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Glutamate Transmission in the Pathogenesis of Parkinson’s Disease

  • Chapter
Excitotoxicity in Neurological Diseases

Abstract

Parkinson’s disease (PO), a progressive neurodegenerative disorder, is a common cause of disability. The pathological hallmarks are the presence of Lewy bodies and massive loss of dopaminergic neurons in the pars compacta of the substantia nigra. The current pathophysiological concept of PD postulates a multifactorial origin, where alterations in neurotransmitter content are combined with genetic and environmental factors. With nigrostriatal dopamine depletion, a complex set of changes occurs in the functional anatomy of the basal ganglia circuitry. As a result, the firing pattern of certain glutamatergic pathways has been shown to change significantly, and to play a central role in the pathogenesis of parkinsonian symptoms. Advances in genetics have led to the discovery of gene mutations underlying some forms of PD. The mutated genes encode proteins of unknown function, such as alpha-synuclein and parkin. Moreover, compelling evidence supports the involvement of mitochondrial metabolism failure as an essential cofactor in the pathogenesis of PD. Interestingly, some environmental toxins are thought to be able to act as mitochondrial toxins. The comprehension of the pathways leading to PD requires an intense effort in order to identify and establish a plausible connection between genetic causes, altered neurotransmission and metabolic impairment.

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References

  • Awad, H., Hubert, G.W., Smith, Y., Levey, A.I., Conn, J.P. Activation of metabotropic glutamate receptor 5 has direct excitatory effects and potentiates NMDA receptor currents in neurons of the subthalamic nucleus. J. Neurosci. 2000, 20:7871–7879.

    PubMed  CAS  Google Scholar 

  • Beal, M.F. Experimental models of Parkinson’s disease. Nat. Rev. Neurosci. 2001, 2:325–334.

    Article  PubMed  CAS  Google Scholar 

  • Beal, M.F., Hyman, B.T., and Koroshetz, W. Do detefcts in mitochondrial energy metabolism underlie the pathology of neurodegenerative diseases? Trends Neurosci. 1993, 16:125–130.

    Article  PubMed  CAS  Google Scholar 

  • Bergman, H., Wichmann, T., DeLong, M.R. Reversal of experimental parkinsonism by lesions of the subthalamic nucleus. Science 1990, 249:1436–8.

    Google Scholar 

  • Bergman, H, Wichmann, T., Karmon, B., and DeLong, M.R. The primate subthalamic nucleus. II. Neuronal activity in the MPTP model of parkinsonism. J. Neurophysiol. 1994, 72:507–20.

    PubMed  CAS  Google Scholar 

  • Bergman, H., Wichmann, T., Delong, M.R. Reversal of experimental parkinsonism by lesions of the subthalamic nucleus. Science 2000, 249:1346–1348.

    Google Scholar 

  • Betarbet, R., Sherer, T.B., MacKenzie, G., Garcia-Osuna, M., Panov, A.V., and Greenamyre, J.T. Chronic systemic pesticide exposure reproduces features of Parkinson’s disease. Nat. Neurosci. 2000, 3(12):1301–6.

    Article  PubMed  CAS  Google Scholar 

  • Bevan, M.D., Magill, P.J., Terman, D., Bolam, J.P., and Wilson, C.J. Move to the rhythm: oscillations in the subthalamic nucleus-external globus pallidus network. Trends Neurosci. 2002, 25:525–31.

    Article  PubMed  CAS  Google Scholar 

  • Blanchet, P.J., Konitsiotis, S., and Chase, T.N. Amantadine reduces levodopa-induced dyskinesias in parkinsonian monkeys. Mov. Disord. 1998, 13:798–802.

    Article  PubMed  CAS  Google Scholar 

  • Blanchet, P.J., Konitsiotis, S., Whittemore, E.R., Zhou, Z.L., Woodward, R.M., and Chase, T.N. Differing effects of N-methyl-D-aspartate receptor subtype selective antagonists on dyskinesias in levodopa-treated 1-methyl-4-phenyl-tetrahydropyridine monkeys. J. Pharmacol. Exp. Ther. 1999, 290(3):1034–40.

    PubMed  CAS  Google Scholar 

  • Blandini, F., Nappi, G., and Greenamyre, J.T. Subthalamic infusion of an NMDA antagonist prevents basal ganglia metabolic changes and nigral degeneration in a rodent model of Parkinson’s disease. Ann. Neurol. 2001, 49:525–9.

    Article  PubMed  CAS  Google Scholar 

  • Breysse, N., Baunez, C., Spooren, W., Gasparini, F., and Amalric, M.. Chronic but not acute treatment with a metabotropic glutamate 5 receptor antagonist reverses the akinetic deficits in a rat model of parkinsonism. J. Neurosci. 2002 22, 5669–5678.

