Travel Grants

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Application for Travel grants possible

The NVH awards Travel Grants to junior researchers (PhD students and postdocs). The financial resources come from the former NSFW foundation. The resources are limited, so only a limited number of Travel Grants of 500 euros can be given. To be eligible for this, the applicant must:

  • be a member of the NVF
  • have accepted an abstract for the Spring Meeting visit
  • be prepared to also present during the FIGON Dutch Medicines Days.

Applications can be sent by e-mail to contact@nvfarmacologie.nl.

The NVF board decides on the allocation of the Travel Grants.

The travel grant awardees of 2022

  • Alejandro Marmolejo-Garza
  • Mohammed A. Saleh
  • Naďa Majerníková

Alejandro Marmolejo-Garza

(Department of Molecular Pharmacology, Faculty of Science and Engineering, and Department of Biomedical Science of Cells and Systems, University Medical Center, Groningen, The Netherlands)

 

 

 

 

 

 

Meeting attended: European Calcium Society 2022 and Junior Satellite European Calcium Society meeting
2022, Cork, Ireland.

Testimonials: Grant was used to cover part of the travel and hotel expenses. I had the chance to present my work about mitochondrial calcium uptake as a target against ferroptosis in both an oral presentation and a poster. The field of calcium research is rigorous, inspiring and supportive. I had invaluable experiences, discussions and
opportunities to collaborate further.

Title of the research abstract:

Blockade of mitochondrial calcium uptake protects neurons against ferroptosis

Authors and affiliations:
Alejandro Marmolejo-Garza a,b† , Inge E. Krabbendam a† , Shane J. O’Connor a , Martina Schmidt a ,Muniswamy Madesh c , and Amalia M. Dolga a

a Groningen Research Institute of Pharmacy (GRIP), University of Groningen, The Netherlands; b Department of Biomedical Sciences of Cells & Systems, University Medical Center Groningen, The Netherlands; c Department of Medicine/Cardiology, University of Texas Health San Antonio, United States

Abstract
Ferroptosis is an iron- and reactive oxygen species (ROS)-dependent form of regulated cell death, that has been implicated in Alzheimer’s disease. Initiation of ferroptosis via cysteine/glutamate antiporter inhibition leads to mitochondrial fragmentation, mitochondrial calcium (Ca2+) overload, increased mitochondrial ROS production, disruption of the mitochondrial membrane potential (ΔΨm) and cell death. Recent studies showed that
mitochondrial dysfunction is a characteristic of ferroptosis, that makes preservation of mitochondrial function a potential therapeutic target in degenerative diseases. Mitochondrial calcium levels are controlled via the mitochondrial calcium uniporter (MCU), the main entry point of Ca2+ into the mitochondrial matrix. Therefore, we have hypothesized that inhibition of mitochondrial calcium uptake may confer protection against ferroptosis.
Blocking the activity of MCU significantly reverted the calcium uptake, lipid peroxidation, and mitochondrial ROS that was initiated by erastin and RSL3 challenge, measured by flow cytometry. Co-treatment with RR, MX, Ru265 and MCU-i4 prevented erastin-, and RSL3-, and glutamate-induced cell death, as detected by bright-field microscopy, MTT assay and flow cytometry in a concentration-dependent manner. Additionally, ferroptosis impaired mitochondrial function decreasing the oxygen consumption rate. In conclusion, this study provides the foundation for further investigation into the therapeutic potential of MCU inhibition against ferroptosis or MICU1 deficiencies.

Mohammed A. Saleh

(Systems Pharmacology and Pharmacy, Leiden Academic Center for Drug Research, Leiden, The Netherlands)

 

 

 

 

 

 

 

Meeting attended: Translating PKPD – (retro)perspectives 2022, Uppsala, Sweden

Testimonials: The meeting in Sweden was a great chance to listen to the top scientists of the CNS field from academia and industry. I also had the opportunity to discuss my research with a broader audience. My trip to Sweden was generously sponsored by the Dutch Pharmacological Society (NVF travel grant). I would like to thank the Dutch Pharmacological Society for providing the opportunity to young researchers to explore and learn.

Title of the research abstract
Integration of the LeiCNS-PK3.0 PBPK framework and multiscale data to select anti-COVID19 drugs with favorable brain pharmacokinetics

Authors and affiliations
Mohammed A. A. Saleh 1 , Makoto Hirasawa 1 , Ming Sun 1 , Berfin Gülave 1 , Jeroen Elassaiss-Schaap 2 ,
Elizabeth C. M. de Lange 1

