Skip to main content
SpringerLink
Log in

Increased extracellular glutamate evoked by 1-Methyl-4-phenylpyridinium (MPP+) in the rat striatum is not essential for dopaminergic neurotoxicity and is not derived from released glutathione

  • Published:
Neurotoxicity Research Aims and scope Submit manuscript

Abstract

A number of studies have implicated the interactions of the excitatory amino acid L-glutamate (Glu) with its ionotropic and metabotropic receptors as important components of the mechanism underlying the dopaminergic neurotoxicity of 1-methyl-4-phenylpyridinium (MPP+). Furthermore, microdi-alysis experiments have demonstrated that perfusion of relatively high concentrations of MPP+ into the rat striatum evoke a delayed, massive release of Glu. Interestingly, perfusion of MPP+ also mediates a similar release of glutathione (GSH). Together, these observations raise the possibility that the rise of extracellular Glu mediated by MPP+ may be the result of hydrolysis of released GSH by γ-glutamyl transpeptidase (γ-GT). In the present investigation it is demonstrated that perfusions of solutions of 0.7 and 1.3 mM MPP+ dissolved in artificial cerebro-spinal fluid into the rat striatum evoke neurotoxic damage to dopaminergic terminals, assessed by both a two-day test/challenge procedure and tyro-sine hydroxylase immunoreactivity, but without the release of Glu. Perfusions of ≤ 2.5 mM MPP+ cause more extensive dopaminergic neurotoxicity and a dose-dependent release of Glu. However, neither this release of Glu nor MPP+-induced dopaminergic neurotoxicity are blocked by the irreversible γ-GT inhibitor acivicin. Together, these observations indicate that a rise of extracellular levels of Glu is not essential for the dopaminergic neurotoxicity of MPP+. Furthermore, the rise of extracellular Glu caused by perfusion of ≤ 2.5 mM MPP+ is not the result of the γ-GT-mediated hydrolysis of released GSH. It is possible that the rise of extracellular levels of Glu, L-aspartate, L-glycine and L-taurine evoked by perfusions of ≤ 2.5 mM MPP+ into the rat striatum may reflect, at least in part, the release of these amino acids from astrocytes.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  • Ambrosio S, A Espino, B Cutillas and R Bartrons (1996) MPP+ toxicity in rat striatal slices: relationship between non-selective effects and free radical production.Neurochem. Res. 21, 73–78.

    Article  PubMed  CAS  Google Scholar 

  • Ara J, S Przedborski, AB Naini, V Jackson-Lewis, RR Trifiletti, J Horwitz and H Ischiropoulos (1998) Inactivation of tyrosine hydroxylase by nitration following exposure to peroxynitrite and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP).Proc. Natl. Acad. Sci. USA 95, 7659–7663.

    Article  PubMed  CAS  Google Scholar 

  • Bredt DS, CE Glatt, PM Hwang, M Fotuhi, TM Dawson and SH Snyder (1991) Nitric oxide synthase protein and mRNA are discreetly localized in neuronal populations of the mammalian CNS together with NADPH diaphorase.Neuron 7, 615–624.

    Article  PubMed  CAS  Google Scholar 

  • Carboni S, F Melis, L Pani, M Hadjiconstantinou and ZL Rossetti (1990) The non-competitive NMDA receptor antagonist MK-801 prevents the massive release of glutamate and aspartate from rat striatum induced by 1-methyl-4-phenylpyridinium (MPP+).Neurosci. Lett. 117, 129–133.

    Article  PubMed  CAS  Google Scholar 

  • Chan P, LE Delanney, I Irwin, JW Langston and D Di Monte (1991) Rapid ATP loss caused by MPTP in mouse brain.J. Neurochem. 57, 348–351.

    Article  PubMed  CAS  Google Scholar 

  • Chan P, JW Langston and DA Di Monte (1993) MK-801 temporarily prevents MPTP-induced acute dopamine depletion and MPP+ elimination in the mouse striatum.J. Pharmacol. Exp. Ther. 267, 1515–1520.