    PubMed  CAS  Google Scholar 

  • Calabresi, P., Mercuri, N.B., Sancesario, G., and Bernardi, G. Electrophysiology of dopamine-denervated striatal neurons. Brain 1993, 116:433–452.

    Article  PubMed  Google Scholar 

  • Calabresi, P., Centonze, D., and Bernardi, G. Electrophysiology of dopamine in normal and denervated striatal neurons. Trends Neurosci. 2000, 23 Suppl. 10:S57–63.

    Google Scholar 

  • Ceballos-Bauman, J, Obeso, J., Vitek, J., Delong, M., and Bakay, R. Restoration of thalamocortical activity after posteroventrolateral pallidotomy in Parkinson’s disease. Lancet 1994, 344–814.

    Google Scholar 

  • Chase, T.N., and Oh, J.D. Striatal dopamine and glutamate-mediated dysregulation in experimental parkinsonism. Trends Neurosci. 2000, 23(Suppl. 10):S86–91.

    Article  PubMed  CAS  Google Scholar 

  • Dawson, T.M., Mandir A.S, and Lee, M.K. Animal models of PD: pieces of the same puzzle? Neuron 2002, 35:219–222.

    Article  PubMed  CAS  Google Scholar 

  • Dingledine, R., Borges, K., Bowie, D., and Traynelis, S.F. The glutamate receptor ion channels. Pharmacol. Rev. 1999, 51:7–61.

    PubMed  CAS  Google Scholar 

  • Dunah, A.W., Wang, Y., Yasuda, R.P., Kameyama, K., Huganir, R.L., Wolfe, B.B., and Standaert, D.G. Alterations in subunit expression, composition, and phosphorylation of striatal N-methyl-d-aspartate glutamate receptors in a rat 6-hydroxydopamine model of Parkinson’ s disease. Mol. Pharmacol. 2000, 57:342–352.

    PubMed  CAS  Google Scholar 

  • Greene, J.G., and Greenamyre, T.J. Bioenergetics and glutamate excitotoxicity. Prog. Neurobiol. 1996, 48:613–634.

    Article  PubMed  CAS  Google Scholar 

  • Greenamyre T.J. Glutamatergic influences on the basal ganglia. Clin. Neuropharmacol. 2001, 24:65–70.

    Article  PubMed  CAS  Google Scholar 

  • Heeringa, M.J., and Abercrombie, E.D. Biochemistry of somatodendritic dopamine release in substantia nigra: an in vivo comparison with striatal dopamine release. J. Neurochem. 1995, 65(1):192–200.

    Article  PubMed  CAS  Google Scholar 

  • Kitada, T, Asakawa S, Hattori, N, Matsumine, H., Yamamura, Y., Minoshima, S., Yokochi, M., Mizuno, Y., and Shimizu, N. Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism. Nature 1998, 392:605–608.

    Article  PubMed  CAS  Google Scholar 

  • Klockgether, T., and Turski, L. Toward an understanding of the role of glutamate in experimental parkinsonism: agonist-sensitive sites in the basal ganglia. Ann. Neurol. 1993, 34:585–593.

    Article  PubMed  CAS  Google Scholar 

  • Konieczny, J., Ossowska, K., Wolfarth, S., and Pilc, A. LY354740, a group II metabotropic glutamate receptor agonist with potential antiparkinsonian properties in rats. Naunyn-Schmiedeberg’s Arch Pharmacol. 1998, 358:500–502.

    Article  CAS  Google Scholar 

  • Konitsiotis S, Blanchet PJ, Verhagen L, Lamers E, Chase TN. AMPA receptor blockade improves levodopa-induced dyskinesia in MPTP monkeys. Neurology. 2000 54(8):1589–95.

    Article  PubMed  CAS  Google Scholar 

  • Kruger, R., Kuhn, W., Muller, T, Woitalla, D., Graeber, M., Kosel, S., Przuntek, H., Epplen, J.T., Schols, L., and Riess, O. Ala30Pro mutation in the gene encoding alpha-synuclein in Parkinson’s disease. Nat. Genet. 1998, 18:106–108.

    Article  PubMed  CAS  Google Scholar 

  • Laurie, D.J., and Seeburg, P.H. Ligand affinities at recombinant N-methyl-D-aspartate receptors depend on subunit composition. Eur. J. Pharmacol. 1994, 268:335–345.

    Article  PubMed  CAS  Google Scholar 

  • Lechardeur, D., Castel, M.N., Reibaud, M., Scherman, D., and Laduron, P.M. Axonal transport of dopamine-containing vesicles labelled in vivo with [3H]reserpine. Eur. J. Neurosci. 1993, 5(5):449–53

    Article  PubMed  CAS  Google Scholar 

  • Leroy, E., Boyer, R., Auburger, G., Leube, B., Ulm, G., Mezey, E., Harta, G., Brownstein, M.J., Jonnalagada, S., Chemova, T., Dehejia, A., Lavedan, C., Gasser, T., Steinbach, P.J., Wilkinson, K.D., and Polymeropoulos, M.H. The ubiquitin pathway in Parkinson’s disease. Nature 1998, 395:451–452.

