Skip to main content
SpringerLink
Log in
SpringerLink
Log in

Isoquinolines as Neurotoxins: Action and Molecular Mechanism

  • Chapter
  • First Online:
Isoquinolines And Beta-Carbolines As Neurotoxins And Neuroprotectants

Part of the book series: Current Topics in Neurotoxicity ((Current Topics Neurotoxicity,volume 1))

Abstract

Derivatives from the isoquinoline group were found in many plants, food as well as in the mammalian brain. The interest with these substances appeared about 20 years back, after the exploration of their chemical structures similar to the well-known exogenous neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Tetrahydroisoquinolines such as 1-benzyl-1,2,3,4-tetrahydroisoquinoline (1BnTIQ) and 1-methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline (salsolinol) show the neurotoxic activity to the dopamine neurons and this way it has been proposed as endogenous factors leading risks to Parkinson’s disease. In animals, research indicates that chronic administration of 1BnTIQ as well as salsolinol induced parkinsonian-like symptoms. Both compounds produce disturbances in the function of dopaminergic neurons, intensify oxidative stress, and inhibit mitochondrial complex I and/or II activity. In consequence, this mechanism of action leads to cell death via apoptosis. This review briefly describes the properties of 1BnTIQ and salsolinol in mammalian brain. This chapter presents the chemical structures of both compounds and possible pathways of their synthesis in the brain. A special focus was put on neurochemical effects of acute and chronic administration of 1BnTIQ and salsolinol on dopamine release as well as their metabolism in rat brain. Additionally, the effects of dopamine metabolism have been shown as a source of free radical generation in the brain.

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

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 89.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 119.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Abbreviations

BBB:

Blood–brain barrier

1BnTIQ:

1-Benzyl-1,2,3,4-tetrahydroisoquinoline

COMT:

Catechol-O-methyltransferase

CSF:

Cerebrospinal fluid

DA:

Dopamine

DAT:

Dopamine transporter

DOPAC:

3,4-Dihydroxyphenylacetic acid

H2O2 :

Hydrogen peroxide

HVA:

Homovanilic acid

l-DOPA:

3,4-Dihydroxy-l-phenylalanine

MPTP:

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine

MAO:

Enzyme monoamine oxidase

PEA:

Phenylethylamine

PD:

Parkinson’s disease

ROS:

Reactive oxygen species

TH:

Tyrosine hydroxylase

TIQ:

1,2,3,4-Tetrahydroisoquinoline

References

  • Adams JD Jr, Odunze IN (1991) Oxygen free radicals and Parkinson’s disease. Free Radic Biol Med 10:161–169

    PubMed  CAS  Google Scholar 

  • Antkiewicz-Michaluk L (2002) Endogenous risk factors in Parkinson’s disease: dopamine and tetrahydroisoquinolines. Pol J Pharmacol 54:567–572

    PubMed  CAS  Google Scholar 

  • Antkiewicz-Michaluk L, Michaluk J, Romańska I, Papla I, Vetulani I (2000a) Antidopaminergic effects of 1,2,3,4-tetrahydroisoquinoline and salsolinol. J Neural Transm 107:1009–1019

    Article  PubMed  CAS  Google Scholar 

  • Antkiewicz-Michaluk L, Romańska I, Papla I, Michaluk J et al (2000b) Neurochemical changes induced by acute and chronic administration of 1,2,3,4-tetrahydroisoquinoline and salsolinol in dopaminergic structures of rat brain. Neuroscience 96:59–64

    Article  PubMed  CAS  Google Scholar 

  • Antkiewicz-Michaluk L, Michaluk J, Mokrosz M, Romańska I et al (2001) Different action on dopamine catabolic pathways of two endogenous 1,2,3,4-tetrahydroisoquinolines with similar antidopaminergic properties. J Neurochem 78:100–108

    Article  PubMed  CAS  Google Scholar 

  • Antkiewicz-Michaluk L, Wąsik A, Romańska I, Michaluk J (2010) An endogenous neurotoxin, 1-benzyl-1,2,3,4-tetrahydroisoquinoline impairs of L-DOPA-induced behavioral and biochemical effects on dopamine system in rat. In: 17th international congress of the Polish Pharma-cological Society, Kraków, Pharmacological Reports, vol 62, suppl 35

