Glucosinolates pp 275-299 | Cite as

Neuroprotective Effects of Glucosinolates

  • Cristina AngeloniEmail author
  • Silvana Hrelia
  • Marco Malaguti
Reference work entry
Part of the Reference Series in Phytochemistry book series (RSP)


Oxidative stress, excitotoxicity, inflammation, misfolded proteins, and neuronal loss are common characteristics of a wide range of chronic neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, and amyotrophic lateral sclerosis. For these disorders, the current healthcare outcomes are considered inadequate; in fact these pathologies are treated after onset of the disease, frequently at near end-stages, and pessimistic prognosis considers pandemic scenario for these disorders over the next 10–20 years. Phytochemicals have been regarded as an alternative and preventive therapeutic strategy to control the occurrence and progression of neurodegenerative diseases. Recent research has shown that dietary phytochemicals have pleiotropic behaviors, exerting antioxidant, anti-inflammatory, and cytoprotective effects in neuronal and glial cells. In particular, isothiocyanates, the activated form of glucosinolates present in Brassica vegetables, have shown neuroprotective activity in several experimental paradigms due to their peculiar ability to activate the Nrf2/ARE pathway, playing a role in boosting the neuronal natural phase 2 enzyme antioxidant defense system and functioning as a powerful indirect antioxidant. This chapter summarizes the preventive glucosinolate-derived isothiocyanates effects in neurodegeneration and underscores the powerful preventive role that these compounds play in assisting the body to help fend off a variety of neurodegenerative diseases.


Glucosinolates Isothiocyanates Sulforaphane Oxidative stress Neurodegeneration Parkinson’s disease Alzheimer’s disease Multiple sclerosis Amyotrophic lateral sclerosis 



4-iodophenyl isothiocyanate








Alzheimer’s disease


Advanced glycation end products


Amyotrophic lateral sclerosis


Amyloid precursor protein


Antioxidant response element



Blood brain barrier


Brain-derived neurotropic factor


Choline acetyltransferase


Central nervous system


Creatine phosphokinase






Autoimmune encephalomyelitis


Extracellular signal-regulated kinase


γ-Glutamyl cysteine synthetase






Glutathione peroxidase


Glutathione reductase






Huntington’s disease


Heme oxygenase 1


Heat shock protein 27


Herpes simplex virus 1


Inducible nitric oxide synthase




c-Jun N-terminal protein kinase


Kelch-like-ECH-associated protein 1


Protein 1 light chain 3


Monoamine oxidase


Macrophage migration inhibitory factor


Mixed neural cultures




Multiple sclerosis


Neurofibrillary tangles


Nerve growth factor


NADPH oxidase


NADPH quinone oxidoreductase 1


Nuclear factor NF-E2-related factor 2


Parkinson’s disease


Protein kinase B


Reactive oxygen species




Thioredoxin reductase





This work was supported by MIUR-FIRB (project RBAP11HSZS) and “Fondazione del Monte di Bologna e Ravenna (Italy).”