    Article  PubMed  CAS  Google Scholar 

  • Luginger, E., Wenning, G.K., Bosch, S., and Poewe, W. Beneficial effects of amantadine on L-dopa-induced dyskinesias in Parkinson’s disease. Mov Disord. 2000, 15:873–8.

    Article  PubMed  CAS  Google Scholar 

  • Manning-Bog, A.B., McCormack, A.L., Li, J., Uversky, V.N., Fink, A.L, and Di Monte, D.A. The herbicide paraquat causes up-regulation and aggregation of alpha-synuclein in mice: paraquat and alpha-synuclein, J. Biol. Chem. 2002, 277(3):1641–4.

    Article  PubMed  CAS  Google Scholar 

  • Marti, M., Paganini, F., Stocchi, S., Bianchi, C., Beani, L., Morari, M. Presynaptic group I and II metabotropic glutamate receptors oppositely modulate striatal acetylcholine release. Eur. J. Neurosci. 2001 14:1181–1184.

    Article  PubMed  CAS  Google Scholar 

  • Merello, M., Nouzeilles, MI., Cammarota, A., and Leiguarda, R. Effect of memantine (NMDA antagonist) on Parkinson’s disease: a double-blind crossover randomized study. Clin. Neuropharmacol. 1999, 22:273–276.

    PubMed  CAS  Google Scholar 

  • Murray, T.K., Messenger, M.J., Ward, M.A., Woodhouse, S., Osborne, D.J., Duty, S., O’Neill, M.J. Evaluation of the mGluR2/3 agonist LY379268 in rodent models of Parkinson’s disease. Pharmacol., Biochem., and Behav. 2002, 73:455–466.

    Article  CAS  Google Scholar 

  • Oh, J.D., Russell, D., Vaughan, C.L., and Chase, T.N. Enhanced tyrosine phosphorylation of striatal NMDA receptor subunits: effect of dopaminergic denervation and L-DOPA administration. Brain Res. 1998, 813:150–159.

    Article  PubMed  CAS  Google Scholar 

  • Oh, J.D., Vaughan, C.L., and Chase, T.N. Effect of dopamien denervation and dopamine agonists administration on serine phosphorylation of striatal NMDA receptor subunits. Brain Res. 1999, 821:433–442.

    Article  PubMed  CAS  Google Scholar 

  • Ossowska, K., Konieczny, J., Wolfarth, S., Wieronska, J., and Pile, A. Blockade of the metabotropic glutamate receptor subtype 5 (mGluR5) produces antiparkinsonian-like effects in rats. Neuropharmacology 2001, 41:413–420.

    Article  PubMed  CAS  Google Scholar 

  • Papa, S.M., Boldry, R.C., Engber, T.M., Kask, A.M., and Chase, T.N. Reversal of levodopa-induced motor fluctuations in experimental parkinsonism by NMDA receptor blockade. Brain Res. 1995, 701:13–18.

    Article  PubMed  CAS  Google Scholar 

  • Parsons, C.G., Danysz, W, and Quack, G. Glutamate in CNS disorders as a target for drug development: an update. Drug new Perspect. 1998, 11:523–569.

    Article  CAS  Google Scholar 

  • Parsons, C.G., Danysz, W, and Quack, G. Memantine is a clinically well tolerated N-methyl-D-aspartate (NMDA) receptor antagonist-a review of preclinical data. Neuropharmacology 1999, 38:735–767.

    Article  PubMed  CAS  Google Scholar 

  • Parkinson Study Group. The glutamate receptor antagonist remacemide improves motor performances in levodopa-treated Parkinson’s disease. Neurology 1999, 52(2):A262.

    Google Scholar 

  • Picconi, B., Pisani, A., Centonze, D., Battaglia, G., Storto, M., Nicoletti, F., Bernardi, G., Calabresi, P. Striatal metabotropic glutamate receptor function following experimental parkinsonism and chronic levodopa-treatment. Brain 2002, 125:1–11.

    Article  Google Scholar 

  • Pisani, A., Calabresi, P., Centonze, D., and Bernardi, G. Enhancement of NMDA responses by group I metabotropic glutamate receptors activation in striatal neurons. Br. J. Pharmacol. 1997, 120:1007–1014.

    Article  PubMed  CAS  Google Scholar 

  • Pisani, A., Bonsi, P., Calabresi, P., Centonze, D., Bernardi, G. Functional coexpression of excitatory mGluR1 and mGluR5 on striatal cholinergic interneurons. Neuropharmacology 2001a, 40:460–463.

