NMDA (N-Methyl-D-aspartic acid) is a selective NMDA receptor agonist. NMDA binds to and activates the NMDA receptor to open cation channels, causing Na+ and Ca2+ influx. Overactivation can induce excitotoxicity and neuronal death. NMDA is used in studies related to synaptic plasticity, excitotoxicity, oxidative stress, Alzheimer disease, stroke, and neurodegenerative diseases[1-4].
In vitro, treatment of A549 cells with 300μM NMDA for 1 to 8 hours inhibited Sp1 nuclear protein expression and reduced nuclear translocation[5]. Treatment of RGC-5 cells with 100-800μM NMDA for 48 hours decreased RGC-5 cell viability and induced excitotoxic injury[6]. Treatment of mixed cortical neurons and astrocytes cultures with 12.5μM NMDA for 24 hours induced acute neuronal swelling and extensive necrotic neuronal death[7].
In vivo, a single bilateral intrahippocampal injection of NMDA (12mg/mL; 0.2μL) into Wistar rats damaged neurons in the hippocampal CA1 and CA3 areas, reduced neuronal number, caused glial proliferation, and impaired learning and memory function[8]. A single intravitreal injection of 2μL 30nmol NMDA into C57BL/6 mice and CHOP-deficient mice increased the number of retinal Iba1-positive microglial cells and induced TUNEL-positive apoptotic cells in the retinal ganglion cell layer[9]. After intraperitoneal injection of 4.0g/kg ethanol into Swiss-Webster mice, a single intracerebroventricular injection of 10-500nmol/kg NMDA rapidly and dose-dependently caused loss of righting reflex again[10].
References:
[1] Farber NB. NMDA Antagonists for Treatment-Resistant Depression. Handb Exp Pharmacol. 2019;250:287-305.
[2] Grosjean B, Tsai GE. NMDA neurotransmission as a critical mediator of borderline personality disorder. J Psychiatry Neurosci. 2007 Mar;32(2):103-15.
[3] Low SJ, Roland CL. Review of NMDA antagonist-induced neurotoxicity and implications for clinical development. Int J Clin Pharmacol Ther. 2004 Jan;42(1):1-14.
[4] Kritis AA, Stamoula EG, Paniskaki KA, et al. Researching glutamate-induced cytotoxicity in different cell lines: a comparative/collective analysis/study. Front Cell Neurosci. 2015 Mar 17;9:91.
[5] Li X-H, Fu J-J, Shi X-J, et al. Sp1 mediated the inhibitory effect of glutamate on pulmonary surfactant synthesis. PLoS ONE. 2023 Aug 9;18(8):e0289530.
[6] Li JH, Yu GS, Wang YD, et al. In vitro protective effect of recombinant prominin-1 combined with microRNA-29b on N-methyl-D-aspartate-induced excitotoxicity in retinal ganglion cells. Int J Ophthalmol.
[7] Nicole O, Ali C, Docagne F, et al. Neuroprotection mediated by glial cell line-derived neurotrophic factor: involvement of a reduction of NMDA-induced calcium influx by the mitogen-activated protein kinase pathway. J Neurosci. 2001 May 1;21(9):3024-3033.
[8] Fachim HA, Pereira AC, Iyomasa-Pilon MM, et al. Differential Expression of AMPA Subunits Induced by NMDA Intrahippocampal Injection in Rats. Front Neurosci. 2016 Feb 15;10:32.
[9] Sato K, Sato T, Ohno-Oishi M, et al. CHOP deletion and anti-neuroinflammation treatment with hesperidin synergistically attenuate NMDA retinal injury in mice. Exp Eye Res. 2021 Dec;213:108826.
[10] Ferko AP. NMDA enhances the central depressant properties of ethanol in mice. Pharmacol Biochem Behav. 1992;43(1):297-301.