1 Systems Pharmacology and Pharmacy, LACDR, Leiden, the Netherlands; 2 PD-value, Utrecht, the Netherlands

Abstract
SARS-CoV-2 virus has been shown to infect the brain cells, with viral RNA detectable for up to 230 days [1] . This highlights the need to treat the brain viral load to avoid a latent viral state and recurrent encephalitis. Remdesivir, Molnupiravir, and Nirmatrelvir have been approved for COVID-19 treatment. The aim of the project is to select the anti-COVID-19 drug(s) with favorable brain pharmacokinetics (PK). Hence, we applied LeiCNS-PK3.0, our physiologically based PK (PBPK) framework [2] to predict the PK profiles in the human brain extracellular (brain ECF ) and intracellular (brain ICF ) fluids of the three drugs. The PK predictions were compared against EC 90 of the delta and omicron variants to identify the extent to which effective concentrations in the brain are reached.
Methods: LeiCNS-PK3.0 simulations: Brain PK predictions were simulated using the LeiCNS-PK3.0 framework, physiological parameters of healthy adult human [2] , and the recommended dosing regimen. Intracellular PK assessment: The prodrugs Molnupiravir and Remdesivir are metabolized intracellularly to the active nucleoside analogues, EIDD-2061 and GS-443902, respectively. In vitro [3] and in vivo [4] intracellular kinetic profiles of the parent drugs and their metabolites were used to predict the intracellular levels in the human brain.
Results: The predicted brain ECF PK profile of Nirmatrelvir was above the EC 90 , with an average efficacy of 87
and 96% against the delta and omicron variants, respectively. On the other hand, the brain ECF PK profile of Remdesivir was below the EC 90 of both variants, expect at T max . Also, the intracellular levels of GS-443902 were below the respective EC 90 . Similarly, the predicted brain ECF PK profile of EIDDD-1931, the stable plasma metabolite of Molnupiravir, and EIDD-2061 were below the EC 90 of both variants.
Conclusions: We identified Nirmatrelvir as a promising candidate for future studies investigating the CNS efficacy
of anti-COVID-19 drugs against the delta and the omicron variants.

Naďa Majerníková
(Department of Molecular Pharmacology, University of Groningen, and Department of Pathology and Medical Biology, University Medical Center, Groningen)

 

 

 

 

 

 

 

Meeting attended Iron, reactive oxygen species & ferroptosis in life, death & disease 2022, AWAJI, JAPAN (Cold Spring Harbor Asia) 2022

Testimonials: Grant was used to cover part of the travel and hotel expenses. The field of ferroptosis is very young, supportive and stimulating field. I had the chance to meet the experts of the ferroptosis field face-to-face and further extend my scientific connections and learn about new advances in the field of iron and oxidative stress-related cell death. The current state of the field was discussed in the context of heath (normal non-disease situation) and disease situation. Many different disease models were discussed among which were kidney disease, liver disease, neurodegenerative disease and cancer. The 3h poster session during which I explained my project on ferroptosis in neurodegenerative disease was very fruitful as I received many good questions and constructive feedback. This also provided me with new ideas on how to further improve my research. This meeting allowed me to learn  an incredible amount of new things and meet new people that have impressed me with their scientific skills and their motivation to work together to conquer the big unknown-ferroptosis.  I am very grateful to the NVF for providing me this grant and therefore making my attendance on this very valuable meeting possible.

Title of the research abstract:

The link between ferroptosis-related markers and amyloid β and tau pathology in AD post mortem brain

Authors and affiliations:
Naďa Majerníková 1, 2, 4 , Wilfred F.A. den Dunnen 2, 3 , Amalia M. Dolga 1, 4 *

1 Research School of Behavioural and Cognitive Neuroscience, University of Groningen, Groningen, the Netherlands, 2 Department of Pathology and Medical Biology, University Medical Centre Groningen, University of Groningen, Groningen the Netherlands, 3 Research Institute Brain and Cognition, Molecular Neuroscience and Aging Research (MOLAR), University Medical Centre Groningen, Groningen, the Netherlands, 4 Department of Molecular Pharmacology, Groningen Research Institute of Pharmacy, University of Groningen, the Netherlands

Abstract
Alzheimer’s disease (AD), currently affecting 40-50 million people worldwide, is the most prevalent form of dementia. Treatment strategies aiming to interfere with the formation of amyloid β (Aβ) plaques and neurofibrillary tangles (NFTs), the two major AD hallmarks, have yet to be proven effective. Recent evidence suggests that ferroptosis, a type of programmed cell death caused by iron accumulation and lipid peroxidation, contributes to AD pathology. The existing link between ferroptosis and AD has been largely based on cell
culture and animal studies, while evidence from human studies is limited. In this study we analyse the expression of six ferroptosis-related markers in the occipital cortex of human post-mortem brains of AD patients who died at different stages of the pathology and aged-matched controls. We analysed the difference between groups in grey (GM) and white matter (WM), and studied the relationship between ferroptosis-related markers and both Aβ and tau pathology. Immunohistochemical staining of formaldehyde fixed and paraffin embedded (FFPE) brain tissues combined with positive pixel density scoring revealed that increasing progression of AD was accompanied by decreasing NCOA4 and GPX4 in the grey matter. The expression of ferroportin, NCOA4, GPX4, 4HNE and cytochrome C was significantly lower within the Aβ plaque compared to the area around it while the expression of ferritin was higher in the Aβ plaque compared to the area surrounding the plaque. When looking at the relation between ferroptosis-related markers and tau pathology alone, most of the analysed markers did not show any correlation with tau pathology density. However, a significant positive correlation was observed between tau pathology density and ferroportin protein expression. Our results support the implication of ferroptosis in neurodegeneration and underline the potential of anti-ferroptotic drugs to slow down progression of AD pathology.

