N-Methyl-D-Aspartate (NMDA)-Type Glutamate Receptors and Demyelinating
Disorders: A Neuroimmune Perspective

Amir   Parsa   Abhari; Masoud      Etemadifar; Niloufar      Yazdanpanah; Nima      Rezaei
Abstract

N-methyl-D-aspartate receptors (NMDARs) are ionotropic glutamate receptors, highly important in regulating substantial physiologic processes in the brain and the nervous system, and disturbance in their function could contribute to different pathologies. Overstimulation and hyperactivity of NMDARs, termed glutamate toxicity, could promote cell death and apoptosis. Meanwhile, their blockade could lead to dysfunction of the brain and nervous system. A growing body of evidence has demonstrated the prominent role of NMDARs in demyelinating disorders and anti- NMDAR encephalitis. Herein, we provide an overview of NMDARs’ dysfunction in the physiopathology of demyelinating disorders such as multiple sclerosis and neuromyelitis optica spectrum disorders.
Keywords: NMDAR, neuroimmunology, demyelinating disorders, brain, N-methyl-D-aspartate receptors, glutamate receptors.
Graphical Abstract

[1] 
Paoletti, P.; Bellone, C.; Zhou, Q. NMDA receptor subunit diversity: Impact on receptor properties, synaptic plasticity and disease. Nat. Rev. Neurosci.,  2013, 14(6), 383-400.
[http://dx.doi.org/10.1038/nrn3504] [PMID:  23686171] 
[2] 
Watkins, J.C.; Jane, D.E. The glutamate story. Br. J. Pharmacol.,  2006, 147(S1)(Suppl. 1), S100-S108.
[http://dx.doi.org/10.1038/sj.bjp.0706444] [PMID:  16402093] 
[3] 
Hardingham, G.E.; Bading, H. Synaptic versus extrasynaptic NMDA receptor signalling: Implications for neurodegenerative disorders. Nat. Rev. Neurosci.,  2010, 11(10), 682-696.
[http://dx.doi.org/10.1038/nrn2911] [PMID:  20842175] 
[4] 
Bading, H. Therapeutic targeting of the pathological triad of extrasynaptic NMDA receptor signaling in neurodegenerations. J. Exp. Med.,  2017, 214(3), 569-578.
[http://dx.doi.org/10.1084/jem.20161673] [PMID:  28209726] 
[5] 
Cottrell, J.R.; Dubé, G.R.; Egles, C.; Liu, G. Distribution, density, and clustering of functional glutamate receptors before and after synap-togenesis in hippocampal neurons. J. Neurophysiol.,  2000, 84(3), 1573-1587.
[http://dx.doi.org/10.1152/jn.2000.84.3.1573] [PMID:  10980028] 
[6] 
Li, F.; Tsien, J.Z. Memory and the NMDA receptors. N. Engl. J. Med.,  2009, 361(3), 302-303.
[http://dx.doi.org/10.1056/NEJMcibr0902052] [PMID:  19605837] 
[7] 
Lewerenz, J.; Maher, P. Chronic glutamate toxicity in neurodegenerative diseases-what is the evidence? Front. Neurosci.,  2015, 9, 469.
[http://dx.doi.org/10.3389/fnins.2015.00469] [PMID:  26733784] 
[8] 
Barry, H.; Byrne, S.; Barrett, E.; Murphy, K.C.; Cotter, D.R. Anti-N-methyl-d-aspartate receptor encephalitis: Review of clinical presentati-on, diagnosis and treatment. BJPsych Bull.,  2015, 39(1), 19-23.
[http://dx.doi.org/10.1192/pb.bp.113.045518] [PMID:  26191419] 
[9] 
Ren, Y.; Chen, X.; He, Q.; Wang, R.; Lu, W. Co-occurrence of anti-N-methyl-D-aspartate receptor encephalitis and anti-myelin oligoden-drocyte glycoprotein inflammatory demyelinating diseases: A clinical phenomenon to be taken seriously. Front. Neurol.,  2019, 10, 1271.
[http://dx.doi.org/10.3389/fneur.2019.01271] [PMID:  31866928] 
[10] 
Love, S. Demyelinating diseases. J. Clin. Pathol.,  2006, 59(11), 1151-1159.
[http://dx.doi.org/10.1136/jcp.2005.031195] [PMID:  17071802] 
[11] 
Mehndiratta, M.M.; Gulati, N.S. Central and peripheral demyelination. J. Neurosci. Rural Pract.,  2014, 5(1), 84-86.
[http://dx.doi.org/10.4103/0976-3147.127887] [PMID:  24741263] 
[12] 
Zhou, Y.; Danbolt, N.C. Glutamate as a neurotransmitter in the healthy brain. J. Neural Transm. (Vienna),  2014, 121(8), 799-817.
[http://dx.doi.org/10.1007/s00702-014-1180-8] [PMID:  24578174] 
[13] 
Du, J.; Li, X-H.; Li, Y-J. Glutamate in peripheral organs: Biology and pharmacology. Eur. J. Pharmacol.,  2016, 784, 42-48.
