Several years ago, a team of researchers from the Medical Research Council (MRC) discovered a significant pathway that causes brain cells to die in mice. Now, these researchers have discovered that two common antidepressant drugs are capable of blocking the pathway and preventing neurodegeneration. The side effects of the drugs were minimal in mice – only one of the drugs was previously licensed for use in humans and now ready for clinical trials.
In some neurodegenerative diseases, misfolded proteins build up in the brain. These proteins are a significant factor in dementias, such as Parkinson’s and Alzheimer’s, along with prion diseases. The researchers already discovered the accrual of misfolded proteins in the brain cells of mice with prion disease over activates a natural defense mechanism that “switches off” the essential production of new proteins. Utilizing an experimental drug, the researchers were able to switch the protein production back on, which in turn halted neurodegeneration. The major downside to the drug utilized in this study is it was toxic to the pancreas, rendering it unsuitable for testing in humans.
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The same teach of researchers tested 1040 compounds in Caenorhabditis elegans, a 558-celled worm with a functioning nervous system, making it a prime model organism for screening drugs to be utilized first on the nervous system and eventually in mammalian cells. In this study, a handful of fitting candidate compounds were revealed, so they could now be tested in mice with prion disease and a type of familial tauopathy (FTD – frontotemporal dementia), which had been inoculated by the experimental compounds that were found to be toxic on the pancreas.
Two drugs, Hydrochloride and Trazodone, were identified that could restore protein production rates in mice. Both drugs are a dibenzoylmethane (DBM) and antidepressant. DBM is currently being tested as a cancer treatment drug. When the mice with prion disease were induced with those drugs, the signs of brain cell damage were undetectable and the mice with FTD showed improved memory. The drugs decreased brain shrinkage, characteristic in neurodegenerative disease, in both mouse models.
The lead researcher and professor at MRC Toxicology Unit, Giovanna Mallucci, 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 brains cells in mice with neurodegeneration also applies to people in 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 study was published in the journal Brain on April 19, 2017.