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New anti-inflammatory drugs pinch off reactive oxygen species at the source
Date:6/21/2012

dentification of ebselen, a drug that has been tested previously in clinical trials in acute stroke and more recently, hearing loss. Previous researchers had thought that ebselen acted by another mechanism. Smith and Lambeth say their results do not conflict with earlier reports, and ebselen may have several modes of action depending on the concentration. Ebselen inhibited the Nox2 enzyme and to a lesser extent, Nox1, but not other Nox enzymes.

A side effect of Nox2 inhibition could be impairment of immune responses to bacteria and fungi, Lambeth says. One of Nox2's main functions in immune cells is to produce a toxic burst of ROS for killing bacteria and fungi.

People with an inherited deficiency in Nox2 develop chronic granulomatous disease (CGD), and are unable to fight off common infections. However, short-term or incomplete inhibition could have therapeutic effects without disabling antibacterial activity. CGD carriers who have reduced but residual Nox2 activity do not display symptoms.

Lambeth says the identification of ebselen is a starting point for refining drugs that target Nox2 and other Nox enzymes.

"This is just the tip of the iceberg," he says. "It's a good sign that ebselen is relatively non-toxic. Through medicinal chemistry, it should be possible to generate even more potent inhibitors, which could be candidates for drug development."


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Contact: Quinn Eastman
404-727-7829
Emory University
Source:Eurekalert

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