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A second drug, xamoterol, which activates a specific subset of norepinephrine receptors, had the same effect. However, xamoterol has undesirable side effects–it is a cardiac stimulant currently used to treat heart failure, making it an unlikely candidate for a Down syndrome drug.

L-DOPS was originally developed in Japan as a potential therapy for Parkinson’s disease. It is already sold in Asia for treatment of orthostatic hypotension and is currently being tested in clinical trials in the United States for orthostatic hypotension, fibromyalgia, and attention-deficit hyperactivity disorder (ADHD). Drugs that boost norepinephrine activity by blocking its re-uptake are also available, including atomoxetine (Strattera), which is approved for treatment of ADHD. Salehi now plans to test that drug in mice.

Norepinephrine drugs aren’t the first to show promise for treating the cognitive problems of Down syndrome. For example, memantine, a drug currently used to treat Alzheimer’s disease, also improves cognitive function in animal models of Down syndrome. A clinical trial of the drug in people with the disorder is currently underway. Small studies of a second Alzheimer’s drug, donepezil (Aricept), have shown mixed results in people with Down syndrome.

“Down syndrome is a very complex genetic disorder,” says Frances Wiseman, a scientist at University College London who wrote a commentary accompanying the article. “Therefore it’s likely that a combination of therapies will be needed to treat different aspects of learning and memory.”

Experts say that conducting large clinical trials of these drugs will be a challenge–scientists must develop reliable ways to measure improvement in the types of learning and memory that are most affected in the disorder, and then recruit enough people from the relatively small Down syndrome population to provide the statistical power to detect an improvement. Salehi cautions parents against trying these drugs before they have been tested in large, placebo-controlled clinical trials. “Just because a drug works in mice doesn’t guarantee the same effects in humans,” he says.

Researchers attribute recent advances to a growing understanding of the mechanisms underlying the disorder. “The ability to study the neurophysiology in the animal brain at least is becoming much more sophisticated,” says Charles Epstein, a physician and scientist at the University of California, San Francisco. Epstein says there have been big improvements in researchers’ ability “to look at specific systems and how they function and what might be beneficial in those systems.”

The new findings may also be relevant to Alzheimer’s disease. Patients with Alzheimer’s also show damage in the locus coeruleus, and virtually everyone with Down syndrome develops the plaques and tangles in the brain that characterize Alzheimer’s. To date, few people have studied the effects of drugs such as l-DOPS on Alzheimer’s patients, says Paul Aisen, a physician and scientist at the University of California, San Diego, director of the Alzheimer’s Disease Cooperative Study, and one of the authors on the current study. “This study suggests that we need to explore this strategy further.”

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Credit: National Human Genome Research Institute

Tagged: Biomedicine, Alzheimer's, Down Syndrome, chromosomes

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