PUBLICATION

Metabolism-based drug discovery in zebrafish: An emerging strategy to uncover new anti-seizure therapies

Authors
Ibhazehiebo, K., Rho, J.M., Kurrasch, D.M.
ID
ZDB-PUB-200221-34
Date
2020
Source
Neuropharmacology   167: 107988 (Review)
Registered Authors
Ibhazehiebo, Kingsley, Kurrasch, Deborah
Keywords
Anticonvulsant, Antiepileptic drug, Bioenergetics, Epilepsy, Experimental therapeutics, Ketogenic diet, Metabolism, Mitochondria
MeSH Terms
  • Animals
  • Anticonvulsants/pharmacology
  • Anticonvulsants/therapeutic use*
  • Disease Models, Animal*
  • Drug Discovery/methods*
  • Drug Evaluation, Preclinical/methods
  • Energy Metabolism/drug effects*
  • Energy Metabolism/physiology
  • Humans
  • Mitochondria/drug effects
  • Mitochondria/metabolism
  • Seizures/drug therapy*
  • Seizures/metabolism*
  • Zebrafish
PubMed
32070912 Full text @ Neuropharmacology
Abstract
As one of the most common neurological disorders, epilepsy can occur throughout the lifespan and from a multiplicity of causes, including genetic mutations, inflammation, neurotrauma, or brain malformations. Although pharmacological agents are the mainstay of treatment for seizure control, an unyielding 30-40% of patients remain refractory to these medications and continue to experience spontaneous recurrent seizures with attendant life-long cognitive, behavioural, and mental health issues, as well as an increased risk for sudden unexpected death. Despite over eight decades of antiseizure drug (ASD) discovery and the approval of dozens of new medications, the percentage of this refractory population remains virtually unchanged, suggesting that drugs with new and unexpected mechanisms of action are needed. In this brief review, we discuss the need for new animal models of epilepsy, with a particular focus on the advantages and disadvantages of zebrafish. We also outline the evidence that epilepsy is characterized by derangements in mitochondrial function and introduce the rationale and promise of bioenergetics as a functional readout assay to uncover novel ASDs. We also consider limitations of a zebrafish metabolism-based drug screening approach. Our goal is to discuss the opportunities and challenges of further development of mitochondrial screening strategies for the development of novel ASDs.
Genes / Markers
Figures
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping