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MPTP-induced deficits in motor activity: Neuroprotective effects of the spintrapping agent, α-phenyl-tert-butyl-nitrone (PBN)

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In Experiment 1, groups of mice were administered either saline or MPTP (2 × 30mg/kg, s.c., separated by a 24-hr interval) 30min after being injected either PBN (15, 50 or 150mg/kg, s.c., low, medium and high doses, respectively) or L-Deprenyl (0.25 or 10.0mg/kg, s.c., low and high doses, respectively), the reference compound used, or saline. Tests of spontaneous motor activity 14 days later indicated that the MPTP-induced hypokinesia for locomotion and rearing was alleviated by prior administration with PBN (50 or 150mg/kg) or L-Deprenyl (10.0mg/kg); lower doses of PBN (15mg/kg) and L-Deprenyl (0.25mg/kg) did not affect the MPTP-induced deficits. Dopamine (DA) concentrations in the striatum confirmed a more severe loss of DA in the MPTP, PBN(15) + MPTP and Deprenyl(0.25) + MPTP groups than in the control group. Significant protection of DA was observed in the PBN(50) + MPTP, PBN(150) + MPTP and Deprenyl(10) + MPTP groups that did not exhibit an hypokinetic behaviour. In Experiment 2, the effects of repeated treatment with PBN (50mg/kg, s.c. over 12 days), post-MPTP, were studied in aged (15-month-old) and young (3-month-old) mice. Subchronic administration of PBN increased substantially the motor activity of old and young mice that had received MPTP. Aged control (saline) mice showed an activity deficit compared to young control mice; this deficit was abolished by repeated PBN treatment. The results suggest that moderate-to-high doses of PBN whether injected in a single dose prior to MPTP or subchronically following MPTP injections may afford protective effects against both the functional changes and DA-loss caused by MPTP treatment, possibly through an antioxidant mechanism.

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References

  • Ammassari-Teule M, Fagioli S, Rossi-Arnaud C (1994) Radial maze performance and open-field behaviours in aged C57BL/6 mice. Further evidence for preserved cognitive abilities during senescence. Physiol Behav 55: 341–345

    Google Scholar 

  • Archer T, Fredriksson A, Jonsson G, Lewander T, Mohammed AK, Ross SB, Söderberg U (1986) Central noradrenaline depletion antagonizes aspects of d-amphetamineinduced hyperactivity in the rat. Psychopharmacol 88: 141–146

    Google Scholar 

  • Beai MF, Brouillet E, Jenkins BG, Henshaw DR, Rosen BR, Hyman BT (1993) Age-dependent striatal excitotoxic lesions produced by the endogenous mitochondrial inhibitor malonate. J Neurochem 61: 1147–1150

    Google Scholar 

  • Beal MF, Henshaw DR, Jenkins BG, Rosen BR, Schulz JB (1994) Coenzyme Q10 and nicotinamide block striatal lesions produced by mitochondrial toxin malonate. Ann Neurol 36: 882–888

    Google Scholar 

  • Birkmayer W, Knoll J, Riederer P, Youdim MBH, Hars V, Marton J (1985) Increased life expectancy resulting from addition of L-deprenyl to Madopar treatment in Parkinson's disease; a long-term study. J Neural Transm 64: 113–127

    Google Scholar 

  • Björk L, Cornfield LJ, Nelson DL, Hillver S-E, Andén N-E, Lewander T, Hacksell U (1991) Pharmacology of the novel 5-hydroxytryptaminelA receptor antagonist (S)-5-fluoro-8-hydroxy-2-(dipropylamino)tetralin; inhibition of (R)-8-hydroxy-2-(dipropylamino)tetralin-induced effects. J Pharmacol Exp Ther 258: 58–65

    Google Scholar 

  • Carney JM, Floyd RA (1991) Protection against oxidative damage to CNS by alpha-phenyl-tert-butyl nitrone (PEN) and other spin-trapping agents; a novel series of nonlipid free radical scavengers. J Mol Neurosci 3: 47–57