 

The travel grant awardees of 2019

  • Katja Jansen
  • Bianca van Groen
  • Laurens Verscheijden

Katja Jansen

(Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht, The Netherlands)

Meeting attended: 12th International ISSX Meeting in Portland, US

Testimonials: The opportunity to share research findings on an international/overseas conference is definitely one of the highlights of a PhD. The NFV travel grant took away some financial burden; at the same time, it gave me the feeling of being supported on my journey as member of the Dutch pharmacological society.

Title of the research abstract

A systematic meta-analysis on interspecies differences in renal clearance

Authors and affiliations

Katja Jansen1, Carla Pou Casellas2,3, Lucianne Groenink1, Kimberley E. Wever4, Rosalinde Masereeuw1

¹Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht, The Netherlands; ²Department of Nephrology and Hypertension, University Medical Center Utrecht, Utrecht, The Netherlands; ³Hubrecht Institute – Royal Netherlands Academy of Arts and Sciences, Utrecht, the Netherlands; ⁴Systematic Review Centre for Laboratory animal Experimentation (SYRCLE), Department for Health Evidence, Radboud Institute for Health Sciences, Radboud University Medical Center, Nijmegen, The Netherlands

Abstract

Before new drugs are approved for human use, various animal models are applied to study drug efficacy and safety. Renal clearance (CLr) is a standard safety measure since a significant part of drugs is cleared by the kidneys. It is assumed that glomerular filtration rate and metabolic waste removal are determined by metabolic rate, which in turn scales linearly to body weight. Thus, human CLr should be predictable based on body weight. However, they are biological differences between species which could be reflected in pharmacokinetics. Our aim was to identify species-specific limitations in human CLr extrapolation. Using PubMed and EMBASE, we systematically reviewed human and animal studies that have reported CLr or related outcome measures for 20 renally excreted drugs with different physicochemical properties. Based on the human data and simple allometry, we assessed how much animal models deviate from the expected value, and correlated these differences to the properties of the drugs. In total, we included 264 studies with human or animal CLr data for the selected drugs. For each animal species, we calculated average fold errors per drug, as well as the mean differences with 95% confidence intervals compared to humans. These mean differences varied between -0.56 and 1.74 for mice, -0.24 and 2.86 for rats, -0.77 and 0.57 for rabbits, -0.78 and 2.33 for dogs, and -0.55 and 0.47 for monkeys. Subgroup analyses based on physicochemical drug properties revealed significant alterations between average mean differences, hinting towards critical physiological interspecies differences at play. This systematic meta-analysis presents a novel approach to quantify interspecies differences. We showed that rats tend to overestimate human CLr. In general, however, animals are good predictive models for renal drug excretion.

Laurens Verscheijden

(Department of Pharmacology and Toxicology, Radboud Institute for Molecular Life Sciences, Nijmegen, The Netherlands)

Meeting attended

ASCPT annual meeting 2019, Washington, US

Testimonials: Grant was used to cover part of the travel and hotel expenses

Title of the research abstract

Development of a Paediatric Brain PBPK Model in Children with and Without Meningitis.

Authors and affiliations

Laurens F.M. Verscheijden1, Jan B. Koenderink1, Karel Allegaert2, 3, Saskia N. de Wildt1,2, Frans G.M. Russel1

1Department of Pharmacology and Toxicology, Radboud Institute for Molecular Life Sciences, Nijmegen, The Netherlands, 2Intensive Care and Department of Paediatric Surgery, Erasmus MC-Sophia Children’s Hospital, Rotterdam, The Netherlands, 3Department of Development and Regeneration, KU Leuven, Leuven, Belgium

Abstract

Background
Several paediatric physiologically-based pharmacokinetic (PBPK) models have been developed that incorporate developmental changes affecting plasma drug concentrations. Disposition into cerebrospinal fluid (CSF) is also age-related and influenced by physiological factors, including CSF production rate, but also by brain diseases, such as meningitis, which are associated with impaired blood-brain barrier integrity. Our aim was to develop a paediatric brain PBPK model to predict CSF drug concentrations in children with and without meningitis.

Methods
A paediatric PBPK model was developed incorporating age-appropriate parameters and associated inter-individual variability. The model was validated for paracetamol, ibuprofen, flurbiprofen and naproxen, and for a paediatric meningitis population by estimating meropenem blood-brain barrier penetration using sensitivity analysis. Plasma and CSF drug concentrations derived from literature were used to perform visual predictive checks and to calculate ratios between simulated and observed AUCs in order to evaluate model performance.

Results
Simulated data were comparable to observed over a broad age range (1 day – 15 y postnatal age), for all drugs investigated. The ratios between observed and simulated AUCs were within 2-fold difference both in plasma and in CSF, indicating acceptable model performance. Disposition of meropenem into the brain was slow and CSF concentrations were lower compared to plasma concentrations. In addition, several days were needed to achieve CSF steady-state concentration.

Conclusion
Our paediatric brain PBPK model provides a new tool to predict CSF concentrations in children with and without meningitis and can be used as a template model for other drugs acting in the CNS.