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Surprise in Lab Helps ID Drug to Fight ALS

Study shows apocynin almost doubles life span of mice with inherited Lou Gehrig's disease

THURSDAY, Jan. 24 (HealthDay News) -- A drug that nearly doubles the life span of mice with inherited amyotrophic lateral sclerosis (ALS) has been identified by University of Iowa researchers, who made the finding after discovering an unexpected reaction between proteins in the lab.

The study results, published online Jan. 24 in The Journal of Clinical Investigation, may lead to treatments for some forms of ALS (also known as Lou Gehrig's disease), a fatal neurodegenerative disease that destroys motor nerve cells in the brain and spinal cord.

The researchers were studying the basic biology of cell signaling when they made the unexpected discovery that superoxide dismutase-1 (SOD1) -- a protein that's mutated in inherited forms of ALS -- interacts with Rac1, a protein that regulates production of reaction oxygen species (ROS) by the Nox2 protein complex.

ROS is essential for normal cell function, but abnormal ROS production is a suspected cause of ALS and other neurodegenerative diseases.

This unexpected interaction prompted the researchers to take a closer look.

They first found that deletion of the Nox2 protein almost doubled the life span of mice with inherited ALS. This provided further evidence that Nox-2 generated ROS may play a role in ALS progression. The researchers then found that a drug called apocynin, which blocks Nox2, slows ALS progression and increases life span of mice with inherited ALS.

About 5 percent to 10 percent of ALS cases in the United States are inherited, while 90 percent to 95 percent of ALS cases are not inherited and can affect anyone.

There are no mouse models for sporadic ALS, so the researchers were unable to test whether apocynin has any effect on sporadic ALS. The researchers also noted that extensive safety and efficacy testing in pre-clinical trials must be conducted to determine if apocynin is effective in people.

The discovery of the interaction between SOD1 and Rac1 may prove to have widespread importance.

"It is exciting not only from the standpoint of ALS, but also because of its implications for understanding basic cell biology. Rac1 is implicated in many cellular processes including cellular migration, proliferation and differentiation, and is an important component of inflammatory disease processes," team leader John Engelhardt, head of anatomy and cell biology at UI's Roy J. and Lucille A. Carver College of Medicine, said in a prepared statement.

More information

The Muscular Dystrophy Association has more about ALS.

-- Robert Preidt

SOURCE: University of Iowa, news release, Jan. 24, 2008

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