    Google Scholar 

  • Carrillo M-C, Kanai S, Nokubo M, Kitani K (1991) (−)-Deprenyl induces activities of both superoxide dismutase and catalase but not of glutathione peroxidase in the striatum of young male rats. Life Sci 48: 517–521

    Google Scholar 

  • Chen G, Bray TM, Jansen EG, McCay PB (1990) Excretion, metabolism and tissue distribution of a spin trapping agent, d-pheny-N-tert butylnitrone (PBN) in rats. Free Radie Res Commun 9: 317–323

    Google Scholar 

  • Cheng HY, Liu T, Feuerstein G, Barone FC (1993) Distribution of spin-trapping compounds in rat blood and brain; in vivo microdialysis determination. Free Radie Biol Med 14: 243–350

    Google Scholar 

  • Chiba KA, Trevor A, Castagnoli N (1984) Metabolism of the neurotoxic tertiary amine, MPTP, by brain monoamine oxidase. Biochem Biophysiol Res Commun 120: 574–578

    Google Scholar 

  • Chiueh CC, Huang SJ (1991) MPP+ enhances potassium-evoked striatal dopamine release through a w-conotoxin-insensitive, tetrodotoxin- and nimodipine-sensitive calcium-dependent mechanism. Ann NY Acad Sci 635: 393–396

    Google Scholar 

  • Chiueh CC, Huang SJ, Murphy DL (1992a) Enhanced hydroxyl radical generation by 2′- methyl analog of MPTP. Suppression by clorgyline and deprenyl. Synapse 11: 346–348

    Google Scholar 

  • Chiueh CC, Krishna G, Tulsi P, Obata T, Lang K, Huang SJ, Murphy DL (1992b) Intracranial microdialysis of salicylic acid to detect hydroxyl radical generation through dopamine autoxidation in the caudate nucleus. Effects of MPP+. Free Radie Biol Med 13: 581–583

    Google Scholar 

  • Clough-Helfman C, Phillis JW (1991) The free radical trapping agent N-tert-butyl-alpha-phenylnitrone (PEN) attenuates cerebral ischaemic injury in gerbils. Free Radie Res Commun 15: 177–186

    Google Scholar 

  • Cohen G, Spina MB (1989) Deprenyl suppresses the oxidant stress associated with increased dopamine turnover. Ann Neurol 26: 689–690

    Google Scholar 

  • Duvoisin RC, Heikkila RE, Nicklas WJ (1986) Dopaminergic toxicity of MPTP in the mouse; a murine model of Parkinson's disease. In: Fahn S (ed) Recent developments in Parkinson's disease. Raven Press, New York, pp 147–156

    Google Scholar 

  • Finberg JPM, Tenne M, Youdim MBH (1981) Tyramine antagonistic properties of AGN 1135, an irreversible inhibitor of monoamine oxidase type B. Br J Pharmacol 73: 65–74

    Google Scholar 

  • Forno LS, Langsten JW, Delanney LE, Irwin I, Ricaurte GA (1986) Locus coeruleus lesions and inclusions in MPTP-treated monkeys. Ann Neurol 20: 449–455

    Google Scholar 

  • Forno LS, Langston JW, Delanney LE, Irwin I (1988) An electron microscope study of MPTP-induced inclusion bodies in an old monkey. Brain Res 448: 150–157

    Google Scholar 

  • Fowler CJ, Wiberg A, Oreland L, Marcusson J, Winblad B (1980) The effects of age on the activity and molecular properties of human brain monoamine oxidase. J Neural Transm 49: 1–20

    Google Scholar 

  • Fredriksson A, Archer T (1994) MPTP-induced behavioural and biochemical deficits; a parametric analysis. J Neural Transm [P-D Sect] 7: 123–132

    Google Scholar 

  • Fredriksson A, Plaznik A, Sundström E, Jonsson G, Archer T (1990) MPTP-induced hypoactivity in mice; reversal by L-Dopa. Pharmacol Toxicol 67: 295–301

    Google Scholar 

  • Fredriksson A, Gentsch C, Archer T (1994) Synergistic interactions between NMDA-antagonists and L-Dopa on activity in MPTP-treated mice. J Neural Transm [GenSect] 97: 197–209

