Investigating Dimebon, a promising new drug for Alzheimer’s disease

Lead Investigator: Professor Vladimir Buchman 

Institution: University of Cardiff

Grant type: Project

Grant amount: £204,438

Start date: 01/10/10

Completion date: 25/04/14

Scientific Title: Dimebon, a new drug for treatment of Alzheimer's disease: studies of the mechanisms of disease-modifying action

The Society would like to thank the Trustees of The Milly Apthorp Charitable Trust, for their generosity, which has in part made this project possible.

What was the project, and what did the researchers do?

Previous research indicated that the antihistamine drug Dimebon could prevent the accumulation of proteins that can cause symptoms of dementia. Recently, work on the drug has slowed down as in 2012 a Phase 3 clinical trial testing the effect of Dimebon on Alzheimer's disease was unfortunately shown to be unsuccessful. 

However, the researchers still think this drug could be useful and continue to explore its effects. This project investigated the biological mechanisms of Dimebon in nerve cells using mice that showed symptoms of  Alzheimer's disease. These techniques were used to identify what part of the cell Dimebon targets and how it creates a protective effect. They also tested modified forms of the drug  to see if these had a different effect. 

What were the key results, and how will this help in the fight against dementia?

The results of the study suggest that Dimebon is able to have an effect on some of the underlying mechanisms of Alzheimer's disease. The researchers found that it reduced an Alzheimer's-related effect of the hallmark protein tau in mice showing symptoms of the condition. The modified forms of Dimebon also reduced the effect, but were no different to the results seen with than Dimebon itself. 

Despite the previously disappointing results, the researchers believe that Dimebon may still have potential as a possible treatment for Alzheimer's in the future. However they think that it may only be able to work at particular stages of the disease and in combination with other therapies. While researchers are still unclear what role Dimebon has in the cell, they have been able to rule out two major candidates through this work. This is a step forward in understanding how the drug works, and could help to make improvements in order to produce a better treatment for dementia in the future. 

What happened next? Future work and additional grants

The findings from this study have encouraged the researchers' collaborators in the IPAC (Institute of Physiologically Active Compounds) in Russia to design and produce further modified types of Dimebon. These studies have received financial support from the Russian Academy of Sciences and the first compounds produced are already being scrutinised for their activity. For one of these compounds, expanded preclinical trials started at the end of 2014. 

How were people told about the results? Conferences and Publications

Papers

S.O.Bachurin, T.A.Shelkovnikova, A.A.Ustiugov, O.Peters, I.Khritankova, M.A.Afanasieva, T.V.Tarasova, I.I.Alentov, V.L.Buchman and N.N.Ninkina (2011) Dimebon slows progression of proteinopathy in γ-synuclein transgenic mice. Neurotoxicity Research, 22, 33-42

O.Peters, N.Connor-Robson, V.B.Sokolov, A.Yu.Aksinenko, M.S.Kukharsky, S.O.Bachurin, N.N.Ninkina and V.L.Buchman (2013a) Chronic administration of dimebon ameliorates pathology in tauP301S transgenic mice. Journal of Alzheimer's Disease, 33, 1041-1049

O.Peters, T.A.Shelkovnikova, T.Tarasova, S.Springe, M.S.Kukharsky, G.A.Smith, S.Brooks, S.A.Kozin, Y.Kotelevtsev, S.O.Bachurin, N.N.Ninkina and V.L.Buchman (2013b) Chronic administration of dimebon does not ameliorate Aβ pathology in 5xFAD transgenic mice. Journal of Alzheimer's Disease, 36, 589-596

The researchers also plan to finalise and submit for publication another manuscript describing the latest data on behavioural and biochemical analysis of 5xFAD mice treated with Dimebon bioisosters.

Conference presentations

Alzheimer's Society Annual Conferences, Warwick, 16-18 September 2010 and Birmingham, 14 September 2011

Society for Neuroscience Annual Meeting, Washington, DC, 12-16 November 2011

27th International Conference of Alzheimer's Disease International, London, 7-10 March 2012

10th (Barcelona, 9-13 March 2011) and 11th (Florence, 6-10 March 2013) International Conference on Alzheimer's and Parkinson's Disease

VI Neurotoxicity Society Meeting, Valdivia, 20-24 March 2013, and 38th FEBS Congress, St. Petersburg 6-11 July 2013