[http://dx.doi.org/10.1016/j.ejphar.2016.05.009] [PMID:  27164423] 
[14] 
Fadel, F.I.; Elshamaa, M.F.; Essam, R.G.; Elghoroury, E.A.; El-Saeed, G.S.; El-Toukhy, S.E.; Ibrahim, M.H. Some amino acids levels: Glutamine, glutamate, and homocysteine, in plasma of children with chronic kidney disease. Int. J. Biomed. Sci.,  2014, 10(1), 36-42.
[PMID:  24711748] 
[15] 
Leung, J.C.; Marphis, T.; Craver, R.D.; Silverstein, D.M. Altered NMDA receptor expression in renal toxicity: Protection with a receptor antagonist. Kidney Int.,  2004, 66(1), 167-176.
[http://dx.doi.org/10.1111/j.1523-1755.2004.00718.x] [PMID:  15200423] 
[16] 
Brosnan, M.E.; Brosnan, J.T. Hepatic glutamate metabolism: A tale of 2 hepatocytes. Am. J. Clin. Nutr.,  2009, 90(3), 857S-861S.
[http://dx.doi.org/10.3945/ajcn.2009.27462Z] [PMID:  19625684] 
[17] 
Eweka, A.; Igbigbi, P.; Ucheya, R. Histochemical studies of the effects of monosodium glutamate on the liver of adult wistar rats. Ann. Med. Health Sci. Res.,  2011, 1(1), 21-29.
[PMID:  23209951] 
[18] 
Eisenkraft, A.; Falk, A.; Finkelstein, A. The role of glutamate and the immune system in organophosphate-induced CNS damage. Neurotox. Res.,  2013, 24(2), 265-279.
[http://dx.doi.org/10.1007/s12640-013-9388-1] [PMID:  23532600] 
[19] 
Ganor, Y.; Levite, M. The neurotransmitter glutamate and human T cells: Glutamate receptors and glutamate-induced direct and potent effects on normal human T cells, cancerous human leukemia and lymphoma T cells, and autoimmune human T cells. J. Neural Transm. (Vienna),  2014, 121(8), 983-1006.
[http://dx.doi.org/10.1007/s00702-014-1167-5] [PMID:  24584970] 
[20] 
Hawkins, R.A.; Viña, J.R. How glutamate is managed by the blood-brain barrier. Biology (Basel),  2016, 5(4), 37.
[http://dx.doi.org/10.3390/biology5040037] [PMID:  27740595] 
[21] 
Schousboe, A. Glutamate metabolism in the brain focusing on astrocytes. In: Glutama-te and ATP at the Interface of Metabolism and Signaling in the Brain. Advances in Neurobiology; Parpura, V.; Schousboe, A.; Verkhratsky, A., Eds.; Springer: Cham, 2014; pp. 13-30.
[http://dx.doi.org/10.1007/978-3-319-08894-5_2] 
[22] 
Brady, S.; Siegel, G.; Albers, R.W.; Price, D. Basic Neurochemistry: Molecular, Cellular and Medical Aspects; Academic Press: Cambridge, Massachusetts, 2005. 
[23] 
Flores-Soto, M.E.; Chaparro-Huerta, V.; Escoto-Delgadillo, M.; Vazquez-Valls, E.; González-Castañeda, R.E.; Beas-Zarate, C. [Structure and function of NMDA-type glutamate receptor subunits]. Neurologia,  2012, 27(5), 301-310.
[http://dx.doi.org/10.1016/j.nrl.2011.10.014] [PMID:  22217527] 
[24] 
Chen, T-J.; Kukley, M. Glutamate receptors and glutamatergic signalling in the peripheral nerves. Neural Regen. Res.,  2020, 15(3), 438-447.
[http://dx.doi.org/10.4103/1673-5374.266047] [PMID:  31571652] 
[25] 
Malet, M.; Brumovsky, P.R. VGLUTs and glutamate synthesis-focus on DRG neurons and pain. Biomolecules,  2015, 5(4), 3416-3437.
[http://dx.doi.org/10.3390/biom5043416] [PMID:  26633536] 
[26] 
Steel, A.; Mikkelsen, M.; Edden, R.A.E.; Robertson, C.E. Regional balance between glutamate+glutamine and GABA+ in the resting human brain. Neuroimage,  2020, 220, 117112.
[http://dx.doi.org/10.1016/j.neuroimage.2020.117112] [PMID:  32619710] 
[27] 
Michaelis, E.K. Molecular biology of glutamate receptors in the central nervous system and their role in excitotoxicity, oxidative stress and aging. Prog. Neurobiol.,  1998, 54(4), 369-415.
[http://dx.doi.org/10.1016/S0301-0082(97)00055-5] [PMID:  9522394] 
[28] 
Vyklicky, V.; Korinek, M.; Smejkalova, T.; Balik, A.; Krausova, B.; Kaniakova, M.; Lichnerova, K.; Cerny, J.; Krusek, J.; Dittert, I.; Ho-rak, M.; Vyklicky, L. Structure, function, and pharmacology of NMDA receptor channels. Physiol. Res.,  2014, 63(Suppl. 1), S191-S203.
