Scientists say they are optimistic about possible ways of preventing dementia in humans following a study,* published today in the journal Brain, in which drugs were used in mice to stop neurodegeneration.
A team of Medical Research Council (MRC) scientists, who identified a pathway that leads to brain cell death in mice a few years ago, have now found two drugs which block the pathway and prevent neurodegeneration.
Misfoldedproteins build up in the brain in several neurodegenerative diseases and are a major factor in dementias such as Alzheimer’s and Parkinson’s as well as prion diseases.
In their previous work, the team of researchers 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, but the drug tested was toxic to the pancreas and not suitable for testing in humans.
In the latest study, published in Brain,the team tested 1,040 compounds from the National Institute for Neurological Disorders and Stroke, and eventually identified two drugs that restored protein production rates in mice.
These were the licensed antidepressant trazodone hydrochloride 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 mice with front otemporaldementia (FTD). In both mouse models, the drugs reduced brain shrinkage.
Professor Giovanna Mallucci, who led the team from the MRC’s Toxicology Unit in Leicester and the University of Cambridge, said: “We know that trazodone is safe to usein 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.”
The research was funded by the MRC and Professor Mallucci was also funded by a grant from Alzheimer’s Society and Alzheimer’s Drug Discovery Foundation.
Dr Rob Buckle, chief science officer at the MRC, said: “The two drugs identified remain experimental but they were shown to protect the mice even when given after the processes underlying neurodegeneration had become established.
“We currently have no way of treating these diseases so the prospect of finding drugs that can slow or stop them from progressing is extremely exciting.”
Dr Doug Brown, director of research and development at the Alzheimer's Society, said: “We’re excited by the potential of these findings. 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.
* Halliday M, Radford H, Zents KAM, et al. Repurposed drugs targeting eIF2α-P-mediated translational repression prevent neurodegeneration in mice. Brain, 19 April 2017, awx074. DOI:10.1093/brain/awx074