Intake of Tomato-Enriched Diet Protects from 6-Hydroxydopamine-Induced Degeneration of Rat Nigral Dopaminergic Neurons

  • Vincenzo di MatteoEmail author
  • Massimo Pierucci
  • Giuseppe Di Giovanni
  • Luana Katia Dragani
  • Stefania Murzilli
  • Andreina Poggi
  • Ennio Esposito
Part of the Journal of Neural Transmission. Supplementa book series (NEURALTRANS, volume 73)


There is extensive evidence that oxidative damage of dopamine (DA)-containing neurons in the substantia nigra pars compacta (SNc) may contribute to the pathogenesis of Parkinson’s disease (PD). We evaluated the potential neuroprotective effect of diets enriched with wild-type Red Setter (RS) tomato or transgenic High Carotene (HC) tomato, rich in β-carotene, obtained by the activation of lycopene β-cyclase (tlcy-b), in an animal model of PD. Male Fischer 344 rats were fed for 14 days with standard AltrominMT diet, 5% RS- or 5% HC-enriched diet. Seven days after the beginning of this diet regimen, the rats were lesioned by 6-hydroxydopamine (6-OHDA) injected into the left SNc. After further 7 days, the rats were sacrificed, and DA and 3,4-dihydroxyphenylacetic acid (DOPAC) levels in both the left (ipsilateral) and the right (contralateral) striata were measured. Striatal DA levels were reduced by 86.5 ± 5.0% in control, 86.2 ± 5.0% in HC-, and 56.0 ± 9.0% in RS-fed group. Striatal DOPAC was decreased by 85.6 ± 5.0% in controls, 83.0 ± 6.0% in HC-, and 58.9 ± 10.0% in RS-fed group. Blood was obtained from the rats on day 14 and the plasma level of licopene and β-carotene was measured by liquid chromatography-atmospheric pressure chemical ionization-mass spectrometry (LC-APCI-MS) for the determination of lycopene and β-carotene levels. The plasma level of lycopene was 4.7 ± 0.2 ng/ml in 5% RS-fed rats, while it was undetectable (< 2.5 ng ml−1) in control and HC-fed rats. The efficacy of RS diet to preserve striatal dopaminergic innervation can be attributed to the ability of lycopene to prevent the degeneration of DA-containing neurons in the SNc.


Diet Dopamine Lycopene Parkinson’s disease Striatum β-carotene 





Analysis of variance


Butylated hydroxytoluene


Cauliflower mosaic virus 35S




3,4-dihydroxyphenylacetic acid




High carotene


High performance liquid chromatography


Liquid chromatography-atmospheric pressure chemical ionization-mass spectrometry




Parkinson’s disease


Protected least significance difference


Reactive oxygen species


Red Setter


Substantia nigra pars compacta


Tomato lycopene β-cyclase.



This study has been carried out in the frame of a MIUR L.297/96-financed project (SAFE) to Agrobios Metapontum. We thank Dr. Francesco Cellini and Dr. Angelo Petrozza, Agrobios Metapontum for kindly supplying RS and HC tomatoes and Dr. Gianluigi Forloni, Mario Negri Institute for Pharmacological Research, for the helpful discussion.


