Researchers found two drugs that block a major pathway which leads to brain cell death in mice and prevent neurodegeneration. The drugs caused minimal side effects in the mice and one is already licensed for use in humans, so is ready for clinical trials, researchers at Medical Research Council’s (MRC) Toxicology Unit in Leicester, UK said. 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.
Many neurodegenerative diseases involve the production of faulty proteins that activate the same defences, but with more severe consequences. The brain cells shut down production for so long that they eventually starve themselves to death.
This process, repeated in neurons throughout the brain, can destroy movement, memory or even kill, depending on the disease. It is thought to take place in many forms of neurodegeneration, so safely disrupting it could treat a wide range of diseases. In the initial study, the researchers used a compound that prevented the defence mechanism kicking in. It halted the progress of prion disease in mice – the first time any neurodegenerative disease had been halted in any animal. Further studies showed the approach could halt a range of degenerative diseases.
In the latest study, published in the journal Brain, the team tested 1,040 compounds, first in worms (C elegans) which have a functioning nervous system and are a good experimental model for screening drugs to be used on the nervous system and then in mammalian cells. The researchers identified two drugs that restored protein production rates in mice – trazodone hydrochloride, a licensed antidepressant, and dibenzoylmethane, 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 frontotemporal dementia (FTD) mice. In both mouse models, the drugs reduced brain shrinkage which is a feature of neurodegenerative disease. “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,” said Professor Giovanna Mallucci, who led the team from the MRC.