  1. 1.
    Hung CW, Chen YC, Hsieh WL, Chiou SH, Kao CL (2010) Ageing and neurodegenerative diseases. Ageing Res Rev 9(Suppl 1):S36–S46CrossRefGoogle Scholar
  2. 2.
    Olesen J, Gustavsson A, Svensson M et al (2012) The economic cost of brain disorders in Europe. Eur J Neurol 19:155–162CrossRefGoogle Scholar
  3. 3.
    McKinnon C, Tabrizi SJ (2014) The ubiquitin-proteasome system in neurodegeneration. Antioxid Redox Signal 21:2302–2321CrossRefGoogle Scholar
  4. 4.
    Motori E, Puyal J, Toni N et al (2013) Inflammation-induced alteration of astrocyte mitochondrial dynamics requires autophagy for mitochondrial network maintenance. Cell Metab 18:844–859CrossRefGoogle Scholar
  5. 5.
    Deger JM, Gerson JE, Kayed R (2015) The interrelationship of proteasome impairment and oligomeric intermediates in neurodegeneration. Aging Cell 14:715–724CrossRefGoogle Scholar
  6. 6.
    Cobb CA, Cole MP (2015) Oxidative and nitrative stress in neurodegeneration. Neurobiol Dis 84:4–21CrossRefGoogle Scholar
  7. 7.
    Santos R, de Almodóvar CR, Bulteau AL, Gomes CM (2013) Neurodegeneration, neurogenesis, and oxidative stress. Oxid Med Cell Longev 2013:730581Google Scholar
  8. 8.
    White A, Culmsee C, Beart P (2013) Oxidative stress and neurodegeneration. Neurochem Int 62:521CrossRefGoogle Scholar
  9. 9.
    Querfurth HW, LaFerla FM (2010) Alzheimer’s disease. N Engl J Med 362:329–344CrossRefGoogle Scholar
  10. 10.
    Markesbery WR, Carney JM (1999) Oxidative alterations in Alzheimer's disease. Brain Pathol 9:133–146CrossRefGoogle Scholar
  11. 11.
    Angeloni C, Zambonin L, Hrelia S (2014) Role of methylglyoxal in Alzheimer’s disease. BioMed Res Intl 2014:238485–238485Google Scholar
  12. 12.
    Saleem M, Herrmann N, Swardfager W, Eisen R, Lanctôt KL (2015) Inflammatory markers in mild cognitive impairment: a meta-analysis. J Alzheimers Dis 47:669–679CrossRefGoogle Scholar
  13. 13.
    Dawson TM, Dawson VL (2003) Molecular pathways of neurodegeneration in Parkinson's disease. Science 302:819–822CrossRefGoogle Scholar
  14. 14.
    Lotharius J, Brundin P (2002) Pathogenesis of Parkinson’s disease: dopamine, vesicles and alpha-synuclein. Nat Rev Neurosci 3:932–942CrossRefGoogle Scholar
  15. 15.
    Calne S, Schoenberg B, Martin W, Uitti RJ, Spencer P, Calne DB (1987) Familial Parkinson’s disease: possible role of environmental factors. Can J Neurol Sci 14:303–305CrossRefGoogle Scholar
  16. 16.
    Schoenberg BS (1987) Environmental risk factors for Parkinson’s disease: the epidemiologic evidence. Can J Neurol Sci 14:407–413CrossRefGoogle Scholar
  17. 17.
    Kitada T, Asakawa S, Hattori N et al (1998) Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism. Nature 392:605–608CrossRefGoogle Scholar
  18. 18.
    Polymeropoulos MH, Lavedan C, Leroy E et al (1997) Mutation in the alpha-synuclein gene identified in families with Parkinson’s disease. Science 276:2045–2047CrossRefGoogle Scholar
  19. 19.
    Spillantini MG, Schmidt ML, Lee VM, Trojanowski JQ, Jakes R, Goedert M (1997) Alpha-synuclein in Lewy bodies. Nature 388:839–840CrossRefGoogle Scholar
  20. 20.
    Valente EM, Abou-Sleiman PM, Caputo V et al (2004) Hereditary early-onset Parkinson’s disease caused by mutations in PINK1. Science 304:1158–1160CrossRefGoogle Scholar
  21. 21.
    Sherer TB, Betarbet R, Greenamyre JT (2001) Pathogenesis of Parkinson’s disease. Curr Opin Investig Drugs 2:657–662Google Scholar
  22. 22.
    Jenner P (2003) Oxidative stress in Parkinson’s disease. Ann Neurol 53(Suppl 3):S26–S36, discussion S36–S28CrossRefGoogle Scholar
  23. 23.
    Maker HS, Weiss C, Silides DJ, Cohen G (1981) Coupling of dopamine oxidation (monoamine oxidase activity) to glutathione oxidation via the generation of hydrogen peroxide in rat brain homogenates. J Neurochem 36:589–593CrossRefGoogle Scholar
  24. 24.
    Lee SY, Moon Y, Hee Choi D, Jin Choi H, Hwang O (2007) Particular vulnerability of rat mesencephalic dopaminergic neurons to tetrahydrobiopterin: relevance to Parkinson’s disease. Neurobiol Dis 25:112–120CrossRefGoogle Scholar
  25. 25.
    Dunnett SB, Bjorklund A (1999) Prospects for new restorative and neuroprotective treatments in Parkinson’s disease. Nature 399:A32–A39CrossRefGoogle Scholar
  26. 26.
    Conway KA, Rochet JC, Bieganski RM, Lansbury PT Jr (2001) Kinetic stabilization of the alpha-synuclein protofibril by a dopamine-alpha-synuclein adduct. Science 294:1346–1349CrossRefGoogle Scholar
  27. 27.
    Browne P, Chandraratna D, Angood C et al (2014) Atlas of multiple sclerosis 2013: a growing global problem with widespread inequity. Neurology 83:1022–1024CrossRefGoogle Scholar
  28. 28.
    Sospedra M, Martin R (2005) Immunology of multiple sclerosis. Annu Rev Immunol 23:683–747CrossRefGoogle Scholar
  29. 29.
    Awad AM, Stüve O (2010) Immunopathogenesis of multiple sclerosis: new insights and therapeutic implications. Continuum (Minneap Minn) 16:166–180Google Scholar
