Title:N-Methyl D-Aspartate (NMDA) Receptor Antagonists and Memantine Treatment for Alzheimer’s Disease, Vascular Dementia and Parkinson’s Disease
Volume: 9
Issue: 6
Author(s): David Olivares, Varun K. Deshpande, Ying Shi, Debomoy K. Lahiri, Nigel H. Greig, Jack T. Rogers and Xudong Huang
Affiliation:
Keywords:
Alzheimer’s disease, Parkinson’s disease, vascular dementia, memantine, NMDAR, amantadine, epigenetic, antagonists, amyloid precursor protein
Abstract: Memantine, a partial antagonist of N-methyl-D-aspartate receptor (NMDAR), approved for moderate to severe
Alzheimer’s disease (AD) treatment within the US and Europe under brand name Namenda (Forest), Axura and Akatinol
(Merz), and Ebixa and Abixa (Lundbeck), may have potential in alleviating additional neurological conditions, such as
vascular dementia (VD) and Parkinson’s disease (PD). In various animal models, memantine has been reported to be a
neuroprotective agent that positively impacts both neurodegenerative and vascular processes. While excessive levels of
glutamate result in neurotoxicity, in part through the over-activation of NMDARs, memantine—as a partial NMDAR antagonist,
blocks the NMDA glutamate receptors to normalize the glutamatergic system and ameliorate cognitive and
memory deficits. The key to memantine’s therapeutic action lies in its uncompetitive binding to the NMDAR through
which low affinity and rapid off-rate kinetics of memantine at the level of the NMDAR-channel preserves the physiological
function of the receptor, underpinning memantine’s tolerability and low adverse event profile. As the biochemical
pathways evoked by NMDAR antagonism also play a role in PD and since no other drug is sufficiently effective to substitute
for the first-line treatment of L-dopa despite its side effects, memantine may be useful in PD treatment with possibly
fewer side effects. In spite of the relative modest nature of its adverse effects, memantine has been shown to provide only
a moderate decrease in clinical deterioration in AD and VD, and hence efforts are being undertaken in the design of new
and more potent memantine-based drugs to hopefully provide greater efficacy.