    Google Scholar 

  • Gupta M, Thomas R, Bruemmer V, Feiten DL, Gupta BK, Sladek JR (1986) Aged mice are more sensitive to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine treatment than young adults. Neurosci Lett 70: 326–331

    Google Scholar 

  • Hallman H, Lange J, Olson L, Strömberg I, Jonsson G (1985) Neurochemical and histochemical characterisation of neurotoxic effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) on brain catecholamine neurons in the mouse. J Neurochem 44: 117–127

    Google Scholar 

  • Ikegami S (1994) Behavioural impairment in radial-arm maze learning and acetylcholine content of the hippocampus and cerebral cortex in aged mice. Behav Brain Res 65: 103–111

    Google Scholar 

  • Kirk RE (1982) Experimental design: procedures for the behavioral sciences. Brooks/Cole Publishing, Belmont Ca

    Google Scholar 

  • Knoll J (1987) (−) Deprenyl (selegiline, MoverganR) facilitates the activity of the nigrostriatal neuron. J Neural Transm [Suppl] 25: 45–66

    Google Scholar 

  • Knoll J (1989) The pharmacology of selegiline [(−)deprenyl]. New aspects. Acta Neurol Scand 80: 83–91

    Google Scholar 

  • Lai EK, Crossley C, Sridhar R, Misra HP, Janzen EG, McCay PB (1986) In vivo spin trapping of free radicals generated in brain, spleen, and liver during gamma radiation of mice. Arch Biochem Biophysiol 244: 156–160

    Google Scholar 

  • Lange KW (1990) Behavioural effects and supersensitivity in the rat following intranigral MPTP and MPP + administration. Eur J Pharmacol 175: 57–61

    Google Scholar 

  • Langston JW (1985) MPTP neurotoxicity; an overview and characterisation of phases of toxicity. Life Sci 36: 201–206

    Google Scholar 

  • Langston JW, Irwin I, Ricaurte GA (1987) Neurotoxins, parkinsonism and Parkinson's disease. Pharmacol Ther 32: 19–49

    Google Scholar 

  • Mytilineou C, Cohen G (1985) Deprenyl protects dopamine neurons from the neurotoxic effects of 1-methyl-4-phenylpyridinium ion. J Neurochem 45: 1951–1953

    Google Scholar 

  • Ovadia A, Zhang Z, Gash DM (1995) Increased susceptibility to MPTP toxicity in middle-aged rhesus monkeys. Neurobiol Aging 16: 931–937

    Google Scholar 

  • Ricaurte GA, Irwin I, Forno LS, DeLanney LE, Langston E, Langston JW (1987) Aging and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced degeneration of dopaminergic neurons in the substantia nigra. Brain Res 403: 43–51

    Google Scholar 

  • Rose S, Nomoto M, Jackson EA, Gibb WR, Jaehnig P, Jenner P, Marsden CD (1993) Age-related effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine treatment of common marmosets. Eur J Pharmacol 230: 177–185

    Google Scholar 

  • Schulz JB, Henshaw DR, Matthews RT, Beai MF (1995a) Coenzyme Q10 and nicotinamide and a free radical spin trap protect against MPTP neurotoxicity. Exp Neurol 132: 279–283

    Google Scholar 

  • Schulz JB, Henshaw DR, Siwek D, Jenkins BG, Ferrante RJ, Cipolloni PB, Kowall NW, Rosen BR, Beai MF (1995b) Involvement of free radicals in excitotoxicity in vivo. J Neurochem 64: 2239–2247

    Google Scholar 

  • Sen S, Phillis JW (1993) Alpha-phenyl-tert-butyl-nitrone (PBN) attenuates hydroxyl radical production during ischemia-reperfusion injury of rat brain; an EPR study. Free Radie Res Commun 19: 255–265

    Google Scholar 

  • Serchen H, Mason MF, Hashim A, Lajtha A (1985) Effect of N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) on age related changes in dopamine turnover and transport function in the mouse striatum. Eur J Pharmacol 113: 135–136

