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Pain Reliever May Provide Clues for Treating Spinal Muscular Atrophy

For release: Thursday, March 3, 2005

New research suggests that an off-the-market pain reliever called indoprofen may be a starting point for finding a new drug to treat spinal muscular atrophy (SMA), a devastating childhood neurological disorder.

The discovery of the linkage between indoprofen and SMA resulted from the National Institute of Neurological Disorders and Stroke (NINDS)-sponsored Drug Screening Consortium, which screened a collection of 1040 clinically approved drugs for possible activity against amyotrophic lateral sclerosis and other neurodegenerative disorders in 2001 and 2002.

SMA is the most common genetic cause of infant mortality in the United States and Western Europe, affecting about 600 children a year in the U.S.  It results from mutations in a gene called SMN1 that lead to an abnormally low level of survival motor neuron (SMN) protein.  Without a normal amount of SMN, motor neurons in the spinal cord degenerate, causing problems with movement, muscle tone, and functions like breathing and swallowing.  There are three forms of childhood-onset SMA, which vary in severity depending on how much SMN protein is produced.  Children with type 1 SMA have very severe symptoms, never learn to sit or stand, and usually die by their second birthday.  Those with type 2 SMA usually develop symptoms in early childhood, while those with type 3 SMA may reach adolescence before showing symptoms. 

Researchers have discovered that, in addition to SMN1, a gene called SMN2 produces a small amount of SMN protein that can reduce the severity of the disease.  They have previously identified several compounds that can increase the amount of functional SMN protein produced by this gene.  Three of these drugs — valproic acid, phenylbutyrate, and hydroxyurea — are now in preliminary clinical trials.  However, these drugs have serious side effects and have not yet been shown to benefit SMA patients.  Therefore, researchers are continuing to look for drugs that can increase the amount of SMN protein with less toxicity.

In the new study, Brent R. Stockwell, Ph.D., of Columbia University, Charlotte J. Sumner, M.D., of the NINDS, and colleagues tested approximately 47,000 compounds in skin cells from SMA patients.  Of these compounds, only indoprofen and a drug called aclarubicin, both from the NINDS Drug Screening Consortium collection, increased the amount of SMN protein produced by the cells.  Indoprofen treatment increased the amount of SMN the cells produced by approximately 13 percent.  The study appears in the November 2004 issue of Chemistry & Biology.[1]

The researchers also studied the effects of indoprofen in pregnant mice to see whether indoprofen might protect embryos with SMN mutations.  They found that the drug increased the number of these embryos that survived.

Previous studies have shown that aclarubicin, a cancer drug, can increase SMN2 activity, but this study is the first to show that indoprofen may have a similar function.

While indoprofen is chemically similar to the pain reliever ibuprofen, the researchers found no benefit from treatment with ibuprofen or any other pain relievers, Dr. Stockwell says.  Indoprofen was taken off the market in the 1980s after reports of severe gastrointestinal bleeding in people who were taking the drug.  It also sometimes causes intestinal tumors in animals.  In addition, indoprofen does not readily cross the blood brain barrier, so it would not be likely to reach motor neurons at a high enough concentration to benefit SMA patients.   Because of these problems, the drug needs to be refined and carefully tested before it can be used in children with SMA, the researchers caution.

Indoprofen appears to increase the amount of functional SMN in a different way than other potential drugs for SMA.  Therefore, a combination treatment of a drug derived from indoprofen plus one of the other potential drugs may eventually prove more beneficial than either drug alone, says Dr. Stockwell.

Indoprofen and several other drugs are now under investigation as part of the NINDS-sponsored SMA Project (, an effort to accelerate drug development for SMA.  As part of the project, Dr. Stockwell is working with medicinal chemists to try to find ways of reducing indoprofen’s harmful side effects while increasing its effectiveness against SMA and its ability to cross the blood brain barrier.  Indoprofen may be useful as a tool to help identify new drugs that alter SMN activity, he says.

As part of their work, Dr. Stockwell and his colleagues developed a software tool, called Small Laboratory Information Management System (SLIMS) to help them manage and analyze the large amount of data collected during their thousands of drug screening tests.  This software is described in the November 2004 issue of Chemistry & Biology[2] and it is available free of charge to other researchers at the website

The NINDS is a component of the National Institutes of Health within the Department of Health and Human Services and is the nation’s primary supporter of biomedical research on the brain and nervous system.

-By Natalie Frazin, NINDS Office of Communications and Public Liaison

[1]Lunn MR, Root DE, Martino AM, Flaherty SP, Kelley BP, Coovert DD, Burghes AH, thi Man N, Morris GE, Zhou J, Androphy EJ, Sumner CJ, Stockwell BR.  “Indoprofen Upregulates the Survival Motor Neuron Protein through a Cyclooxygenase-Independent Mechanism.”  Chemistry & Biology, November 2004, Vol. 11, pp. 1489-1493.

[2]Kelley BP, Lunn MR, Root DE, Flaherty SP, Martino AM, Stockwell BR.  “A Flexible Data Analysis Tool for Chemical Genetic Screens.”  Chemistry & Biology, November 2004, Vol. 11, pp. 1495-1503.

Last Modified March 9, 2005