Abstract
There is accumulating evidence that excitotoxicity and oxidative stress resulting from excessive activation of glutamate (N-methyl-d-aspartate) NMDA receptors are major participants in striatal degeneration associated with 3-nitropropionic acid (3NP) administration. Although excitotoxic and oxidative mechanisms are implicated in 3NP toxicity, there are conflicting reports as to whether NMDA receptor antagonists attenuate or exacerbate the 3NP-induced neurodegeneration. In the present study, we investigated the involvement of NMDA receptors in striatal degeneration, protein oxidation and motor impairment following systemic 3NP administration. We examined whether NMDA receptor antagonists, memantine and ifenprodil, influence the neurotoxicity of 3NP. The development of striatal lesion and protein oxidation following 3NP administration is delayed by memantine but not affected by ifenprodil. However, in behavioral experiments, memantine failed to improve and ifenprodil exacerbated the motor deficits associated with 3NP toxicity. Together, these findings suggest caution in the application of NMDA receptor antagonists as a neuroprotective agent in neurodegenerative disorders associated with metabolic impairment.
Similar content being viewed by others
References
Beal MF (1994) Neurochemistry and toxin models in Huntington’s disease. Curr Opin Neurol 7:542–547. doi:10.1097/00019052-199412000-00012
Palfi S, Ferrante RJ, Brouillet E et al (1996) Chronic 3-nitropropionic acid treatment in baboons replicates the cognitive and motor deficits of Huntington’s disease. J Neurosci 16:3019–3025
Borlongan CV, Koutouzis TK, Sanberg PR (1997) 3-Nitropropionic acid animal model and Huntington’s disease. Neurosci Biobehav Rev 21:289–293. doi:10.1016/S0149-7634(96)00027-9
Beal MF, Brouillet E, Jenkins BG et al (1993) Neurochemical and histologic characterization of striatal excitotoxic lesions produced by the mitochondrial toxin 3-nitropropionic acid. J Neurosci 13:4181–4192
Brouillet E, Jenkins BG, Hyman BT et al (1993) Age-dependent vulnerability of the striatum to the mitochondrial toxin 3-nitropropionic acid. J Neurochem 60:356–359. doi:10.1111/j.1471-4159.1993.tb05859.x
Borlongan CV, Koutouzis TK, Freeman TB et al (1997) Hyperactivity and hypoactivity in a rat model of Huntington’s disease: the systemic 3-nitropropionic acid model. Brain Res Brain Res Protoc 1:253–257. doi:10.1016/S1385-299X(96)00037-2
Gould DH, Wilson MP, Hamar DW (1985) Brain enzyme and clinical alterations induced in rats and mice by nitroaliphatic toxicants. Toxicol Lett 27:83–89. doi:10.1016/0378-4274(85)90123-7
Pang Z, Umberger GH, Geddes JW (1996) Neuronal loss and cytoskeletal disruption following intrahippocampal administration of the metabolic inhibitor malonate: lack of protection by MK-801. J Neurochem 66:474–484
Brouillet E, Guyot MC, Mittoux V et al (1998) Partial inhibition of brain succinate dehydrogenase by 3-nitropropionic acid is sufficient to initiate striatal degeneration in rat. J Neurochem 70:794–805
Novelli A, Reilly JA, Lysko PG et al (1988) Glutamate becomes neurotoxic via the N-methyl-D-aspartate receptor when intracellular energy levels are reduced. Brain Res 451:205–212. doi:10.1016/0006-8993(88)90765-2
Albin RL, Greenamyre JT (1992) Alternative excitotoxic hypotheses. Neurology 42:733–738
Beal MF, Hyman BT, Koroshetz W (1993) Do defects in mitochondrial energy metabolism underlie the pathology of neurodegenerative diseases? Trends Neurosci 16:125–131. doi:10.1016/0166-2236(93)90117-5
