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Advanced Neurology NMDA receptors in neuropsychiatric diseases

ketamine, which was tested in MDD patients, displayed The clinical trials concerning NMDAR antagonists,
potential clinical effectiveness [167] . Two enantiomers including selective GluN2B antagonists, for use in the
of ketamine, arketamine and esketamine, show treatment of TBI were also unsuccessful [261] . Although
antidepressant activity with different degree of affinity to overactivation of NMDARs is toxic, functional recovery
NMDAR [243] . Recently, the treatment of esketamine for after TBI requires physiological activation of NMDARs [262] .
MDD has been approved by the USA and Europe FDA [244] .
It has been suggested that the dysfunction of glutamatergic 3.7. Epilepsy
transmission may associated with MDD, and NMDAR Epilepsy is a very common neuropsychiatric disorder
attracts considerable attention with respect to its biological that causes abnormal brain activity, seizures, unusual
function in the CNS [245] . Studies with MDD patients behavior sensations, and sometimes, loss of consciousness.
showed significantly reduction of GluN2A and GluN2B Glutamate-mediated excitability changes could be involved
subunits of NMDAR but did not change GluN1 protein in the pathogenesis of epileptic discharge [263] . NMDAR
level compared to the controls, along with reduced level may be involved in the seizure-induced excitotoxic cell
of PSD-95 in prefrontal cortex, indicating an abnormal death of hippocampal neuronal populations, as NMDAR
signaling in the synaptic transmission within MDD [246] . antagonists provide protection against such damage [264] .
However, in the lateral amygdala and locus coeruleus of Many animal models of epilepsy have been developed,
depressed subjects, increased levels of GluN2A and GluN2C including chemical induction models (such as kainic acid,
expression have been detected [247,248] . A recent research pilocarpine, picrotoxin, or bicuculline), physical models
showed that α7nAChR-NMDAR complex may play a role (such as hyperthermia, or photic or auditory stimuli), genetic
in the MDD, and disruption of this complex with a peptide models (such as mutations, transgenes, or knockouts),
exhibits antidepressant effects [249] . Moreover, another study electrical stimulation models, and spontaneous seizure
suggested that the antidepressant mechanism of ketamine models (such as post-kindling). Due to the differences
is NMDAR-independent but related to AMPAR [250] . Taken in animal models, brain regions, and NMDAR subunits
together, these studies reveal a crucial role of NMDAR examined, the results of these studies vary. A study found
in MDD, underlining the significance of NMDAR in the that seizure enhances expression of GluN1 mRNA and
development of next-generation antidepressants. protein in rat cerebral cortex [265] . Another study indicated
3.6. Stroke and traumatic brain injury (TBI) that the mRNA of GluN1 is continuously increased in
cortex of amygdaloid kindled rat [266] . However, application
In stroke and TBI, extracellular glutamate is continuously of picrotoxin (500 μM) caused a decrease in mRNA levels
elevated, causing excitotoxicity and acute neuronal of GluN2A and GluN2B, while the mRNA level of GluN1
death [251] . The NMDAR-mediated excitotoxicity is a major remained unchanged [267] . Besides, a study demonstrated
cause of acute neuronal death after ischemia or injury. that mRNA and protein levels of GluN2A and GluN2B
Studies have suggested that NMDAR antagonists could were increased in spontaneous seizure, but not in kindled
inhibit ischemic cell death [252,253] . NMDAR antagonists seizure [268] . Kainic acid-induced seizure reduces the mRNA
protect neurons against ischemic cell death if they have level of GluN1 in CA1 and CA3 pyramidal cells, but not
been applied before [254-256] , but not 30 min [254] or 3 h [255] after dentate gyrus [269] .
stroke in animal models. However, it has also been reported
that GluN2B antagonists applied 2 h poststroke could reduce NMDAR antagonists are proven to be anticonvulsant in
®
brain infarct volume [257] . Intriguingly, NMDAR-mediated several animal models of epilepsy. Felbamate (Felbatol ) is
excitotoxicity appears to be subunit-dependent: GluN2A used in patients with intractable partial seizures, infantile
antagonist aggravates but GluN2B antagonist blocks the spasms, or Lennox-Gastaut syndrome [270,271] . Some studies
ischemic cell death [255,256] . Probably due to the intolerable reported that felbamate inhibits the NMDAR by binding to
side effects of NMDAR antagonists and the level of elevated the glycine site [271-273] , while others showed that felbamate
extracellular glutamate that last less than an hour, the clinical binds with the site of channel pore [274] . Therefore, the
trials concerning the application of NMDAR antagonists in binding site remains unsolved. Ifenprodil, a GluN2B-
stroke have so far been unsuccessful [218] . In addition to the selective antagonist, has been reported to have effects on
direct inhibition of NMDAR activity, neuronal protection many animal models of seizure [275-277] , except for seizure
can be achieved by disrupting the interactions between induced by imipenem or pefloxacin in DBA/2 mice [278] .
NMDARs and their scaffold proteins, including PSD-95, Memantine, a blocker of NMDARs, exerts anticonvulsant
phosphatase and tensin homolog, and associated signaling effects in seizures [279-281] by blocking the NMDAR ion
molecules in stroke animal models [258,259] and in humans [260] . channel pore. However, many clinical trials have failed
This could be a new strategy targeting NMDAR-associated due to the side effects. In experimental models of epilepsy,
signaling in stroke. the combination of conventional antiepileptic drugs with

Volume 1 Issue 2 (2022) 11 https://doi.org/10.36922/an.v1i2.148