  1. Al-Babili S, Beyer P (2005) Golden Rice-five years on the road-five years to go? Trends Plant Sci 10:565–73CrossRefPubMedGoogle Scholar
  2. Barak Y, Wohl Y, Greenberg Y, Bar Dayan Y, Friedman T, Shoval G, Knobler HY (2005) Affective psychosis following Accutane (isotretinoin) treatment. Int Clin Psychopharmacol 20:39–41CrossRefPubMedGoogle Scholar
  3. Blum D, Torch S, Lambeng N, Nissou M-F, Benabid A-L, Sadoul R, Verna J-M (2001) Molecular pathways involved in the neurotoxicity of 6-OHDA, dopamine and MPTP: contribution to the apoptotic theory in Parkinson’s disease. Prog Neurobiol 65:135–172CrossRefPubMedGoogle Scholar
  4. Bremner JD, McCaffey P (2008) The neurobiology of retinoic acid in affective disorders. Prog NeuroPsychopharmacol Biol Psychiatry 32:315–331CrossRefPubMedGoogle Scholar
  5. Brooks DJ (1998) The early diagnosis of Parkinson’s disease. Ann Neurol 44(Suppl):S19–S31Google Scholar
  6. Carta M, Stancapiano R, Tronci E, Collu M, Usiello A, Morelli M, Fadda F (2006) Vitamin A deficiency induces motor impairements and striatal cholinergic dysfunction in rats. Neuroscience 139: 1163–1172CrossRefPubMedGoogle Scholar
  7. D’Ambrosio C, Giorio G, Marino I, Merendino A, Petrozza A, Salfi L, Stilliani AL, Cellini F (2004) Virtually complete conversion of lycopene into β-carotene in fruits of tomato plants transformed with the tomato lycopene β-cyclase (tlcy-b) cDNA. Plant Science 166:207–214CrossRefGoogle Scholar
  8. Dawson TM, Dawson VL (2002) Neuroprotective and neurorestorative strategies for Parkinson's disease. Nat Neurosci 5:S1058–S1061CrossRefGoogle Scholar
  9. Dexter DT, Carayon A, Javoy-Agid F, Agid Y, Wells SE, Jenner P, Marsden C (1991) Alterations in the levels of iron, ferritin and other trace metals in Parkinson’s disease and other neurodegenerative diseases affecting the basal ganglia. Brain 114:1953–1975CrossRefPubMedGoogle Scholar
  10. Dexter DT, Holley AE, Flitter WD, Slater TF, Wells FR, Daniel S, Lees AJ, Marsden CD (1994) Increased levels of lipid hydroperoxides in the Parkinsonian substantia nigra: an HPLC and ESR study. Mov Disord 9:92–97CrossRefPubMedGoogle Scholar
  11. Di Giovanni G (2008) Will it be possible to prevent nigral neurodegeneration? CNS Neurol Disord Drug Targets 7:28–44CrossRefPubMedGoogle Scholar
  12. Di Matteo V, Pierucci M, Di Giovanni G, Di Santo A, Poggi A, Benigno A, Esposito E (2006a) Aspirin protects striatal dopaminergic neurons from neurotoxin-induced degeneration: an in vivo microdialysis study. Brain Res 1095:167–177CrossRefPubMedGoogle Scholar
  13. Di Matteo V, Benigno A, Pierucci M, Giuliano DA, Crescimanno G, Esposito E, Di Giovanni G (2006b) 7-nitroindazole protects striatal dopaminergic neurons against MPP+-induced degeneration: an in vivo microdialysis study. Ann NY Acad Sci 1089:462–471CrossRefPubMedGoogle Scholar
  14. Ebadi M, Srinivasan SK, Baxi MD (1996) Oxidative stress and antioxidant therapy in Parkinson’s disease. Progr Neurobiol 48:1–19CrossRefGoogle Scholar
  15. Esposito E, Rotilio D, Di Matteo V, Di Giulio C, Cacchio M, Algeri S (2002) A review of specific antioxidants and the effects on biochemical mechanisms related to neurodegenerative processes. Neurobiol Aging 23:719–735CrossRefPubMedGoogle Scholar
  16. Esposito E, Capasso M, di Tomasso N, Corona C, Pellegrini F, Uncini A, Vitaglione P, Fogliano V, Piantelli M, Sensi SL (2007) Antioxidant strategies based on tomato-enriched food or pyruvate do not affect disease onset and survival in an animal model of amyotrophic lateral sclerosis. Brain Res 1168:90–96CrossRefPubMedGoogle Scholar
  17. Fahn S (1991) An open trial of high-dosage antioxidants in early Parkinson’s disease. Am J Clin Nutr 53:380S–382SPubMedGoogle Scholar