Volbracht C, Van Beek JV, Zhu C et al (2006) Neuroprotective properties of memantine in different in vitro and in vivo models of excitotoxicity. Eur J NeuroSci 23:2611–2622. doi:10.1111/j.1460-9568.2006.04787.x
Nowak L, Bregestovski P, Ascher P et al (1984) Magnesium gates glutamate-activated channels in mouse central neurons. Nature 307:462–465. doi:10.1038/307462a0
Choi DW (1985) Glutamate neurotoxicity in cortical cell culture is calcium dependent. Neurosci Lett 58:293–297. doi:10.1016/0304-3940(85)90069-2
Rothman SM, Thurston JH, Hauhart RE (1987) Delayed neurotoxicity of excitatory amino acids in vitro. Neuroscience 22:471–480. doi:10.1016/0306-4522(87)90347-2
Olney JW (1990) Excitotoxicity: an overview. Can Dis Wkly Rep 16(Suppl 1E):47–57 Discussion 57–58
Beal MF, Brouillet E, Jenkins B et al (1993) Age-dependent striatal excitotoxic lesions produced by the endogenous mitochondrial inhibitor malonate. J Neurochem 61:1147–1150. doi:10.1111/j.1471-4159.1993.tb03633.x
Simpson JR, Isacson O (1993) Mitochondrial impairment reduces the threshold for in vivo NMDA-mediated neuronal death in the striatum. Exp Neurol 121:57–64. doi:10.1006/exnr.1993.1071
Calabresi P, Gubellini P, Picconi B et al (2001) Inhibition of mitochondrial complex II induces a long-term potentiation of NMDA-mediated synaptic excitation in the striatum requiring endogenous dopamine. J Neurosci 21:5110–5120
Jacquard C, Trioulier Y, Cosker F et al (2006) Brain mitochondrial defects amplify intracellular [Ca2+] rise and neurodegeneration but not Ca2+ entry during NMDA receptor activation. FASEB 20:245–259. doi:10.1096/fj.05-5085fje
Christopherson KS, Hillier BJ, Lim WA et al (1999) PSD-95 assembles a ternary complex with the N-methyl-D-aspartic acid receptor and a bivalent neuronal NO synthase PDZ domain. J Biol Chem 274:27467–27473. doi:10.1074/jbc.274.39.27467
Sattler R, Xiong Z, Lu WY et al (1999) Specific coupling of NMDA receptor activation to nitric oxide neurotoxicity by PSD-95 protein. Science 284:1845–1848. doi:10.1126/science.284.5421.1845
Beckman JS (1996) Oxidative damage and tyrosine nitration from peroxynitrite. Chem Res Toxicol 9:836–844. doi:10.1021/tx9501445
Beckman JS, Koppenol WH (1996) Nitric oxide, superoxide, and peroxynitrite: the good, the bad, and ugly. Am J Physiol 271:1424–1437
Halliwell B (1997) What nitrates tyrosine? Is nitrotyrosine specific as a biomarker of peroxynitrite formation in vivo? FEBS Lett 411:157–160. doi:10.1016/S0014-5793(97)00469-9
Coyle JT, Puttfarcken P (1993) Oxidative stress, glutamate, and neurodegenerative disorders. Science 262:689–695. doi:10.1126/science.7901908
Ischiropoulos H, al-Mehdi AB (1995) Peroxynitrite-mediated oxidative protein modifications. FEBS Lett 364:279–282. doi:10.1016/0014-5793(95)00307-U
Beal MF, Ferrante RJ, Browne SE et al (1997) Increased 3-nitrotyrosine in both sporadic and familial amyotrophic lateral sclerosis. Ann Neurol 42:644–654. doi:10.1002/ana.410420416
Berlett BS, Friguet B, Yim MB et al (1996) Peroxynitrite-mediated nitration of tyrosine residues in Escherichia coli glutamine synthetase mimics adenylylation: relevance to signal transduction. Proc Natl Acad Sci USA 93:1776–1780. doi:10.1073/pnas.93.5.1776
