April 20, 2017

expert reaction to study investigating two repurposed drugs and neurodegeneration in mice

A study published in Brain discusses the identification of two drugs (trazodone hydrochloride, a licensed antidepressant; and dibenzoylmethane) which reportedly block the brain cell death pathway and stop neurodegeneration in mouse models of prion disease frontotemporal dementia.

Dr Payam Rezaie, Reader in Neuropathology, The Open University, said:

“The possibility for repurposing existing (clinically-approved) drugs and testing their potential therapeutic relevance across multiple modalities of human diseases is a strategy that is being pursued for a number of illnesses. Building on previous work, this study provides compelling evidence at multiple levels (molecular, cellular and whole organism) for such a strategy to be deployed for neurodegenerative diseases, showing the potential of a target compound – trazodone hydrochloride (used more conventionally as an antidepressant drug which can cross the blood-brain barrier and is apparently also tolerated well in the elderly), to operate as a ‘disease-modifying’ drug in experimental mouse models of prion disease and tauopathy-frontotemporal dementia.

“Supporting evidence is provided for neuroprotection and for the arrest of behavioural decline, irrespective of the build-up of abnormally misfolded protein aggregates (prion protein or phosphorylated tau) within the brain, following a course of treatment that was started after neurological symptoms in these mice had been established (i.e. once neurodegeneration had already advanced), meaning that the drug can potentially reduce or halt progression of disease, which would otherwise be inevitable.

“This is not a cure for neurodegenerative diseases or dementia, it will not reverse the course of illness, and the neuroprotective effects were observed in the majority of, but not in all experimental animals. Nevertheless, it could represent a significant step forward in attempting to halt these diseases in their tracks, and as the researchers state, considering its existing license for use in elderly patients, trazodone in particular would be a potential candidate for clinical trials moving forward.”

Prof. Paul Matthews, Edmond and Lily Safra Chair, Division of Brain Sciences, Imperial College London, said:

“Discoveries of new treatment targets usually hit the headlines.  Here Halliday and colleagues address the equally important question of how to find a molecule that can be used as a drug for a new target.

“In this case, they are following up on their earlier elegant work implicating a cellular stress response mediated by the protein eIF2 alpha in causing neurodegeneration by shutting down new protein synthesis in the context of pathological, misfolded brain proteins.

“The new, thorough report describes well-designed assays to allow efficient screening of compound libraries for identifying promising drug candidates able to delay or prevent neurodegeneration in animal models of Creuzfeldt-Jacob disease (“mad cow” disease) and frontotemporal dementia, a rare form of dementia typically occurring in later life.  In demonstrating the assay methods, this new report also provides evidence that a well-known anti-depressant, trazodone, is an “off the shelf” candidate treatment ready for clinical trials with these terrible diseases.  This is translational science at its best!”

Dr Doug Brown, Director of Research and Development at the Alzheimer’s Society, said:

“We’re excited by the potential of these findings, from this well-conducted and robust study.  They show that a treatment approach originally discovered in mice with prion disease might also work to prevent the death of brain 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.

“The drug blocks a natural defence mechanism in cells which is overactive in the brains of people with Alzheimer’s disease, frontotemporal dementia, a rare form of dementia, and Parkinson’s, so has the potential to work for several conditions.  So far it has only been tested in mice with frontotemporal dementia but Alzheimer’s Society is now funding the researchers to test it in models of Alzheimer’s too.”

Dr David Dexter, Deputy Director Research at Parkinson’s UK, and Visiting Professor of Neuropharmacology, Division of Brain Sciences, Imperial College London, said:

“This is a very robust and important study where Halliday and colleagues have clearly demonstrated that two repurposed drugs, Trazodone hydrochloride (a licenced antidepressant) and Dibenzoylmethane (a curcumin analogue) were neuroprotective in a prion and frontotemporal dementia mouse model.

“Protein misfolding is a common feature of several neurodegenerative disorders such as Parkinson’s and Alzheimer’s, and no disease modifying therapies currently exist.  Over-activation of the unfolded protein response (UPR), particularly the Pancreatic ER kinase (PERK) branch of the UPR, has been implicated in this process since high levels of activated PERK and its downstream target, eukaryotic initiation factor 2 (eIF2α), are found in the brains of patients affected by such disorders.  The importance of these pathways in the neurodegenerative process has been highlighted in the past since the PERK inhibitor GSK2606414 was shown to be neuroprotective, but its translation into the clinic was prevented by pancreatic toxicity.  Hence, there has been intense interest in finding a non-toxic compound which works via a similar mechanism.

“Halliday and colleagues screened 1040 compounds in the NINDS compound library, of which ~75% are FDA approved drugs, using a C. Elegans roundworm model, and lead compounds were shown to be working downstream in the PERK pathway in in vitro cell culture and in vivo models.  From these, Trazodone hydrochloride and Dibenzoylmethane were selected for testing in mice models of prion disease and frontotemporal dementia, where drug treatment was associated with a behavioural improvement due to a significant neuroprotection.  Importantly, the neuroprotective effects of Trazodone hydrochloride and Dibenzoylmethane were observed without any pancreatic toxicity.

“In conclusion, if these studies were replicated in human clinical trials, both Trazodone hydrochloride and Dibenzoylmethane could represent a major step forward in the development of disease modifying therapies for diseases like Alzheimer’s.”

Dr Mark Dallas, Lecturer in Cellular and Molecular Neuroscience, University of Reading, said:

“This study takes the focus away from tackling disease specific proteins to restore brain function and points to a global pathway that can be targeted to benefit a range of brain diseases.  Encouragingly, long term treatment, with a currently available antidepressant, prevented brain cell death in different mouse models of brain disease.

“In addition, and of interest to the Alzheimer’s community, the authors present evidence that the drug can prevent memory loss typically seen in a model of dementia in mice.

“The study presents a strong scientific basis for this global approach, but it remains to be seen if a single drug can provide widespread benefits for an array of human brain diseases.  Indeed, while this antidepressant is ready to try in human clinical trials, the timing of diagnosis of dementia or Parkinson’s and treatment will be critical to the future success of any forthcoming clinical trials.”

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.”

* ‘Repurposed drugs targeting eIF2α-P-mediated translational repression prevent neurodegeneration in mice’ by Mark Halliday et al. published in Brain on Thursday 20 April 2017. 

Declared interests

Dr Payam Rezaie: “None.”

Prof. Paul Matthews: “PMM is funded by the Medical Research Council, the National Institutes of Health Research and the EPSRC.  He receives industry support for development of a database tool for multiple sclerosis from Biogen and for imaging from GlaxoSmithKline, who both are developing drugs for neurodegeneration.  He holds stock in GlaxoSmithKline and his institution or he have received honoraria or educational support funds from Biogen, Novartis, Roche, OrbiMed Consulting and Adelphi Communications.”

Dr Doug Brown: “Dr Brown is the Director of Research and Development at Alzheimers Society who have contributed £85,000 to Professor Giovanna Mallucci’s research through their Drug Discovery programme.”

Dr Mark Dallas: “I have no conflicts of interest with this study.”

None others received.