A California team has shown that monoacylglycerol lipase, which controls levels of a pain-reducing metabolite in the brain, also regulates neuroinflammation.1 The researchers have proof of concept that a small molecule inhibitor of the target blocks inflammation and decreases neurodegeneration in a mouse model of Parkinson's disease, and they are now studying the compound in additional neurodegenerative and neurological diseases.

Newco Abide Therapeutics Inc. is exercising an option to license the monoacylglycerol lipase (MAGL) inhibitors.

MAGL is a serine hydrolase enzyme that degrades 2-arachidonoylglycerol (2-AG), a ligand of pain-relieving cannabinoid receptors in the brain. In 2008, a team led by Benjamin Cravatt identified a brain-permeable small molecule inhibitor of MAGL that causes 2-AG levels to increase in the brain, inducing analgesia in mice.2

Cravatt is chair of the Department of Chemical Physiology at The Scripps Research Institute.

At the time, Cravatt and collaborators observed that in addition to boosting 2-AG levels, MAGL inhibitors also triggered a decrease in brain levels of arachidonic acid, the precursor molecule to inflammatory prostaglandins.2,3 Phospholipase enzymes had previously been considered the principle regulators of arachidonic acid levels, and these observations suggested a link between MAGL activity and prostaglandin-mediated neuroinflammation.

Based on this, a team led by Cravatt and Daniel Nomura, an assistant professor in the Department of Nutritional Science and Toxicology at the University of California, Berkeley, has now looked more closely at the impact of blocking MAGL on brain inflammation.

In mice stimulated with lipopolysaccharide (LPS) to induce neuroinflammation, Magl deficiency or a MAGL inhibitor prevented increases in inflammatory prostaglandins and cytokines and blocked microglial activation compared with Magl expression or vehicle (see "Connecting cannabinoid and prostaglandin pathways").

Moreover, blocking Magl reduced LPS-stimulated increases in brain prostaglandin levels at least three-fold, whereas blocking cPla2 (phospholipase A2 group IVA cytosolic calcium-dependent; Pla2g4a), which is a known regulator of prostaglandin production in neuroinflammation, only resulted in an approximately 20% decrease in LPS-induced prostaglandins.

In a mouse model of neurotoxin-induced Parkinson's disease (PD), the MAGL inhibitor reduced neuroinflammation and dopaminergic neurodegeneration compared with vehicle.

Finally, the team asked whether MAGL also controlled inflammation in peripheral tissues. In LPS-treated mice, Magl regulated prostaglandin levels in the liver and lung, whereas cPla2-a controlled levels in the gut and spleen. Neither Magl nor cPla2-a regulated prostaglandin production in the heart and kidney.

Results were published in Science.

"It's been thought since the early 1900s that phospholipases dominate the production of arachidonic acid," said Nomura. It now appears there are tissue-specific mechanisms that control production, he added.

Casting a MAGL net

The work "opens up another angle to approach inflammation in the brain," said Johan Luthman, leader of the Early Development Neuroscience and Ophthalmology Franchise at Merck & Co. Inc. "Targeting MAGL might provide a combined pain and
anti-inflammatory mechanism that could be interesting not only for PD but also for many other neurological diseases."

The weakness of the paper is the use of an acute, neurotoxin-based PD model, said Luthman. He noted that results from this model have not translated well into the clinic and suggested the authors should test MAGL inhibitors in newer PD models, such as the so-called MitoPark mouse, which better recapitulates the chronic neurodegeneration of the human disease.

Whether neuroinflammation is a cause or a symptom in PD and other chronic neurodegenerative diseases is still unclear, added Luthman. "The general idea is that neuroinflammation is a contributor and not causative, although this can be debated."

Thus, Luthman said it is more likely that a MAGL inhibitor would improve symptoms but not affect the underlying disease process.

Luthman told SciBX that MAGL inhibitors also could be interesting to test in multiple sclerosis (MS), in which "the ongoing brain and spinal cord inflammation not only leads to physical disability but also commonly to sensory problems and pain." Compared with current anti-inflammatory approaches, "the interesting angle is that this is a more brain-specific pathway," he said.

The California team now is looking at the effects of MAGL inhibitors in genetic models of PD, as well as in MS and Alzheimer's disease (AD) models, said Nomura.

He added that the team also would like to explore the therapeutic potential of blocking MAGL in acute neurological diseases. "An interesting avenue may be stroke or brain injury, where you could simultaneously enhance cannabinoid and decrease prostaglandin signaling in an acute treatment regimen."

Given MAGL's involvement in liver and lung inflammation, Nomura said inhibitors might also have a therapeutic benefit in fibrosis of those tissues.

Scripps holds patents on the MAGL inhibitor used in the Science paper. Abide Therapeutics, which was cofounded in 2011 by Cravatt to develop serine hydrolase inhibitors, is exercising its exclusive option to license patents covering MAGL inhibitors, according to CEO Alan Ezekowitz. "The MAGL program is the most advanced program, and the company intends to explore MAGL inhibitors in the treatment of pain, neuroinflammation and potentially neurodegenerative diseases like Parkinson's disease," said Ezekowitz.

Kotz, J. SciBX 4(45); doi:10.1038/scibx.2011.1254
Published online Nov. 17, 2011

REFERENCES

1.   Nomura, D.K. et al. Science; published online Oct. 20, 2011; doi:10.1126/science.1209200
Contact: Benjamin F. Cravatt, The Scripps Research Institute, La Jolla, Calif.
e-mail: cravatt@scripps.edu
Contact: Daniel K. Nomura, University of California, Berkeley, Calif.
e-mail: dnomura@berkeley.edu

2.   Long, J.Z. et al. Nat. Chem. Biol. 5, 37-44 (2009)

3.   Nomura, D.K. et al. Nat. Chem. Biol. 4, 373-378 (2008)

COMPANIES AND INSTITUTIONS MENTIONED

      Abide Therapeutics Inc., Princeton, N.J.

      Merck & Co. Inc. (NYSE:MRK), Whitehouse Station, N.J.

      The Scripps Research Institute, La Jolla, Calif.

      University of California, Berkeley, Calif.