Role of NMDA Receptors in Alzheimer's Disease Pathology and Potential NMDA Receptor Blockers from Medicinal Plants - A Review


  • Al Shifa College of Pharmacy, Department of Pharmacology, Kizhattoor, Kerala, 679325, India
  • Annamalai University, Department of Pharmacy, Annamalai Nagar, Tamil Nadu, India


Alzheimer’s disease is responsible for 60-70 percent of dementia cases worldwide. Globally, there are 24.3 million cases. Researchers have attempted to develop multi-target medications to suppress several mechanisms in Alzheimer’ Disease, like protein mis-folding and related beta amyloid aggregation, oxidative stress, and decreasing Acetyl choline levels. NMDA-mediated neurotoxicity is often linked to cognitive impairment, as shown in Alzheimer’s disease. NMDA receptors found to have to connection with beta amyloid peptide and tau protein deposition which are major characteristics of Alzheimer’s disease. NMDA receptor antagonists are a viable therapy option for a many neurological disorders, as well as Alzheimer’s disease. Currently, majority of the drugs used in the management of Alzheimer’s disease are Acetyl choline Esterase inhibitors. Memantine is the only approved NMDA blocker, to be used in Alzheimer’s disease, which is found to be effective only to a certain extend. There is a need for better therapeutic agents belonging to this class. This paper intends to provide a rapid reference about the involvement of NMDA receptors in the pathogenesis of Alzheimer’s disease, as well as phyto constituents that have been identified to inhibit NMDA receptors.


Alzheimer’s Disease, Cognitive Functions, Dementia, Excitotoxicity, N-Methyl-D-Aspartate (NMDA) Receptor

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Alzheimer's Disease International. In: World Alzheimer Report 2015-the Global Impact of Dementia: An Analysis of Prevalence, Incidence, Cost and Trends, London; 2015.

Sharma K. Cholinesterase Inhibitors as Alzheimer's Therapeutics (Review). Mol. Med. Rep., 2019; 1479-1487. PMid:31257471 PMCid:PMC6625431.

Russo P, Frustaci A, Del Bufalo A, Fini M, Cesario A. Multitarget drugs of plants origin acting on Alzheimer's disease. Curr. Med. Chem., 2013; 1686-1693. PMid:23410167.

Azam F, Amer AM, Abulifa AR, Elzwawi MM. Ginger components as new leads for the design and development of novel multi-targeted anti-alzheimer's drugs: A computational investigation. Drug Des Devel Ther., 2014; 8:2045-2059. PMid: 25364231 PMCid: PMC4211852.

Parsons CG, Danysz W, Quack G. Glutamate in CNS disorders as a target for drug development: An update. Drug News Perspect., 1998; 11(9):523-529. PMid:15616669.

Francis PT. Glutamatergic systems in Alzheimer's disease. Int. J. Geriatr. Psychiatry, 2003; 18(1):15-21. PMid:12973746.

Cortese BM, Phan KL. The role of glutamate in anxiety and related disorders. CNS Spectr., 2005; 10(10):820-30. PMid:16400245.

Fan MM, Raymond LA. N-Methyl-D-Aspartate (NMDA) receptor function and excitotoxicity in Huntington's disease. Prog. Neurobiol., 2007; 81(5-6):272-293. PMid:17188796.

Mathews DC, Henter ID, Zarate CA Jr. Targeting the glutamatergic system to treat major depressive disorder: Rationale and progress to date. Drugs, 2012; 72:13131333. PMid:22731961 PMCid:PMC3439647.

Ghasemi M, Schachter SC. The NMDA receptor complex as a therapeutic target in epilepsy: A review. Epilepsy Behav., 2011; 22:617-640. PMid: 22056342.

Schoepp DD. Unveiling the functions of presynaptic metabotropic glutamate receptors in the central nervous system. J. Pharmacol. Exp. Ther., 2001; 299(1):12-20.

Santangelo RM, Acker TM, Zimmerman SS, Katzman BM, Strong KL, Traynelis SF, Liotta DC. Novel NMDA receptor modulators: An update. EOTPEG, 2012; 22:1337-1352. PMid: 23009122 PMCid: PMC3677696.