    Google Scholar 

  • Socci DJ, Crandall BM, Arendash GW (1995) Chronic antioxidant treatment improves the cognitive performance of aged rats. Brain Res 693: 88–94

    Google Scholar 

  • Sun CJ, Johanessen JN, Gessner W, Namura I, Singhaniyom W, Brossi A, Chiueh CC (1988) Neurotoxic damage to the nigrostriatal system in rats following intranigral administration of MPDP + and MPP +. J Neural Transm 74: 75–86

    Google Scholar 

  • Sundström E, Strömberg I, Tsutsumi T, Oison L, Jonsson G (1987) Studies on the effect of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPP +) on central catecholamine neurons in C57 Bl/6 mice. Comparison with three other strains of mice. Brain Res 405: 26–38

    Google Scholar 

  • Sundström E, Fredriksson A, Archer T (1990) Chronic neurochemical and behavioural changes in MPTP-lesioned C57 B1/6 mice; a model for Parkinson's disease. Brain Res 528: 181–188

    Google Scholar 

  • Tetrud JW, Langston JW (1989) The effect of deprenyl (Selegiline) on the natural history of Parkinson's disease. Science 245: 519–522

    Google Scholar 

  • Thiffault C, Quirion R, Aumont N, Poirier J (1992) The effect of L-deprenyl and MPTP on superoxide dismutase activity in the striatum of C57B1/6 mice. Soc Neurosci Abstr 18: 1443

    Google Scholar 

  • Tipton KF, Singer TP (1993) Advances in our understanding of the mechanisms of the toxicity of MPTP and related compounds. J Neurochem 61: 1191–1206

    Google Scholar 

  • Tolliver TI, Huang SJ, Chiueh CC, Murphy DL, Tolliver JM (1993) A comparison of deprenyl (selegiline) and MPP+ on cocaine-sensitive dopamine uptake sites. Soc Neurosci Abstr 19: 402

    Google Scholar 

  • Walsh SL, Wagner GC (1989) Age-dependent effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP); correlation with monoamine oxidase-B. Synapse 3: 308–314

    Google Scholar 

  • Wu R-M, Chiueh CC, Pert A, Murphy DL (1993) Apparent antioxidant effect of 1-deprenyl on hydroxyl radical formation and nigral injury elicited by MPP + in vivo. Eur J Pharmacol 243: 241–247

    Google Scholar 

  • Wu R-M, Mohanakumar KP, Murphy DL, Chiueh CC (1994) Antioxidant mechanism and protection of nigral neurons against MPP + toxicity by deprenyl (selegiline). Ann NY Acad Sci 738: 214–221

    Google Scholar 

  • Wu R-M, Murphy DL, Chiueh CC (1994) Protection of nigral neurons against MPP + induced oxidative injury by deprenyl (selegiline), U-78517F, and DMSO. New Trends Clin Neuropharm 8: 187–188

    Google Scholar 

  • Ye Liu Y, Yu H, Mohell N, Nordvall G, Lewander T, Hacksell U (1995) Derivatives of cis-2-amino-8-hydroxy-1-methyltetralin; Mixed 5-HTlA-receptor agonists and dopamine-D2-receptor antagonists. J Med Chem 38: 150–160

    Google Scholar 

  • Yue TL, Gu JL, Lysko PG, Cheng HY, Barone FC, Feuerstein G (1992) Neuroprotective effects of phenyl-t-butyl-nitrone in gerbil global brain ischemia and in cultured rat cerebellar neurons. Brain Res 574: 193–197

    Google Scholar 

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  1. A. Fredriksson

    Present address: Department of Psychiatry, University of Uppsala, Uppsala

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  1. Department of Environmental Toxicology, University of Uppsala, Uppsala

    P. Eriksson

  2. Department of Psychology, University of Göteborg, Göteborg, Sweden

    T. Archer

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Fredriksson, A., Eriksson, P. & Archer, T. MPTP-induced deficits in motor activity: Neuroprotective effects of the spintrapping agent, α-phenyl-tert-butyl-nitrone (PBN). J. Neural Transmission 104, 579–592 (1997). https://doi.org/10.1007/BF01291877

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