Rejected neurodegeneration drug partially rehabilitated
An international team of researchers, led by Professor of neurology and psychiatry Sam Gandy from Mount Sinai Medical School, New York, demonstrated that the drug latrepiridine, formerly known as dimebone, in a mouse model reduces the levels of at least two proteins associated with neurodegeneration. The authors believe that the drug has great potential as a treatment for Parkinson's and Alzheimer's diseases, sleep disorders and other neurodegenerative diseases.
In 1983, latrepiridine received official approval in Russia as an antihistamine. However, in the 90s, scientists showed the effectiveness of the drug against early animal models of Alzheimer's disease. The results of a phase II clinical trial conducted in Russia under the supervision of a commission of medical experts from the United States also indicated a significant stable improvement in the cognitive behavior of patients with Alzheimer's disease. At the same time, taking the drug caused only minimal side effects. However, a later phase III clinical trial conducted in the United States did not show any improvement in patients with Alzheimer's disease. After that, disappointed sponsors stopped funding clinical trials of the drug.
Even before the failure of the last clinical study, Professor Gandhi, who is the director of the Center for Cognitive Health, part of the Mount Sinai structure, and his group began to study the mechanisms by which latrepirdin exerts its effect.
Despite the unsuccessful attempt to reproduce the positive results of the Russian study, the authors received unexpected evidence that latrepiridine is a potential treatment for a number of neurodegenerative diseases. The results of their work indicate that this compound prevents neurodegeneration through several mechanisms.
The results of earlier work showed that in a mouse model latrepiridine blocked the toxicity of beta-amyloid aggregates by triggering autophagy in the brains of animals with simulated Alzheimer's disease. The essence of the experiment was that animals with early stages of the disease were randomly divided into 2 groups, one of which was given latrepiridine, and the other was given a placebo.
In the latest study, the drug was tested on three different model systems – yeast, mice and mammalian cells – prone to the accumulation of alpha-synuclein protein, known as the cause of neurodegeneration.
Scientists have found that in all three systems latrepiridine activated autophagy – the "self-eating" of cells that protects the brain from degeneration. This process was directed against cells with alpha-synuclein deposits and prevented the toxic effect of this protein on the brain. The data obtained indicate that latrepiridine simultaneously stimulates the destruction of alpha-synuclein and protects cells from poisoning by this protein.
However, to their surprise, the researchers found that by protecting yeast cells from the influence of alpha-synuclein, latrepiridine does not prevent their death as a result of the toxic action of proteins that kill neurons in Huntington's disease and a wide range of other neurodegenerative diseases, including Lou Gehrig's disease, amyotrophic lateral sclerosis and frontotemporal dementia.
The authors believe that a clinical trial of the drug conducted in the USA failed due to a lack of information about the mechanisms of its operation. It is possible that many participants in the Russian study had a form of Alzheimer's disease characterized by the accumulation of alpha-synuclein, which caused their increased susceptibility to latrepiridine. This form of the disease occurs in about a third of patients.
Currently, Professor Gandhi's group is studying the possibilities of using latrepiridine for the treatment and prevention of diseases associated with high levels of alpha-synuclein, such as Parkinson's disease; dementia accompanied by the formation of Levi's bodies, and disorders of the rapid phase of sleep.
Article by J W Steele et al. Latrepirdine stimulates autophagy and reduces accumulation of alfa-synuclein in cells and in mouse brain published in the journal Molecular Psychiatry.
Evgeniya Ryabtseva
Portal "Eternal youth" http://vechnayamolodost.ru based on the materials of Mount Sinai Medical Center:
Rejected Drug Could Protect Against Parkinson's And Alzheimer's.
16.08.2012