An international team of scientists led by researchers at Mount Sinai School Medicine have discovered that a drug that had previously yielded conflicting results in clinical trials for Alzheimer's disease effectively stopped the progression of memory deterioration and brain pathology in mouse models of early stage Alzheimer's disease. The findings, published July 31, 2012 in Molecular Psychiatry, demonstrate renewed potential for this compound and could lead to clinical trials in patients with early stages of the disease.
Latrepirdine, known commercially as Dimebon, was initially sold as an antihistamine in Russia, approved for use there in 1983. In the 1990s, researchers at the Institute of Physiologically Active Compounds in Moscow determined that the compound appeared effective in treating Alzheimer's disease in animals. They continued their research in humans and performed several studies, including Phase I and II trials, all of which showed significant and sustained improvement in cognitive behavior with minimal side effects. The Phase II trials, performed in Russia, were overseen by U.S. Alzheimer's researchers, including Mary Sano, PhD, Director of the Mount Sinai Alzheimer's Disease Research Center.
However, when research was continued in the United States in a Phase III trial, the drug did not demonstrate any improvement in people with the disease, causing the sponsors to halt further clinical study of the drug in Alzheimer's disease. Some researchers have speculated that the Russian patients might have had different disease stage or subtype of Alzheimer's, and therefore were more responsive to treatment than the patients in the Phase III trials in the United States.
Before the failed trials were announced, researchers at Mount Sinai School of Medicine, led by Sam Gandy, MD, PhD, Professor of Neurology, and Psychiatry, and Director of the Mount Sinai Center for Cognitive Health, began studying the mechanism of action behind latrepirdine in the current study, which is supported by the Cure Alzheimer's Fund.
Dr. Gandy's team randomly administered either latrepirdine or placebo to mice engineered to present the early stages of Alzheimer's disease and found that the drug halted both behavioral decline and progression of neuropathology. In evaluating how latrepirdine improved memory, John Steele, PhD, a neuroscience graduate student working with Dr. Gandy, and Lenard Lachenmayer, MD, a postdoctoral fellow working under the supervision of Zhenyu Yue, PhD, Associate Professor of Neurology at Mount Sinai, found that the drug enhanced autophagy, the so-called "self-eating" process of cells that protects the brain from neurodegeneration.
"When we learned that latrepirdine failed in patients in the United States in 2010, scientists around the world were disappointed and perplexed," Dr. Gandy said. "We wanted to find out why the drug did so well in Russia but then showed no effect in the global studies. The findings from our animal model studies indicated that this drug should not be discarded, and that, if its mechanism of action can be optimized, it still has potential."