    PubMed  CAS  Google Scholar 

  • Dawson TM and SH Snyder (1994) Gases as biological messengers: nitric oxide and carbon monoxide in the brain.J. Neurosci. 14, 5147–5159.

    PubMed  CAS  Google Scholar 

  • Dexter DT, J Sian, S Rose, JG Hindmarsh, VM Mann, JM Cooper, FR Wells, SE Daniel, AJ Lees, AHV Schapira, P Jenner and CD Marsden (1994) Indices of oxidative stress and mitochondrial function in individuals with incidental Lewy body disease.Ann. Neurol. 35, 38–44.

    Article  PubMed  CAS  Google Scholar 

  • Di Monte DA, EY Wu, LE Delanney, I Irwin and JW Langston (1992) Toxicity of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in primary cultures of mouse astrocytes.J. Pharmacol. Exp. Ther. 261, 44–49.

    PubMed  Google Scholar 

  • Dringen R, JM Gutterer, C Gros and J Hirrlinger (2001) Aminopeptidase N mediates the utilization of the GSH precursor CysGly by cultured neurons.J. Neurosci. Res. 66, 1003–1008.

    Article  PubMed  CAS  Google Scholar 

  • Dummis A, JP Pin, K Oomagari, M Sebben and J Bockaert (1990) Arachidonic acid released from striatal neurons by joint stimulation of ionotropic and metabotropic quisqualate receptors.Nature 347, 182–184.

    Article  Google Scholar 

  • Ferrara TN, GT Golden, M De Mattai, TA Hare and RG Fariello (1986) Effect of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) on levels of glutathione in the extrapyramidal system of the mouse.Neuropharmacology 25, 1071–1074.

    Article  Google Scholar 

  • Foster SF, MZ Wrona, J Han and G Dryhurst (2003) The parkinso-nian neurotoxin 1-methyl-4-phenylpyridinium (MPP+) mediates release of L-3,4-dihydroxyphenylalanine (L-DOPA) and inhibition of L-DOPA decarboxylase in the rat striatum: a microdialy-sis study.Chem. Res. Toxicol. 16, 1372–1384.

    Article  PubMed  CAS  Google Scholar 

  • Gainetdinov RR, F Fumagelli, SR Jones and MG Caron (1997) Dopamine transporter is required forin vivo MPTP neurotoxic-ity: evidence from mice lacking the transporter.J. Neurochem. 69, 1322–1325.

    PubMed  CAS  Google Scholar 

  • Giovanni A, B-A Sieber, RE Heikkila and PK Sonsalla (1994) Studies on species sensitivity to the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Part 2: Central administration of 1-methyl-4-phenylpyridinium.J. Pharmacol. Exp. Ther. 270, 1008–1014.

    PubMed  CAS  Google Scholar 

  • Grundemann D, AC Koschker, C Haag, C Honold, T Zimmermann and E Schomig (2002) Activation of the extraneuronal mono-amine transporter (EMT) from rat expressed in 293 cells.Br. J. Pharmacol. 137, 910–918.

    Article  PubMed  CAS  Google Scholar 

  • Halliwell B and JM Gutteridge (1991)Free Radicals in Biology and Medicine (Clarendon Press: Oxford).

    Google Scholar 

  • Han J, F-C Cheng, Z Yang and G Dryhurst (1999) Inhibitors of mitochondrial respiration, iron (II) and hydroxyl radical evoke release and hydrolysis of glutathione in rat striatum and sub-stantia nigra: potential implications to Parkinson’s disease.J. Neurochem. 73, 1683–1695.

    Article  PubMed  CAS  Google Scholar 

  • Inazu M, H Takeda and T Matsumiya (2003) Expression and functional characterization of the extraneuronal monoamine transporter in normal human astrocytes.J. Neurochem. 84, 43–52.