Kodis EJ, Choi S, Swanson E, Ferreira G, Bloom GS. N-methyl- D-aspartate receptor-mediated calcium influx connects amyloid-b oligomers to ectopic neuronal cell cycle re-entry in Alzheimer's disease. Alzheimer's Dement., 2018; 14:1302-1312. PMid: 30293574 PMCid: PMC8363206.

Wang R, Reddy PH. Role of glutamate and NMDA receptors in Alzheimer's disease. J Alzheimer's Dis., 2017; 57:10411048. PMid:27662322 PMCid:PMC5791143.

Luscher C, Malenka RC. NMDA receptor-dependent longterm potentiation and long-term depression (LTP/LTD). Cold Spring Harb. Perspect. Biol., 2012; 4(6):a005710. PMid:225104 60 PMCid: PMC3367554.

Ogden KK, Traynelis SF. New advances in NMDA receptor pharmacology. Trends Pharmacol. Sci., 2011; 32:726-733. PMid:21996280 PMCid:PMC3223280.

Paoletti P, Neyton J. NMDA receptor subunits: Function and pharmacology. COPHAR, 2007; 7:39-47. PMid:17088105.

Morris GP, Clark IA, Vissel B. Questions concerning the role of amyloid-b in the definition, aetiology and diagnosis of Alzheimer's disease. Acta Neuropathologica, 2018; 136:663-689. PMid:30349969 PMCid:PMC6208728.

Roberson ED, Scearce-Levie K, Palop JJ, Yan F, Cheng IH, Wu T, et al. Reducing endogenous tau ameliorates amyloid-induced deficits in an Alzheimer's disease mouse model. Science, 2007; 316:750-754. science.1141736. PMid:17478722.

Chang L, Zhang Y, Liu J, Song Y, Lv A, Li Y. Differential regulation of N-methyl-D-aspartate receptor subunits is an early events in the actions of soluble amyloid-b1 40 oligomers on hippocampal neurons. J. Alzheimer's Dis., 2016; 51:197-212. PMid:26836185.

Palop JJ, Mucke L. Amyloid-b-induced neuronal dysfunction in Alzheimer's disease from synapses toward neural networks. Nat. Neurosci., 2010; 13:812-818. PMid:20581818 PMCid: PMC3072750.

Shankar GM, Bloodgood BL, Townsend M, Walsh DM, Selkoe DJ, Sabatini BL. Natural oligomers of the Alzheimer amyloidprotein induce reversible synapse loss by modulating an NMDA-type glutamate receptor-dependent signaling pathway. J Neurosci., 2007; 27:2866-2875. https:// 4970-06.2007. PMid:173609 08 PMCid: PMC6672572.

Liu J, Chang L, Song Y, Li H, Wu Y. Role of NMDA Receptors in Alzheimer's disease. Front Neurosci., 2019; 13:43. PMid:30800052 PMCid:PMC6375899.

Pierson TM, Yuan H, Marsh ED, Fuentes-Fajardo K, Adams DR, Markello T. GRIN2A mutation and early-onset epileptic encephalopathy: personalized therapy with memantine. ACTN, 2014; 1:190-198. PMid:24839611 PMCid:PMC4019449.

Song X, Jensen MO, Jogini V, Stein RA, Lee C, Mchaourab HS., et al.. Mechanism of NMDA receptor channel block by MK-801 and memantine. Nature, 2018; 556(7702):515519. PMid: 29670280 PMCid: PMC5962351.

Parsons CG, Stoffler A, Danysz, W. Memantine: A NMDA receptor antagonist that improves memory by restoration of homeostasis in the glutamatergic system - Too little activation is bad, too much is even worse. Neuropharmacology, 2007; 53:699-723. 2007.07.013. PMid:17904591.

Danysz W, Parsons CG. Alzheimer's disease, b-amyloid, glutamate, NMDA receptors and memantine - Searching for the connections. Br. J. Pharmacol., 2012; 167:324-352. PMid:22 646481 PMCid:PMC3481041.

Wu H, Tzeng, N, Qian, L, Wei, S, Hu, X, Chen, S. Novel neuroprotective mechanisms of memantine: Increase in neurotrophic factor release from astroglia and anti-inflammation by preventing microglial activation. Neuro Psychopharmacology, 2009; 34:2344-2357. PMid:19536110 PMCid: PMC 3655438.

Liang W, Lam WP, Tang HC, Leung PC, Yew DT. Current evidence of Chinese herbal constituents with effects on NMDA receptor blockade. Pharmaceuticals, 2013; 6:10391054. PMid:24276380 PMCid:PMC3817734.