[http://dx.doi.org/10.33549/physiolres.932678] [PMID:  24564659] 
[29] 
Hansen, K.B.; Yi, F.; Perszyk, R.E.; Furukawa, H.; Wollmuth, L.P.; Gibb, A.J.; Traynelis, S.F. Structure, function, and allosteric modula-tion of NMDA receptors. J. Gen. Physiol.,  2018, 150(8), 1081-1105.
[http://dx.doi.org/10.1085/jgp.201812032] [PMID:  30037851] 
[30] 
Pachernegg, S.; Strutz-Seebohm, N.; Hollmann, M. GluN3 subunit-containing NMDA receptors: not just one-trick ponies. Trends Neurosci.,  2012, 35(4), 240-249.
[http://dx.doi.org/10.1016/j.tins.2011.11.010] [PMID:  22240240] 
[31] 
Hogan-Cann, A.D.; Anderson, C.M. Physiological roles of non-neuronal NMDA receptors. Trends Pharmacol. Sci.,  2016, 37(9), 750-767.
[http://dx.doi.org/10.1016/j.tips.2016.05.012] [PMID:  27338838] 
[32] 
Lynch, G.; Larson, J.; Kelso, S.; Barrionuevo, G.; Schottler, F. Intracellular injections of EGTA block induction of hippocampal long-term potentiation. Nature,  1983, 305(5936), 719-721.
[http://dx.doi.org/10.1038/305719a0] [PMID:  6415483] 
[33] 
Nabavi, S.; Fox, R.; Proulx, C.D.; Lin, J.Y.; Tsien, R.Y.; Malinow, R. Engineering a memory with LTD and LTP. Nature,  2014, 511(7509), 348-352.
[http://dx.doi.org/10.1038/nature13294] [PMID:  24896183] 
[34] 
Liu, J.; Chang, L.; Song, Y.; Li, H.; Wu, Y. The role of NMDA receptors in Alzheimer’s disease. Front. Neurosci.,  2019, 13, 43.
[http://dx.doi.org/10.3389/fnins.2019.00043] [PMID:  30800052] 
[35] 
Káradóttir, R.; Cavelier, P.; Bergersen, L.H.; Attwell, D. NMDA receptors are expressed in oligodendrocytes and activated in ischaemia. Nature,  2005, 438(7071), 1162-1166.
[http://dx.doi.org/10.1038/nature04302] [PMID:  16372011] 
[36] 
Saab, A.S.; Tzvetavona, I.D.; Trevisiol, A.; Baltan, S.; Dibaj, P.; Kusch, K.; Möbius, W.; Goetze, B.; Jahn, H.M.; Huang, W.; Steffens, H.; Schomburg, E.D.; Pérez-Samartín, A.; Pérez-Cerdá, F.; Bakhtiari, D.; Matute, C.; Löwel, S.; Griesinger, C.; Hirrlinger, J.; Kirchhoff, F.; Na-ve, K.A. Oligodendroglial NMDA receptors regulate glucose import and axonal energy metabolism. Neuron,  2016, 91(1), 119-132.
[http://dx.doi.org/10.1016/j.neuron.2016.05.016] [PMID:  27292539] 
[37] 
Krasnow, A.M.; Attwell, D. NMDA receptors: Power switches for oligodendrocytes. Neuron,  2016, 91(1), 3-5.
[http://dx.doi.org/10.1016/j.neuron.2016.06.023] [PMID:  27387644] 
[38] 
Kaindl, A.M.; Degos, V.; Peineau, S.; Gouadon, E.; Chhor, V.; Loron, G.; Le Charpentier, T.; Josserand, J.; Ali, C.; Vivien, D.; Collingrid-ge, G.L.; Lombet, A.; Issa, L.; Rene, F.; Loeffler, J.P.; Kavelaars, A.; Verney, C.; Mantz, J.; Gressens, P. Activation of microglial N-methyl-D-aspartate receptors triggers inflammation and neuronal cell death in the developing and mature brain. Ann. Neurol.,  2012, 72(4), 536-549.
[http://dx.doi.org/10.1002/ana.23626] [PMID:  23109148] 
[39] 
Raghunatha, P.; Vosoughi, A.; Kauppinen, T.M.; Jackson, M.F. Microglial NMDA receptors drive pro-inflammatory responses via PARP-1/TRMP2 signaling. Glia,  2020, 68(7), 1421-1434.
[http://dx.doi.org/10.1002/glia.23790] [PMID:  32036619] 
[40] 
Jimenez-Blasco, D.; Santofimia-Castaño, P.; Gonzalez, A.; Almeida, A.; Bolaños, J.P. Astrocyte NMDA receptors’ activity sustains neuro-nal survival through a Cdk5-Nrf2 pathway. Cell Death Differ.,  2015, 22(11), 1877-1889.
[http://dx.doi.org/10.1038/cdd.2015.49] [PMID:  25909891] 
[41] 
Basuroy, S.; Leffler, C.W.; Parfenova, H. CORM-A1 prevents blood-brain barrier dysfunction caused by ionotropic glutamate receptor-mediated endothelial oxidative stress and apoptosis. Am. J. Physiol. Cell Physiol.,  2013, 304(11), C1105-C1115.
