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Little Fish Makes Big Splashes in Biomedical Research

Tags: 3Rs, zebrafish

The zebrafish, a small minnow-like species, has proven to be a powerful research tool for genetics, developmental biology, toxicology, neuroscience, oncology, drug discovery, metabolism, immunology, cardiovascular disease and function, and many others. One of the newest applications is the use of zebrafish larvae (around one week old) to investigate epilepsy and to screen new pharmaceutical compounds for unintended induction of seizures or for the potential to treat epilepsy.

Why use fish for this type of work? Scientists conducting biomedical research are always searching for ways to improve research methods and follow the principles of 3Rs (reduction, refinement, and replacement). In recent years, some scientists have been accomplishing this through the use of zebrafish - either adults or their developing offspring - as a research model. One of the advantages to zebrafish research is that much of the experimental work can be done in embryos or early-staged larvae without the need to treat or euthanize any adult animals.

Zebrafish larvae are particularly suited for seizure research as they have been found to respond to chemicals that induce epilepsy-like seizures and drugs that block those seizures in a manner that is similar to humans and other mammals. In addition, zebrafish larvae are inexpensive to obtain and work with. For example, locomotion monitoring tests can be conducted with many larvae arrayed in multi-well plates and monitored through a specialized video camera and video analysis software.

Initial research found that zebrafish larvae tended to respond to proconvulsant compounds (ones that were known to induce seizures in humans and/or mammalian laboratory models) with movements and behaviors that were consistent with tonic and clonic seizures, and it was found that these effects could be reduced or blocked by anticonvulsant compounds (ones that were known to be effective in preventing seizures in humans and/or mammalian models). However, it was not known whether these anticonvulsant effects were due to true anticonvulsant activity in the brain.

To answer this question, scientists in Belgium used electroencephalography (EEG) in the brains of zebrafish larvae.[1] The electrographic data that Tatiana Afrikanova and her colleagues recently published indicates that electric activity in the brain is consistent with changes observed in larval movement assays, suggesting that such locomotor assays may be reliable indicators of convulsant or anticonvulsant potential.

Here at Charles River we exploring the possibility that exposure to proconvulsant or anticonvulsant compounds during embryonic development may have lasting, but initially “invisible”, effects on the susceptibility to seizures later. It is becoming increasingly clear through epidemiological and laboratory research that embryos and fetuses are susceptible to alterations in physiology or organ function that, while not evident at birth or possibly even well into adulthood, may still result in an increased risk for a variety of health consequences, including cardiovascular and metabolic disease.[2] It is therefore conceivable that in utero exposure to epilepsy medications or a chemical with the potential to cause seizures might alter one’s seizure susceptibility later in life. As with so many other areas of current biomedical research, zebrafish larvae are performing a critical role in these ongoing investigations.


[1] Afrikanova T, Serruys AS, Buenafe OE, Clinckers R, Smolders I, de Witte PA, Crawford AD, Esguerra CV. Validation of the zebrafish pentylenetetrazol seizure model: locomotor versus electrographic responses to antiepileptic drugs. PLoS One. 2013;8(1):e54166.

[2] Barker DJ. The developmental origins of adult disease.J Am Coll Nutr. 2004 Dec;23(6 Suppl):588S-595S.
 


Dr. Kimberly Brannen is a Reproductive Toxicology study director in the Charles River, Preclinical Services group at Horsham, PA. Her training is in developmental toxicology, and she has particular interests in the use of alternative models and investigative research. Dr. Brannen has been working with zebrafish as a research model since 2003.



 

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