Matteucci A, Frank C, Domenici MR, Balduzzi M, Paradisi S, Carnovale-Scalzo D, Scorcia G, Malchiodi-Albedi F. Curcumin treatment protects rat retinal neurons against excitotoxicity: Effect on N-methyl-D-aspartate-induced intracellular Ca2+ increase. Exp. Brain Res., 2005; 167:641-648. PMid:16078027.

Shen H, Yuan Y, Ding F, Liu J, Gu X. The protective effects of Achyranthes bidentata polypeptides against NMDA-induced cell apoptosis in cultured hippocampal neurons through differential modulation of NR2A- and NR2B-containing NMDA receptors. Brain Res. Bull., 2008; 77:274-281. PMid:18765272.

Shen H, Yuan Y, Ding F, Hu N, Liu J, Gu X. Achyranthes bidentata polypeptides confer neuroprotection through inhibition of reactive oxygen species production, Bax expression, and mitochondrial dysfunction induced by overstimulation of N-methyl-D-aspartate receptors. J Neurosci. Res., 2010; 88:669-676. jnr.22221 PMid:19774671.

Kim S, Ahn K, Oh TH, Nah S-Y, Rhim H. Inhibitory effect of ginsenosides on NMDA receptor-mediated signals in rat hippocampal neurons. Biochem. Biophys. Res. Commun., 2002; 296:247-254. S0006-291X(02)00870-7.

Birks J, Grimley EJ, Ginkgo biloba for cognitive impairment and dementia. Cochrane Database Syst. Rev., 2007; 18(2):CD00312. 120.pub2.

Le Bars PL, Katz MM, Berman N, Itil TM, Freedman AM, Schatzberg AF. A placebo controlled, double-blind, randomized trial of an extract of Ginkgo biloba for dementia. North American Egb Study Group. JAMA, 1997; 278:1327-1332. PMid:9343463.

Li S, Luo J, Wang X, Guan B-C, Sun C-K. Effects of Ginkgo biloba extracts on NMDA activated currents in acutely isolated hippocampal neurons of the rat. Phytother Res., 2011; 25:137-141. PMid:20632296

Ahlemeyer B, Krieglstein J. Neuroprotective effects of Ginkgo biloba extract. Cell. Mol. Life Sci., 2003; 60:1779-1782. PMid: 14523543.

Weichel O, Hilger M, Chatterjee SS, Lehr M, Klein J. Bilobalide, a constituent of Ginkgo biloba, inhibits NMDA induced phospholipase A2 activation and phospholipid breakdown in rat hippocampus. Naunyn Schmiedebergs Arch. Pharmacol., 1999; 360:609-615. PMid:10619176.

Kim SR, Kim YC. Neuroprotective phenylpropanoid esters of rhamnose isolated from roots of Scrophularia buergeriana. Phytochemistry, 2000; 54:503-509.

Kim SR, Koo KA, Sung SH, Ma CJ, Yoon JS, Kim YC. Iridoids from Scrophularia buergeriana attenuate glutamate-induced neurotoxicity in rat cortical cultures. J. Neurosci. Res., 2003; 74:948-955. PMid:24276380 PMCid:PMC3817734.

Zhang C, Du F, Shi M, Ye R, Cheng H, Han J, Ma L, Cao R, Rao Z, Zhao G. Ginsenoside Rd protects neurons against glutamate-induced excitotoxicity by inhibiting Ca2+ influx. Cell. Mol. Neurobiol., 2012; 32:121-128. PMid:21811848.

Sun X, Chan LN, Gong X, Sucher NJ. N-Methyl-D-Aspartate receptor antagonist activity in traditional Chinese stroke medicines. Neurosignals, 2003; 12:31-38 PMid: 12624526.

Shin IJ, Son SU, Park H, Kim Y, Park SH et al. Preclinical evidence of rapid-onset antidepressant-like effect in radix polygalae extract. PLoS One, 2014; 9(2):1-10. PMid:24520403 PMCid:PMC3919798.

Kawakami Z, Ikarashi Y, Kase Y. Isoliquiritigenin is a Novel NMDA receptor antagonist in Kampo Medicine Yokukansan. Cell. Mol. Neurobiol., 2011; 31:1203-1212. PMid:21691759.


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