9 January 2008
Amsterdam — In a study published this month in the Journal of Alzheimer’s Disease, researchers from the University of Aberdeen report that the drug memantine, used for the treatment of Alzheimer’s disease and praised as “the first and only representative of a new class of Alzheimer drugs” works in fact similar to other existing compounds, and is beneficial only in a narrow concentration range. They further indicate that the complex pharmacological profile of memantine requires careful consideration concerning suitable doses and suitable patient groups, so that the best use can be achieved for patients suffering from Alzheimer’s disease.
Dementia is an ever-increasing problem in today’s aging societies, with millions of patients and their carers affected worldwide. About one in five people over the age of 80 suffers from Alzheimer’s disease, the most common type of dementia. There is no cure and little hope is available for treatment, thus leaving the prospect of years or even decades of progressive mental deterioration.
In Alzheimer’s disease, two systems necessary for the communication of brain cells fail: The stimulatory brain messenger acetylcholine is down-regulated, while over-activation of the messenger glutamate leads to the death of neurones.
The first-generation of compounds aimed to boost the brain’s acetylcholine levels led to the development of drugs such as Aricept™ (donepezil) and Excelon™ (rivastigmine). Attempts to develop drugs that block the action of glutamate by a considerable number of pharmaceutical companies and researchers were not successful for a long time, since these receptors are also required for normal brain function, learning and memory in particular. It was therefore considered a major breakthrough when a drug called memantine was discovered to have beneficial effects in Alzheimer’s disease, which did not affect the normal function of glutamate signalling, but only the excessive actions leading to cell death. Memantine (trade names: Namenda™, Axura®, Ebixa®) was approved in 2002 by the European Agency for the Evaluation of Medicinal Products and in 2003 by the US FDA (Food and Drug Administration) for the treatment of moderate-to-severe Alzheimer’s disease. The arrival of this compound was greeted with great expectations since it could potentially be beneficial not only for Alzheimer’s disease, but also for other brain disorders that involve excess glutamate stimulation, such as trauma and stroke.
In the UK, much debate has centred on the recommendation of drugs which may help Alzheimer patients with day to day tasks. Cost-benefit analysis has led NICE (National Institute for Clinical Excellence (http://guidance.nice.org.uk/TA111/) to issue guidelines limiting the availability of Alzheimer-related drugs to specific patient groups. This decision has been widely criticized by patient representatives and Alzheimer support charities such as the Alzheimer’s Research Trust.
In the present study, researchers report that memantine has a much more complex pharmacological profile than originally described. It does in fact work rather similar to the originally introduced drugs that affect acetylcholine-related signalling, in addition to weak actions on glutamate, and has negative effects on neuronal communication at high concentrations. At lower concentrations, memantine was able to enhance signalling between neurones of the hippocampus (the main brain area affected in Alzheimer’s disease) and was indeed able to reverse learning and memory deficits. However, a pharmacological analysis showed that this was not due to its ability to block glutamate signalling, but rather to an additional and more potent action on the acetylcholine system.
Therefore, the investigators’ data do confirm that memantine shows promising aspects for the treatment of AD, but only in a narrow concentration range. More importantly, its complex pharmacological profile requires careful considerations concerning suitable doses and suitable patient groups, so that the best use can be achieved for patients suffering from Alzheimer’s disease.
Lead investigator Dr. Bettina Platt, University of Aberdeen, Institute of Medical Sciences, commented, “Clearly, the claim that memantine’s beneficial action is due to the reduction of glutamate signalling needs to be revised. It is highly unlikely that compounds directly targeting glutamate receptors will be successfully introduced into the clinic, since major side-effects must be expected.”
The article, "Memantine acts as a cholinergic stimulant in the mouse hippocampus" by Benjamin D. Drever, William G.L. Anderson, Helena Johnson, Matthew O’Callaghan, Sangwon Seo, Deog-Young Choi, Gernot Riedel, Bettina Platt, appears in the Journal of Alzheimer’s Disease, Volume 12, Issue 4 published by IOS Press.