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Biological Chemistry

Nerve Agents Hit Cannabinoid System

Sarin homolog inhibits enzymes in endocannabinoid system

by Celia Henry Arnaud
May 12, 2008 | A version of this story appeared in Volume 86, Issue 19

Isopropyl dodecylfluorophosphonate
(IDFP) inhibits the enzymes MAGL and FAAH that degrade the endocannabinoids 2-arachidonylglycerol and anandamide to arachidonic acid and either glycerol or ethanolamine.

Organophosphorus nerve agents activate the endocannabinoid system, the same one affected by Δ9-tetrahydrocannabinol (THC), the psychoactive ingredient in marijuana. The finding could lead to a better understanding of the endocannabinoid system and the action of nerve agents, as well as potential therapeutic applications.

Researchers have long suspected that some effects of sublethal doses of nerve agents can't be attributed to the inhibition of acetylcholinesterase, the primary target responsible for their toxicity. A team led by John E. Casida of the University of California, Berkeley, and Benjamin F. Cravatt of Scripps Research Institute, in La Jolla, Calif., used a sarin homolog—isopropyl dodecylfluorophosphonate (IDFP)—that is not selective for acetylcholinesterase to identify possible secondary targets (Nat. Chem. Biol., DOI: 10.1038.nchembio.86).

They found that IDFP inhibits the two enzymes primarily responsible for endocannabinoid degradation—monoacylglycerol lipase (MAGL), which metabolizes 2-arachidonylglycerol (2-AG), and fatty acid amide hydrolase (FAAH), which metabolizes anandamide. Shutting down both enzymes raises the level of 2-AG and anandamide in the brain 10-fold. In mice injected with IDFP, the researchers see full-blown cannabinoid effects similar to those of cannabinoid receptor agonists such as THC.

Previous work from Cravatt's lab has shown that selective FAAH inhibitors raise anandamide levels and elicit the antianxiety and analgesic therapeutic effects of cannabinoids without the cognitive effects. The new findings suggest that dual inhibitors of FAAH and MAGL "would not be an attractive way to go therapeutically," Cravatt says, because they would cause not only good cannabinoid effects, such as antianxiety and analgesic activity, but also bad ones such as unfavorable cognitive effects.

It is unknown, however, what happens if only MAGL is inhibited. "The uniqueness of our study lies in the fact that IDFP is one of the first compounds capable of blocking MAGL in vivo," says Daniel K. Nomura, a graduate student working with Casida. The team hopes to develop compounds that target MAGL without also targeting FAAH.

The researchers saw another surprising effect. An increase in the 2-AG level leads to a decrease in the level of arachidonic acid—a precursor of prostaglandins, which cause inflammation, pain, and fever. These findings challenge the conventional wisdom that phospholipase A2 is the main enzyme responsible for the release of arachidonic acid.

George Kunos, a researcher who studies endocannabinoids at the National Institutes of Health, finds the results interesting but raises a caveat. IDFP also binds to the cannabinoid receptor, but the evidence suggests that it is neither an agonist nor an antagonist. "If the compound binds but is neither an agonist nor an antagonist, what does it do?" Kunos asks. Answering his own question, Kunos speculates that IDFP "may be some kind of allosteric modulator that sensitizes the receptor to agonists." Kunos adds that the new findings "will create a lot of interest among scientists interested in the endocannabinoid system, but even beyond to those who are working on prostanoids and lipid signaling." Prostanoids are a class of fatty acids largely associated with inflammation responses.



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