[http://dx.doi.org/10.1152/ajpcell.00023.2013] [PMID:  23576575] 
[42] 
Mattson, M.P.; LaFerla, F.M.; Chan, S.L.; Leissring, M.A.; Shepel, P.N.; Geiger, J.D. Calcium signaling in the ER: Its role in neuronal plas-ticity and neurodegenerative disorders. Trends Neurosci.,  2000, 23(5), 222-229.
[http://dx.doi.org/10.1016/S0166-2236(00)01548-4] [PMID:  10782128] 
[43] 
Magi, S.; Piccirillo, S.; Amoroso, S.; Lariccia, V. Excitatory amino acid transporters (EAATs): Glutamate transport and beyond. Int. J. Mol. Sci.,  2019, 20(22), 5674.
[http://dx.doi.org/10.3390/ijms20225674] [PMID:  31766111] 
[44] 
Vandenberg, R.J.; Ryan, R.M. Mechanisms of glutamate transport. Physiol. Rev.,  2013, 93(4), 1621-1657.
[http://dx.doi.org/10.1152/physrev.00007.2013] [PMID:  24137018] 
[45] 
Underhill, S.M.; Ingram, S.L.; Ahmari, S.E.; Veenstra-VanderWeele, J.; Amara, S.G. Neuronal excitatory amino acid transporter EAAT3: Emerging functions in health and disease. Neurochem. Int.,  2019, 123, 69-76.
[http://dx.doi.org/10.1016/j.neuint.2018.05.012] [PMID:  29800605] 
[46] 
Malik, A.R.; Willnow, T.E. Excitatory amino acid transporters in physiology and disorders of the central nervous system. Int. J. Mol. Sci.,  2019, 20(22), 5671.
[http://dx.doi.org/10.3390/ijms20225671] [PMID:  31726793] 
[47] 
Reissner, K.J. The cystine/glutamate antiporter: When too much of a good thing goes bad. J. Clin. Invest.,  2014, 124(8), 3279-3281.
[http://dx.doi.org/10.1172/JCI76627] [PMID:  25036700] 
[48] 
Stojanovic, I.R.; Kostic, M.; Ljubisavljevic, S. The role of glutamate and its receptors in multiple sclerosis. J. Neural Transm. (Vienna),  2014, 121(8), 945-955.
[http://dx.doi.org/10.1007/s00702-014-1188-0] [PMID:  24633998] 
[49] 
Tilleux, S.; Hermans, E. Neuroinflammation and regulation of glial glutamate uptake in neurological disorders. J. Neurosci. Res.,  2007, 85(10), 2059-2070.
[http://dx.doi.org/10.1002/jnr.21325] [PMID:  17497670] 
[50] 
Ye, L.; Huang, Y.; Zhao, L.; Li, Y.; Sun, L.; Zhou, Y.; Qian, G.; Zheng, J.C. IL-1β and TNF-α induce neurotoxicity through glutamate production: A potential role for neuronal glutaminase. J. Neurochem.,  2013, 125(6), 897-908.
[http://dx.doi.org/10.1111/jnc.12263] [PMID:  23578284] 
[51] 
Clark, I.A.; Vissel, B. Excess cerebral TNF causing glutamate excitotoxicity rationalizes treatment of neurodegenerative diseases and neu-rogenic pain by anti-TNF agents. J. Neuroinflammation,  2016, 13(1), 236.
[http://dx.doi.org/10.1186/s12974-016-0708-2] [PMID:  27596607] 
[52] 
Tolosa, L.; Caraballo-Miralles, V.; Olmos, G.; Lladó, J. TNF-α potentiates glutamate-induced spinal cord motoneuron death via NF-κB. Mol. Cell. Neurosci.,  2011, 46(1), 176-186.
[http://dx.doi.org/10.1016/j.mcn.2010.09.001] [PMID:  20849956] 
[53] 
Viviani, B.; Bartesaghi, S.; Gardoni, F.; Vezzani, A.; Behrens, M.M.; Bartfai, T.; Binaglia, M.; Corsini, E.; Di Luca, M.; Galli, C.L.; Mari-novich, M. Interleukin-1β enhances NMDA receptor-mediated intracellular calcium increase through activation of the Src family of kina-ses. J. Neurosci.,  2003, 23(25), 8692-8700.
[http://dx.doi.org/10.1523/JNEUROSCI.23-25-08692.2003] [PMID:  14507968] 
[54] 
Fogal, B.; Hewett, S.J. Interleukin-1β: A bridge between inflammation and excitotoxicity? J. Neurochem.,  2008, 106(1), 1-23.
[http://dx.doi.org/10.1111/j.1471-4159.2008.05315.x] [PMID:  18315560] 
[55] 
Novelli, A.; Reilly, J.A.; Lysko, P.G.; Henneberry, R.C. Glutamate becomes neurotoxic via the N-methyl-D-aspartate receptor when intra-cellular energy levels are reduced. Brain Res.,  1988, 451(1-2), 205-212.