  30. 30.
    Simpson S, Taylor BV, van der Mei I (2015) The role of epidemiology in MS research: past successes, current challenges and future potential. Mult Scler 21:969–977CrossRefGoogle Scholar
  31. 31.
    Kiernan MC, Vucic S, Cheah BC et al (2011) Amyotrophic lateral sclerosis. Lancet 377:942–955CrossRefGoogle Scholar
  32. 32.
    de Paula CZ, Gonçalves BD, Vieira LB (2015) An overview of potential targets for treating amyotrophic lateral sclerosis and huntington’s disease. Biomed Res Int 73(12):1026–1037Google Scholar
  33. 33.
    Souza PV, Pinto WB, Chieia MA, Oliveira AS (2015) Clinical and genetic basis of familial amyotrophic lateral sclerosis. Arq Neuropsiquiatr 73:1026–1037Google Scholar
  34. 34.
    Zarei S, Carr K, Reiley L et al (2015) A comprehensive review of amyotrophic lateral sclerosis. Surg Neurol Int 6:171CrossRefGoogle Scholar
  35. 35.
    Middleton E Jr (1998) Effect of plant flavonoids on immune and inflammatory cell function. Adv Exp Med Biol 439:175–182CrossRefGoogle Scholar
  36. 36.
    Hollman PC, Katan MB (1999) Health effects and bioavailability of dietary flavonols. Free Radic Res 31(Suppl):S75–S80CrossRefGoogle Scholar
  37. 37.
    Eastwood MA (1999) Interaction of dietary antioxidants in vivo: how fruit and vegetables prevent disease? QJM 92:527–530CrossRefGoogle Scholar
  38. 38.
    Clarke DB (2010) Glucosinolates, structures and analysis in food. Anal Methods 2:15CrossRefGoogle Scholar
  39. 39.
    James D, Devaraj S, Bellur P, Lakkanna S, Vicini J, Boddupalli S (2012) Novel concepts of broccoli sulforaphanes and disease: induction of phase II antioxidant and detoxification enzymes by enhanced-glucoraphanin broccoli. Nutr Rev 70:654–665CrossRefGoogle Scholar
  40. 40.
    Navarro A, Boveris A (2009) Brain mitochondrial dysfunction and oxidative damage in Parkinson's disease. J Bioenerg Biomembr 41:517–521CrossRefGoogle Scholar
  41. 41.
    Navarro SL, Li F, Lampe JW (2011) Mechanisms of action of isothiocyanates in cancer chemoprevention: an update. Food Funct 2:579–587CrossRefGoogle Scholar
  42. 42.
    Fahey JW, Zalcmann AT, Talalay P (2001) The chemical diversity and distribution of glucosinolates and isothiocyanates among plants. Phytochemistry 56:5–51CrossRefGoogle Scholar
  43. 43.
    Shapiro TA, Fahey JW, Wade KL, Stephenson KK, Talalay P (1998) Human metabolism and excretion of cancer chemoprotective glucosinolates and isothiocyanates of cruciferous vegetables. Cancer Epidemiol Biomarkers Prev 7:1091–1100Google Scholar
  44. 44.
    Bones AM, Rossiter JT (2006) The enzymic and chemically induced decomposition of glucosinolates. Phytochemistry 67:1053–1067CrossRefGoogle Scholar
  45. 45.
    Halkier BA, Gershenzon J (2006) Biology and biochemistry of glucosinolates. Annu Rev Plant Biol 57:303–333CrossRefGoogle Scholar
  46. 46.
    Matusheski NV, Juvik JA, Jeffery EH (2004) Heating decreases epithiospecifier protein activity and increases sulforaphane formation in broccoli. Phytochemistry 65:1273–1281CrossRefGoogle Scholar
  47. 47.
    Verkerk R, Schreiner M, Krumbein A et al (2009) Glucosinolates in Brassica vegetables: the influence of the food supply chain on intake, bioavailability and human health. Mol Nutr Food Res 53(Suppl 2):S219CrossRefGoogle Scholar
  48. 48.
    Cooper DA, Webb DR, Peters JC (1997) Evaluation of the potential for olestra to affect the availability of dietary phytochemicals. J Nutr 127:1699S–1709SGoogle Scholar
  49. 49.
    Winiwarter S, Bonham NM, Ax F, Hallberg A, Lennernas H, Karlen A (1998) Correlation of human jejunal permeability (in vivo) of drugs with experimentally and theoretically derived parameters. A multivariate data analysis approach. J Med Chem 41:4939–4949CrossRefGoogle Scholar
  50. 50.
    Zhang Y, Callaway EC (2002) High cellular accumulation of sulphoraphane, a dietary anticarcinogen, is followed by rapid transporter-mediated export as a glutathione conjugate. Biochem J 364:301–307CrossRefGoogle Scholar
  51. 51.
    Clarke JD, Riedl K, Bella D, Schwartz SJ, Stevens JF, Ho E (2011) Comparison of isothiocyanate metabolite levels and histone deacetylase activity in human subjects consuming broccoli sprouts or broccoli supplement. J Agric Food Chem 59:10955–10963CrossRefGoogle Scholar
  52. 52.
    Jakubikova J, Sedlak J, Mithen R, Bao Y (2005) Role of PI3K/Akt and MEK/ERK signaling pathways in sulforaphane- and erucin-induced phase II enzymes and MRP2 transcription, G2/M arrest and cell death in Caco-2 cells. Biochem Pharmacol 69:1543–1552CrossRefGoogle Scholar
  53. 53.
    Hanlon N, Coldham N, Sauer MJ, Ioannides C (2009) Modulation of rat pulmonary carcinogen-metabolising enzyme systems by the isothiocyanates erucin and sulforaphane. Chem Biol Interact 177:115–120CrossRefGoogle Scholar
  54. 54.
