Memantine and Alzheimer disease

Memantine has more complex pharmacological profile than originally described, works rather similarly to other drugs that affect acetylcholine-related signaling

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 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 disease.

In Alzheimer disease, 2 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 neurons.

The first-generation of compounds aimed to boost the brain’s acetylcholine levels led to the development of drugs such as donepezil (Aricept™) and rivastigmine ( Excelon™). 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 the drug memantine was discovered to have beneficial effects in Alzheimer disease, which did not affect the normal function of glutamate signaling, but only the excessive actions leading to cell death. Memantine (Namenda™, Axura®, Ebixa®) was approved in 2002 by the European Agency for the Evaluation of Medicinal Products and in 2003 by the US FDA for the treatment of moderate-to-severe Alzheimer disease. The arrival of this compound was greeted with great expectations since it could potentially be beneficial not only for Alzheimer disease, but also for other brain disorders that involve excess glutamate stimulation, such as trauma and stroke.

In the United Kingdom, much debate has centered 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 similarly to the originally introduced drugs that affect acetylcholine-related signaling, 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 signaling between neurons of the hippocampus 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 signaling, 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 Alzheimer disease, 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 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 signaling 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.”

Source: News Release
IOS Press
January 10, 2008