scholarly journals A zebrafish-centric approach to antiepileptic drug development

2021 ◽  
Vol 14 (7) ◽  
Author(s):  
Scott C. Baraban
Keyword(s):  
Drug Development ◽  
High Throughput ◽  
Drug Screening ◽  
Danio Rerio ◽  
Genetic Manipulation ◽  
Dravet Syndrome ◽  
Developmental Studies ◽  
Compassionate Use ◽  
Larval Zebrafish ◽  
The Common

ABSTRACT Danio rerio (zebrafish) are a powerful experimental model for genetic and developmental studies. Adaptation of zebrafish to study seizures was initially established using the common convulsant agent pentylenetetrazole (PTZ). Larval PTZ-exposed zebrafish exhibit clear behavioral convulsions and abnormal electrographic activity, reminiscent of interictal and ictal epileptiform discharge. By using this model, our laboratory developed simple locomotion-based and electrophysiological assays to monitor and quantify seizures in larval zebrafish. Zebrafish also offer multiple advantages for rapid genetic manipulation and high-throughput phenotype-based drug screening. Combining these seizure assays with genetically modified zebrafish that represent Dravet syndrome, a rare genetic epilepsy, ultimately contributed to a phenotype-based screen of over 3500 drugs. Several drugs identified in these zebrafish screens are currently in clinical or compassionate-use trials. The emergence of this ‘aquarium-to-bedside’ approach suggests that broader efforts to adapt and improve upon this zebrafish-centric strategy can drive a variety of exciting new discoveries.

scholarly journals The swimming plus-maze test: a novel high-throughput model for assessment of anxiety-related behaviour in larval zebrafish. (Danio rerio)

2018 ◽  
Author(s):  
Zoltán K Varga ◽  
Áron Zsigmond ◽  
Diána Pejtsik ◽  
Máté Varga ◽  
Kornél Demeter ◽  
...  
Keyword(s):  
High Throughput ◽  
Danio Rerio ◽  
High Throughput Screening ◽  
Larval Fish ◽  
Imaging Techniques ◽  
Experimental Conditions ◽  
Larval Zebrafish ◽  
Throughput Model ◽  
Plus Maze ◽  
Resolution Imaging

AbstractLarval zebrafish (Danio rerio) has the potential to supplement rodent models due to the availability of resource efficient methods implying high-throughput screening and high-resolution imaging techniques. Although behavioural models are available in larvae, only a few, insensitive approaches can be employed to assess anxiety. Here we present the swimming plus-maze (SPM) test paradigm to assess anxiety-related states in young zebrafish. The “+” shaped apparatus consists of arms of different depth representing differentially aversive context. The paradigm was validated i.) in larval and juvenile zebrafish, ii.) after administration of compounds affecting human anxiety and iii.) in differentially aversive experimental conditions. Furthermore, we compared the SPM with conventional “anxiety tests” of larvae such as the open tank and light/dark tank tests to identify their shared characteristics. We clarified that the preference towards deeper water is conserved trough the ontogenesis and can be abolished by anxiolytic or enhanced by anxiogenic agents, respectively. The behavioural read-out is insensitive to the aversiveness of the platform and unrelated to behaviours assessed by conventional tests utilizing larval fish. Taken together, we developed a sensitive high-throughput test measuring anxiety-related responses of larval zebrafish, which likely reflect bottom-dwelling behaviour of adults, potentially supporting larva-based integrative approaches.

Organ-on-Chip Devices Toward Applications in Drug Development and Screening

2018 ◽  
Vol 12 (4) ◽  
Author(s):  
Christopher Uhl ◽  
Wentao Shi ◽  
Yaling Liu
Keyword(s):  
Drug Development ◽  
High Throughput ◽  
Drug Screening ◽  
Large Scale ◽  
Three Dimensional ◽  
3D Cell Culture ◽  
Throughput Capacity ◽  
Comprehensive Overview ◽  
The Past ◽  
High Throughput Drug Screening

As a necessary pathway to man-made organs, organ-on-chips (OOC), which simulate the activities, mechanics, and physiological responses of real organs, have attracted plenty of attention over the past decade. As the maturity of three-dimensional (3D) cell-culture models and microfluidics advances, the study of OOCs has made significant progress. This review article provides a comprehensive overview and classification of OOC microfluidics. Specifically, the review focuses on OOC systems capable of being used in preclinical drug screening and development. Additionally, the review highlights the strengths and weaknesses of each OOC system toward the goal of improved drug development and screening. The various OOC systems investigated throughout the review include, blood vessel, lung, liver, and tumor systems and the potential benefits, which each provides to the growing challenge of high-throughput drug screening. Published OOC systems have been reviewed over the past decade (2007–2018) with focus given mainly to more recent advances and improvements within each organ system. Each OOC system has been reviewed on how closely and realistically it is able to mimic its physiological counterpart, the degree of information provided by the system toward the ultimate goal of drug development and screening, how easily each system would be able to transition to large scale high-throughput drug screening, and what further improvements to each system would help to improve the functionality, realistic nature of the platform, and throughput capacity. Finally, a summary is provided of where the broad field of OOCs appears to be headed in the near future along with suggestions on where future efforts should be focused for optimized performance of OOC systems in general.

