Over 5 million people worldwide suffer from Alzheimer's disease, an incurable, progressive neurodegenerative disease that is the leading cause of dementia in the elderly, whilst around 1 million people in the U.S. suffer from Parkinson's disease, a progressive disorder that leads to muscle stiffness, tremors and slowed movements and gait.
Latrepirdine was approved in Russia in 1983 as an antihistamine. However, in the 90s, researchers discovered that the drug seemed to be effective in the earliest animal models of Alzheimer's disease. A high- profile Phase II clinical trial in Russia demonstrated that latrepirdine showed a considerable and sustained improvement in cognitive behavior in Alzheimer's patients with minimal side effects. A panel of U.S. clinical experts oversaw the trial. The panel included Mary Sano, PhD, Professor of Psychiatry and Director of the Mount Sinai Alzheimer's Disease Research Center. However, later tests of latripirdine in a U.S. Phase III trial failed to show any improvement in those affected by Alzheimer's, which prompted the sponsors to stop further clinical trials of the drug for Alzheimer's disease.
Prior to the failed trials Sam Gandy, MD, PhD, Professor of Neurology, and Psychiatry, and Director of the Mount Sinai Center for Cognitive Health and his team started investigating the way in which latrepirdine functions. Dr. Gandy declares:
"Despite the failure to replicate the positive Russian trial results in U.S. patients, we found unexpected evidence that latrepirdine had potential as a treatment for a number of neurodegenerative disorders. Our study shows that the compound prevents neurodegeneration in multiple ways and should remain a contender for battling these devastating diseases. The anti-amyloid approach - most recently exemplified by reports that a second bapineuzumab trial has failed - might only help patients if begun before the brain pathology begins to build up."
Their new study entailed administering the drug to three different systems, including yeast, mice and mammal cells that all showed a build-up of alpha-synuclein, i.e. a protein that is known to cause neurodegeneration.
They discovered determined that latrepiridine activated autophagy in all three systems, the "self-eating" process of cells that protects the brain from neurodegeneration, which targeted synuclein and protected against its toxicity. They discovered that the drug decreased the amount of synuclein accumulated in the brain of mice through autophagy.
This is the second study published in Molecular Psychiatry by Dr. Gandy's team. Their first study, which appeared in the July 31 issue, revealed that a mice study showed that latrepiridine stopped the toxicity of amyloid-beta protein accumulation by inducing autophagy in animals with Alzheimer's disease. The study entailed randomly administrating latrepirdine or placebo to mice with early stages of Alzheimer's disease, revealed that the drug improved memory through autophagy.
To his surprise, Dr. Petsko, an expert in protein structure, Professor of Neurology and Neuroscience at Weill Cornell Medical College, observed that latrepirdine protects yeast cells from the toxicity of alpha-synuclein and leaves the cells vulnerable so that they can be killed by either the Huntington's disease protein or by either of the two key proteins responsible for ALS-FTD. ALS-FTD is a range of diseases, including Lou Gehrig's disease and frontotemporal dementia.
Petsko stated: "The specificity of latrepirdine protection of yeast cells from alpha-synuclein poisoning was unexpected but highly specific and, we believe, occurs at doses of drug potentially relevant to the clinic."
Dr. Sano of the Mount Sinai Alzheimer's Disease Research Center, continued:
"We believe that the U.S. latrepirdine trial failed because of a lack of understanding of how latrepirdine works. Many of the patients in the Russian trial may have had a subtype of Alzheimer's disease that includes excess buildup of alpha-synuclein, making them more responsive to latrepirdine. We know that this occurs by chance in about one-third of Alzheimer's patients. The data indicating that latrepirdine both stimulates alpha-synuclein breakdown and protects cells from alpha-synuclein poisoning are highly intriguing."
Dr. Gandy and Dr. Yue are currently investigating potential benefits of latrepirdine for treating or preventing disorders linked to high levels of alpha-synuclein like Parkinson's disease, Lewy body dementia, and REM sleep disorder.
Written by Petra Rattue