A team of scientists from the Medical Research Council (MRC) in the UK have found two drugs, which block brain cell death and prevent neurodegeneration in preclinical studies. Their findings were published today in Brain.
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 as well as prion diseases. In previous studies, the team found that the accumulation of misfolded proteins in mice with prion disease over-activates a natural defense 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.
In the latest study, published today in Brain, the team tested 1040 compounds from the National Institute for Neurological Disorders and Stroke. They found a number of suitable candidate compounds that could be tested in models of prion disease and a form of frontotemporal dementia (FTD), both of which causes minimal side effects.
The researchers identified two drugs that restored protein production rates in mice—trazodone hydrochloride, a licensed antidepressant, and dibenzoylmethane (DBM), a drug now in clinical trials to treat cancer. 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, was today announced as one of the five associate directors of the UK Dementia Research Institute. She said:
“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 two to three 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.
Halliday, M et al. Repurposed drugs targeting eIF2α-P-mediated translational repression prevent neurodegeneration in mice. Brain; 20 April 2017; DOI: 10.1093/brain/awx074