Susceptibility of larval zebrafish to the seizurogenic activity of GABA type A receptor antagonists
| Autor: | Brandon Pressly, Suren B. Bandara, Vikrant Singh, Danielle J Harvey, Pamela J. Lein, Heike Wulff, Natalia Vasylieva, Dennis R. Carty |
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| Rok vydání: | 2019 |
| Předmět: |
TETS
Bridged-Ring Compounds Chemical threat agents animal structures Drug Evaluation Preclinical Neurodegenerative Pharmacology Biology Toxicology Article 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Seizures medicine Animals Picrotoxin GABA-A Receptor Antagonists Receptor Zebrafish 030304 developmental biology 0303 health sciences Epilepsy General Neuroscience Allopregnanolone fungi Neurosciences Antagonist Brain Pharmacology and Pharmaceutical Sciences biology.organism_classification Preclinical Brain Disorders Good Health and Well Being chemistry embryonic structures Convulsant Drug Evaluation Pentylenetetrazole Tetramethylenedisulfotetramine Diazepam 030217 neurology & neurosurgery medicine.drug |
| Zdroj: | Neurotoxicology |
| ISSN: | 1872-9711 |
| Popis: | Previous studies demonstrated that pentylenetetrazole (PTZ), a GABA type A receptor (GABA(A)R) antagonist, elicits seizure-like phenotypes in larval zebrafish (Danio rerio). Here, we determined whether the GABA(A)R antagonists, tetramethylenedisulfotetramine (TETS) and picrotoxin (PTX), both listed as credible chemical threat agents, similarly trigger seizures in zebrafish larvae. Larvae of three, routinely used laboratory zebrafish lines, Tropical 5D, NHGRI and Tupfel long fin, were exposed to varying concentrations of PTZ (used as a positive control), PTX or TETS for 20 min at 5 days post fertilization (dpf). Acute exposure to PTZ, PTX or TETS triggered seizure behavior in the absence of morbidity or mortality. While the concentration-effect relationship for seizure behavior was similar across zebrafish lines for each GABA(A)R antagonist, significantly less TETS was required to trigger seizures relative to PTX or PTZ. Recordings of extracellular field potentials in the optic tectum of 5 dpf Tropical 5D zebrafish confirmed that all three GABA(A)R antagonists elicited extracellular spiking patterns consistent with seizure activity, although the pattern varied between chemicals. Post-exposure treatment with the GABA(A)R positive allosteric modulators (PAMs), diazepam, midazolam or allopregnanolone, attenuated seizure behavior and activity but did not completely normalize electrical field recordings in the optic tectum. These data are consistent with observations of seizure responses in mammalian models exposed to these same GABA(A)R antagonists and PAMs, further validating larval zebrafish as a higher throughput-screening platform for antiseizure therapeutics, and demonstrating its appropriateness for identifying improved countermeasures for TETS and other convulsant chemical threat agents that trigger seizures via GABA(A)R antagonism. |
| Databáze: | OpenAIRE |
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