Test reveals effectiveness of potential Huntington's disease drugs

A test using cultured cells provides an effective way to screen drugs against Huntington's disease and shows that two compounds – memantine and riluzole – are most effective at keeping cells alive under conditions that mimic the disorder, UT Southwestern Medical Center researchers report.

"These drugs have been tested in a variety of Huntington's disease models and some HD human trials and results are very difficult to interpret," said Dr. Ilya Bezprozvanny, associate professor of physiology and senior author of the study, available online and published in today's issue of Neuroscience Letters. "For some of these drugs conflicting results were obtained by different research groups, but it is impossible to figure out where the differences came from because studies were not conducted in parallel.

"We systematically and quantititatively tested the clinically relevant drugs side-by-side in the same HD model. That has never been done before," said Dr. Bezprozvanny.

Huntington's disease is a fatal genetic disorder, manifesting in adulthood, in which certain brain cells die. The disease results in uncontrolled movements, emotional disturbance and loss of mental ability. The offspring of a person with Huntington's have a 50 percent chance of inheriting it.

More than 250,000 people in the United States have the disorder or are at risk for it. There is no cure, but several drugs are used or are being tested to relieve symptoms or slow Huntington's progression.

The disease affects a part of the brain called the striatum, which is involved in the control of movement and of "executive function," or planning and abstract thinking. It primarily attacks nerve cells called striatal medium spiny neurons, the main component of the striatum.

Dr. Bezprozvanny's group previously demonstrated that Huntington's striatal neurons are oversensitive to glutamate, a compound that nerve cells use to communicate with each other.

In the latest UT Southwestern study, the researchers cultured striatal spiny neurons from the brains of mice genetically engineered to express the mutant human Huntington gene. As predicted, glutamate killed the Huntington's neurons, but the scientists also tested five clinically relevant glutamate inhibitors to assess their protective ability.

Folic acid has been suggested as a treatment for people with Huntington's because it interacts with homocysteine, a compound that makes nerve cells more vulnerable to glutamate. Gabapentin and lamotrigine, both glutamate inhibitors, are used in epilepsy treatment and as a mood stabilizer, respectively. These three compounds did not significantly protect the cultured cells.

However, a drug called memantine, which is used to treat Alzheimer's disease, and riluzole, used in amyotrophic lateral sclerosis, did protect the cells. Memantine demonstrated a stronger effect in the study. Memantine has also shown evidence of retarding the progression of Huntington's in people, while riluzole has helped relieve some symptoms.

"Our results provide the first systematic comparison of various clinically relevant glutamate pathway inhibitors for HD treatment and indicate that memantine holds the most promise based on its in vitro efficacy," Dr. Bezprozvanny said. "Whole animal studies of memantine in an HD mouse model will be required to validate these findings."

Source: UT Southwestern Medical Center

Related stories:

FDA approves first drug for Huntington's disease
The U.S. Food and Drug Administration today approved tetrabenazine, the first drug approved for use in the United States to treat Huntington's disease, a fatal, inherited neurodegenerative disorder for which there is no cure. The action comes about eight months after an advisory panel unanimously voted to advise FDA to make the medication available to treat the disease.
Scientists create 20 disease-specific stem cell lines
(PhysOrg.com) -- Harvard Stem Cell Institute researcher George Q. Daley, associate director of the Stem Cell Program at Children's Hospital Boston, has with HSCI colleagues Chad Cowan and Konrad Hochedlinger of Massachusetts General Hospital produced a robust new collection of disease-specific stem cell lines, all of which were developed using the new induced pluripotent stem cell (iPS) technique. The work is described in a paper published in today's online edition of the journal Cell.
Researchers uncover mechanism of action of antibiotic able to reduce neuronal cell death in brain
Virginia Commonwealth University researchers have discovered how an antibiotic works to modulate the activity of a neurotransmitter that regulates brain functions, which eventually could lead to therapies to treat Alzheimer’s disease, Huntington’s disease, epilepsy, stroke, dementia and malignant gliomas.
Spit tests may soon replace many blood tests
One day soon patients may spit in a cup, instead of bracing for a needle prick, when being tested for cancer, heart disease or diabetes. A major step in that direction is the cataloguing of the “complete” salivary proteome, a set of proteins in human ductal saliva, identified by a consortium of three research teams, according to an article published today in the Journal of Proteome Research. Replacing blood draws with saliva tests promises to make disease diagnosis, as well as the tracking of treatment efficacy, less invasive and costly.
Promising new drug targets identified for Huntington's disease
Research funded by the Wellcome Trust has provided a number of promising new drug targets for Huntington's disease, a neurodegenerative disease. Scientists at the University of Cambridge have identified a number of candidate drugs to investigate further which encourage cells to "eat" the malformed proteins that lead to the disease.
US stands to lose a generation of young researchers
Five consecutive years of flat funding the budget of the National Institutes of Health (NIH) is deterring promising young researchers and threatening the future of Americans’ health, a group of seven preeminent academic research institutions warned today.
New stem cell technique improves genetic alteration
UC Irvine researchers have discovered a dramatically improved method for genetically manipulating human embryonic stem cells, making it easier for scientists to study and potentially treat thousands of disorders ranging from Huntington’s disease to muscular dystrophy and diabetes.
Rusty Worms in the Brain
Iron is vital to human life; for example, it is a component of hemoglobin, the substance that makes our blood red and supplies our cells with oxygen. However, iron can also cause heavy damage; it is thought that iron deposits in the brain contribute to certain forms of neurodegenerative diseases such as Parkinsons’s, Huntington’ s, and Alzhiemer’s.

News discussion:

Medicine & Health news