[http://dx.doi.org/10.1016/0006-8993(88)90765-2] [PMID:  2472189] 
[56] 
Tobore, T.O. Towards a comprehensive etiopathogenetic and pathophysiological theory of multiple sclerosis. Int. J. Neurosci.,  2020, 130(3), 279-300.
[http://dx.doi.org/10.1080/00207454.2019.1677648] [PMID:  31588832] 
[57] 
Stover, J.F.; Pleines, U.E.; Morganti-Kossmann, M.C.; Kossmann, T.; Lowitzsch, K.; Kempski, O.S. Neurotransmitters in cerebrospinal fluid reflect pathological activity. Eur. J. Clin. Invest.,  1997, 27(12), 1038-1043.
[http://dx.doi.org/10.1046/j.1365-2362.1997.2250774.x] [PMID:  9466133] 
[58] 
Pampliega, O.; Domercq, M.; Villoslada, P.; Sepulcre, J.; Rodríguez-Antigüedad, A.; Matute, C. Association of an EAAT2 polymorphism with higher glutamate concentration in relapsing multiple sclerosis. J. Neuroimmunol.,  2008, 195(1-2), 194-198.
[http://dx.doi.org/10.1016/j.jneuroim.2008.01.011] [PMID:  18378006] 
[59] 
Srinivasan, R.; Sailasuta, N.; Hurd, R.; Nelson, S.; Pelletier, D. Evidence of elevated glutamate in multiple sclerosis using magnetic reso-nance spectroscopy at 3 T. Brain,  2005, 128(Pt 5), 1016-1025.
[http://dx.doi.org/10.1093/brain/awh467] [PMID:  15758036] 
[60] 
Azevedo, C.J.; Kornak, J.; Chu, P.; Sampat, M.; Okuda, D.T.; Cree, B.A.; Nelson, S.J.; Hauser, S.L.; Pelletier, D. In vivo evidence of gluta-mate toxicity in multiple sclerosis. Ann. Neurol.,  2014, 76(2), 269-278.
[http://dx.doi.org/10.1002/ana.24202] [PMID:  25043416] 
[61] 
Klauser, A.M.; Wiebenga, O.T.; Eijlers, A.J.; Schoonheim, M.M.; Uitdehaag, B.M.; Barkhof, F.; Pouwels, P.J.; Geurts, J.J. Metabolites predict lesion formation and severity in relapsing-remitting multiple sclerosis. Mult. Scler.,  2018, 24(4), 491-500.
[http://dx.doi.org/10.1177/1352458517702534] [PMID:  28406063] 
[62] 
Macrez, R.; Stys, P.K.; Vivien, D.; Lipton, S.A.; Docagne, F. Mechanisms of glutamate toxicity in multiple sclerosis: Biomarker and thera-peutic opportunities. Lancet Neurol.,  2016, 15(10), 1089-1102.
[http://dx.doi.org/10.1016/S1474-4422(16)30165-X] [PMID:  27571160] 
[63] 
Werner, P.; Pitt, D.; Raine, C.S. Multiple sclerosis: Altered glutamate homeostasis in lesions correlates with oligodendrocyte and axonal damage. Ann. Neurol.,  2001, 50(2), 169-180.
[http://dx.doi.org/10.1002/ana.1077] [PMID:  11506399] 
[64] 
Pampliega, O.; Domercq, M.; Soria, F.N.; Villoslada, P.; Rodríguez-Antigüedad, A.; Matute, C. Increased expression of cystine/glutamate antiporter in multiple sclerosis. J. Neuroinflammation,  2011, 8(1), 63.
[http://dx.doi.org/10.1186/1742-2094-8-63] [PMID:  21639880] 
[65] 
Szabó, C.; Ischiropoulos, H.; Radi, R. Peroxynitrite: biochemistry, pathophysiology and development of therapeutics. Nat. Rev. Drug Discov.,  2007, 6(8), 662-680.
[http://dx.doi.org/10.1038/nrd2222] [PMID:  17667957] 
[66] 
Kuzmina, U.S.; Zainullina, L.F.; Vakhitov, V.A.; Bakhtiyarova, K.Z.; Vakhitova, Y.V. [The role of glutamate in the pathogenesis of multi-ple sclerosis Zh. Nevrol. Psikhiatr. Im. S. S. Korsakova,  2019, 119(8), 160-167.
[http://dx.doi.org/10.17116/jnevro2019119081160] [PMID:  31626185] 
[67] 
Castegna, A.; Palmieri, L.; Spera, I.; Porcelli, V.; Palmieri, F.; Fabis-Pedrini, M.J.; Kean, R.B.; Barkhouse, D.A.; Curtis, M.T.; Hooper, D.C. Oxidative stress and reduced glutamine synthetase activity in the absence of inflammation in the cortex of mice with experimental allergic encephalomyelitis. Neuroscience,  2011, 185, 97-105.
[http://dx.doi.org/10.1016/j.neuroscience.2011.04.041] [PMID:  21536110] 
[68] 
Evonuk, K.S.; Doyle, R.E.; Moseley, C.E.; Thornell, I.M.; Adler, K.; Bingaman, A.M.; Bevensee, M.O.; Weaver, C.T.; Min, B.; DeSilva, T.M. Reduction of AMPA receptor activity on mature oligodendrocytes attenuates loss of myelinated axons in autoimmune neuroinflam-mation. Sci. Adv.,  2020, 6(2), eaax5936.
