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A team of scientists from the Medical Research Council (MRC) have identified two drugs which block the pathway to brain cell death and prevent neurodegeneration.
The trial, which was conducted on mice, caused minimal side effects and one is already licensed for use in humans, so is ready for clinical trials.
The scientists explained that misfolded proteins build up in the brain in several neurodegenerative diseases and are a major factor in dementias such as Alzheimer’s and Parkinson’s diseases. Previously, the team found that the accumulation of misfolded proteins in mice with prion disease over-activates a natural defence mechanism, ‘switching off’ the vital production of new proteins in brain cells.
They then found switching protein production back on with an experimental drug halted neurodegeneration. However, the drug tested was toxic to the pancreas and not suitable for testing in humans.
However, in the latest study, published in Brain, the team tested 1040 compounds from the National Institute for Neurological Disorders and Stroke, first in worms (C.elegans) and then in mammalian cells.
The researchers identified two drugs that restored protein production rates in mice – trazodone hydrochloride, a licensed antidepressant, and dibenzoylmethane (DBM), a compound being trialled as an anti-cancer drug. Both drugs prevented the emergence of signs of brain cell damage in most of the prion-diseased mice and restored memory in the FTD mice. In both mouse models, the drugs reduced brain shrinkage which is a feature of neurodegenerative disease.
Professor Giovanna Mallucci, who led the team from the Medical Research Council’s (MRC) Toxicology Unit in Leicester and the University of Cambridge, commented: “We know that trazodone is safe to use in humans, so a clinical trial is now possible to test whether the protective effects of the drug we see on brain cells in mice with neurodegeneration also applies to people in the early stages of Alzheimer’s disease and other dementias. We could know in 2-3 years whether this approach can slow down disease progression, which would be a very exciting first step in treating these disorders.
“Interestingly, Trazodone has been used to treat the symptoms of patients in later stages of dementia, so we know it is safe for this group. We now need to find out whether giving the drug to patients at an early stage could help arrest or slow down the disease through its effects on this pathway.”
Dr Doug Brown, director of Research and Development at the Alzheimer's Society, said: “We’re excited by the potential of these findings. They show that a treatment approach originally discovered in mice with prion disease might also work to prevent the death of brain cells in some forms of dementia. This research is at a very early stage and has not yet been tested in people - but as one of the drugs is already available as a treatment for depression, the time taken to get from the lab to the pharmacy could be dramatically reduced.
“The drug blocks a natural defence mechanism in cells which is overactive in the brains of people with frontotemporal dementia, Alzheimer’s disease and Parkinson’s, so has the potential to work for several conditions. So far it has only been tested in mice with frontotemporal dementia but Alzheimer’s Society is now funding the researchers to test it in models of Alzheimer’s too.”
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