Kong SK, Yim MB, Stadtman ER et al (1996) Peroxynitrite disables the tyrosine phosphorylation regulatory mechanism: Lymphocyte-specific tyrosine kinase fails to phosphorylate nitrated cdc2 (6–20) NH2 peptide. Proc Natl Acad Sci USA 93:3377–3382. doi:10.1073/pnas.93.8.3377
Ha HC, Snyder SH (2000) Poly(ADP-ribose) polymerase-1 in the nervous system. Neurobiol Dis 7:225–239. doi:10.1006/nbdi.2000.0324
Laemmli UK (1970) Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature 227:680–685. doi:10.1038/227680a0
Vezzani A, Serafini R, Stasi MA et al (1989) Kinetics of MK-801 and its effect on quinolinic acid-induced seizures and neurotoxicity in rats. J Pharmacol Exp Ther 249:278–283
Lipton SA (1993) Prospects for clinically tolerated NMDA antagonists: open-channel blockers and alternative redox states of nitric oxide. Trends Neurosci 16:527–532. doi:10.1016/0166-2236(93)90198-U
Gallagher MJ, Huang H, Grant ER et al (1997) The NR2B-specific interactions of polyamines and protons with the N-methyl-D-aspartate receptor. J Biol Chem 272:24971–24979. doi:10.1074/jbc.272.40.24971
Laurie DJ, Bartke I, Schoepfer R et al (1997) Regional, developmental and interspecies expression of the four NMDAR2 subunits, examined using monoclonal antibodies. Brain Res Mol Brain Res 51:23–32. doi:10.1016/S0169-328X(97)00206-4
Butler TW, Blake JF, Bordner J et al (1998) (3R, 4S)-3-[4-(4-fluorophenyl)-4-hydroxypiperidin-1-yl]chroman-4, 7-diol: a conformationally restricted analogue of the NR2B subtype-selective NMDA antagonist (1S, 2S)-1-(4-hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidino)- 1-propanol. J Med Chem 41:1172–1184. doi:10.1021/jm9707986
Goebel DJ, Poosch MS (1999) NMDA receptor subunit gene expression in the rat brain: a quantitative analysis of endogenous mRNA levels of NR1Com, NR2A, NR2B, NR2C, NR2D and NR3A. Brain Res Mol Brain Res 69:164–170. doi:10.1016/S0169-328X(99)00100-X
Arai Y, Nakazato K, Kinemuchi H et al (1991) Inhibition of rat brain monoamine oxidase activity by cerebral anti-ischemic agent, ifenprodil. Neuropharmacology 30:809–812. doi:10.1016/0028-3908(91)90190-M
Kurihara J, Tamaoki S, Kato H (1993) Blockade of alpha 2-adrenoceptors protects the vagal baroreflex system from transient global cerebral ischemia in dogs. Eur J Pharmacol 240:73–76. doi:10.1016/0014-2999(93)90547-U
McCool BA, Lovinger DM (1995) Ifenprodil inhibition of the 5-hydroxytryptamine3 receptor. Neuropharmacology 34:621–629. doi:10.1016/0028-3908(95)00030-A
Chenard BL, Menniti FS (1999) Antagonists selective for NMDA receptors containing the NR2B subunit. Curr Pharm Des 5:381–404
Ambrozi L, Danielczyk W (1988) Treatment of impaired cerebral function in psychogeriatric patients with memantine–results of a phase II double-blind study. Pharmacopsychiatry 21:144–146
Parsons CG, Danysz W, Quack G (1999) Memantine is a clinically well tolerated N-methyl-D-aspartate (NMDA) receptor antagonist–a review of preclinical data. Neuropharmacology 38:735–767. doi:10.1016/S0028-3908(99)00019-2
Parsons CG, Danysz W, Quack G (2000) Memantine and the amino-alkyl-cyclohexane MRZ 2/579 are moderate affinity uncompetitive NMDA receptor antagonists–in vitro characterisation. Amino Acids 19:157–166. doi:10.1007/s007260070044
Palmer GC (2001) Neuroprotection by NMDA receptor antagonists in a variety of neuropathologies. Curr Drug Targets 2:241–271. doi:10.2174/1389450013348335
Finucane TE (2004) Memantine for patients with Alzheimer disease. JAMA 291:1695. doi:10.1001/jama.291.14.1695-a
Hirsch CH (2004) Memantine was better than placebo in Alzheimer disease already being treated with donepezil. ACP J Club 141:38
