Biology subjects

Faas, G. C.

Publications and source records attributed to Faas, G. C..

4 recordsLinked to original sources

bioRxiv2026

PN6047 Demonstrates Broad Preclinical Efficacy in Headache Models as a Novel Delta-Opioid Receptor Agonist

BackgroundThe Delta-opioid receptor (DOR) has gained attention as a promising target for the treatment of migraine and headache disorders. This is largely attributed to its unique pharmacological profile, which suggests that DOR-targeting treatment offers effective therapeutic benefit with a lower risk of medication overuse headache (MOH), reduced abuse liability, and minimal potential for physical dependence. These advantages have driven the development of a novel DOR agonist PN6047 (3-[[4-(dimethylcarbamoyl) phenyl]-[1-(thiazol-5-ylmethyl)-4-piperidylidene] methyl]benzamide), which has completed Phase I clinical trial and showed a favorable safety and tolerability profile. Although PN6047 has shown promising effects in neuropathic pain models, its efficacy in preclinical models of headache-associated pain remains to be evaluated. Here, we investigated the effects of PN6047 in models of migraine-associated pain and aura as well as post-traumatic headache (PTH) and MOH. MethodsC57BL6/J mice were used to examine the effects of PN6047 in the following migraine models: chronic intermittent nitroglycerin (NTG)-induced migraine-associated pain, PTH, KCl-induced cortical spreading depression (CSD), and optogenetic evoked CSD in a freely behaving transgenic mice expressing ChR2-eYFP. In addition, we tested whether chronic PN6047 induced MOH and whether it could prevent the development of MOH induced by sumatriptan. ResultsA single injection of PN6047 blocked chronic cephalic allodynia established by chronic intermittent NTG and PTH. Moreover, chronic PN6047 treatment prevented the development of MOH induced by sumatriptan, without causing MOH itself. In addition, PN6047 significantly reduced the number of CSD events in the KCl-induced CSD model, and delayed CSD onset triggered in freely behaving mice along with subsequent CSD-evoked allodynia. ConclusionPN6047, a novel DOR agonist, strikingly blocks headache-associated mechanism and symptoms in preclinical models of chronic migraine, migraine aura, PTH, and MOH. Importantly, prolonged PN6047 treatment did not induce MOH or analgesic tolerance. Together, these data demonstrate that despite the distinct mechanisms underlying migraine and headache disorder, PN6047 exhibits robust efficacy without inducing MOH, and displays a favorable safety and tolerability profile.

neuroscience↗

bioRxiv2024

Fitting and comparison of calcium-calmodulin kinetic schemes to a common data set using non-linear mixed effects modelling

Calmodulin is a calcium binding protein that is essential in calcium signalling in the brain. There are many computational models of calcium-calmodulin binding that capture various calmodulin features. However, existing models have generally been fit to different data sets, with some publications not reporting their training and validation performance. Moreover, there is no model comparison using a common benchmark data set as is common practice in other modeling domains. Finally, some calmodulin models have been fit as a part of a larger kinetic scheme, which may have resulted in parameters being underdetermined. We address these three limitations of previous models by fitting the published calcium-calmodulin schemes to a common calcium-calmodulin data set comprising of equlibrium data from Shifman et al. and dynamical data from Faas et al. Due to technical limitations, the amount of uncaged calcium in Faas et al. data could not be predicted with certainty. To find good parameter fits, despite this uncertainty, we used non-linear mixed effects modelling as implemented in the Pumas.jl package. The Akaike information criterion values for our reaction rates were significantly lower than for the published parameters, indicating that the published parameters are suboptimal. Moreover, there were significant differences in calmodulin activation, both between the schemes and between our reaction rate and those previously published. A kinetic scheme with independent lobes and unique, rather than identical, binding sites fit the data best. Our results support two hypotheses: (1) partially bound calmodulin is important in cellular signalling; (2) calcium binding sites within a calmodulin lobe are kinetically distinct rather than identical. We conclude that more attention should be given to validation and comparison of models of individual molecules. Author summaryLearning and memory depend on changes in synapses, the connections between nerve cells. To understand how learning and memory work, it is important to understand how the proteins involved in these changes are regulated. Computational modelling of biochemical reactions has been used to understand the regulation processes involved in learning and memory. However, computational models often rely on simplifications of biochemical reaction schemes, and it can be difficult to tell which simplifications are "the best", i.e. capture important aspects of a proteins behaviour. It is also difficult to estimate the best model parameters, such as binding reaction rates or binding strengths. Modellers often base their estimates on known experimental results, but often not in a structured way. We examine and compare a variety of computational models of calmodulin, a protein necessary for changes in synaptic strength. We apply a new approach to infer the model parameters that best fit two published datasets, and compare our parameters to previously published ones. We find that some simplified reaction schemes are more successful than others in capturing the activation pattern of calmodulin. We also find that the parameter sets found through our approach outperform previously published parameter sets in fitting the experimental data.

systems biology↗

bioRxiv2021

TUSX: an accessible toolbox for transcranial ultrasound simulation

AO_SCPLOWBSTRACTC_SCPLOWNormally, the complicated nature of acoustic simulation makes it infeasible for most research groups doing individual transcranial ultrasound studies, hindering interpretation of results and complicating the determination of safety limits. We present here an open-source MATLAB toolbox to perform acoustic simulations using subject-specific medical images for transcranial ultrasound experiments. This toolbox, Transcranial Ultrasound Simulation Toolbox (TUSX), consists of an integrated processing pipeline that takes in structural MR or CT images, processes them for accurate simulation, and runs the simulations using k-Wave, an existing open-source acoustics package. We describe here the processing TUSX performs, along with its reasoning. We also validate its output using real-world pressure measurements in a water tank.

neuroscience↗

bioRxiv2021

Ultrasound stimulation of the motor cortex during tonic muscle contraction

AO_SCPLOWBSTRACTC_SCPLOWTranscranial ultrasound stimulation (tUS) shows potential as a noninvasive brain stimulation (NIBS) technique, offering increased spatial precision compared to other NIBS techniques. However, its reported effects on primary motor cortex (M1) are limited. We aimed to better understand tUS effects in human M1 by performing tUS of the hand area of M1 (M1hand) during tonic muscle contraction of the index finger. Stimulation during muscle contraction was chosen because of the transcranial magnetic stimulation-induced phenomenon known as cortical silent period (cSP), in which transcranial magnetic stimulation (TMS) of M1hand involuntarily suppresses voluntary motor activity. Since cSP is widely considered an inhibitory phenomenon, it presents an ideal parallel for tUS, which has often been proposed to preferentially influence inhibitory interneurons. Recording electromyography (EMG) of the first dorsal interosseous (FDI) muscle, we investigated effects on muscle activity both during and after tUS. We found no change in FDI EMG activity concurrent with tUS stimulation. Using single-pulse TMS, we found no difference in M1 excitability before versus after sparsely repetitive tUS exposure. Using acoustic simulations in models made from structural MRI of the participants that matched the experimental setups, we estimated in-brain pressures and generated an estimate of cumulative tUS exposure experienced by M1hand for each subject. We were unable to find any correlation between cumulative M1hand exposure and M1 excitability change. We also present data that suggest a TMS-induced MEP always preceded a near-threshold cSP.

neuroscience↗