NMDA (N-Methyl-D-aspartic acid)

NMDA is an agonist of NMDA-receptor [1].

NMDA is a glutamate-like excitatory substance and is a particularly potent excitant. NMDA binds to NMDA-receptor and interacts with it. This interaction causes a conformational change in the receptor or associated membrane molecules, which opened pores to allow extracellular sodium ions to flow down their electrochemical gradient and depolarise the cell. However, NMDA is proved to be a poor substrate for the uptake transporters, suggesting that the excitatory effect could not be an indirect consequence of glutamate uptake. Besides that, NMDA is found to increase intracellular calcium and release arachidonic acid, both of which generate oxygen radicals, subsequently inducing neuronal death [1, 2].

References:
[1] Watkins JC, Jane DE. The glutamate story. Br J Pharmacol. 2006 Jan;147 Suppl 1:S100-8.
[2] Lafon-Cazal M, Pietri S, Culcasi M, Bockaert J. NMDA-dependent superoxide production and neurotoxicity. Nature. 1993 Aug 5;364(6437):535-7.

Recovery from severe frontotemporal dysfunction at 3years after N-methyl-d-aspartic acid (NMDA) receptor antibody encephalitis.[Pubmed:23313527]

J Clin Neurosci. 2013 Apr;20(4):611-3.

Encephalitis associated with antibodies against N-methyl-d-aspartic acid (NMDA) receptor is characterized by severe memory deficits, decreased consciousness, epileptic seizures and movement disorders and occurs most commonly in young women. Recovery is mostly good but little is known about the disease course in patients whose treatment has been delayed severely. We present a 16-year-old girl with a 36-month follow-up. A single course of methylprednisolone attenuated some symptoms but severe and incapacitating frontotemporal syndrome remained. Second-line treatment with rituximab was initiated 12months after the onset of symptoms. A surprising recovery occurred 18months after treatment and 30months after onset. Recovery in NMDA receptor antibody-associated encephalitis can be severely delayed and does not have to be linear. Whether delayed therapy contributed to recovery in this patient cannot be answered with certainty. Spontaneous recovery independent of therapy is possible, as it has been observed previously as late as 3years after onset. Although serum antibodies disappeared with recovery in this patient, previous cases have shown serum antibodies to be unreliable markers of disease activity. Second-line treatment, especially with substances as well tolerated as rituximab, should at least be considered in NMDA receptor encephalitis with persistent neuropsychiatric syndromes after first-line therapy.

3-Fluoro-N-methyl-D-aspartic acid (3F-NMDA) stereoisomers as conformational probes for exploring agonist binding at NMDA receptors.[Pubmed:22692769]

Chemistry. 2012 Jul 9;18(28):8813-9.

N-Methyl-D-aspartate (NMDA) is the prototypical agonist of the NMDA receptor subtype of ionotropic glutamate receptors. Stereogenic placement of a C-F bond at the 3-position of (S)-NMDA generates either the (2S,3S)- or (2S,3R)- diastereoisomers of 3F-NMDA. The individual diastereoisomers were prepared by synthesis in enantiomerically pure forms and it was found that (2S,3S)-3F-NMDA is an agonist with a comparable potency to NMDA itself, whereas the (2S,3R)-diastereoisomer has negligible potency. The difference in potency of these stereoisomers is attributed to a preference of the C-F bond (2S,3S)-3F-NMDA to adopt a gauche conformation to the C-N(+) bond in the binding conformation, whereas the (2S,3R)-3F-NMDA forces these bonds anti, losing electrostatic stabilisation, to achieve the required binding conformation. These observations illustrate the utility of stereoselective fluorination in influencing the molecular conformation of beta-fluorinated amino acids and thus probing the active conformations of bioactive compounds at receptors.

[Review of the psychiatric aspects of anti-NMDA (N-methyl-D-aspartic acid) receptor encephalitis, case report, and our plans for a future study].[Pubmed:28259863]

Neuropsychopharmacol Hung. 2016 Dec;18(4):199-208.

Anti-NMDAR (N-methyl-D-aspartic acid receptor) encephalitis, first described in 2007, is a rare, autoimmune limbic encephalitis. In half of the cases anti-NMDAR antibodies are paraneoplastic manifestations of an underlying tumor (mostly ovarian teratoma). In the early stage of the disease psychiatric symptoms are prominent, therefore 60-70% of the patients are first treated in a psychiatric department. In most of the cases, typical neurological symptoms appear later. Besides the clinical picture and typical symptoms, verifying presence of IgG antibodies in the serum or CSF is necessary to set up the diagnosis. Other diagnostic tools, including laboratory tests, MRI, lumbar puncture or EEG are neither specific, nor sensitive enough. Therapy is based on supportive care, plasma exchange and immune suppression, intensive care administration can be necessary. If there is an underlying tumor, tumor removal is the first-line treatment. The disease can cause fatal complications in the acute phase but with adequate therapy long-term prognosis is good, although rehabilitation can last for months. In the past few years besides the typical clinical picture and illness course an increasing number of case reports described no typical neurological symptoms, only psychiatric symptoms, including psychosis, disorganized behavior, and catatonic symptoms. Immune suppressive treatment was still effective in most of these cases. Such cases present a difficult diagnostic challenge. These patients may receive unnecessary antipsychotic treatment because of the suspected schizophrenia, although they often suffer from serious extrapyramidal side effects. A few years ago there was a hypothesis that a small part of the patients who are treated with therapy-resistant schizophrenia may suffer from anti-NMDAR encephalitis, so they require a different kind of medication. Evidence from the latest publications did not confirm this hypothesis, although the connection between anti-NMDAR antibodies and disorders with psychotic symptoms is still not clear. After reviewing the most important studies regarding the psychiatric aspects of anti-NMDAR encephalitis, we present a case report of a patient with a pure psychiatric manifestation of this disease. We conclude with a short outline of the design and plan of our future study.

Using an experimental medicine model to understand the antidepressant potential of the N-Methyl-D-aspartic acid (NMDA) receptor antagonist memantine.[Pubmed:22596208]

J Psychopharmacol. 2012 Nov;26(11):1417-23.

There is growing interest in the role of the glutamatergic system both in depression and as a novel target for treatments. Preclinical studies suggested that the non-competitive N-Methyl-D-aspartic acid (NMDA) receptor antagonist memantine might have antidepressant properties, but a randomised controlled trial failed to support this. A healthy volunteer model of emotional processing was used to assess the neuropsychological profile of action of memantine. Healthy volunteers (n=32) were randomised to receive a single dose of memantine (10 mg) or placebo, and subsequently completed a battery of tasks measuring emotional processing, including facial expression recognition, emotional memory, dot-probe and emotion-potentiated startle tasks, as well as working and verbal memory. Memantine treated volunteers showed an increased emotion-potentiated startle, and a reduced bias for negative items in emotional recognition memory. There were no effects of the drug on any other aspect of emotional or non-emotional information processing. These results suggest that a single dose of memantine produces an early anxiogenic response in the emotion-potentiated startle similar to that seen following a single dose of the selective serotonin reuptake inhibitor, citalopram. However, the overall profile of effects is more limited than that which might be expected in response to a conventional antidepressant.

NMDA is a specific agonist for NMDA receptor mimicking the action of glutamate, the neurotransmitter which normally acts at that receptor.

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