Skip to main content
Log in

Mesencephalic neuron death induced by congeners of nitrogen monoxide is prevented by the lazaroid U-83836E

  • Research Article
  • Published:
Experimental Brain Research Aims and scope Submit manuscript

Abstract

We explored the effects of congeners of nitrogen monoxide (NO) on cultured mesencephalic neurons. Sodium nitroprusside (SNP) was used as a donor of NO, the congeners of which have been found to exert either neurotoxic or neuroprotive effects depending on the surrounding redox milieu. In contrast to a previous report that suggests that the nitrosonium ion (NO+) is neuroprotective to cultured cortical neurons, we found that the nitrosonium ion reduces the survival of cultured dopamine neurons to 32% of control. There was a trend for further impairment of dopamine neuron survival, to only 7% of untreated control, when the cultures were treated with SNP plus ascorbate, i.e. when the nitric oxide radical (NO) had presumably been formed. We also evaluated the effects of an inhibitor of lipid peroxidation, the lazaroid U-83836E, against SNP toxicity. U-83836E exerted marked neuroprotective effects in both insult models. More than twice as many dopamine neurons (75% of control) survival when the lazaroid was added to SNP-treated cultures and the survival was increased eight-fold (to 55% of control) when U-83836E was added to cultures treated with SNP plus ascorbate. We conclude that the congeners of NO released by SNP are toxic to mesencephalic neurons in vitro and that the lazaroid U-83836E significantly increases the survival of dopamine neurons in situations where congeners of NO are generated.

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

Access this article

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

Instant access to the full article PDF.

Similar content being viewed by others

References

  • Althaus JS, Oien TT, Fici GJ, Scherch HM, Strautmann AF, Sethy VH, Von Voigtlander PF (1993) Peroxynitrite (POX) scavengers: possible neuroprotectants against nitric oxide (NO)-dependent toxicity. Soc Neurosci Abstr 609.2

  • Bates JN, Baker MT, Guerra R, Harrison DG (1991) Nitric oxide generation from nitroprusside by vascular tissue. Biochem Pharmacol [Suppl] 42: S157-S165

    Article  CAS  Google Scholar 

  • Beckman JS, Beckman TW, Chen J, Marshall PA, Freeman BA (1990) Apparent hydroxyl radical production by peroxynitrite: implications for endothelial injury from nitric oxide and superoxide. Proc Natl Acad Sci USA 87: 1620–1624

    Article  PubMed  CAS  Google Scholar 

  • Beckman JS, Ischiropoulos H, Zhu L, Woerd M van der, Smith C, Chen J, Harrison J, Martin JC, Tasi M (1992) Kinetics of superoxide dismutase- and iron-catalyzed nitration of phenolics by peroxynitrite. Arch Biochem Biophys 298: 438–445

    Article  PubMed  CAS  Google Scholar 

  • Beckman JS, Carson M, Smith CS, Koppenol WH (1993) ALS, SOD and peroxynitrite. Nature 364: 584

    Article  PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  • Dawson VL, Dawson TM, London ED, Bredt DS, Snyder SH (1991) Nitric oxide mediates glutamate neuotoxicity in primary cortical cultures. Proc Natl Acad Sci USA 88: 6368–6371

    Article  PubMed  CAS  Google Scholar 

  • Dawson TM, Dawson VL, Snyder SH (1992) A novel neuronal meassenger molecule in brain: the free radical nitric oxide. Ann Neurol 32: 297–311

    Article  PubMed  CAS  Google Scholar 

  • Dawson VL, Dawson TM, Bartley DA, Uhl GR, Snyder SH (1993) Mechanisms of nitric oxide-mediated neurotoxicity in primary brain cultures. J Neurosci 13: 2651–2661

    PubMed  CAS  Google Scholar 

  • Dawson TM, Zhang J, Dawson VL, Snyder SH (1994) Nitric oxide: cellular regulation and neuronal injury. Prog Brain Res 103: 365–369

    Article  PubMed  CAS  Google Scholar 

  • Dexter DT, Carter CJ, Wells FR, Javoy-Agid F, Agid Y, Lees AJ, Jenner P, Marsden CD (1989) basal lipid peroxidation in substantia nigra is increased in Parkinson’s disease. J Neurochem 52: 381–389

    PubMed  CAS  Google Scholar 

  • Dexter DT, Holley AE, Flitter WD, Slator TF, Wells FR, Daniel SE, Lees AJ, Jenner P, Marsden CD (1994) Increased levels of lipid hydroperoxides in the parkinsonian substantia nigra: an HPLC and ESR study. Mov Disorders 9: 92–97

    Article  CAS  Google Scholar 

  • DiFiglia M (1990) Excitotoxic injury of the neostriatum: a model for Huntington’s disease. Trends Neurosci 13(7): 286–289.

