Drugs found to prevent brain degeneration in mice

Brain: Repurposed drugs targeting eIF2α-P-mediated translational repression prevent neurodegeneration in mice.

Researchers in Cambridge and Leicester have identified two drugs that protect against brain damage in mice with features of neurodegenerative diseases. Their findings, which are published today (Thursday 20 April) in the journal Brain, indicate the drugs could hold potential for treating multiple brain diseases and could now be taken forward towards clinical trials in people.

Neurodegenerative diseases like Alzheimer’s involve the build-up of abnormally folded proteins that cause damage to nerve cells. These misfolded proteins can trigger a cellular defence mechanism known as the unfolded protein response (UPR). This process causes a cell to temporarily shut down normal protein production and attempt to clear away the harmful misfolded proteins. While the UPR is normally beneficial, cells need to make proteins in order to survive. If the UPR continues for too long – as in certain forms of dementia – it could cause lasting damage to cells in the brain.

A protein called eIF2α plays an important role in the UPR and has been shown to be overactive in diseases like Alzheimer’s. The researchers in this study set out to find drugs that could target this protein and limit the effects of the UPR, screening a library of over 1,000 existing drugs. Two drugs, trazodone, a licensed antidepressant and dibenzoylmethane, which is being investigated in research studies as a potential cancer treatment, showed signs of the effect they were looking for.

The researchers tested the drugs in two groups of mice with features of different degenerative brain diseases. One group had features of prion disease and the other had features of frontotemporal dementia. Prion disease is caused by the misfolded prion protein, which causes Creutzfeldt-Jakob disease (CJD) in people. Frontotemporal dementia (FTD) is a common cause of younger-onset dementia and often involves a protein called tau, which is also a hallmark of Alzheimer’s disease. In both groups of mice, the two drugs protected the brain from damage and limited memory problems. In the FTD mice, trazodone also reduced the build-up of tau protein in the brain. The findings indicate these drugs could be effective in multiple neurodegenerative diseases.

Dr David Reynolds, Chief Scientific Officer at Alzheimer’s Research UK, said:

“Neurodegenerative diseases affect more than a million people in the UK, including 850,000 with a form of dementia. The huge complexity of the brain and the difficulty of accurately diagnosing specific diseases, means that treating neurodegeneration is an enormous scientific challenge. But as researchers learn more about the brain, they are revealing more promising targets for future treatments. Despite having different underlying causes, there are common patterns in the biology of different neurodegenerative diseases. A broad-spectrum treatment that works across multiple diseases would be a significant breakthrough for those affected and their families.

“This robust research in mice highlights drugs that could help tackle more than one neurodegenerative disease, but what is true in animals does not always hold true in people. Ultimately the only way to see if the drugs identified in this study could help people with these diseases is through clinical trials in people. As trazadone is a licensed antidepressant, and already used in some cases to help manage symptoms in Alzheimer’s, information already exists about its safety. We will now need to see if long-term treatment with trazodone in the early stages of dementia could slow down damage to the brain in disease like Alzheimer’s.

“In order to develop effective drugs sooner, it is vital that researchers come at these diseases from as many different angles as possible. Alzheimer’s Research UK is working to bring about a life-changing dementia treatment by 2025, and while pioneering research like this is driving progress towards this target, such innovation must be supported with significant and sustained investment in research.”