    Melchini A, Costa C, Traka M et al (2009) Erucin, a new promising cancer chemopreventive agent from rocket salads, shows anti-proliferative activity on human lung carcinoma A549 cells. Food Chem Toxicol 47:1430–1436CrossRefGoogle Scholar
  55. 55.
    Kassahun K, Davis M, Hu P, Martin B, Baillie T (1997) Biotransformation of the naturally occurring isothiocyanate sulforaphane in the rat: identification of phase I metabolites and glutathione conjugates. Chem Res Toxicol 10:1228–1233CrossRefGoogle Scholar
  56. 56.
    Gasper AV, Al-Janobi A, Smith JA et al (2005) Glutathione S-transferase M1 polymorphism and metabolism of sulforaphane from standard and high-glucosinolate broccoli. Am J Clin Nutr 82:1283–1291Google Scholar
  57. 57.
    Shapiro TA, Fahey JW, Wade KL, Stephenson KK, Talalay P (2001) Chemoprotective glucosinolates and isothiocyanates of broccoli sprouts: metabolism and excretion in humans. Cancer Epidemiol Biomarkers Prev 10:501–508Google Scholar
  58. 58.
    Egner PA, Chen JG, Wang JB et al (2011) Bioavailability of Sulforaphane from two broccoli sprout beverages: results of a short-term, cross-over clinical trial in Qidong, China. Cancer Prevent Res 4:384–395CrossRefGoogle Scholar
  59. 59.
    Clarke JD, Hsu A, Williams DE et al (2011) Metabolism and tissue distribution of sulforaphane in Nrf2 knockout and wild-type mice. Pharm Res 28:3171–3179CrossRefGoogle Scholar
  60. 60.
    Dinkova-Kostova AT, Kostov RV (2012) Glucosinolates and isothiocyanates in health and disease. Trends Mol Med 18:337–347CrossRefGoogle Scholar
  61. 61.
    Veeranki OL, Bhattacharya A, Marshall JR, Zhang Y (2013) Organ-specific exposure and response to sulforaphane, a key chemopreventive ingredient in broccoli: implications for cancer prevention. Br J Nutr 109:25–32CrossRefGoogle Scholar
  62. 62.
    Bollard M, Stribbling S, Mitchell S, Caldwell J (1997) The disposition of allyl isothiocyanate in the rat and mouse. Food Chem Toxicol 35:933–943CrossRefGoogle Scholar
  63. 63.
    Conaway CC, Jiao D, Kohri T, Liebes L, Chung FL (1999) Disposition and pharmacokinetics of phenethyl isothiocyanate and 6-phenylhexyl isothiocyanate in F344 rats. Drug Metab Dispos 27:13–20Google Scholar
  64. 64.
    Munday R, Mhawech-Fauceglia P, Munday CM et al (2008) Inhibition of urinary bladder carcinogenesis by broccoli sprouts. Cancer Res 68:1593–1600CrossRefGoogle Scholar
  65. 65.
    Eklind KI, Morse MA, Chung FL (1990) Distribution and metabolism of the natural anticarcinogen phenethyl isothiocyanate in A/J mice. Carcinogenesis 11:2033–2036CrossRefGoogle Scholar
  66. 66.
    Ioannou YM, Burka LT, Matthews HB (1984) Allyl isothiocyanate: comparative disposition in rats and mice. Toxicol Appl Pharmacol 75:173–181CrossRefGoogle Scholar
  67. 67.
    Halliwell B (1992) Reactive oxygen species and the central nervous system. J Neurochem 59:1609–1623CrossRefGoogle Scholar
  68. 68.
    Hamilton ML, Van Remmen H, Drake JA et al (2001) Does oxidative damage to DNA increase with age? Proc Natl Acad Sci U S A 98:10469–10474CrossRefGoogle Scholar
  69. 69.
    Aruoma OI (2002) Neuroprotection by dietary antioxidants: new age of research. Nahrung 46:381–382CrossRefGoogle Scholar
  70. 70.
    Niedzielska E, Smaga I, Gawlik M, et al (2015) Oxidative stress in neurodegenerative diseases. Mol Neurobiol pp. 1–32. doi:10.1007/s12035-015-9337-5Google Scholar
  71. 71.
    Shcherbatykh I, Carpenter DO (2007) The role of metals in the etiology of Alzheimer’s disease. J Alzheimers Dis 11:191–205CrossRefGoogle Scholar
  72. 72.
    Eckert A, Keil U, Marques CA et al (2003) Mitochondrial dysfunction, apoptotic cell death, and Alzheimer’s disease. Biochem Pharmacol 66:1627–1634CrossRefGoogle Scholar
  73. 73.
    Colton CA, Chernyshev ON, Gilbert DL, Vitek MP (2000) Microglial contribution to oxidative stress in Alzheimer’s disease. Ann N Y Acad Sci 899:292–307CrossRefGoogle Scholar
  74. 74.
    Shimohama S, Tanino H, Kawakami N et al (2000) Activation of NADPH oxidase in Alzheimer’s disease brains. Biochem Biophys Res Commun 273:5–9CrossRefGoogle Scholar
  75. 75.
    Wallace MN, Geddes JG, Farquhar DA, Masson MR (1997) Nitric oxide synthase in reactive astrocytes adjacent to beta-amyloid plaques. Exp Neurol 144:266–272CrossRefGoogle Scholar
  76. 76.
    Lambeth JD (2004) NOX enzymes and the biology of reactive oxygen. Nat Rev Immunol 4:181–189CrossRefGoogle Scholar
  77. 77.
    Fischer MT, Sharma R, Lim JL et al (2012) NADPH oxidase expression in active multiple sclerosis lesions in relation to oxidative tissue damage and mitochondrial injury. Brain 135:886–899CrossRefGoogle Scholar
  78. 78.
    Liu JS, Zhao ML, Brosnan CF, Lee SC (2001) Expression of inducible nitric oxide synthase and nitrotyrosine in multiple sclerosis lesions. Am J Pathol 158:2057–2066CrossRefGoogle Scholar
  79. 79.
