Alzheimer's disease (AD) is the most common form of
dementia, as least in western countries. It has been estimated that the cost to society for caring for AD patients will consume the entire gross national product of the U.S.A. by the middle of this century if left unabated. Until recently, the only available drugs for this condition were
cholinergic treatments, which symptomatically enhance cognitive state to some degree, but they were not neuroprotective. In fact, many potential
neuroprotective drugs tested in clinical trials failed because they were poorly tolerated. However, after our discovery of its clinically-tolerated mechanism of action, one
neuroprotective drug,
memantine, was recently approved by the European Union and the U.S. Food and Drug Administration (FDA) for the treatment of
Alzheimer's disease. Recent phase 3 clinical trials have shown that
memantine is effective in the treatment of moderate-to-severe
Alzheimer's disease and possibly
vascular dementia (
multi-infarct dementia). Here we review the molecular mechanism of
memantine's action and also the basis for the
drug's use in these neurological diseases, which are mediated at least in part by excitotoxicity. Excitotoxicity is defined as excessive exposure to the
neurotransmitter glutamate or overstimulation of its membrane receptors, leading to neuronal injury or death. Excitotoxic neuronal cell death is mediated in part by overactivation of
N-methyl-d-aspartate (
NMDA)-type
glutamate receptors, which results in excessive Ca(2+) influx through the receptor's associated
ion channel. Physiological
NMDA receptor activity, however, is also essential for normal neuronal function. This means that potential
neuroprotective agents that block virtually all
NMDA receptor activity will very likely have unacceptable clinical side effects. For this reason many previous
NMDA receptor antagonists have disappointingly failed advanced clinical trials for a number of
neurodegenerative disorders. In contrast, studies in our laboratory have shown that the
adamantane derivative,
memantine, preferentially blocks excessive
NMDA receptor activity without disrupting normal activity.
Memantine does this through its action as an uncompetitive, low-affinity, open-channel blocker; it enters the receptor-associated
ion channel preferentially when it is excessively open, and, most importantly, its off-rate is relatively fast so that it does not substantially accumulate in the channel to interfere with normal synaptic transmission. Clinical use has corroborated the prediction that
memantine is thus well tolerated. Besides
Alzheimer's disease,
memantine is currently in trials for additional
neurological disorders, including other forms of
dementia, depression,
glaucoma, and severe
neuropathic pain. A series of second-generation
memantine derivatives are currently in development and may prove to have even greater neuroprotective properties than
memantine. These second-generation drugs take advantage of the fact that the
NMDA receptor has other modulatory sites in addition to its
ion channel that potentially could also be used for safe but effective clinical intervention.