Tariot PN, Farlow M, Grossberg GT et al (2004) Memantine treatment in patients with moderate to severe Alzheimer disease already receiving donepezil: a randomized controlled trial. JAMA 291:317–324. doi:10.1001/jama.291.3.317
Blanpied TA, Boeckman FA, Aizenman E et al (1997) Trapping channel block of NMDA-activated responses by amantadine and memantine. J Neurophysiol 77:309–323
Chen HS, Lipton SA (1997) Mechanism of memantine block of NMDA-activated channels in rat retinal ganglion cells: uncompetitive antagonism. J Physiol 499:27–46
Danysz W, Parsons CG, Kornhuber J et al (1997) Aminoadamantanes as NMDA receptor antagonists and antiparkinsonian agents–preclinical studies. Neurosci Biobehav Rev 21:455–468. doi:10.1016/S0149-7634(96)00037-1
Bossi SR, Simpson JR, Isacson O (1993) Age dependence of striatal neuronal death caused by mitochondrial dysfunction. NeuroReport 4:73–76. doi:10.1097/00001756-199301000-00019
Guyot MC, Hantraye P, Dolan R (1997) Quantifiable bradykinesia, gait abnormalities and Huntington’s disease-like striatal lesions in rats chronically treated with 3-nitropropionic acid. Neuroscience 79:45–56. doi:10.1016/S0306-4522(96)00602-1
Lee ST, Chu K, Park JE et al (2006) Memantine reduces striatal cell death with decreasing calpain level in 3-nitropropionic model of Huntington’s disease. Brain Res 1118:199–207. doi:10.1016/j.brainres.2006.08.035
Ouary S, Bizat N, Altairac S et al (2000) Major strain differences in response to chronic systemic administration of the mitochondrial toxin 3-nitropropionic acid in rats: implication for neuroprotection studies. Neuroscience 97:521–530. doi:10.1016/S0306-4522(00)00020-8
Teunissen CE, Markerink-van Ittersum M, de Bruijn C et al (2002) Evaluation of 3-nitrotyrosine as a marker for 3-nitropropionic acid-induced oxidative stress in Lewis and Wistar rats and strain-specific whole brain spheroid cultures. Brain Res 931:5–20. doi:10.1016/S0006-8993(01)03331-5
Nasr P, Gursahani HI, Pang Z et al (2003) Influence of cytosolic and mitochondrial Ca(2+), ATP, mitochondrial membrane potential, and calpain activity on the mechanism of neuron death induced by 3-nitropropionic acid. Neurochem Int 43:89–99. doi:10.1016/S0197-0186(02)00229-2
Pang Z, Geddes JW (1997) Mechanisms of cell death induced by the mitochondrial toxin 3-nitropropionic acid: acute excitotoxic necrosis and delayed apoptosis. J Neurosci 17:3064–3073
Kim GW, Copin JC, Kawase M et al (2000) Excitotoxicity is required for induction of oxidative stress and apoptosis in mouse striatum by the mitochondrial toxin, 3-nitropropionic acid. J Cereb Blood Flow Metab 20:119–129. doi:10.1097/00004647-200001000-00016
Karanian DA, Baude AS, Brown QB et al (2006) 3-Nitropropionic acid toxicity in hippocampus: protection through N-methyl-D-aspartate receptor antagonism. Hippocampus 16:834–842. doi:10.1002/hipo.20214
Tozzi A, Costa C, Di Filippo M et al (2007) Memantine reduces neuronal dysfunction triggered by in vitro ischemia and 3-nitropropionic acid. Exp Neurol 207:218–226. doi:10.1016/j.expneurol.2007.06.008
Ikonomidou C, Stefovska V, Turski L (2000) Neuronal death enhanced by N-methyl-D-aspartate antagonists. Proc Natl Acad Sci USA 97:12885–12890. doi:10.1073/pnas.220412197
Frankiewicz T, Parsons CG (2004) Chronic memantine does not block 3-nitropropionic acid-delayed ischaemic tolerance in rat hippocampal slices ex vivo. Neurotox Res 5:617–622