scholarly journals Microengineered cultures containing human hepatic stellate cells and hepatocytes for drug development

2017 ◽  
Vol 9 (8) ◽  
pp. 662-677 ◽  
Author(s):  
Matthew D. Davidson ◽  
David A. Kukla ◽  
Salman R. Khetani
Keyword(s):  
Drug Development ◽  
High Throughput ◽  
Drug Screening ◽  
Hepatic Stellate Cells ◽  
Stellate Cells ◽  
Human Hepatocytes ◽  
Alcoholic Steatohepatitis

Micropatterned tri-cultures (MPTCs) containing human hepatocytes, hepatic stellate cells, and fibroblasts in a high-throughput format are used to mimic aspects of non-alcoholic steatohepatitis (NASH) for drug screening.

High-Throughput Drug Screening of FDA-Approved Cancer Drugs Reveals Novel Therapies for Patients with Chordomas

2019 ◽  
Author(s):  
Philip Tatman ◽  
Anthony Fringuello ◽  
Denise Damek ◽  
Samy Youssef ◽  
Randy Jensn ◽  
...  
Keyword(s):  
High Throughput ◽  
Drug Screening ◽  
Novel Therapies ◽  
Cancer Drugs ◽  
High Throughput Drug Screening

High-Throughput Drug Screening of ECM Deposition Inhibitors for Antifibrotic Drug Discovery

2019 ◽  
Author(s):  
Michael Gerckens ◽  
Hani Alsafadi ◽  
Darcy Wagner ◽  
Katharina Heinzelmann ◽  
Kenji Schorpp ◽  
...  
Keyword(s):  
Drug Discovery ◽  
High Throughput ◽  
Drug Screening ◽  
High Throughput Drug Screening

Therapeutic stratification of acute leukemia using high throughput drug screening

2020 ◽  
Author(s):  
S Bhatia ◽  
H Ahlert ◽  
N Dienstbier ◽  
J Schliehe-Diecks ◽  
M Sönnichsen ◽  
...  
Keyword(s):  
Acute Leukemia ◽  
High Throughput ◽  
Drug Screening ◽  
High Throughput Drug Screening

scholarly journals Efficacy, tolerability, and retention of fenfluramine for the treatment of seizures in patients with Dravet syndrome: Compassionate use program in Germany

Epilepsia ◽  
2021 ◽  
Author(s):  
Adam Strzelczyk ◽  
Milka Pringsheim ◽  
Thomas Mayer ◽  
Tilman Polster ◽  
Kerstin A. Klotz ◽  
...  
Keyword(s):  
Dravet Syndrome ◽  
Compassionate Use

scholarly journals High-throughput drug screening identifies the ATR-CHK1 pathway as a therapeutic vulnerability of CALR mutated hematopoietic cells

2021 ◽  
Vol 11 (7) ◽  
Author(s):  
Ruochen Jia ◽  
Leon Kutzner ◽  
Anna Koren ◽  
Kathrin Runggatscher ◽  
Peter Májek ◽  
...  
Keyword(s):  
High Throughput ◽  
Drug Screening ◽  
Synthetic Lethality ◽  
Myeloproliferative Neoplasms ◽  
Hematopoietic Cells ◽  
Replication Stress ◽  
Phase Cell ◽  
Nuclear Staining ◽  
Wild Type ◽  
High Throughput Drug Screening

AbstractMutations of calreticulin (CALR) are the second most prevalent driver mutations in essential thrombocythemia and primary myelofibrosis. To identify potential targeted therapies for CALR mutated myeloproliferative neoplasms, we searched for small molecules that selectively inhibit the growth of CALR mutated cells using high-throughput drug screening. We investigated 89 172 compounds using isogenic cell lines carrying CALR mutations and identified synthetic lethality with compounds targeting the ATR-CHK1 pathway. The selective inhibitory effect of these compounds was validated in a co-culture assay of CALR mutated and wild-type cells. Of the tested compounds, CHK1 inhibitors potently depleted CALR mutated cells, allowing wild-type cell dominance in the co-culture over time. Neither CALR deficient cells nor JAK2V617F mutated cells showed hypersensitivity to ATR-CHK1 inhibition, thus suggesting specificity for the oncogenic activation by the mutant CALR. CHK1 inhibitors induced replication stress in CALR mutated cells revealed by elevated pan-nuclear staining for γH2AX and hyperphosphorylation of RPA2. This was accompanied by S-phase cell cycle arrest due to incomplete DNA replication. Transcriptomic and phosphoproteomic analyses revealed a replication stress signature caused by oncogenic CALR, suggesting an intrinsic vulnerability to CHK1 perturbation. This study reveals the ATR-CHK1 pathway as a potential therapeutic target in CALR mutated hematopoietic cells.

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