    Google Scholar 

  • Ben-Shachar D, Eschel G, Finberg JPM, Youdim MB (1991a) The iron chelator desferrioxamine (desferal) retards 6-hydroxydopamine-induced degeneration of nigrostriatal dopamine neurons. J Neurochem 56:1441–1444

    Article  PubMed  CAS  Google Scholar 

  • Ben-Shachar D, Riederer P, Youdim MB (1991b) Ironmelanin interaction and lipid peroxidation: implications for Parkinson’s disease. J Neurochem 57:1609–1614

    Article  PubMed  CAS  Google Scholar 

  • Berman SB, Hastings TG (1999) Dopamine oxidation alters mitochondrial respiration and induces permeability transition in brain mitochondria: implications for Parkinson’s disease. J Neurochem 73(3):1127–1137

    Article  PubMed  CAS  Google Scholar 

  • Bulteau AL, Ikeda-Saito M, Szweda LI (2003) Redox-dependent modulation of aconitase activity in intact mitochondria. Biochemistry 23:14846–14855

    Article  PubMed  CAS  Google Scholar 

  • Bunik VI, Romash OG, Gomazkova VS (1990) Inactivation of alpha-ketoglutarate dehydrogenase during enzyme catalyzed reaction. Biochem Int 22(6):967–976

    Article  PubMed  CAS  Google Scholar 

  • Bunik VI (2003) 2-Oxo acid dehydrogenase complexes in redox regulation. Eur J Biochem 270(6):1036–1042

    Article  PubMed  CAS  Google Scholar 

  • Burke D, Gasdaska P, Hartwell L (1989) Dominant effects of tubulin overexpression in Saccharomyces cerevisiae. Mol Cell Biol 9:1049–1059

    Article  PubMed  CAS  Google Scholar 

  • Burns RS, Lewitt PA, Ebert H, Pakkenberg H, Kopin IJ (1985) The clinical syndrome of striatal dopamine deficiency: parkinsonism induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). N Engl J Med 312:1418–1421

    Article  PubMed  CAS  Google Scholar 

  • Cadenas E, Sies H (1998) The lag phase. Free Radic Res 28(6):601–609

    Article  PubMed  CAS  Google Scholar 

  • Chan PH (1998) Oxygen radical mechanisms in cerebral ischemia and reperfusion, in ischemic stroke. In: Hsu CY (ed) Basic mechanisms to new drug development. Monogr Clin Neurosci 16:14–17

    Article  PubMed  CAS  Google Scholar 

  • Cohen G, Collins MA (1970) Alkaloids from catecholamines in adrenal tissue: possible role in addiction. Science 167:1749–1751

    Article  PubMed  CAS  Google Scholar 

  • Cohen G, Farooqui R, Kesler N (1997) Parkinson disease: a new link between monoamine oxidase and mitochondrial electron flow. Proc Natl Acad Sci USA 13; 94(10):4890–4894

    Article  PubMed  CAS  Google Scholar 

  • Collins MA, Nijim WP, Borge GF, Teas G et al (1979) Dopamine-related tetrahydroisoquinolines: significant urinary excretion by alcoholics after alcohol consumption. Science 206:1184–1186

    Article  PubMed  CAS  Google Scholar 

  • Dostert P, Strolin Benedetti M, Dordain G, Vernay D (1989) Enantiomeric composition of urinary salsolinol in parkinsonian patients after Madopar. J Neural Transm Park Dis Dement Sect 1:61–74

    Article  Google Scholar 

  • Dykens JA (1999) Free radicals and mitochondria dysfunction in excitotoxicity and neurodegenerative disease. In: Koliatsos VE, Ratan RR (eds) Cell death and diseases of the nervous system. Humana, Totowa, pp 45–68

    Chapter  Google Scholar 

  • Enoch WS, Sarna T, Zecca L, Riley PA et al (1994) The roles of neuromelanin, binding of metal ions, and the oxidative cytotoxicity in the pathogenesis of Parkinson’s disease: a hypothesis. J Neural Transm 7:83–100

    Article  Google Scholar 

  • Fornstedt B, Pileblad E, Carlsson A (1990) In vivo autoxidation of dopamine in guinea pig striatum increases with age. J Neurochem 55:655–659

