Scientists discover two repurposed drugs that arrest neurodegeneration in mice

April 20, 2017
Scientists discover two repurposed drugs that arrest neurodegeneration in mice
PET scan of a human brain with Alzheimer's disease. Credit: US National Institute on Aging, Alzheimer's Disease Education and Referral Center

A team of scientists who a few years ago identified a major pathway that leads to brain cell death in mice, have now found two drugs that block the pathway 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.

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. Previously, the team found that the accumulation of misfolded proteins in with prion disease over-activates a natural defence mechanism, 'switching off' the vital production of new proteins in . They then found switching protein production back on with an experimental 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 1,040 compounds from the National Institute for Neurological Disorders and Stroke, 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. This revealed a number of suitable candidate compounds that could then be tested in mouse models of prion disease and a form of familial tauopathy (frontotemporal dementia - FTD), both of which had been protected by the experimental - but toxic - compounds in the team's previous studies.

The researchers identified two drugs that restored 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 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 is now based at 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 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: "This study builds on previous work by this team and is a great example of how really innovative discovery science can quite quickly translate into the possibility of real drugs to treat disease."

Dr Doug Brown, Director of Research and Development at the Alzheimer's Society, said: "We're excited by the potential of these findings. They show that a treatment approach originally discovered in mice with might also work to prevent the death of cells in some forms of dementia. 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."

Explore further: Researchers 'switch off' neurodegeneration in mice

More information: Mark Halliday et al. Repurposed drugs targeting eIF2α-P-mediated translational repression prevent neurodegeneration in mice, Brain (2017). DOI: 10.1093/brain/awx074

Related Stories

Researchers 'switch off' neurodegeneration in mice

May 8, 2012
Researchers at the Medical Research Council (MRC) Toxicology Unit at the University of Leicester have identified a major pathway leading to brain cell death in mice with neurodegenerative disease. The team was able to block ...

Alzheimer's advance: Early stage study in mice show new drugs restore memory loss and prolong life

December 19, 2016
"We have treated mice with a new type of drug, and found that these drugs can not only improve symptoms of brain degeneration, such as cognitive decline, but can also extend the life-span of these terminally-sick mice. Our ...

Boosting a cell-protecting protein may help slow Alzheimer's disease progression

March 2, 2017
A new study of Alzheimer's disease by Fiona Kerr and Linda Partridge at University College London, uses mouse and fruit fly models to show that Keap1, which inhibits the protective protein Nrf2, is a promising target for ...

Caffeine boosts enzyme that could protect against dementia, study finds

March 7, 2017
A study by Indiana University researchers has identified 24 compounds—including caffeine—with the potential to boost an enzyme in the brain shown to protect against dementia.

Treatment approach used in cancer holds promise for Alzheimer's disease

October 21, 2016
Researchers have developed a novel treatment that could block the development of Alzheimer's disease using microscopic droplets of fat to carry drugs into the brain. This treatment approach, which is used to target drugs ...

Lab mice breakthrough offers Alzheimer's hope (Update)

October 10, 2013
Scientists on Thursday said they had tested a drug that in mice prevented the death of brain cells, boosting hopes in the fight against Alzheimer's, Parkinson's and other neurodegenerative diseases.

Recommended for you

The neural codes for body movements

July 21, 2017
A small patch of neurons in the brain can encode the movements of many body parts, according to researchers in the laboratory of Caltech's Richard Andersen, James G. Boswell Professor of Neuroscience, Tianqiao and Chrissy ...

Faulty support cells disrupt communication in brains of people with schizophrenia

July 20, 2017
New research has identified the culprit behind the wiring problems in the brains of people with schizophrenia. When researchers transplanted human brain cells generated from individuals diagnosed with childhood-onset schizophrenia ...

Scientists discover combined sensory map for heat, humidity in fly brain

July 20, 2017
Northwestern University neuroscientists now can visualize how fruit flies sense and process humidity and temperature together through a "sensory map" within their brains, according to new research.

Scientists reveal how patterns of brain activity direct specific body movements

July 20, 2017
New research by Columbia scientists offers fresh insight into how the brain tells the body to move, from simple behaviors like walking, to trained movements that may take years to master. The discovery in mice advances knowledge ...

Team traces masculinization in mice to estrogen receptor in inhibitory neurons

July 20, 2017
Researchers at Cold Spring Harbor Laboratory (CSHL) have opened a black box in the brain whose contents explain one of the remarkable yet mysterious facts of life.

Speech language therapy delivered through the Internet leads to similar improvements as in-person treatment

July 20, 2017
Telerehabilitation helps healthcare professionals reach more patients in need, but some worry it doesn't offer the same quality of care as in-person treatment. This isn't the case, according to recent research by Baycrest.

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.