumental to memory formation and consolidation, thus setting off a “gold rush” for new drugs that could be effective for the treatment of cognitive deficits. In this article, we summarize the state of the art on the neurochemistry of the cGMP system and then review the pre-clinical and clinical evidence on the use of cGMP enhancers in Alzheimer’s disease (AD) therapy. Although preclinical data demonstrates the beneficial effects of cGMP on cognitive deficits in AD animal models, the results of the clinical studies carried out to date are not conclusive. More trials with a dose-finding design on selected AD patient’s cohorts, possibly investigating also combination therapies, are still needed to evaluate the clinical potential of cGMP enhancers.

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The effects of the soluble guanylate cyclase stimulator riociguat on memory performance in healthy volunteers with a biperiden-induced memory impairment

Cited by 12 publications

References 33 publications

Biperiden Challenge Model in Healthy Elderly as Proof‐of‐Pharmacology Tool: A Randomized, Placebo‐Controlled Trial

Biperiden Challenge Model in Healthy Elderly as Proof‐of‐Pharmacology Tool: A Randomized, Placebo‐Controlled Trial

The sGC stimulator BAY-747 and activator runcaciguat can enhance memory in vivo via differential hippocampal plasticity mechanisms

Memory Enhancers for Alzheimer’s Dementia: Focus on cGMP

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