Shaking Off the (Brain) Rust
Researchers at the Technion-Israel Institute of Technology have developed three drugs to remove excess iron from the brains of patients with neurodegenerative diseases. The presence of too much iron in the brain is a hallmark of such diseases. The drugs, VK-28, HLA-20 and M30, mop up the iron before it can trigger a "brain rust" chemical reaction where highly active oxygen particles destroy brain cells.
Professor Moussa Youdim of the Faculty of Medicine and his colleagues – Prof. Avraham Warshawsky (now deceased), Prof. Mati Fridkin and Ph.D. student Hailin Zheng from China – have received U.S. and worldwide patents on VK-28, HLA-20 and M30. Youdim says the three drugs could treat and perhaps prevent a range of diseases including Parkinson’s, Alzheimer’s, Huntington’s and amyotrophic lateral sclerosis (ALS).
Unlike other drugs currently used against these disorders – which attempt to replace the functions lost by dying neurons – these drugs halt the neuron destruction itself. Normally, iron is a helpful partner in the body’s metabolism, shuttling electrons between molecules in chemical reactions that break down fats, carbohydrates and proteins, and provide energy to cells. Because iron is so reactive, the body usually keeps tight control over the amount and activity of iron circulating in the brain and other organs.
When these control mechanisms fail, however, too much "free" iron can participate in rust-like reactions that produce damaging byproducts such as oxygen free radicals. These highly active particles hurtle themselves at cells with destructive force, collapsing and eventually killing them. The deadly bombardment might explain why neurons die off in the iron-rich brain tissue of Parkinson’s and Alzheimer’s patients, Youdim says.
Youdim and his former student, Dr. Dorit Ben Shachar, were the first to suggest that iron chelators could prevent the neurotoxicity of iron in an animal model of Parkinson’s disease with Desferal, a well-known iron chelator. Iron chelators are small molecules that bind to excess iron and prevent it from participating in chemical reactions that could damage neurons and other cells.
But they discovered that Desferal needed to be directly injected into the brain, leading to the new VK-28, which can cross into the brain via the bloodstream. The other two drugs – HLA-20 and M30 – are combination drugs. They increase Dopamine levels and remove excess iron that could cause further damage to the neurons that transmit dopamine. "Drugs with multiple actions may be more effective in controlling and treating neurodegenerative disorders," he explains.
The work of Youdim and his colleagues appears in the November 2004 Nature Review Neuroscience. The have also published several other papers on their iron chelator research, including articles in the Annals of the New York Academy of Sciences (January 2004) and Neuropharmacology (January 2004) earlier this year. They will also be published in Trends in Pharmacological Sciences later this year. The researchers are now in negotiations with several American, British and Israeli companies for development of these drugs through Varinel Inc.
Youdim also discovered and co-developed Rasagiline, a drug that boosts levels of a brain chemical called dopamine that is normally depleted in Parkinson’s patients; and Ladostigil, which boosts levels of acetylcholine in Alzheimer’s patients. Rasagiline has received a letter of approval from the FDA, while Ladostigil is currently in the clinical trials phase.
The Technion-Israel Institute of Technology is Israel’s leading science and technology university and home to the country’s only winners of the Nobel Prize in science. It commands a worldwide reputation for its pioneering work in computer science, biotechnology, water-resource management, materials engineering, aerospace and medicine. The majority of the founders and managers of Israel’s high-tech companies are alumni. Based in New York City, the American Technion Society is the leading American organization supporting higher education in Israel, with more than 20,000 supporters and 19 offices around the country.