    Article  PubMed  CAS  Google Scholar 

  • Katsuki H and S Okuda (1995) Arachidonic acid as a neurotoxic and neurotrophic substance.Progr. Neurobiol. 46, 607–636.

    Article  CAS  Google Scholar 

  • Kawahara K, T Kosugi, M Tanaka, T Nakajima and T Yamada (2004) Reversed operation of glutamate transporter GLT-1 is crucial to the development of preconditioning-induced ischemic tolerance of neurons in neuron/astrocyte co-cultures.Glia 49, 349–359.

    Article  Google Scholar 

  • Klivenyi P, MF Beal, RJ Ferrante, OA Andreassen, M Wermer, M-R Chin and JV Bonventre (1998) Mice deficient in group IV cytosolic phospholipase A2 are resistant to MPTP neurotoxicity.J. Neurochem. 71, 2634–2637.

    Article  PubMed  CAS  Google Scholar 

  • Klockgether T and L Turski (1989) Excitatory amino acids and the basal ganglia: implications for the therapy in Parkinson’s disease.Trends Neurosci. 12, 285–286.

    Article  PubMed  CAS  Google Scholar 

  • Kramer BC, JA Yabut, J Cheong, R Jnobaptiste, T Robakis, CW Olanow and C Mytilineou (2004) Toxicity of glutathione depletion in mesencephalic cultures: a role for arachidonic acid and its lipoxygenase metabolites.Eur. J. Neurochem. 19, 280–286.

    Article  Google Scholar 

  • Kukreja RC, HA Kontos, ML Hess and EF Ellis (1986) PGE syn-thase and lipoxygenase generate superoxide in the presence of NADH or NADPH.Circ. Res. 59, 612–619.

    PubMed  CAS  Google Scholar 

  • Kupsch A, PA Löschmann, H Saver, G Arnold, P Renner, D Putal, M Burg, H Wachtel, G Ten Bruggencate and WH Oertel (1992) Do NMDA receptor antagonists protect against MPTP toxicity? Biochemical and immunocytochemical analyses in black mice.Brain Res. 592, 74–78.

    Article  PubMed  CAS  Google Scholar 

  • Lehre KP, LM Levy, OP Otterson, J Storm-Mathisen and NC Danbolt (1995) Differential expression of two glial glutamate transporters in the rat brain: quantitative and immunocytochemi-cal observations.J. Neurosci. 15, 1835–1853.

    PubMed  CAS  Google Scholar 

  • Liberatore GT, V Jackson-Lewis, S Vukosavic, AS Mandir, M Vila, WG McAuliffee, VL Dawson, TM Dawson and S Przedborski (1999) Inducible nitric oxide synthase stimulates dopaminergic neurodegeneration in the MPTP model of Parkinson’s disease.Nat. Med. 5, 1403–1409.

    Article  PubMed  CAS  Google Scholar 

  • Mandir AS, S Przedborski, V Jackson-Lewis, ZQ Wang, CM Simbulan-Rosenthal, ME Smulson, BE Hoffman, DB Guastella, VL Dawson and TM Dawson (1999) Poly(ADP-ribose)polymerase activation mediates 1-methyl-4-phenyl-1,2,3,6-tetrahydropyri-dine (MPTP)-induced parkinsonism.Proc. Natl. Acad. Sci. USA 96, 5774–5779.

    Article  PubMed  CAS  Google Scholar 

  • Martel F and I Azevedo (2003) An update on the extraneuronal monoamine transporter (EMT): characteristics, distribution and regulation.Curr. Drug Metab. 4, 313–318.

    Article  PubMed  CAS  Google Scholar 

  • Matarredona ER, M Santiago, JL Venero, J Cano and A Machado (2001) Group II metabotropic glutamate receptor activation protects striatal dopaminergic nerve terminals against MPP+-induced neurotoxicity along with brain-derived neurotrophic factor induction.J. Neurochem. 76, 351–360.