    Chen JW, Breckwoldt MO, Aikawa E, Chiang G, Weissleder R (2008) Myeloperoxidase-targeted imaging of active inflammatory lesions in murine experimental autoimmune encephalomyelitis. Brain 131:1123–1133CrossRefGoogle Scholar
  80. 80.
    Lu F, Selak M, O'Connor J et al (2000) Oxidative damage to mitochondrial DNA and activity of mitochondrial enzymes in chronic active lesions of multiple sclerosis. J Neurol Sci 177:95–103CrossRefGoogle Scholar
  81. 81.
    Yoritaka A, Hattori N, Uchida K, Tanaka M, Stadtman ER, Mizuno Y (1996) Immunohistochemical detection of 4-hydroxynonenal protein adducts in Parkinson disease. Proc Natl Acad Sci U S A 93:2696–2701CrossRefGoogle Scholar
  82. 82.
    Yasuhara T, Hara K, Sethi KD, Morgan JC, Borlongan CV (2007) Increased 8-OHdG levels in the urine, serum, and substantia nigra of hemiparkinsonian rats. Brain Res 1133:49–52CrossRefGoogle Scholar
  83. 83.
    Beal MF, Ferrante RJ, Browne SE, Matthews RT, Kowall NW, Brown RH (1997) Increased 3-nitrotyrosine in both sporadic and familial amyotrophic lateral sclerosis. Ann Neurol 42:644–654CrossRefGoogle Scholar
  84. 84.
    Rizzardini M, Mangolini A, Lupi M, Ubezio P, Bendotti C, Cantoni L (2005) Low levels of ALS-linked Cu/Zn superoxide dismutase increase the production of reactive oxygen species and cause mitochondrial damage and death in motor neuron-like cells. J Neurol Sci 232:95–103CrossRefGoogle Scholar
  85. 85.
    Talalay P, De Long MJ, Prochaska HJ (1988) Identification of a common chemical signal regulating the induction of enzymes that protect against chemical carcinogenesis. Proc Natl Acad Sci U S A 85:8261–8265CrossRefGoogle Scholar
  86. 86.
    Itoh K, Wakabayashi N, Katoh Y et al (1999) Keap1 represses nuclear activation of antioxidant responsive elements by Nrf2 through binding to the amino-terminal Neh2 domain. Genes Dev 13:76–86CrossRefGoogle Scholar
  87. 87.
    Turpaev KT (2013) Keap1-Nrf2 signaling pathway: mechanisms of regulation and role in protection of cells against toxicity caused by xenobiotics and electrophiles. Biochemistry (Mosc) 78:111–126CrossRefGoogle Scholar
  88. 88.
    Baird L, Dinkova-Kostova AT (2011) The cytoprotective role of the Keap1-Nrf2 pathway. Arch Toxicol 85:241–272CrossRefGoogle Scholar
  89. 89.
    Marini MG, Chan K, Casula L, Kan YW, Cao A, Moi P (1997) hMAF, a small human transcription factor that heterodimerizes specifically with Nrf1 and Nrf2. J Biol Chem 272:16490–16497CrossRefGoogle Scholar
  90. 90.
    Nguyen T, Huang HC, Pickett CB (2000) Transcriptional regulation of the antioxidant response element. Activation by Nrf2 and repression by MafK. J Biol Chem 275:15466–15473CrossRefGoogle Scholar
  91. 91.
    Itoh K, Chiba T, Takahashi S et al (1997) An Nrf2/small Maf heterodimer mediates the induction of phase II detoxifying enzyme genes through antioxidant response elements. Biochem Biophys Res Commun 236:313–322CrossRefGoogle Scholar
  92. 92.
    Dinkova-Kostova AT, Holtzclaw WD, Kensler TW (2005) The role of Keap1 in cellular protective responses. Chem Res Toxicol 18:1779–1791CrossRefGoogle Scholar
  93. 93.
    Hong F, Freeman ML, Liebler DC (2005) Identification of sensor cysteines in human Keap1 modified by the cancer chemopreventive agent sulforaphane. Chem Res Toxicol 18:1917–1926CrossRefGoogle Scholar
  94. 94.
    Zhang DD, Hannink M (2003) Distinct cysteine residues in Keap1 are required for Keap1-dependent ubiquitination of Nrf2 and for stabilization of Nrf2 by chemopreventive agents and oxidative stress. Mol Cell Biol 23:8137–8151CrossRefGoogle Scholar
  95. 95.
    Hu C, Eggler AL, Mesecar AD, van Breemen RB (2011) Modification of keap1 cysteine residues by sulforaphane. Chem Res Toxicol 24:515–521CrossRefGoogle Scholar
  96. 96.
    Juge N, Mithen RF, Traka M (2007) Molecular basis for chemoprevention by sulforaphane: a comprehensive review. Cell Mol Life Sci 64:1105–1127CrossRefGoogle Scholar
  97. 97.
    Dinkova-Kostova AT, Talalay P (2008) Direct and indirect antioxidant properties of inducers of cytoprotective proteins. Mol Nutr Food Res 52(Suppl 1):S128–S138Google Scholar
  98. 98.
    Angeloni C, Leoncini E, Malaguti M, Angelini S, Hrelia P, Hrelia S (2009) Modulation of phase II enzymes by sulforaphane: implications for its cardioprotective potential. J Agric Food Chem 57:5615–5622CrossRefGoogle Scholar
  99. 99.
    Tarozzi A, Morroni F, Merlicco A et al (2009) Sulforaphane as an inducer of glutathione prevents oxidative stress-induced cell death in a dopaminergic-like neuroblastoma cell line. J Neurochem 111:1161–1171CrossRefGoogle Scholar
  100. 100.
    Tarozzi A, Morroni F, Bolondi C et al (2012) Neuroprotective Effects of Erucin against 6-Hydroxydopamine-Induced Oxidative Damage in a Dopaminergic-like Neuroblastoma Cell Line. Int J Mol Sci 13:10899–10910CrossRefGoogle Scholar
  101. 101.
