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| Anti-inflammatories: Fishing for COX inhibitors
FitzGerald and colleagues describe how the zebrafish could provide crucial insights into the biology and pharmacology of the target for non-steroidal anti-inflammatory drugs. How can the humble fish help to design a new generation of more specific non-steroidal anti-inflammatory drugs (NSAIDs)? Reporting in the Proceedings of the National Academy of Sciences, FitzGerald and colleagues describe how the zebrafish could provide crucial insights into the biology and pharmacology of the target for NSAIDs — the cyclooxygenase (COX)-1 and COX-2 enzymes.
As COX-2 is usually highly inducible (for example, at sites of inflammation), whereas COX-1 is involved in other important functions in the body, creating NSAIDs that specifically target COX-2 could help treat pain with fewer harmful side effects. However, current mouse models used to investigate the COX enzymes are limited by the importance of COX-2 in development. In search of a more appropriate model, FitzGerald and colleagues turned to the zebrafish — a model organism used in vertebrate biology and genetic studies — and identified homologues of the human COX1 and COX2 genes, which they called zCOX1 and zCOX2. Sequence analysis showed that the zebrafish proteins are 67% similar to their human counterparts, and all the putative domain structures and residues that are key to the activity of the enzymes are conserved. The authors found that the zCOXs share many pharmacological and functional characteristics of the human homologues. Both indomethacin (a non-specific COX inhibitor) and NS-398 (a COX-2-specific inhibitor) suppressed the formation of prostaglandin (PG)E2 — the main product of zCOX expression — which indicates that COX-2 is the main source of PGE2. But only indomethacin prevented spontaneous and induced thrombocyte aggregation, and increased the bleeding time. This shows that zebrafish thrombocytes, like human platelets, express only COX-1. One advantage of the zebrafish model is its ease of detecting gene expression during development, and reverse-transcriptase PCR showed that both zCOXs are expressed widely during embryonic development. Another advantage is that specific genes of interest can be transiently inactivated (knockdown), and FitzGerald and colleagues showed that knockdown of zCOX1 caused growth arrest during early embryogenesis. They say that if they had created Cox1-knockout mice, this type of early developmental phenotype might have been obscured by the maternal generation of PGs. So, the authors conclude that the detectable expression of both zCOX enzymes, the apparent recapitulation of the human pharmacology of inhibitors, the applicability to high-throughput analysis of drug effect and mutant analysis, and the potential for gene inactivation and overexpression, all indicate that the zebrafish model could be important in advancing our understanding of the COX enzyme system. Simon Frantz References
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