  18. Fall PA, Fredrikson M, Axelson O, Granérus AK (1999) Nutritional and occupational factors influencing the risk of Parkinson's disease: a case-control study in southeastern Sweden. Mov Disord 14:28–37CrossRefPubMedGoogle Scholar
  19. Fearnley JM, Lees AJ (1991) Ageing and Parkinson's disease: SNc regional selectivity. Brain 114:2283–2301CrossRefPubMedGoogle Scholar
  20. Ferguson SA, Cisneros FJ, Gough BJ, Ali SF (2005) Four weeks of oral isotretinoin treatment causes few signs of general toxicity in male and female Sprague-Dawley rats. Food Chem Toxicol 43:1289–1296CrossRefPubMedGoogle Scholar
  21. Ferreira AL, Yeum K-J, Liu C, Smith D et al (2000) Tissue distribution of lycopene in ferrets and rats after lycopene supplementation. J Nutr 130:1256–60PubMedGoogle Scholar
  22. Goodman AB (1998) Three independent lines of evidence suggest retinoids as causal to schizophrenia. Proc Natl Acad Sci USA 95:7240–7244CrossRefPubMedGoogle Scholar
  23. Goodman DS, Huang HS (1965) Biosynthesis of vitamin A with rat intestinal enzymes. Science 149:879–880CrossRefPubMedGoogle Scholar
  24. Halliwell B, Gutteridge JMC (1985) Oxygen radicals and the nervous system. Trends Neurosci 6:22–26CrossRefGoogle Scholar
  25. Hsiao G, Fong TH, Tzu NH, Lin KH, Chou DS, Sheu JR (2004) A potent antioxidant, lycopene, affords neuroprotection against microglia activation and focal cerebral ischemia in rats. In Vivo 18:351–356PubMedGoogle Scholar
  26. Jellinger K (1989) Pathology of Parkinson’s disease. In: Calne DB (ed) Handbook of experimental pharmacology, vol 8. Springer, Berlin, pp 47–112Google Scholar
  27. Jenner P, Dexter DT, Sian J, Schapira AHV, Marsden CD (1992) Oxidative stress as a cause of nigral cell death in Parkinson’s disease and incident Lewy body disease. Ann Neurol 32:582–587CrossRefGoogle Scholar
  28. Krezel W, Ghyselinck N, Samad TA, Dupé V, Kastner P, Borrelli E, Chambon P (1998) Impaired locomotion and dopamine signaling in retinoid receptor mutant mice. Science 279:863–867CrossRefPubMedGoogle Scholar
  29. Lang AE, Lozan AM (1998) Parkinson’s disease first of two parts. New Engl J Med 339:1044–1053CrossRefPubMedGoogle Scholar
  30. Mabrouk OS, Roth BL, Sivagnaniar I, Pehek EA (2003) Vitamin A derivative 13-cis retinoic acid (Accutane) modulates stress induced dopamine release in the rat medial prefrontal cortex. Society for Neuroscience Abstracts (2003 Abstract Viewer/Itinerary Planner), 461.14Google Scholar
  31. Mattson MP, Chan SL, Duan W (2002) Modification of brain aging and neurodegenerative disorders by genes, diet, and behavior. Physiol Rev 82:637–672PubMedGoogle Scholar
  32. Nagao A (2004) Oxidative conversion of carotenoids to retinoids and other products. J Nutr 134:273S–240SGoogle Scholar
  33. Nguyen ML, Schwartz SJ (1998) Lycopene stability during food processing. Proc Soc Exp Biol Med 218:101–105PubMedGoogle Scholar
  34. Olson JA, Hayaisshi O (1965) The enzymatic cleavage of β-carotene into vitamin A by soluble enzymes of rat liver and intestine. Proc Natl Acad Sci USA 54:1364–1370CrossRefPubMedGoogle Scholar
  35. Paxinos G, Watson C (1986) The rat brain in stereotaxic coordinates. Academic, New YorkGoogle Scholar
  36. Perry TL, Yong VW, Hansen S, Jones K, Bergeron C, Foulks JG, Wright JM (1987) α-Tocopherol and β-carotene do not protect marmosets against the dopaminergic neurotoxicity of N-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine. J Neurol Sci 81:321–331CrossRefPubMedGoogle Scholar
  37. Rao AV, Agarwal S (2000) Role of antioxidant lycopene in cancer and heart disease. J Am Coll Nutr 19:563–569PubMedGoogle Scholar