    Innamorato NG, Rojo AI, Garcia-Yague AJ, Yamamoto M, de Ceballos ML, Cuadrado A (2008) The transcription factor Nrf2 is a therapeutic target against brain inflammation. J Immunol 181:680–689CrossRefGoogle Scholar
  102. 102.
    Schachtele SJ, Hu S, Lokensgard JR (2012) Modulation of experimental herpes encephalitis-associated neurotoxicity through sulforaphane treatment. PLoS One 7:e36216CrossRefGoogle Scholar
  103. 103.
    Negi G, Kumar A, Sharma SS (2011) Nrf2 and NF-kappaB modulation by sulforaphane counteracts multiple manifestations of diabetic neuropathy in rats and high glucose-induced changes. Curr Neurovasc Res 8:294–304CrossRefGoogle Scholar
  104. 104.
    Mas S, Gasso P, Trias G, Bernardo M, Lafuente A (2012) Sulforaphane protects SK-N-SH cells against antipsychotic-induced oxidative stress. Fundam Clin Pharmacol 26:712–721CrossRefGoogle Scholar
  105. 105.
    Mizuno K, Kume T, Muto C et al (2011) Glutathione biosynthesis via activation of the nuclear factor E2-related factor 2 (Nrf2)--antioxidant-response element (ARE) pathway is essential for neuroprotective effects of sulforaphane and 6-(methylsulfinyl) hexyl isothiocyanate. J Pharmacol Sci 115:320–328CrossRefGoogle Scholar
  106. 106.
    Deng C, Tao R, Yu SZ, Jin H (2012) Sulforaphane protects against 6-hydroxydopamine-induced cytotoxicity by increasing expression of heme oxygenase-1 in a PI3K/Akt-dependent manner. Mol Med Rep 5:847–851Google Scholar
  107. 107.
    Jazwa A, Rojo AI, Innamorato NG, Hesse M, Fernandez-Ruiz J, Cuadrado A (2011) Pharmacological targeting of the transcription factor Nrf2 at the basal ganglia provides disease modifying therapy for experimental parkinsonism. Antioxid Redox Signal 14:2347–2360CrossRefGoogle Scholar
  108. 108.
    Reggiori F, Komatsu M, Finley K, Simonsen A (2012) Autophagy: more than a nonselective pathway. Int J Cell Biol 2012:219625Google Scholar
  109. 109.
    Vidal RL, Matus S, Bargsted L, Hetz C (2014) Targeting autophagy in neurodegenerative diseases. Trends Pharmacol Sci 35:583–591CrossRefGoogle Scholar
  110. 110.
    Hochstrasser M (1992) Ubiquitin and intracellular protein degradation. Curr Opin Cell Biol 4:1024–1031CrossRefGoogle Scholar
  111. 111.
    Kwak MK, Cho JM, Huang B, Shin S, Kensler TW (2007) Role of increased expression of the proteasome in the protective effects of sulforaphane against hydrogen peroxide-mediated cytotoxicity in murine neuroblastoma cells. Free Radic Biol Med 43:809–817CrossRefGoogle Scholar
  112. 112.
    Kwak MK, Wakabayashi N, Greenlaw JL, Yamamoto M, Kensler TW (2003) Antioxidants enhance mammalian proteasome expression through the Keap1-Nrf2 signaling pathway. Mol Cell Biol 23:8786–8794CrossRefGoogle Scholar
  113. 113.
    Park HM, Kim JA, Kwak MK (2009) Protection against amyloid beta cytotoxicity by sulforaphane: role of the proteasome. Arch Pharm Res 32:109–115CrossRefGoogle Scholar
  114. 114.
    Gan N, Wu YC, Brunet M et al (2010) Sulforaphane activates heat shock response and enhances proteasome activity through up-regulation of Hsp27. J Biol Chem 285:35528–35536CrossRefGoogle Scholar
  115. 115.
    Mi L, Gan N, Chung FL (2011) Isothiocyanates inhibit proteasome activity and proliferation of multiple myeloma cells. Carcinogenesis 32:216–223CrossRefGoogle Scholar
  116. 116.
    Liu Y, Hettinger CL, Zhang D, Rezvani K, Wang X, Wang H (2014) Sulforaphane enhances proteasomal and autophagic activities in mice and is a potential therapeutic reagent for Huntington’s disease. J Neurochem 129:539–547CrossRefGoogle Scholar
  117. 117.
    Jo C, Gundemir S, Pritchard S, Jin YN, Rahman I, Johnson GV (2014) Nrf2 reduces levels of phosphorylated tau protein by inducing autophagy adaptor protein NDP52. Nat Commun 5:3496Google Scholar
  118. 118.
    Jo C, Kim S, Cho SJ et al (2014) Sulforaphane induces autophagy through ERK activation in neuronal cells. FEBS Lett 588:3081–3088CrossRefGoogle Scholar
  119. 119.
    Lee DW, Andersen JK, Kaur D (2006) Iron dysregulation and neurodegeneration: the molecular connection. Mol Interv 6:89–97CrossRefGoogle Scholar
  120. 120.
    Xiao F, Li XG, Zhang XY et al (2011) Combined administration of D-galactose and aluminium induces Alzheimer-like lesions in brain. Neurosci Bull 27:143–155CrossRefGoogle Scholar
  121. 121.
    Dawson GR, Heyes CM, Iversen SD (1992) Pharmacological mechanisms and animal models of cognition. Behav Pharmacol 3:285–297CrossRefGoogle Scholar
  122. 122.
    Cavanaugh SE, Pippin JJ, Barnard ND (2014) Animal models of Alzheimer disease: historical pitfalls and a path forward. ALTEX 31:279–302CrossRefGoogle Scholar
  123. 123.
    Kim HV, Kim HY, Ehrlich HY, Choi SY, Kim DJ, Kim Y (2013) Amelioration of Alzheimer’s disease by neuroprotective effect of sulforaphane in animal model. Amyloid 20:7–12CrossRefGoogle Scholar
  124. 124.
    Chen G, Fang Q, Zhang J, Zhou D, Wang Z (2011) Role of the Nrf2-ARE pathway in early brain injury after experimental subarachnoid hemorrhage. J Neurosci Res 89:515–523CrossRefGoogle Scholar
