The widely used model organism zebrafish may help shed light on blood-brain barrier

Zebrafish were the original pet-store Glofish, popular for tropical aquaria despite their Himalayan origins. In science, they have proved to be valuable models for many investigations, including studying blood diseases, muscular dystrophy, osteoporosis, heart disease, leukemia, and other disorders -- and soon perhaps for studying the blood-brain barrier, an obstacle for treating brain cancer. 

Inexpensive zebrafish also have brief lifecycles and are easy to care for, making them attractive research models. 

New research focused on four zebrafish genes that are similar, or homologous, to a human gene that act as a barrier protecting the brain from exposure to foreign compounds, including cancer drugs. These four transporter genes are homologous to the human gene, ABCG2, yet little is known about them. 

A collaboration involving Frederick National Laboratory for Cancer Research scientists investigated the function of all four homologous zebrafish genes, results of which were published in the BMC journal Fluids and Barriers of the CNS.  

The scientists exposed the zebrafish genes to a series of compounds that are known to be toxic to cells. All four zebrafish genes conferred some resistance to at least some of the test compounds, with the gene Abcg2a marshalling the most resistance across the board. In additional experiments, they isolated Abcg2a to the blood-brain barrier of the adult zebrafish. They further identified Abcd2a at five days post fertilization in the brain vasculature of developing zebrafish. Finally, the researchers concluded that Abcg2a is most like the human ABCG2. 

While the overall research suggests that the zebrafish is a relevant model for studying transport of drugs across the blood-brain barrier, additional research is needed to answer unresolved questions. For one, zebrafish genes evolved to protect against toxins in a marine environment, so their drug specificities may differ from those of human ABCG2. 

Experiments in mouse models pointed to the key role of ABCG2 and related proteins in keeping targeted therapies from entering the brain, limiting the usefulness of drugs such as those that might target glioblastoma and other brain tumors. But mouse models are more expensive, have longer lifecycles, and are more difficult to image than zebrafish with their transparent bodies.  

Additional research could help establish the utility of zebrafish as models for studying the blood-brain barrier. 

The current study was led by Michael Gottesman of the National Cancer Institute’s Center for Cancer Research, with first author Joanna Thomas and FNL collaborators Andrew Warner, Donna Butcher, Jennifer Matta, Tamara Morgan, and Elijah Edmondson.