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Scibx Highlights ANALYSIS FROM THE MAKERS OF AND NOvember 17, 2011 • vOLUme 4 / NUmber 45 THIS WEEK ANALYSIS Dampening COVER STORY 1 Dampening neuroinflammation A California team has shown that inhibiting MAGL reduces neuroinflammation neuroinflammation in a mouse model of Parkinson’s disease. The researchers are now investigating the By Joanne Kotz, Senior Editor small molecule’s effects in other neurodegenerative and A California team has shown that monoacylglycerol lipase, which con- neurological diseases, and newco Abide Therapeutics is trols levels of a pain-reducing metabolite in the brain, also regulates exercising an option to license the MAGL inhibitors. neuroinflammation.1 The researchers have proof of concept that a small TARGETS & MECHANISMS molecule inhibitor of the target blocks inflammation and decreases 4 SEMA4D in osteoporosis neurodegeneration in a mouse model of Parkinson’s disease, and they Tokyo researchers have suggested that blocking the are now studying the compound in additional neurodegenerative and membrane protein SemA4D could directly promote bone formation in osteoporosis, and they plan to investigate the neurological diseases. target for arthritis and bone metastasis. Vaccinex already Newco Abide Therapeutics is exercising an option to license the has an inhibitor in Phase I trials for cancer. monoacylglycerol lipase (MAGL) inhibitors. MAGL is a serine hydrolase enzyme that degrades TRANSLATIONAL NOTES 2-arachidonoylglycerol (2-AG), a ligand of pain-relieving cannabinoid 6 Cancer matchmaker Cancer research UK is brokering partnerships between its receptors in the brain. In 2008, stable of academics and companies looking for a stake in a team led by Benjamin Cravatt “Targeting MAGL might early cancer discoveries. AstraZeneca is the charity’s anchor identified a brain-permeable provide a combined pain collaborator with three projects, including one involving small molecule inhibitor of and anti-inflammatory Senectus Therapeutics. MAGL that causes 2-AG mechanism that could be 7 MD Anderson’s private screening levels to increase in the brain, interesting not only for PD Alvos and Ablaris are using peptide-receptor pairs identified inducing analgesia in mice.2 but also for many other by MD Anderson researchers to target therapeutic payloads Cravatt is chair of the in cancer and obesity. The center now has provided Department of Chemical neurological diseases.” preclinical proof-of-concept data and preliminary patient —Johan Luthman, Merck & Co. Inc. Physiology at The Scripps validation for the companies’ products that are based on the technology. Research Institute. At the time, Cravatt and collaborators observed that in addition THE DISTILLERY to boosting 2-AG levels, MAGL inhibitors also triggered a decrease 9 This week in therapeutics in brain levels of arachidonic acid, the precursor molecule to Treating osteoarthritis by inhibiting complement 5; inflammatory prostaglandins.2,3 Phospholipase enzymes had previously ameliorating hemophilia with variants of factor IX; promoting been considered the principle regulators of arachidonic acid levels, nerve regeneration by inhibiting PTeN and SOCS3; and and these observations suggested a link between MAGL activity and more… prostaglandin-mediated neuroinflammation. 15 This week in techniques Based on this, a team led by Cravatt and Daniel Nomura, an assistant Gram-scale preparation of paclitaxel precursors for professor in the Department of Nutritional Science and Toxicology at synthesis of taxane analogs; target-specific, near-infrared the University of California, Berkeley, has now looked more closely at photoimmunotherapy to treat cancer; intra-arterial catheter for in vivo microstructural and molecular imaging; and the impact of blocking MAGL on brain inflammation. more… In mice stimulated with lipopolysaccharide (LPS) to induce neuroinflammation, Magl deficiency or a MAGL inhibitor prevented INDEXES increases in inflammatory prostaglandins and cytokines and blocked 16 Company and institution index microglial activation compared with Magl expression or vehicle (see 16 Target and compound index Figure 1, “Connecting cannabinoid and prostaglandin pathways”). Moreover, blocking Magl reduced LPS-stimulated increases in brain prostaglandin levels at least three-fold, whereas blocking 1 ANALYSIS COVER STORY cPla2-a (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. EDITORIAL Editor-in-Chief: Karen Bernstein, Ph.D. Finally, the team asked whether MAGL also controlled inflammation Managing Editor: Gaspar Taroncher-Oldenburg, Ph.D. in peripheral tissues. In LPS-treated mice, Magl regulated