    Article  PubMed  CAS  Google Scholar 

  • Merino M, MI Vizuete, J Cano and A Machado (1999) The non-NMDA glutamate receptor antagonists 6-cyano-7-nitroquinoxa-line-2,3-dione and 2,3-dihydroxy-6-nitro-7-sulfamoylbenzo(f) quinoxaline, but not NMDA antagonists, block the intrastriatal neurotoxic effect of MPP+.J. Neurochem. 73, 750–757.

    Article  PubMed  CAS  Google Scholar 

  • Moore SA, E Yoder, S Murphy, GR Dulton and AA Spector (1991) Astrocytes, not neurons, produce docosahexaenoic acid (22:6a-3) and arachidonic acid (20:4a-6).J. Neurochem. 56, 518–524.

    Article  PubMed  CAS  Google Scholar 

  • Oishi T, E Hasegawa and Y Murai (1993) Sulfhydryl drugs reduce neurotoxicity of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in the mouse.J. Neural Transm. Park. Dis. Dementia Sect. 6, 45–52.

    Article  CAS  Google Scholar 

  • Pennathur S, V Jackson-Lewis, S Przedborski and JW Heinecke (1999) Mass spectrometric quantification of 3-nitrotyrosine,ortho-tyrosine, ando,o’-dityrosine in brain tissue of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated mice, a model of oxidative stress in Parkinson’s disease.J. Biol. Chem. 274, 34621–34628.

    Article  PubMed  CAS  Google Scholar 

  • Phillis JW and MH O’Regan (2003) Characterization of modes of release of amino acids in the ischemic/reperfused rat cerebral cortex.Neurochem. Int. 43, 461–467.

    Article  PubMed  CAS  Google Scholar 

  • Piomelli D (1993) Arachidonic acid in cell signalling.Curr. Opin. Cell. Biol. 5, 274–280.

    Article  PubMed  CAS  Google Scholar 

  • Przedborski S, V Kostic, V Jackson-Lewis, AB Naini, S Simonelta, S Fah, E Carlson, CJ Epstein and JL Cadet (1992) Transgenic mice with increased Cu/Zn superoxide dismutase activity are resistent toN-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced neurotoxicity.J. Neurosci. 12, 1658–1667.

    PubMed  CAS  Google Scholar 

  • Przedborski S, V Jackson-Lewis, R Yokoyama, T Shibata, VL Dawson and TM Dawson (1996) Role of neuronal nitric oxide in 1 -methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced dopaminergic neurotoxicity.Proc. Natl. Acad. Sci. USA 93, 4565–4571.

    Article  PubMed  CAS  Google Scholar 

  • Przedborski S, Q Chen, M Vila, BI Giasson, R Djaldatti, S Vukosavic, JM Souza, V Jackson-Lewis, V. VM-Y Lee and H Ischiropoulos (2001) Oxidative post-translational modifications of a-synuclein in the 1-methyl-4-phenyl-1,2,3,6-tetrahy-dropyridine (MPTP) mouse model of Parkinson’s disease.J. Neurochem. 76, 637–640.

    Article  PubMed  CAS  Google Scholar 

  • Qu Y, L Arckens, E Vandenbussche, S Geeraerts and F Vandesande (1998) Simultaneous determination of total and extracellular concentrations of the amino acid neurotransmitters in cat visual cortex by microbore liquid chromatography and electrochemical detection.J. Chromatogr. A. 798, 19–26.

    Article  PubMed  CAS  Google Scholar 

  • Ramsay RR, MJ Krueger, SK Youngster, MR Gluck, JE Casida and TP Singer (1991) Interaction of 1-methyl-4-phenylpyridinium ion (MPP+) and its analogs with the rotenone/piericidin binding site of NADH dehydrogenase.J. Neurochem. 56, 1184–1190.

