Search

Aim Dysfunction of nitric oxide (NO) – soluble guanylate cyclase (sGC) – cyclic guanosine monophosphate (cGMP) signalling is implicated in the pathophysiology of cognitive impairment and dementia. Zagociguat is a central nervous system-(CNS-) penetrant sGC stimulator designed to amplify NO-cGMP signalling in the CNS. This article reports on a phase 1b study evaluating the safety and pharmacodynamic effects of zagociguat. Methods In this randomized crossover study, 24 healthy participants ≥65 years of age were planned to receive 15 mg zagociguat or placebo once daily for two 15-day periods separated by a 27-day washout. Adverse events, vital signs, electrocardiograms, and laboratory tests to assess safety. Pharmacokinetics of zagociguat were evaluated in blood and CSF. Pharmacodynamic assessments included evaluation of cerebral blood flow, CNS tests, pharmaco-electroencephalography, passive leg movement, and biomarkers in blood, cerebrospinal fluid, and brain. Results Twenty-four participants were enrolled and 12 participants completed both treatment periods, while 12 participants completed only one treatment period. Zagociguat was well tolerated and penetrated the blood-brain barrier. Zagociguat induced modest decreases in blood pressure. No consistent effects of zagociguat on other pharmacodynamic parameters were detected. Conclusion Zagociguat was well tolerated and induced modest systemic blood pressure reductions consistent with other sGC stimulators. No clear pharmacodynamic effects of zagociguat were detected, perhaps due to optimal CNS function in healthy participants. Studies in participants with proven reduced cerebral blood flow or CNS function may be an avenue for further evaluation of the compound.

Purpose/Background: Biperiden is a muscarinic antagonist that produces memory impairments without impairing attention or motor functions in healthy subjects. It has been suggested that a biperiden-induced memory deficit could model age- and dementia-related memory impairments. The goal of the current study was to determine the dose- and time-dependent effects of biperiden on cognition in healthy volunteers.Methods/Procedures: Twenty-one healthy volunteers participated in a placebo-controlled, 3-way, crossover study. After a baseline test, cognitive performance was tested at 3 time points after a single dose of biperiden 2 or 4 mg, or placebo. Episodic memory was measured using a 15-word verbal learning task (VLT). Furthermore, n-back tasks, a sustained attention to response task and a reaction time task were used, as well as subjective alertness and a side effects questionnaire. In addition, blood serum values and physiological measures were taken.Findings/Results: Biperiden decreased the number of words recalled in immediate and delayed recall of the VLT 90 minutes after drug intake. A dose-dependent impairment was found for the delayed recall, whereas the immediate recall was equally impaired by the 2 doses. Biperiden did not affect the performance on the VLT 4 hours after administration. Performance in the n-back task and the sustained attention to response task were not affected by biperiden at any time point. Both doses were well tolerated as reported side effects were mild at Tmax and were minimal at the other time points.Implications/Conclusions: Biperiden exerts effects on episodic memory without negatively affecting other cognitive performance and behavioral measures that were assessed in this study. The data provide further evidence that biperiden has selective effects on cognition, even after a high dose.

RATIONALE: After stimulation with nitric oxide, soluble guanylate cyclase (sGC) produces cyclic guanosine monophosphate (cGMP), which stimulates an important signalling pathway for long-term potentiation (LTP). By upregulating cGMP, LTP could be stimulated and thereby enhancing memory processes. The present study investigated the effects of the sGC stimulator riociguat on cognition in healthy volunteers. Participants were pre-treated with and without biperiden, which impairs memory performance, to investigate the memory-enhancing effects of riociguat.METHODS: Twenty volunteers participated in a double-blind placebo-controlled six-way crossover design with a cognitive test battery including the verbal learning task (VLT), n-back task, spatial memory test, the attention network test, and a reaction time task. Treatments were placebo and riociguat 0.5 mg, placebo and riociguat 1.0 mg, biperiden 2.0 mg and placebo, biperiden 2.0 mg and riociguat 0.5 mg and biperiden 2.0 mg and riociguat 1.0 mg.RESULTS: Blood pressure was found to be decreased and heart rate to be increased after administration of riociguat. Cognitive performance was not enhanced after administration of riociguat. Biperiden decreased episodic memory on the VLT, yet this deficit was not reversed by riociguat.CONCLUSION: This supports the notion that biperiden might be a valuable pharmacological model to induce episodic memory impairments as observed in AD/MCI.

The processing of novel stimuli is known to take place in the hippocampus and frontal cortex, and is influenced by the cholinergic system. This ability is crucial to help detect changes in the environment and adapt behaviour accordingly. Previous research has shown that acetylcholine (ACh) can interact with serotonin (5-HT) at the hippocampal level, which may have consequences for cognitive functioning. However, little is known about the exact nature of this ACh and 5-HT interaction as well their possible interactive effects on novelty processing. We investigated the interactive role of ACh and 5-HT in novelty processing in healthy young participants. Levels of these neurotransmitters were manipulated with the muscarinic M1 antagonist biperiden, and with acute tryptophan depletion (ATD). Participants received either placebo, biperiden, ATD, or a combination of both in a double-blind cross-over design. Auditory event-related potentials (ERPs) were recorded while a novelty oddball task was presented. Our results showed that biperiden affected ERP components considered to reflect attentional mechanisms; it increased the P50 amplitude and decreased that of the P200. Furthermore, a decrease of N100 amplitude by ATD was reversed by biperiden. The treatments did not affect the mismatch negativity (MMN) component, which is elicited when a deviant stimulus is presented in a sequence of repetitive stimuli. Importantly, biperiden decreased the amplitude of the ERP component related to novelty processing (P3a). The current study's results did not reveal an interactive effect of ACh and 5-HT on novelty processing. However, the data do suggest that ACh is involved in novelty processing and that it influences basic stimulus processing, without affecting sound-discrimination accuracy.

Background Research on the neurobiological foundations of memory has shown that multiple neurotransmitters play an important role in memory processing. To study the interaction between neurotransmitters such as acetylcholine and serotonin, pharmacological models can be used. In this study, we tested the effects of the muscarinic M1 antagonist biperiden, acute tryptophan depletion (ATD), and the interaction between the two on episodic memory using the verbal learning task. Methods The study was conducted according to a double-blind, placebo-controlled, four-way crossover design. Seventeen participants received biperiden (2.0 mg), ATD (SolugelP), a combination of both, or a placebo in counterbalanced order with a wash out of at least 7 days. A verbal learning task was performed while recording electroencephalography. The task consisted of an immediate and delayed recall as well as a recognition part. Results Results revealed decreased scores on the delayed recall after biperiden and ATD separately but no significant interaction between the two. However, the event-related potential components P3b, N400, and P600 did show an interaction during encoding. Conclusion These results indicate that both BIP and ATD impair episodic memory. However, an interaction between the serotonergic and cholinergic system on memory performance is not supported.