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Discovering novel neuroactive drugs through high-throughput behavior-based chemical screening in the zebrafish.

Bruni G, Lakhani P, Kokel D - Front Pharmacol (2014)

Bottom Line: These compounds are powerful tools for understanding CNS signaling pathways.However, given the molecular genetic similarities between humans and zebrafish, it is likely that some of these compounds will have translational utility.We predict that the greatest new successes in CNS drug discovery will leverage many model systems, including in vitro assays, cells, rodents, and zebrafish.

View Article: PubMed Central - PubMed

Affiliation: Cardiovascular Research Center, Massachusetts General Hospital and Harvard Medical School Charlestown, MA, USA.

ABSTRACT
Most neuroactive drugs were discovered through unexpected behavioral observations. Systematic behavioral screening is inefficient in most model organisms. But, automated technologies are enabling a new phase of discovery-based research in central nervous system (CNS) pharmacology. Researchers are using large-scale behavior-based chemical screens in zebrafish to discover compounds with new structures, targets, and functions. These compounds are powerful tools for understanding CNS signaling pathways. Substantial differences between human and zebrafish biology will make it difficult to translate these discoveries to clinical medicine. However, given the molecular genetic similarities between humans and zebrafish, it is likely that some of these compounds will have translational utility. We predict that the greatest new successes in CNS drug discovery will leverage many model systems, including in vitro assays, cells, rodents, and zebrafish.

No MeSH data available.


How many drugs work in both humans and zebrafish? Not all drugs that work in zebrafish will also work in humans. Because so many more compounds can be screened in zebrafish, it is likely that some will translate to the clinic. However, the precise level of overlap (indicated by X) is difficult to predict.
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Figure 3: How many drugs work in both humans and zebrafish? Not all drugs that work in zebrafish will also work in humans. Because so many more compounds can be screened in zebrafish, it is likely that some will translate to the clinic. However, the precise level of overlap (indicated by X) is difficult to predict.

Mentions: Many compounds work in humans, many work in zebrafish, and some fraction is likely to work in both–although the exact level of overlap is difficult to predict (Figure 3). Humans and zebrafish are closely related (Howe et al., 2013), but there are many differences at the phenotypic, neuronal network, and molecular levels. When a new bioactive compound is first discovered in zebrafish, it will be difficult to predict its potential therapeutic utility in humans. Many compounds that appear to work well in mice and other animal models subsequently fail to translate to humans. The same will surely be true of zebrafish. The problem is especially relevant in neuropharmacology, where CNS disorders are poorly understood and difficult to model. Despite the challenges, in the upcoming years we are likely to see at least a few compounds identified in zebrafish screens translate from bench to bedside.


Discovering novel neuroactive drugs through high-throughput behavior-based chemical screening in the zebrafish.

Bruni G, Lakhani P, Kokel D - Front Pharmacol (2014)

How many drugs work in both humans and zebrafish? Not all drugs that work in zebrafish will also work in humans. Because so many more compounds can be screened in zebrafish, it is likely that some will translate to the clinic. However, the precise level of overlap (indicated by X) is difficult to predict.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4109429&req=5

Figure 3: How many drugs work in both humans and zebrafish? Not all drugs that work in zebrafish will also work in humans. Because so many more compounds can be screened in zebrafish, it is likely that some will translate to the clinic. However, the precise level of overlap (indicated by X) is difficult to predict.
Mentions: Many compounds work in humans, many work in zebrafish, and some fraction is likely to work in both–although the exact level of overlap is difficult to predict (Figure 3). Humans and zebrafish are closely related (Howe et al., 2013), but there are many differences at the phenotypic, neuronal network, and molecular levels. When a new bioactive compound is first discovered in zebrafish, it will be difficult to predict its potential therapeutic utility in humans. Many compounds that appear to work well in mice and other animal models subsequently fail to translate to humans. The same will surely be true of zebrafish. The problem is especially relevant in neuropharmacology, where CNS disorders are poorly understood and difficult to model. Despite the challenges, in the upcoming years we are likely to see at least a few compounds identified in zebrafish screens translate from bench to bedside.

Bottom Line: These compounds are powerful tools for understanding CNS signaling pathways.However, given the molecular genetic similarities between humans and zebrafish, it is likely that some of these compounds will have translational utility.We predict that the greatest new successes in CNS drug discovery will leverage many model systems, including in vitro assays, cells, rodents, and zebrafish.

View Article: PubMed Central - PubMed

Affiliation: Cardiovascular Research Center, Massachusetts General Hospital and Harvard Medical School Charlestown, MA, USA.

ABSTRACT
Most neuroactive drugs were discovered through unexpected behavioral observations. Systematic behavioral screening is inefficient in most model organisms. But, automated technologies are enabling a new phase of discovery-based research in central nervous system (CNS) pharmacology. Researchers are using large-scale behavior-based chemical screens in zebrafish to discover compounds with new structures, targets, and functions. These compounds are powerful tools for understanding CNS signaling pathways. Substantial differences between human and zebrafish biology will make it difficult to translate these discoveries to clinical medicine. However, given the molecular genetic similarities between humans and zebrafish, it is likely that some of these compounds will have translational utility. We predict that the greatest new successes in CNS drug discovery will leverage many model systems, including in vitro assays, cells, rodents, and zebrafish.

No MeSH data available.