Two existing drugs have shown promise for the treatment of neurodegenerative disease, after halting brain cell death in mice.
In a new study, researchers from the Medical Research Council (MRC) in the United Kingdom reveal how a licensed antidepressant and a compound currently being trialled as a cancer drug blocked brain cell death, reduced brain shrinkage, and restored memory in mouse models of prion disease and frontotemporal dementia (FTD).
Study leader Prof. Giovanna Mallucci, of the MRC's Toxicology Unit and the University of Cambridge in the U.K., and colleagues believe that their findings could lead to much-needed treatments for Alzheimer's disease and other neurodegenerative diseases in as little as 2 to 3 years.
Clinical trials are needed to determine the safety and efficacy of the compounds for neurodegenerative disease in humans, but the fact that one of the compounds is already used for the treatment of depression could speed up the process.
Prof. Mallucci and her team recently reported their findings in the journal Brain.
Restoring protein production in brain cells
Neurodegenerative disease is an umbrella term for numerous conditions that involve the damage and loss of brain cells. Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis are all examples of neurodegenerative disease.
In a study published in 2013, Prof. Mallucci and her team uncovered a specific pathway that contributes to brain cell death.
The researchers found that misfolded proteins in the brain - which are abundant in the brains of patients with Alzheimer's and other neurodegenerative disorders - over-activate an unfolded protein response, which hampers the production of new proteins in brain cells. This "starves" the brain cells and kills them.
In their 2013 study, the team used an experimental drug to reactivate protein production in brain cells. While it was successful in halting brain cell death, the compound was toxic to the pancreas and unsafe for human testing.
Now, the researchers have identified two new compounds that have not only proven effective for preventing brain cell death in mice, but they also had minimal side effects.
Neurodegeneration prevented in mice
For the new study, Prof. Mallucci and colleagues tested more than 1,000 compounds on roundworms, or Caenorhabditis elegans. The team notes that roundworms have a functioning nervous system and are commonly used to screen drugs that might be effective in mammals.
The researchers identified a number of compounds that showed promise for restoring protein production in the brain cells of neurodegenerative disease mouse models.
The team then tested these compounds on mouse models of prion disease - a group of neurodegenerative diseases caused by proteins called prions, which prompt the misfolding of healthy proteins - and a familial form of FTD.
FTD is a type of dementia caused by the loss of brain cells in the frontal lobes of the brain.
Two compounds were found to be effective: trazodone and dibenzoylmethane (DBM). Trazodone is a medication used for the treatment of depression, while DBM is a licorice-derived compound currently undergoing testing as an anti-cancer drug.
In most of the mouse models of prion disease, both drugs prevented signs of brain cell death by recovering protein production, and in FTD mouse models, the drugs restored memory.
Additionally, the researchers found that the drugs led to a decrease in brain shrinkage in both mouse models. Brain shrinkage is a hallmark of neurodegenerative disease.
The team notes that the side effects of both drugs were minimal.
An 'exciting first step' for the treatment of neurodegenerative disease
The next step for the researchers is to conduct clinical trials to determine the safety and efficacy of trazodone and DBM for the treatment of neurodegenerative disease in humans.
Trazodone is the most promising candidate, since its safety has already been established in humans.
"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 to 3 years whether this approach can slow down disease progression, which would be a very exciting first step in treating these disorders."
Prof. Giovanna Mallucci
Dr. Doug Brown, director of research and development at the Alzheimer's Society in the U.K., says that he is "excited by the potential of these findings."
"They show that a treatment approach originally discovered while researching prion disease might also work to prevent the death of brain cells in some forms of dementia," he adds.
"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."