Oops! Memantine's actions really aren't all that and a bag of chips

Memantine is the most recent weapon in the fight against Alzheimer's. There's been a lot of hype surrounding the drug because....

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.

Sounds awesome, right? Well, things aren't always what they seem.

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.

The press release mentions that there's a lot of hope that memantine can be applied to other brain disorders that involve exessive glutamate release, such as following stroke or trauma.

This isn't to say that memantine doesn't work. But we do need to be judicious in how we apply these drugs as they have a presumed mechanism of action, but the targeted mechanism may not be the primary one affected in humans.