  125. 125.
    Lee S, Kim J, Seo SG, Choi BR, Han JS, Lee KW (2014) Sulforaphane alleviates scopolamine-induced memory impairment in mice. Pharmacol Res 85:23–32CrossRefGoogle Scholar
  126. 126.
    Zhang R, Zhang J, Fang L et al (2014) Neuroprotective effects of sulforaphane on cholinergic neurons in mice with Alzheimer's disease-like lesions. Int J Mol Sci 15:14396–14410CrossRefGoogle Scholar
  127. 127.
    Kim JK, Shin EC, Kim CR et al (2013) Effects of brussels sprouts and their phytochemical components on oxidative stress-induced neuronal damages in PC12 cells and ICR mice. J Med Food 16:1057–1061CrossRefGoogle Scholar
  128. 128.
    Ganguly R, Guha D (2008) Alteration of brain monoamines & EEG wave pattern in rat model of Alzheimer’s disease & protection by Moringa oleifera. Indian J Med Res 128:744–751Google Scholar
  129. 129.
    Lavich IC, de Freitas BS, Kist LW et al (2015) Sulforaphane rescues memory dysfunction and synaptic and mitochondrial alterations induced by brain iron accumulation. Neuroscience 301:542–552CrossRefGoogle Scholar
  130. 130.
    Angeloni C, Zambonin L, Hrelia S (2014) Role of methylglyoxal in Alzheimer’s disease. BioMed Res Int 2014:238485Google Scholar
  131. 131.
    Rahmadi A, Steiner N, Munch G (2011) Advanced glycation end products as gerontotoxins and biomarkers for carbonyl-based degenerative processes in Alzheimer’s disease. Clin Chem Lab Med: CCLM/FESCC 49:385–391CrossRefGoogle Scholar
  132. 132.
    Chellan P, Nagaraj RH (1999) Protein crosslinking by the Maillard reaction: dicarbonyl-derived imidazolium crosslinks in aging and diabetes. Arch Biochem Biophys 368:98–104CrossRefGoogle Scholar
  133. 133.
    Edison P, Archer HA, Gerhard A et al (2008) Microglia, amyloid, and cognition in Alzheimer's disease: an [11C](R)PK11195-PET and [11C]PIB-PET study. Neurobiol Dis 32:412–419CrossRefGoogle Scholar
  134. 134.
    Hickman SE, Allison EK, El Khoury J (2008) Microglial dysfunction and defective beta-amyloid clearance pathways in aging Alzheimer’s disease mice. J Neurosci 28:8354–8360CrossRefGoogle Scholar
  135. 135.
    Krautwald M, Leech D, Horne S et al (2011) The advanced glycation end product-lowering agent ALT-711 is a low-affinity inhibitor of thiamine diphosphokinase. Rejuvenation Res 14:383–391CrossRefGoogle Scholar
  136. 136.
    Gubellini P, Kachidian P (2015) Animal models of Parkinson’s disease: An updated overview. Rev Neurol (Paris) 171(11):750–761CrossRefGoogle Scholar
  137. 137.
    Meredith GE, Sonsalla PK, Chesselet MF (2008) Animal models of Parkinson’s disease progression. Acta Neuropathol 115:385–398CrossRefGoogle Scholar
  138. 138.
    Morroni F, Tarozzi A, Sita G et al (2013) Neuroprotective effect of sulforaphane in 6-hydroxydopamine-lesioned mouse model of Parkinson’s disease. Neurotoxicology 36C:63–71CrossRefGoogle Scholar
  139. 139.
    Trinh K, Moore K, Wes PD et al (2008) Induction of the phase II detoxification pathway suppresses neuron loss in Drosophila models of Parkinson’s disease. J NeuroScience 28:465–472CrossRefGoogle Scholar
  140. 140.
    Han JM, Lee YJ, Lee SY et al (2007) Protective effect of sulforaphane against dopaminergic cell death. J Pharmacol Exp Ther 321:249–256CrossRefGoogle Scholar
  141. 141.
    Siebert A, Desai V, Chandrasekaran K, Fiskum G, Jafri MS (2009) Nrf2 activators provide neuroprotection against 6-hydroxydopamine toxicity in rat organotypic nigrostriatal cocultures. J Neurosci Res 87:1659–1669CrossRefGoogle Scholar
  142. 142.
    Deng C, Tao R, Yu SZ, Jin H (2012) Inhibition of 6-hydroxydopamine-induced endoplasmic reticulum stress by sulforaphane through the activation of Nrf2 nuclear translocation. Mol Med Rep 6:215–219Google Scholar
  143. 143.
    Vauzour D, Buonfiglio M, Corona G et al (2010) Sulforaphane protects cortical neurons against 5-S-cysteinyl-dopamine-induced toxicity through the activation of ERK1/2, Nrf-2 and the upregulation of detoxification enzymes. Mol Nutr Food Res 54:532–542CrossRefGoogle Scholar
  144. 144.
    Spencer JP, Whiteman M, Jenner P, Halliwell B (2002) 5-s-Cysteinyl-conjugates of catecholamines induce cell damage, extensive DNA base modification and increases in caspase-3 activity in neurons. J Neurochem 81:122–129CrossRefGoogle Scholar
  145. 145.
    Vauzour D, Ravaioli G, Vafeiadou K, Rodriguez-Mateos A, Angeloni C, Spencer JP (2008) Peroxynitrite induced formation of the neurotoxins 5-S-cysteinyl-dopamine and DHBT-1: implications for Parkinson’s disease and protection by polyphenols. Arch Biochem Biophys 476:145–151CrossRefGoogle Scholar
  146. 146.
    Vauzour D, Vafeiadou K, Spencer JP (2007) Inhibition of the formation of the neurotoxin 5-S-cysteinyl-dopamine by polyphenols. Biochem Biophys Res Commun 362:340–346CrossRefGoogle Scholar
  147. 147.
