N-Methyl D-Aspartate (NMDA) Receptor Antagonists and Memantine Treatment for Alzheimer’s Disease, Vascular Dementia and Parkinson’s Disease

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.

Immunosuppression by N-Methyl-d-Aspartate Receptor Antagonists Is Mediated through Inhibition of Kv1.3 and KCa3.1 Channels in T Cells

“…NMDAR antagonists are in use and are promising candidates for therapy of various neuronal diseases, including Alzheimer's disease, Parkinson's disease, depression, and other neuropsychiatric disorders (6). The use of these pharmaceuticals necessitates thorough evaluation of their possible effects on lymphocytes, for which NMDAR expression has been reported (13).…”

“…NMDAR activity is effectively blocked by ifenprodil, a noncompetitive antagonist that binds to the GluN2B subunits of NMDARs, and by the noncompetitive open-channel blockers MK801 and memantine (5). These pharmaceuticals have been neuroprotective in animal models of stroke, epilepsy, and experimental autoimmune encephalomyelitis, and memantine is used to treat Alzheimer's disease (6). NMDARs themselves can be targets of immune attack as in anti-NMDAR encephalitis, which is caused by autoantibodies directed against the GluN1 subunit of NMDARs (7).…”

Management of Alzheimers Disease: Role of Existing Therapies, Traditional Medicines and New Treatment Targets

“…It has shown to have multiple actions, which could be beneficial in patients with AD. Its adverse effects are mild and reversible [32] . It offers minimal benefits in moderate to severe AD when used as a monotherapy.…”

Metal Exposure and Alzheimer’s Pathophysiology

“…As shown in the Figure 1 from one of our recent review paper [5], Aβ amyloid peptides (39-43 amino acid residues, ͌ 4 kDa), the main constituents of both senile plaques and cerebrovascular amyloid deposits [3,4], are generated from a much larger metalloproteinamyloid precursor protein (APP) [6][7][8]. APP cleavage by α-secretase generates neurotrophic APP(s), while its synergistic cleavage by β-and γ-secretases leads to production of a pool of Aβ peptides with carboxyl-terminal heterogeneity [9]: Aβ1-40 (40 amino acid residues) is the major soluble Aβ species, which is found in the CSF at low nanomolar concentrations [10]; Aβ1-42 (42 residues) is a minor Aβ species, but more neurotoxic than Aβ1-40, and is heavily enriched in interstitial plaque amyloid.…”

“…The majority of AD cases are sporadic while 5-10% of cases are early-onset familial AD (FAD) with an autosomal dominant inheritance pattern. The neuropathology of AD is characterized by the accumulation of insoluble Aβ amyloid peptides, neurofibrillary tangles (NFTs, the misfolded microtubuleassociated tau protein), neuropil threads, and neuronal losses in postmortem AD brains [3,4].As shown in the Figure 1 from one of our recent review paper [5], Aβ amyloid peptides (39-43 amino acid residues, ͌ 4 kDa), the main constituents of both senile plaques and cerebrovascular amyloid deposits [3,4], are generated from a much larger metalloproteinamyloid precursor protein (APP) [6][7][8]. APP cleavage by α-secretase generates neurotrophic APP(s), while its synergistic cleavage by β-and γ-secretases leads to production of a pool of Aβ peptides with carboxyl-terminal heterogeneity [9]: Aβ1-40 (40 amino acid residues) is the major soluble Aβ species, which is found in the CSF at low nanomolar concentrations [10]; Aβ1-42 (42 residues) is a minor Aβ species, but more neurotoxic than Aβ1-40, and is heavily enriched in interstitial plaque amyloid.…”