Aspirin is one of the most versatile drugs known. It reduces pain, fever, clotting, and inflammation and lowers the risk of heart disease, colon cancer, and possibly breast cancer. Yet for much of its existence, aspirin has remained as much mystery as miracle.
Recently, aspirin revealed some of its secrets, which paves the way for what may become a new, more effective anti-inflammatory drug. The research was conducted by NIGMS grantee Dr. Charles Serhan of Brigham and Women's Hospital and Harvard Medical School.
Several years ago, Dr. Serhan noted that separate long-term studies linked aspirin with a reduced risk of breast and colon cancer. Neither study could explain why. Using the techniques of structural biochemistry, Dr. Serhan set out to do so.
Traditionally, aspirin was thought to reduce pain and clotting by blocking the synthesis of two natural compounds--prostaglandins and thromboxanes. Yet no one knew how aspirin alleviated inflammation. In 1997, Dr. Serhan dislodged the common dogma of aspirin's action and elucidated its anti-inflammatory role. He found that aspirin does not merely block the synthesis of prostaglandins and thromboxanes, it also triggers a biochemical pathway that produces the body's own potent anti-inflammatory molecule, 15-epi-lipoxin A4.
He then designed and synthesized a series of chemical variations on the molecule and applied them to inflamed mouse ears. He found that one of the synthetic variations reduced inflammation by 85 percent, making it more effective than aspirin and twice as potent as dexamethasone, a steroid that is one of the most powerful anti-inflammatory agents known.
Dr. Serhan has since modified his synthetic molecule to shield it from the body's degradative enzymes and to make it more easily absorbed as a drug. He has also identified a receptor in the body that binds to the molecule and facilitates its effects.
This work has piqued commercial interest. Dr. Serhan is now collaborating with Berlex Biosciences, a pharmaceutical company, to chemically massage the molecule into a form that might be an effective anti-inflammatory drug for topical delivery. Now that he has worked out details of how the molecule functions in the body, he will attempt to design a drug that offers the benefits of both aspirin and topical steroids without the negative side effects of these widely used drugs. He continues to study how the anti-inflammatory effects of aspirin play a role in reducing the risk of breast and colon cancer.
Sections of mouse ear as seen under a microscope:
Previously inflamed tissue treated with one of Dr. Serhan's synthetic anti-inflammatory molecules
Images reproduced from The Journal of Experimental Medicine, 1997, Vol. 185, No. 9, pp. 1693-1704 by copyright permission of The Rockefeller University Press.
Takano T, Fiore S, Maddox JF, Brady HR, Petasis NA, Serhan CN. Aspirin-triggered 15-Epi-Lipoxin A 4 (LXA 4) and LXA 4 Stable Analogues Are Potent Inhibitors of Acute Inflammation: Evidence for Anti-inflammatory Receptors. J. Exp. Med. Vol. 185, No. 9, May 5, 1997:1693-1704.
The full text of the journal article is available at http://www.jem.org/cgi/content/full/185/9/1693.
Reporters may call Alisa Zapp Machalek at (301) 496-7301 to obtain the name of a scientist in the NIGMS Division of Pharmacology, Physiology, and Biological Chemistry who can comment on this work.
This page last reviewed on
10/22/2018 9:37 AM
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