    Article  PubMed  CAS  Google Scholar 

  • Ransom BR, DM Kunis, I Irwin and JW Langston (1987) Astrocytes convert the parkinsonism inducing neurotoxin, MPTP, to its active metabolite, MPP+.Neurosci. Lett. 75, 323–328.

    Article  PubMed  CAS  Google Scholar 

  • Robinson MB (1999) The family of sodium-dependent glutamate transporters: a focus on the GLT1/EAAT2 subtype.Neurochem. Int. 33, 1835–1853.

    Google Scholar 

  • Royland JE and JW Langston (1998) MPTP. A dopaminergic neurotoxin, In:Highly Selective Neurotoxins: Basic and Clinical Applications (Kostrzewa RM, Ed.) (Humana Press: Totowa, New Jersey), pp 141–194.

    Google Scholar 

  • Russ H, K Staudt, F Martel, M Gliese and E Schömig (1996) The extraneuronal transporter for monoamine neurotransmitters exists in cells derived from human central nervous system glia.Eur. J. Neurosci. 8, 1256–1264.

    Article  PubMed  CAS  Google Scholar 

  • Sanfeliu C, A Hunt and AJ Patel (1990) Exposure toN-methyl-D-aspartate increases release of arachidonic acid in primary cultures of rat hippocampal neurons and not in astrocytes.Brain Res. 526, 241–248.

    Article  PubMed  CAS  Google Scholar 

  • Santiago M, JL Venero, A Machado and J Cano (1992)In vivo protection of striatum from MPP+ neurotoxicity byN-methyl-D-aspartate antagonists.Brain Res. 586, 203–207.

    Article  PubMed  CAS  Google Scholar 

  • Santiago M, A Machado and J Cano (2001) Validity of a quantitative technique to study striatal dopaminergic neurodegeneration byin vivo microdialysis.J. Neurosci. Meth. 108, 181–187.

    Article  CAS  Google Scholar 

  • Sapirstein A and JV Bonventre (2000) Specific physiological roles of cytosolic phospholipase A2 as defined by gene knockouts.Biochim. Biophys. Acta 1488, 139–148.

    PubMed  CAS  Google Scholar 

  • Seki Y, PJ Feustel, RW Keller, BI Tranmer and HK Kimelberg (1999) Inhibition of ischemia-induced glutamate release in rat striatum by dihydrokinate and an anion channel blocker.Stroke 30, 433–440.

    PubMed  CAS  Google Scholar 

  • Sian J, D Dexter, A Lees, S Daniel, Y Agid, F Javoy-Agid, P Jenner and CD Marsden (1994a) Alterations in glutathione levels in Parkinson’s disease and other neurodegenerative disorders affecting the basal ganglia.Ann. Neurol. 36, 348–355.

    Article  PubMed  CAS  Google Scholar 

  • Sian J, DT Dexter, AJ Lees, S Daniel, P Jenner and CD Marsden (1994b) Glutathione-related enzymes in brain in Parkinson’s disease.Ann. Neurol. 36, 356–361.

    Article  PubMed  CAS  Google Scholar 

  • Sonsalla PK, GD Zeevalk, L Manzino, A Giovanni and WJ Nicklas (1992) MK-801 fails to protect against the dopaminergic neu-ropathology produced by systemic MPTP in mice or intranigral MPTP in rats.J. Neurochem. 58, 398–400.

    Article  Google Scholar 

  • Sonsalla PK, DS Albers and GD Zeevalk (1998) Role of glutamate in the neurodegeneration of dopamine neurons in several animal models of Parkinson’s disease.Amino Acids 14, 69–74.

    Article  PubMed  CAS  Google Scholar 

  • Sriram K, KS Pai, MR Boyd and V Ravindranath (1997) Evidence for generation of oxidative stress in brain by MPTP:in vitro andin vivo studies in mice.Brain Res. 749, 44–52.