    Article  PubMed  CAS  Google Scholar 

  • Pisani, A., Gubellini, P., Bonsi, P., Conquet, F., Picconi, B., Centonze, D., Bernardi, G., and Calabresi, P. Metabotropic glutamate receptor 5 mediates the potentiation of NMDA responses in medium spiny striatal neurons. Neuroscience 2001, 106:579–587.

    Article  PubMed  CAS  Google Scholar 

  • Planells-Cases, R., Montoliu, C., Humet, M., Fernandez, A.M., Garcia-Martinez, C., Valera, E., Merino, J.M., Perez-Paya, E., Messeguer, A., Felipo, V., and Ferrer-Montiel, A. A novel N-methyl-D-aspartate receptor open channel blocker with in vivo neuroprotectant activity. J. Pharmacol. Exp. Ther. 2002 Jul; 302(1):163–73

    Article  PubMed  CAS  Google Scholar 

  • Polymeropoulos, M.H., Lavedan, C, Leroy, E., Ide, S.E., Dehejia, A., Dutra, A., Pike, B., Root, H., Rubinstein, j., Boyer, R., Stenroos, E.S., Chandrasekharappa, S., Athanassiadou, A., Papapetropoulos, T, Johnson, W.G., Lazzarini, A.M., Duvoisin, R.C., Di Iorio, G., Golbe, L.L, and Nussbaum, R.L. (1997) Mutation in the alpha-synuclein geneidentified in families with Parkinson’s disease. Science 276:2045–2047.

    Article  PubMed  CAS  Google Scholar 

  • Rascol, O. The pharmacological therapeutic management of levodopa-induced dyskinesias in patients with Parkinson’s disease. J Neurol. 2000, 247 Suppl. 2:1151–7.

    Google Scholar 

  • Schwarting R.K., and Huston, J.P. Unilateral 6-hydroxydopamine lesions of meso-striatal dopamine neurons and their physiological sequelae. Prog Neurobiol. 1996, 49(3):215–66.

    Article  PubMed  CAS  Google Scholar 

  • Silverdale, M.A., Crossman, A.R., and Brotchie, J.M. Striatal AMPA receptor binding is unaltered in the MPTP-lesioned macaque model of Parkinson’s disease and dyskinesia. Exp Neurol. 2002 174:21–8.

    Article  PubMed  CAS  Google Scholar 

  • Testa, C.M., Standaert, D.G., Young, A.B., and Penney, J.B. Jr. Metabotropic glutamate receptor mRNA expression in the basal ganglia of the rat. J. Neurosci. 1994 14:3005–3018.

    PubMed  CAS  Google Scholar 

  • Ungerstedt, U., and Arbuthnott, G.W. Quantitative recording of rotational behavior in rats after 6-hydroxydopamine lesions of the nigrostriatal dopamine system. Brain Res. 1970, 24:485–493.

    Article  PubMed  CAS  Google Scholar 

  • Vaughan, J.R., Davis, M.B., and Wood, N.W. (2001). Genetics of parkinsonism: a review. Ann. Hum. Genet. 65:111–126.

    Article  PubMed  CAS  Google Scholar 

  • Verhagen Metman, L., Blanchet, P.J., Mouradian, M.M., and Chase, T.N. Dextromethorphan and levodopa combination therapy in Parkinson’s disease patients with motor fluctuations. Mov. Disord. 1996, 11:184.

    Article  Google Scholar 

  • Vitek, J., Ashe, J, and Kaneoke, Y. Spontaneous neuronal activity in the motor thalamus: alteration in pattern and rate in parkinsonism. Neuroscience 1994, 20:561.

    Google Scholar 

  • Wichmann, T., Bergman, H., and DeLong, M.R. The primate subth alamic nucleus. I. Functional properties in intact animals. J Neurophysiol. 1994, 72(2):494–506.

    PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Clinica Neurologica, Dipartimento di Neuroscienze, Università di Roma Tor Vergata, and Fondazione Santa Lucia IRCCS, Rome, Italy

    Antonio Pisani & Paolo Calabresi

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  1. Antonio Pisani
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  2. Paolo Calabresi
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Editors and Affiliations

  1. Department of Neurology and Neuroscience, University of Milano-Bicocca, Ospedale San Gerardo, Monza (Milano), Italy

    Carlo Ferrarese

  2. Department of Neurology and Neuroscience, Weill Medical College of Cornell University, New York, NY, USA

    M. Flint Beal

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Pisani, A., Calabresi, P. (2004). Glutamate Transmission in the Pathogenesis of Parkinson’s Disease. In: Ferrarese, C., Beal, M.F. (eds) Excitotoxicity in Neurological Diseases. Springer, Boston, MA. https://doi.org/10.1007/978-1-4419-8959-8_12

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  • DOI: https://doi.org/10.1007/978-1-4419-8959-8_12

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