    Morroni F, Sita G, Tarozzi A, Cantelli-Forti G, Hrelia P (2014) Neuroprotection by 6-(methylsulfinyl)hexyl isothiocyanate in a 6-hydroxydopamine mouse model of Parkinson’s disease. Brain Res 1589:93–104CrossRefGoogle Scholar
  148. 148.
    Galuppo M, Iori R, De Nicola GR, Bramanti P, Mazzon E (2013) Anti-inflammatory and anti-apoptotic effects of (RS)-glucoraphanin bioactivated with myrosinase in murine sub-acute and acute MPTP-induced Parkinson’s disease. Bioorg Med Chem 21:5532–5547CrossRefGoogle Scholar
  149. 149.
    Lee JA, Son HJ, Park KD et al (2015) A novel compound ITC-3 activates the Nrf2 signaling and provides neuroprotection in Parkinson’s disease models. Neurotox Res 28:332–345CrossRefGoogle Scholar
  150. 150.
    Wellejus A, Elbrønd-Bek H, Kelly NM, Weidner MS, Jørgensen SH (2012) 4-iodophenyl isothiocyanate: a neuroprotective compound. Restor Neurol Neurosci 30:21–38Google Scholar
  151. 151.
    Fletcher JM, Lalor SJ, Sweeney CM, Tubridy N, Mills KH (2010) T cells in multiple sclerosis and experimental autoimmune encephalomyelitis. Clin Exp Immunol 162:1–11CrossRefGoogle Scholar
  152. 152.
    Giacoppo S, Galuppo M, Iori R et al (2013) Protective role of (RS)-glucoraphanin bioactivated with myrosinase in an experimental model of multiple sclerosis. CNS Neurosci Ther 19:577–584CrossRefGoogle Scholar
  153. 153.
    Li B, Cui W, Liu J et al (2013) Sulforaphane ameliorates the development of experimental autoimmune encephalomyelitis by antagonizing oxidative stress and Th17-related inflammation in mice. Exp Neurol 250:239–249CrossRefGoogle Scholar
  154. 154.
    Kithcart AP, Cox GM, Sielecki T et al (2010) A small-molecule inhibitor of macrophage migration inhibitory factor for the treatment of inflammatory disease. FASEB J 24:4459–4466CrossRefGoogle Scholar
  155. 155.
    Niino M, Ogata A, Kikuchi S, Tashiro K, Nishihira J (2000) Macrophage migration inhibitory factor in the cerebrospinal fluid of patients with conventional and optic-spinal forms of multiple sclerosis and neuro-Behçet’s disease. J Neurol Sci 179:127–131CrossRefGoogle Scholar
  156. 156.
    Cross JV, Rady JM, Foss FW, Lyons CE, Macdonald TL, Templeton DJ (2009) Nutrient isothiocyanates covalently modify and inhibit the inflammatory cytokine macrophage migration inhibitory factor (MIF). Biochem J 423:315–321CrossRefGoogle Scholar
  157. 157.
    Ouertatani-Sakouhi H, El-Turk F, Fauvet B et al (2009) A new class of isothiocyanate-based irreversible inhibitors of macrophage migration inhibitory factor. Biochemistry 48:9858–9870CrossRefGoogle Scholar
  158. 158.
    Brown KK, Blaikie FH, Smith RA et al (2009) Direct modification of the proinflammatory cytokine macrophage migration inhibitory factor by dietary isothiocyanates. J Biol Chem 284:32425–32433CrossRefGoogle Scholar
  159. 159.
    Angeloni C, Turroni S, Bianchi L et al (2013) Novel targets of sulforaphane in primary cardiomyocytes identified by proteomic analysis. PLoS One 8:e83283CrossRefGoogle Scholar
  160. 160.
    Galuppo M, Giacoppo S, De Nicola GR et al (2014) Antiinflammatory activity of glucomoringin isothiocyanate in a mouse model of experimental autoimmune encephalomyelitis. Fitoterapia 95:160–174CrossRefGoogle Scholar
  161. 161.
    Galuppo M, Giacoppo S, Iori R, De Nicola GR, Bramanti P, Mazzon E (2015) Administration of 4-(α-L-rhamnosyloxy)-benzyl isothiocyanate delays disease phenotype in SOD1(G93A) rats: a transgenic model of amyotrophic lateral sclerosis. Biomed Res Int 2015: 259417Google Scholar
  162. 162.
    Rowland LP, Shneider NA (2001) Amyotrophic lateral sclerosis. N Engl J Med 344:1688–1700CrossRefGoogle Scholar
  163. 163.
    Malaguti M, Angeloni C, Garatachea N et al (2009) Sulforaphane treatment protects skeletal muscle against damage induced by exhaustive exercise in rats. J Appl Physiol (1985) 107:1028–1036CrossRefGoogle Scholar
  164. 164.
    Duan W, Li X, Shi J, Guo Y, Li Z, Li C (2010) Mutant TAR DNA-binding protein-43 induces oxidative injury in motor neuron-like cell. Neuroscience 169:1621–1629CrossRefGoogle Scholar
  165. 165.
    Wijesekera LC, Leigh PN (2009) Amyotrophic lateral sclerosis. Orphanet J Rare Dis 4:3CrossRefGoogle Scholar
  166. 166.
    Yokoseki A, Shiga A, Tan CF et al (2008) TDP-43 mutation in familial amyotrophic lateral sclerosis. Ann Neurol 63:538–542CrossRefGoogle Scholar
  167. 167.
    Chang G, Guo Y, Jia Y et al (2010) Protective effect of combination of sulforaphane and riluzole on glutamate-mediated excitotoxicity. Biol Pharm Bull 33:1477–1483CrossRefGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2017

Authors and Affiliations

  • Cristina Angeloni
    • 1
    Email author
  • Silvana Hrelia
    • 1
  • Marco Malaguti
    • 1
  1. 1.Dipartimento di Scienze per la Qualità della VitaAlma Mater Studiorum, Università di BolognaRiminiItaly

Personalised recommendations