    Article  PubMed  CAS  Google Scholar 

  • Ferrante RJ, Kowall NW, Beal MF, Richardson EP, Bird ED, Martin JB (1985) Selective sparing of a class of striatal neurons in Huntington’s disease 230: 561–563

    CAS  Google Scholar 

  • Fici GJ, Althaus JS, Zhang ED, Hall ED, Von Voigtlander PF (1994) Peroxynitrite toxicity in cerebellar granule cells: reversal by tirilazad mesylate (U-740006F). Soc. Neurosci Abstr 675.7

  • Fornstedt B (1990) Cysteinyl adducts as putative indices of catechol autooxidation in dopaminergic brain regions. Thesis of the Department of Pharmacology, University of Götenborg, Sweden

  • Frodl EM, Nakao N, Brundin P (1994) Lazaroids improve the survival of cultured rat embryonic mesencephalic neurons. Neuroreport 5: 2393–2396

    Article  PubMed  CAS  Google Scholar 

  • Grasbon-Frodl EM, Andersson A, Brundin P (1996) Lazaroid treatment prevent death of cultured rat embryonic mesencephalic neurons following glutathione depletion. J Neurochem (in press)

  • Huang Z, Huang PL, Panahian N, Dalkara T, Fishman MC, Moskowitz MA (1994) Effects of cerebral ischemia in mice deficient in neuroanl nitric oxide synthase. Science 265: 1883–1885

    PubMed  CAS  Google Scholar 

  • Hunot S, Boissiere F, Faucheux B, Brugg B, Mouatt-Prigent A, Agid Y, Hirsch EC (1996) Nitric oxide synthase and neuronal vulnerability in Parkinson’s disease. Neuroscience 72: 355–341

    Article  PubMed  CAS  Google Scholar 

  • Hyman BT, Marzloff K, Wenniger JJ, Dawson TM, Bredt DS, Snyder SH (1992) Relative sparing of nitric oxide synthase-containing neurons in the hippocampal formation in Alzheimer’s disease. Ann Neurol 32(6):818–820

    Article  PubMed  CAS  Google Scholar 

  • Izumi Y, Benz AM, Clifford DB, Zorumski CF (1992) Nitric oxide inhibitors attenuateN-methyl-d-aspartate excitotoxicity in rat hippocampal slices. Neurosci Lett 135:227–230

    Article  PubMed  CAS  Google Scholar 

  • Koh JY, Choi DW (1988) Cultured striatal neurons containing NADPH-diaphorase or acetylcholinesterase are selectively resistant to injury by NMDA receptor agonists. Brain Res 446(2):374–378

    Article  PubMed  CAS  Google Scholar 

  • Kollegger H, McBean GJ, Tipton KF (1993) Reduction of striatal N-methyl-D-aspartate toxicity by inhibition of nitric oxide synthase. Biochem Pharmacol 45(1):260–264

    Article  PubMed  CAS  Google Scholar 

  • Lei SZ, Pan ZH, Aggarwal SK, Chen HSV, Hartman J, Sucher NJ, Lipton SA (1992) Effect of nitric oxide production on the redox modulatory sites of the NMDA receptor-channel complex. Neuron 8:1087–1099

    Article  PubMed  CAS  Google Scholar 

  • Lipton SA, Choi YB, Pan ZH, Li SZ, Chen HSV, Sucher NJ, Loscalzo J, Singel DJ, Stamler JS (1993) A redox-based mechanism for the neuroprotective and neurodestructive effects of nitric oxide and related nitroso-compounds. Nature 364: 626–632

    Article  PubMed  CAS  Google Scholar 

  • Lustg HS, von Brauchitsch KL, Chan J, Greenberg DA (1992) Cyclic GMP modulators and excitotoxic injury in cerebral cortical cultures. Brain Res 577: 343–346