Stefani A, Chen Q, Hernandez J et al (1998) Physiological and molecular properties of AMPA/Kainate receptors expressed by striatal medium spiny neurons. Dev Neurosci 20:242–252. doi:10.1159/000017318
Le Page F, Schreiber V, Dherin C et al (2003) Poly(ADP-ribose) polymerase-1(PARP-1) is required in murine cell lines for base excision repair of oxidative DNA damage in absence of DNA polymerase beta. J Biol Chem 278:18471–18477. doi:10.1074/jbc.M212905200
Kaufmann SH (1989) Induction of endonucleolytic DNA cleavage in human acute myelogenous leukemia cells by etoposide, camptothecin, and other cytotoxic anticancer drugs: a cautionary note. Cancer Res 49:5870–5878
Lazebnik YA, Kaufmann SH, Desnoyers S et al (1994) Cleavage of poly(ADP-ribose) polymerase by a proteinase with properties like ICE. Nature 371:346–347. doi:10.1038/371346a0
Shah GM, Shah RG, Poirier GG et al (1996) Different cleavage pattern for poly(ADP-ribose) polymerase during necrosis and apoptosis in HL-60 cells. Biochem Biophys Res Commun 229:838–844. doi:10.1006/bbrc.1996.1889
Gobeil S, Boucher CC, Nadeau D et al (2001) Characterization of the necrotic cleavage of poly(ADP-ribose) polymerase (PARP-1): implication of lysosomal proteases. Cell Death Differ 8:588–594. doi:10.1038/sj.cdd.4400851
Andreassen OA, Ferrante RJ, Hughes DB et al (2000) Malonate and 3-nitropropionic acid neurotoxicity are reduced in transgenic mice expressing a caspase-1 dominant-negative mutant. J Neurochem 75:847–852. doi:10.1046/j.1471-4159.2000.0750847.x
McCracken E, Dewar D, Hunter AJ (2001) White matter damage following systemic injection of the mitochondrial inhibitor 3-nitropropionic acid in rat. Brain Res 892:329–335. doi:10.1016/S0006-8993(00)03266-2
Schulz JB, Matthews RT, Beal MF (1995) Role of nitric oxide in neurodegenerative diseases. Curr Opin Neurol 8:480–486. doi:10.1097/00019052-199512000-00016
Schulz JB, Matthews RT, Jenkins BG et al (1995a) Blockade of neuronal nitric oxide synthase protects against excitotoxicity in vivo. J Neurosci 15:8419–8429
Behrens MI, Koh J, Canzoniero LM et al (1995b) 3-Nitropropionic acid induces apoptosis in cultured striatal and cortical neurons. NeuroReport 6:545–548. doi:10.1097/00001756-199502000-00034
Muir KW, Lees KR (1995) Clinical experience with excitatory amino acid antagonist drugs. Stroke 26:503–513
Davis SM, Albers GW, Diener HC et al (1997) Termination of acute stroke studies involving selfotel treatment ASSIST steering committed. Lancet 349:32. doi:10.1016/S0140-6736(05)62166-6
Ferger B, Eberhardt O, Teismann P et al (1999) Malonate-induced generation of reactive oxygen species in rat striatum depends on dopamine release but not on NMDA receptor activation. J Neurochem 73:1329–1332. doi:10.1046/j.1471-4159.1999.0731329.x
Bekkers JM, Stevens CF (1989) NMDA and non-NMDA receptors are co-localized at individual excitatory synapses in cultured rat hippocampus. Nature 341:230–233. doi:10.1038/341230a0
Bloom FE (1990) In: Goodman Gilman A, Rall TW, Nies AS, Taylor P (eds) The pharmacological basis of therapeutics. Pergamon, New York, pp 244–268
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Nasr, P., Carbery, T. & Geddes, J.W. N-Methyl-d-aspartate Receptor Antagonists Have Variable Affect in 3-Nitropropionic Acid Toxicity. Neurochem Res 34, 490–498 (2009). https://doi.org/10.1007/s11064-008-9809-3
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11064-008-9809-3