[http://dx.doi.org/10.1126/sciadv.aax5936] [PMID:  31934627] 
[69] 
Evonuk, K.S.; Baker, B.J.; Doyle, R.E.; Moseley, C.E.; Sestero, C.M.; Johnston, B.P.; De Sarno, P.; Tang, A.; Gembitsky, I.; Hewett, S.J.; Weaver, C.T.; Raman, C.; DeSilva, T.M. Inhibition of system Xc− transporter attenuates autoimmune inflammatory demyelination. J. Immunol.,  2015, 195(2), 450-463.
[http://dx.doi.org/10.4049/jimmunol.1401108] [PMID:  26071560] 
[70] 
Sulkowski, G.; Dąbrowska-Bouta, B.; Chalimoniuk, M.; Strużyńska, L. Effects of antagonists of glutamate receptors on pro-inflammatory cytokines in the brain cortex of rats subjected to experimental autoimmune encephalomyelitis. J. Neuroimmunol.,  2013, 261(1-2), 67-76.
[http://dx.doi.org/10.1016/j.jneuroim.2013.05.006] [PMID:  23746391] 
[71] 
O’Grady, K.P.; Dula, A.N.; Lyttle, B.D.; Thompson, L.M.; Conrad, B.N.; Box, B.A.; McKeithan, L.J.; Pawate, S.; Bagnato, F.; Landman, B.A.; Newhouse, P.; Smith, S.A. Glutamate-sensitive imaging and evaluation of cognitive impairment in multiple sclerosis. Mult. Scler.,  2019, 25(12), 1580-1592.
[http://dx.doi.org/10.1177/1352458518799583] [PMID:  30230400] 
[72] 
Turalde, C.W.R.; Espiritu, A.I.; Anlacan, V.M.M. Memantine for multiple sclerosis: A systematic review and meta-analysis of randomized trials. Front. Neurol.,  2020, 11, 574748.
[PMID:  33658967] 
[73] 
Wingerchuk, D.M.; Banwell, B.; Bennett, J.L.; Cabre, P.; Carroll, W.; Chitnis, T.; de Seze, J.; Fujihara, K.; Greenberg, B.; Jacob, A.; Jarius, S.; Lana-Peixoto, M.; Levy, M.; Simon, J.H.; Tenembaum, S.; Traboulsee, A.L.; Waters, P.; Wellik, K.E.; Weinshenker, B.G. International consensus diagnostic criteria for neuromyelitis optica spectrum disorders. Neurology,  2015, 85(2), 177-189.
[http://dx.doi.org/10.1212/WNL.0000000000001729] [PMID:  26092914] 
[74] 
da Silva, A.P.B.; Souza, D.G.; Souza, D.O.; Machado, D.C.; Sato, D.K. Role of glutamatergic excitotoxicity in neuromyelitis optica spec-trum disorders. Front. Cell. Neurosci.,  2019, 13, 142.
[http://dx.doi.org/10.3389/fncel.2019.00142] [PMID:  31031597] 
[75] 
Nakamura, M.; Miyazawa, I.; Fujihara, K.; Nakashima, I.; Misu, T.; Watanabe, S.; Takahashi, T.; Itoyama, Y. Preferential spinal central gray matter involvement in neuromyelitis optica. An MRI study. J. Neurol.,  2008, 255(2), 163-170.
[http://dx.doi.org/10.1007/s00415-008-0545-z] [PMID:  18231705] 
[76] 
Hinson, S.R.; Roemer, S.F.; Lucchinetti, C.F.; Fryer, J.P.; Kryzer, T.J.; Chamberlain, J.L.; Howe, C.L.; Pittock, S.J.; Lennon, V.A. Aquapo-rin-4-binding autoantibodies in patients with neuromyelitis optica impair glutamate transport by down-regulating EAAT2. J. Exp. Med.,  2008, 205(11), 2473-2481.
[http://dx.doi.org/10.1084/jem.20081241] [PMID:  18838545] 
[77] 
Maciulaitiene, R.; Pakuliene, G.; Kaja, S.; Pauza, D.H.; Kalesnykas, G.; Januleviciene, I. Glioprotection of retinal astrocytes after intravi-treal administration of memantine in the mouse optic nerve crush model. Med. Sci. Monit.,  2017, 23, 1173-1179.
[http://dx.doi.org/10.12659/MSM.899699] [PMID:  28265105] 
[78] 
Bradl, M.; Reindl, M.; Lassmann, H. Mechanisms for lesion localization in neuromyelitis optica spectrum disorders. Curr. Opin. Neurol.,  2018, 31(3), 325-333.
[http://dx.doi.org/10.1097/WCO.0000000000000551] [PMID:  29465432] 
[79] 
Dalmau, J.; Lancaster, E.; Martinez-Hernandez, E.; Rosenfeld, M.R.; Balice-Gordon, R. Clinical experience and laboratory investigations in patients with anti-NMDAR encephalitis. Lancet Neurol.,  2011, 10(1), 63-74.