  38. Rao AV, Balachandran B (2002) Role of oxidative stress and antioxidants in neurodegenerative diseases. Nutr Neurosci 5:291–309CrossRefPubMedGoogle Scholar
  39. Rao AV (2004) Processed tomato products as a source of dietary lycopene: bioavailability and antioxidant properties. Can J Diet Pract Res 65:161–165CrossRefPubMedGoogle Scholar
  40. Ribaya-Mercado JD, Holmgren SC, Fox JG, Russell RM (1989) Dietary β-carotene absorption and metabolism in ferrets and rats. J Nutr 119:665–668PubMedGoogle Scholar
  41. Riso P, Visioli F, Erba D, Testolin G, Porrini M (2004) Lycopene and vitamin C concentrations increase in plasma and lymphocytes after tomato intake. Effect on cellular antioxidant protection. Eur J Clin Nutr 58:1350–1358CrossRefPubMedGoogle Scholar
  42. Rissanen TH, Voutilainen S, Nyyssonen K, Lakka TA, Sivenius J, Salonen R, Kaplan GA, Salonen JT (2001) Low serum lycopene concentration is associated with an excess incidence of acute coronary events and stroke: the Kuopio Ischaemic Hearth Disease Risk Factor Study. Br J Nutr 85:749–754CrossRefPubMedGoogle Scholar
  43. Saga Y, Kobayashi M, Ohta H, Murai N, Nakai N, Oshima M, Taketo MM (1999) Impaired extrapyramidal function caused by the targeted disruption of retinoid receptor RXRγ1 isoform. Genes Cells 4:219–228CrossRefPubMedGoogle Scholar
  44. Samad TA, Krezel W, Chambon P, Borrelli E (1997) Regulation of dopaminergic pathway by retinoids: Activation of D2 receptor promoter by members of the retinoic acid receptor-retinoid X receptor family. Proc Natl Acad Sci USA 94:14349–14354CrossRefPubMedGoogle Scholar
  45. Scherman D, Desnos C, Darchen F, Pollak P, Javoy-Agid F, Agid Y (1989) Striatal dopamine deficiency in Parkinson's disease: role of aging. Ann Neurol 26:551–557CrossRefPubMedGoogle Scholar
  46. Simonian NA, Coyle JT (1996) Oxidative stress in neurodegenerative diseases. Annu Rev Pharmacol Toxicol 36:83–106CrossRefPubMedGoogle Scholar
  47. Suganuma H, Hirano T, Arimoto Y, Inakuma T (2002) Effect of tomato intake on striatal monoamine level in a mouse model of experimental Parkinson’s disease. J Nutr Sci Vitaminol 48:251–254PubMedGoogle Scholar
  48. Talalay P (2000) Chemoprotection against cancer by induction of phase 2 enzyme. Biofactors 12:5–11CrossRefPubMedGoogle Scholar
  49. Veldink JH, Kalmijn S, Groeneveld GJ, Wunderink W, Koster A, de Vries JH, van der Luyt J, Wokke JH, Van den Berg LH (2007) Intake of polyunsaturated fatty acids and vitamin E reduces the risk of developing amyotrophic lateral sclerosis. J Neurol Neurosurg Psychiatry 78:367–371CrossRefPubMedGoogle Scholar
  50. von Bohlen und Halbach O, Schober A, Krieglstein K (2004) Genes, proteins, and neurotoxins involved in Parkinson’s disease. Prog Neurobiol 73:151–177CrossRefGoogle Scholar
  51. Zetterström RH, Lindqvist E, de Urquiza AM, Tomac A, Eriksson U, Perlmann T, Olson L (1999) Role of retinoids in the CNS: differential expression of retinoid binding proteins and receptors and evidence for presence of retinoic acid. Eur J Neurosci 11: 407–416CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag/Wien Printed in Germany 2009

Authors and Affiliations

  • Vincenzo di Matteo
    • 1
    Email author
  • Massimo Pierucci
    • 1
  • Giuseppe Di Giovanni
    • 2
  • Luana Katia Dragani
    • 1
  • Stefania Murzilli
    • 1
  • Andreina Poggi
    • 1
  • Ennio Esposito
    • 1
  1. 1.Istituto di Ricerche Farmacologiche “Mario Negri”, Consorzio “Mario Negri” SudSanta Maria ImbaroItaly
  2. 2.Dipartimento di Medicina Sperimentale, Sezione di Fisiologia Umana “G. Pagano”Università degli Studi di PalermoPalermoItaly

Personalised recommendations