    Article  Google Scholar 

  • McGeer PL, McGeer EG (1995) The inflammatory response system of brain: implications for the therapy of Alzheimer and other neurodegenerative diseases. Brain Res Rev 21: 195–218

    Article  PubMed  CAS  Google Scholar 

  • Mizuno Y, Ikebe S, Hattori N, Nakagawa-Hattori Y, Mochizuki H, Tanaka M, Ozawa T (1995) Role of mitochondria in the etiology and pathogenesis of Parkinson’s disease. Biochim Biophys Acta 1271: 265–274

    PubMed  Google Scholar 

  • Moncada C, Lekieffre D, Arvin B, Meldrum B (1992) Effect of NO synthase inhibition NMDA- and ischemia-induced hippocampal lesions. Neuroreport 3: 530–532

    PubMed  CAS  Google Scholar 

  • Nakao N, Frodl EM, Duan WM, Widner H, Brudin P (1994) Lazaroids improve the survival of grafted rat embryonic dopamine neurons. Proc Natl Acad Sci USA 91: 12408–12412

    Article  PubMed  CAS  Google Scholar 

  • Olanow CW (1993) A radical hypothesis for neurodegeneration. Trends Neurosci 16: 439–444

    Article  PubMed  CAS  Google Scholar 

  • Perry TL, Godin DV, Hansen S (1982) Parkinson’s disease: a disorder due to nigral glutathione deficiency? Neurosci Lett 33:305–310

    Article  PubMed  CAS  Google Scholar 

  • Radi R, Beckman JS, Bush KM, Feeman BA (1991a) Peroxynitrite-induced membrane lipid peroxidation: the cytotoxic potential of superoxide and nitric oxide. Arch Biochem Biophys 288: 481–487

    Article  PubMed  CAS  Google Scholar 

  • Radi R, Beckman JS, Busch KM, Freeman BA (1991b) Peroxinytrite oxidation of sulfhydryls — the cytotoxic potential of superoxide and nitric oxide. J Biol Chenm 266: 4244–4250

    CAS  Google Scholar 

  • Riederer P, Sofic E, Rausch WD, Schmidt B, Reynold GP, Jellinger K, Youdim MBH (1989) Tansition metals, ferritin, glutathione, and ascorbic acid in parkinsonian brains. J Neurochem 42: 515–520

    Google Scholar 

  • Schulz JB, Beal MF (1994) Mitochondrial dysfunction in movement disorders. Curr Opin Neurol 7: 333–339

    Article  PubMed  CAS  Google Scholar 

  • Schulz JB, Matthews RT, Muqit MMK, Browne SA, Beal MF (1995) Inhibition of nitric oxide synthase by-nitroindazole protects against MPTP-induced neurotoxicity in mice. J Neurochem 64: 936–939

    Article  PubMed  CAS  Google Scholar 

  • Schapira AHV (1995) Oxidative stress in Parkinson’s disease. Neuropathol Appl Neurobiol 21: 3–9

    PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Stamler JS, Singel DJ, Loscalzo J (1992) Biochemistry of nitric oxide and its redox-activated forms. Science 258: 1898–1902

    PubMed  CAS  Google Scholar 

  • Uemura Y, Kowall NW, Beal MF (1990) Selective sparing of NADPH-diaphorase-somatosatin-neuropeptide Y neurons in ischemic gerbil striatum. Ann Neurol 27(6):620–625

    Article  PubMed  CAS  Google Scholar 

  • Van Muiswinkel FL, Steinbusch HWM, Drukarch B, DeVente J (1994) Identification of No-producing and-receptive cells in mesencephalic transplants in a rat model of Parkinson’s disease: a study using NADPH-d enzyme and NOSc/cGMP immunocytochemistry. AnN NY Acad Sci 738: 289–304

    Article  PubMed  Google Scholar 

  • Wallis RA, Panizzon K, Wasterlain CG (1992) Inhibition of nitric oxide synthase protects against hypoxic neuronal injury. Neuroreport 3: 645–648

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to P. Brundin.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Grasbon-Frodl, E.M., Brundin, P. Mesencephalic neuron death induced by congeners of nitrogen monoxide is prevented by the lazaroid U-83836E. Exp Brain Res 113, 138–143 (1997). https://doi.org/10.1007/BF02454149

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF02454149

Key words

Navigation