[http://dx.doi.org/10.1016/S1474-4422(10)70253-2] [PMID:  21163445] 
[80] 
Titulaer, M.J.; Höftberger, R.; Iizuka, T.; Leypoldt, F.; McCracken, L.; Cellucci, T.; Benson, L.A.; Shu, H.; Irioka, T.; Hirano, M.; Singh, G.; Cobo Calvo, A.; Kaida, K.; Morales, P.S.; Wirtz, P.W.; Yamamoto, T.; Reindl, M.; Rosenfeld, M.R.; Graus, F.; Saiz, A.; Dalmau, J. Overlapping demyelinating syndromes and anti-N-methyl-D-aspartate receptor encephalitis. Ann. Neurol.,  2014, 75(3), 411-428.
[http://dx.doi.org/10.1002/ana.24117] [PMID:  24700511] 
[81] 
Zoccarato, M.; Saddi, M.V.; Serra, G.; Pelizza, M.F.; Rosellini, I.; Peddone, L.; Ticca, A.; Giometto, B.; Zuliani, L. Aquaporin-4 antibody neuromyelitis optica following anti-NMDA receptor encephalitis. J. Neurol.,  2013, 260(12), 3185-3187.
[http://dx.doi.org/10.1007/s00415-013-7182-x] [PMID:  24253480] 
[82] 
Luo, J-J.; Lv, H.; Sun, W.; Zhao, J.; Hao, H.J.; Gao, F.; Huang, Y.N. Anti-N-methyl-d-aspartate receptor encephalitis in a patient with neu-romyelitis optica spectrum disorders. Mult. Scler. Relat. Disord.,  2016, 8, 74-77.
[http://dx.doi.org/10.1016/j.msard.2016.05.002] [PMID:  27456878] 
[83] 
Wang, R.; Guan, H.Z.; Ren, H.T.; Wang, W.; Hong, Z.; Zhou, D. CSF findings in patients with anti-N-methyl-D-aspartate receptor-encephalitis. Seizure,  2015, 29, 137-142.
[http://dx.doi.org/10.1016/j.seizure.2015.04.005] [PMID:  26076857] 
[84] 
Iwasaki, A. Immune regulation of antibody access to neuronal tissues. Trends Mol. Med.,  2017, 23(3), 227-245.
[http://dx.doi.org/10.1016/j.molmed.2017.01.004] [PMID:  28185790] 
[85] 
Galli, J.; Clardy, S.L.; Piquet, A.L. NMDAR encephalitis following herpes simplex virus encephalitis. Curr. Infect. Dis. Rep.,  2017, 19(1), 1.
[http://dx.doi.org/10.1007/s11908-017-0556-y] [PMID:  28102519] 
[86] 
Armangue, T.; Spatola, M.; Vlagea, A.; Mattozzi, S.; Cárceles-Cordon, M.; Martinez-Heras, E.; Llufriu, S.; Muchart, J.; Erro, M.E.; Abrai-ra, L.; Moris, G.; Monros-Giménez, L.; Corral-Corral, Í.; Montejo, C.; Toledo, M.; Bataller, L.; Secondi, G.; Ariño, H.; Martínez-Hernández, E.; Juan, M.; Marcos, M.A.; Alsina, L.; Saiz, A.; Rosenfeld, M.R.; Graus, F.; Dalmau, J.; Aguilera-Albesa, S.; Amado-Puentes, A.; Arjona-Padillo, A.; Arrabal, L.; Arratibel, I.; Aznar-Laín, G.; Bellas-Lamas, P.; Bermejo, T.; Boyero-Durán, S.; Camacho, A.; Campo, A.; Campos, D.; Cantarín-Extremera, V.; Carnero, C.; Conejo-Moreno, D.; Dapena, M.; Dacruz-Álvarez, D.; Delgadillo-Chilavert, V.; Deyà, A.; Estela-Herrero, J.; Felipe, A.; Fernández-Cooke, E.; Fernández-Ramos, J.; Fortuny, C.; García-Monco, J.C.; Gili, T.; González-Álvarez, V.; Guerri, R.; Guillén, S.; Hedrera-Fernández, A.; López, M.; López-Laso, E.; Lorenzo-Ruiz, M.; Madruga, M.; Málaga-Diéguez, I.; Martí-Carrera, I.; Martínez-Lacasa, X.; Martín-Viota, L.; Martín Gil, L.; Martínez-González, M-J.; Moreira, A.; Miranda-Herrero, M.C.; Monge, L.; Muñoz-Cabello, B.; Navarro-Morón, J.; Neth, O.; Noguera-Julian, A.; Nuñez-Enamorado, N.; Pomar, V.; Portillo-Cuenca, J.C.; Poyato, M.; Prieto, L.; Querol, L.; Rodríguez-Rodríguez, E.; Sarria-Estrada, S.; Sierra, C.; Soler-Palacín, P.; Soto-Insuga, V.; Toledo-Bravo, L.; Tomás, M.; Torres-Torres, C.; Turón, E.; Zabalza, A. Frequency, symptoms, risk factors, and outcomes of autoimmune encephalitis after herpes simplex encephalitis: A prospective observational study and retrospective analysis. Lancet Neurol.,  2018, 17(9), 760-772.