prostaglandin Executive Editor: Steve Edelson levels in the liver and lung, whereas cPla -a controlled levels in the Senior Editors: Tracey baas, Ph.D.; Joanne Kotz, Ph.D. 2 Writers: Aaron bouchie; Chris Cain, Ph.D.; michael Flanagan; gut and spleen. Neither Magl nor cPla2-a regulated prostaglandin Tim Fulmer, Ph.D.; michael J. Haas; Stephen Hansen; Kai-Jye Lou; production in the heart and kidney. Lauren martz; Lev Osherovich, Ph.D.; Steve Usdin Results were published in Science. Research Director: Walter Yang Research Manager: Kevin Lehnbeuter “It’s been thought since the early 1900s that phospholipases dominate Production Editors: brandy Cafarella; Sabina eberle; Carol evangelista the production of arachidonic acid,” said Nomura. It now appears there Copy Editor: Nicole DeGennaro are tissue-specific mechanisms that control production, he added. Editorial Assistant: Mark Zipkin Design: Claudia bentley; miles Davies For inquiries, contact [email protected] Casting a MAGL net PUBLISHING The work “opens up another angle to approach inflammation in Publisher: Peter Collins, Ph.D. the brain,” said Johan Luthman, leader of the Early Development Associate Publishers: Gaspar Taroncher-Oldenburg, Ph.D.; eric Pierce Marketing: Sara Girard; rosy rogers Neuroscience and Ophthalmology Franchise at Merck & Co. Technology: Anthony barrera; Julia Kulikova Inc. “Targeting MAGL might provide a combined pain and Sales: ron rabinowitz; Dean Sanderson; Tim Tulloch OFFICES BioCentury Publications, Inc. Nature Publishing Group Potential therapeutic target San Francisco New York a PO box 1246 75 varick Street, 9th Floor San Carlos, CA 94070-1246 New York, NY 10013-1917 MAGL T: +1 650 595 5333 T: +1 212 726 9200 b 2-AG Arachidonic acid c Chadds Ford London 223 Wilmington-West Chester Pike The Macmillan Building Prostaglandins Chadds Ford, PA 19317 4 Crinan Street Cannabinoid receptors T: +1 610 558 1873 London N1 9XW Chicago United Kingdom Neuroinflammation 20 N. Wacker Drive, Suite 1465 T: +44 (0)20 7833 4000 Pain Chicago, IL 60606-2902 Tokyo T: +1 312 755 0798 Chiyoda building 6F Oxford 2-37 Ichigayatamachi 287 banbury road Shinjuku-ku, Tokyo 162-0843 Oxford OX4 7JA Japan United Kingdom T: +81 3 3267 8751 T: +44 (0)18 6551 2184 Washington, DC Figure 1. Connecting cannabinoid and prostaglandin pathways. 2008 Q Street, NW, Suite 100 A team led by researchers from The Scripps Research Institute Washington, DC 20009 T: +1 202 462 9582 and the University of California, Berkeley have shown that mono- acylglycerol lipase (mAGL), which controls levels of a pain-reducing SciBX is produced by BioCentury Publications, Inc. and Nature Publishing Group Joint Steering Committee: Karen bernstein, Ph.D., Chairman & editor-in-Chief, metabolite in the brain, also regulates neuroinflammation. Thus, bioCentury; David Flores, President & CeO, bioCentury; bennet Weintraub, Finance blocking MAGL could provide a therapeutic benefit in neurodegen- Director, bioCentury; Steven Inchcoombe, managing Director, Nature Publishing erative disorders characterized by neuroinflammation. Group; Peter Collins, Ph.D., Publishing Director, NPG; Christoph Hesselmann, Ph.D., Chief Financial Officer, NPG. Previous work from Scripps had shown that in mice, a small mol- Copyright © 2011 Nature Publishing Group ALL RIGHTS RESERVED. ecule inhibitor of MAGL [a] increased the levels of 2-arachidonoyl- No part of the SciBX publication or website may be copied, reproduced, glycerol (2-AG) in the brain, which acted through the cannabinoid retransmitted, disseminated, sold, distributed, published, broadcast, circulated, commercially exploited or used to create derivative works without the written receptors to decrease pain [b]. The team has now shown that in a consent of the Publishers. Information provided by the SciBX publication and mouse model of neuroinflammation, inhibiting MAGL lowers the website is gathered from sources that the Publishers believe are reliable; however, production of arachidonic acid to decrease levels of inflammatory the Publishers do not guarantee the accuracy, completeness, or timeliness of the information, nor do the Publishers make any warranties of any kind regarding the prostaglandins and blunt inflammation in the brain [c]. information. The contents of the SciBX publication and website are not intended as In a mouse model of neurotoxin-induced Parkinson’s disease investment, business, tax or legal advice, and the Publishers are not responsible for (PD), a mAGL inhibitor reduced neuroinflammation and dopaminer- any investment, business, tax or legal opinions cited therein. gic neurodegeneration
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