    Article  PubMed  CAS  Google Scholar 

  • Stole E, TK Smith, JM Manning and A Meister (1994) Interaction of gamma-glutamyl transpeptidase with acivicin.J. Biol. Chem. 269, 21435

    PubMed  CAS  Google Scholar 

  • Storey E, BT Hyman, B Jenkins, E Broulliet, JM Miller, BR Rosen and MF Beal (1992) MPP+ produces excitotoxic lesions in rat striatum as a result of impairment of oxidative metabolism.J. Neurochem. 58, 1975–1978.

    Article  PubMed  CAS  Google Scholar 

  • Tariq M, HA Khan, K Al Moutaery and S Al Deeb (2001) Protective effect of quinacrine on stratial dopamine levels in 6-OHDA and MPTP models of parkinsonism in rodents.Brain Res. Bull. 54, 77–82.

    Article  PubMed  CAS  Google Scholar 

  • Tate SS and A Meister (1985) gamma-Glutamyl transpeptidase from kidney.Meth. Enzymol. 113, 400–418.

    Article  PubMed  CAS  Google Scholar 

  • Turski L, K Bressler, KJ Retting, PA Löschmann and H Wachtel (1991) Protection of substantia nigra from MPP+ neurotoxicity byN-methyl-D-aspartate antagonists.Nature 349, 414–418.

    Article  PubMed  CAS  Google Scholar 

  • Wu DC, T Tieu, O Cohen, D Choi, M Vila, V Jackson-Lewis, P Teismann and S Przedborski (2002) Glial cell response: a pathogenic factor in Parkinson’s disease.J. Neurovirol. 8, 551–558.

    Article  PubMed  CAS  Google Scholar 

  • Wu EY, JW Langston and DA Di Monte (1992) Toxicity of MPTP and MPP+ species in primary cultures of mouse astrocytes.J. Pharmacol. Exp. Ther. 262, 225–230.

    PubMed  CAS  Google Scholar 

  • Wu X, Kekuda, R., Huang, W., Fei, Y.-J., Leibach, F.H., Chen, J., Conway, S.J., and Ganapathy, V. (1998) Identity of the organic cation transporter OCT3 as the extraneuronal monoamine transporter (uptake 2) and evidence for the expression of the transporter in the brain.J. Biol. Chem. 273, 32776–32786.

    Article  PubMed  CAS  Google Scholar 

  • Yong VW, TL Perry and AA Krisman (1986) Depletion of glutathi-one in brainstem of mice caused byN-methyl-4-phenyl-1,2,3,6-tetrahydropyridine is prevented by antioxidant pretreatment.Neurosci. Lett. 63, 56–60.

    Article  PubMed  CAS  Google Scholar 

  • Zeevalk GD, L Manzino and PK Sonsalla (2000) NMDA receptors modulate dopamine loss due to energy impairment in the sub-stantia nigra but not striatum.Exp. Neurol. 161, 638–646.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Chemistry and Biochemistry, University of Oklahoma, 73019, Norman, OK, USA

    Steven B. Foster & Glenn Dryhurst

  2. Oklahoma Medical Research Foundation, 73104, Oklahoma City, OK, USA

    Haiwang Tang

  3. Department of Anatomy and Cell Biology, Oklahoma State University Center for Health Sciences, 74107, Tulsa, OK, USA

    Kenneth E. Miller

Authors
  1. Steven B. Foster
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Haiwang Tang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Kenneth E. Miller
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Glenn Dryhurst
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Steven B. Foster or Glenn Dryhurst.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Foster, S.B., Tang, H., Miller, K.E. et al. Increased extracellular glutamate evoked by 1-Methyl-4-phenylpyridinium (MPP+) in the rat striatum is not essential for dopaminergic neurotoxicity and is not derived from released glutathione. neurotox res 7, 251–263 (2005). https://doi.org/10.1007/BF03033883

Download citation

  • Received:

  • Revised:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF03033883

Keywords

Search

Navigation