[http://dx.doi.org/10.1016/S1474-4422(18)30244-8] [PMID:  30049614] 
[87] 
Platt, M.P.; Agalliu, D.; Cutforth, T. Hello from the other side: How autoantibodies circumvent the blood-brain barrier in autoimmune encephalitis. Front. Immunol.,  2017, 8, 442.
[http://dx.doi.org/10.3389/fimmu.2017.00442] [PMID:  28484451] 
[88] 
Li, C.; Xiao, L.; Liu, X.; Yang, W.; Shen, W.; Hu, C.; Yang, G.; He, C. A functional role of NMDA receptor in regulating the differentiation of oligodendrocyte precursor cells and remyelination. Glia,  2013, 61(5), 732-749.
[http://dx.doi.org/10.1002/glia.22469] [PMID:  23440860] 
[89] 
Fleischmann, R.; Prüss, H.; Rosche, B.; Bahnemann, M.; Gelderblom, H.; Deuschle, K.; Harms, L.; Kopp, U.; Ruprecht, K. Severe cogniti-ve impairment associated with intrathecal antibodies to the NR1 subunit of the N-methyl-D-aspartate receptor in a patient with multiple sclerosis. JAMA Neurol.,  2015, 72(1), 96-99.
[http://dx.doi.org/10.1001/jamaneurol.2014.1817] [PMID:  25384024] 
[90] 
Etemadifar, M. “NMDA receptor spectrum disorder” in the differential diagnosis of demyelinating disorders of the CNS: Optic neuritis and myelitis. Neurol. Sci.,  2021, 42(1), 151-157.
[PMID:  32564271] 
[91] 
Gulec, B.; Kurucu, H.; Bozbay, S.; Dikmen, Y.; Sayman, H.; Tuzun, E.; Tutuncu, M.; Uygunoglu, U.; Yalcinkaya, C.; Saip, S.; Siva, A. Co-existence of multiple sclerosis and anti-NMDA receptor encephalitis: A case report and review of literature. Mult. Scler. Relat. Disord.,  2020, 42, 102075.
[http://dx.doi.org/10.1016/j.msard.2020.102075] [PMID:  32388459] 
[92] 
Garré, J.; Sprengers, M.; Van Melkebeke, D.; Laureys, G. EBV-NMDA double positive encephalitis in an immunocompromised patient. J. Neurol. Sci.,  2019, 396, 76-77.
[http://dx.doi.org/10.1016/j.jns.2018.11.001] [PMID:  30419370] 
[93] 
Ramberger, M.; Bsteh, G.; Schanda, K.; Höftberger, R.; Rostásy, K.; Baumann, M.; Aboulenein-Djamshidian, F.; Lutterotti, A.; Deisen-hammer, F.; Berger, T.; Reindl, M. NMDA receptor antibodies: A rare association in inflammatory demyelinating diseases. Neurol. Neuroimmunol. Neuroinflamm.,  2015, 2(5), e141.
[http://dx.doi.org/10.1212/NXI.0000000000000141] [PMID:  26309901] 
[94] 
Tojo, K.; Nitta, K.; Ishii, W.; Sekijima, Y.; Morita, H.; Takahashi, Y.; Tanaka, K.; Ikeda, S. A young man with anti-NMDAR encephalitis following Guillain-Barré syndrome. Case Rep. Neurol.,  2011, 3(1), 7-13.
[http://dx.doi.org/10.1159/000323751] [PMID:  21327179] 
[95] 
Prüss, H.; Hoffmann, C.; Stenzel, W.; Saschenbrecker, S.; Ebinger, M. A case of inflammatory peripheral nerve destruction antedating anti-NMDA receptor encephalitis. Neurol. Neuroimmunol. Neuroinflamm.,  2014, 1(2), e14.
[http://dx.doi.org/10.1212/NXI.0000000000000014] [PMID:  25340067] 
[96] 
Hatano, T.; Shimada, Y.; Kono, A.; Kubo, S.; Yokoyama, K.; Yoritaka, A.; Nakahara, T.; Takahashi, Y.; Hattori, N. Atypical Miller Fisher syndrome associated with glutamate receptor antibodies. BMJ Case Rep.,  2011, 2011, bcr0820103228.
[http://dx.doi.org/10.1136/bcr.08.2010.3228] [PMID:  22707623] 
[97] 
Zhang, M.; Li, W.; Zhou, S.; Zhou, Y.; Yang, H.; Yu, L.; Wang, J.; Wang, Y.; Zhang, L. Clinical features, treatment, and outcomes among Chinese children with anti-methyl-d-aspartate receptor (Anti-NMDAR) encephalitis. Front. Neurol.,  2019, 10, 596.
[http://dx.doi.org/10.3389/fneur.2019.00596] [PMID:  31244759] 
Cite As
Mini-Reviews in Medicinal Chemistry

N-Methyl-D-Aspartate (NMDA)-Type Glutamate Receptors and Demyelinating Disorders: A Neuroimmune Perspective

Abstract

Graphical Abstract