    Article  PubMed  CAS  Google Scholar 

  • Ginos JZ, Doroski D (1979) Dopaminergic antagonists: effects of 1,2,3,4-tetrahydroisoquinoline and its N-methyl and N-propyl homologs on apomorphine- and L-DOPA-induced behavioral effects in rodents. J Pharmacol Exp Ther 209:79–86

    PubMed  CAS  Google Scholar 

  • Gluck M, Ehrhart J, Jayatilleke E, Zeevalk GD (2002) Inhibition of brain mitochondrial respiration by dopamine: involvement of H(2)O(2) and hydroxyl radicals but not glutatione-protein-mixed disulfides. J Neurochem 82(1):66–74

    PubMed  CAS  Google Scholar 

  • Graham DG (1978) Oxidative pathway for catecholamines in the genesis of neuromelanin and cytotoxic quinines. Mol Pharmacol 14:633–643

    PubMed  CAS  Google Scholar 

  • Graham DG, Tiffany SM, Bell WR, Gutknecht WF (1978) Autoxidation versus covalent binding of quinines as the mechanism of toxicity of dopamine, 6-hydroxydopamine, and related compounds toward Cl300 neuroblastoma cells in vitro. Mol Pharmacol 14:644–653

    PubMed  CAS  Google Scholar 

  • Heikkila R, Cohen G, Dembiec D (1971) Tetrahydroisoquinoline alkaloids: uptake by rat brain homogenates and inhibition of catecholamine uptake. J Pharmacol Exp Ther 2:250–258

    Google Scholar 

  • Hermida-Ameijeiras A, Mendez-Alvarez E, Sanchez-Iglesias S, Sanmartin-Suarez C et al (2004) Autoxidation and MAO-mediated metabolism of dopamine as a potential cause of oxidative stress: role of ferrous and ferric ions. Neurochem Int 45:103–116

    Article  PubMed  CAS  Google Scholar 

  • Hirata Y, Minami M, Naoi M, Nagatsu T (1990) Studies on the uptake of N-methylisoquinolinium ion into rat striatal slices using high-performance liquid chromatography with fluorimetric detection. J Chromatogr 9;503(1):189–195

    Article  PubMed  CAS  Google Scholar 

  • Homicsko KG, Kertesz I, Radnai B, Toth BE et al (2003) Binding site of salsolinol: its properties in different regions of the brain and the pituitary gland of the rat. Neurochem Int 42(1):19–26

    Article  PubMed  CAS  Google Scholar 

  • Kikuchi K, Nagatsu Y, Makino Y, Mashino T, Otha S, Hirobe M (1991) Metabolism and penetration through blood-brain barrier of parkinsonism-related compounds 1,2,3,4-tetrahydroisoquinoline and 1-methyl-1,2,3,4-tetrahydroisoquinoline. Drug Metab Dispos 19:257–262

    PubMed  CAS  Google Scholar 

  • Kohta R, Kotake Y, Hosoya T, Hiramatsu T et al (2010) 1-Benzyl-1,2,3,4-tetrahydroisoquinoline binds with tubulin beta, a substrate of parkin, and reduces its polyubiquitination. J Neurochem 114(5):1291–1301

    Article  PubMed  CAS  Google Scholar 

  • Kotake Y, Tasaki Y, Makino Y, Otha S, Hirobe M (1995) 1-Benzyl-1,2,3,4-tetrahydroisoquinoline as a parkinsonism-inducing agent: a novel endogenous amine in mouse brain and parkinsonian CSF. J Neurochem 65(6):2633–2638

    Article  PubMed  CAS  Google Scholar 

  • Kotake Y, Yoshida M, Ogawa M, Tasaki Y, Hirobe M, Ohta S (1996) Chronic administration of 1-benzyl-1,2,3,4-tetrahydroisoquinoline, an endogenous amine in mouse brain and parkinsonian CSF. J Neurochem 65:2633–2638

    Article  Google Scholar 

  • Kotake Y, Ohta S, Kanazawa I, Sakurai M (2003) Neurotoxicity of an endogenous brain amine, 1-benzyl-1,2,3,4-tetrahydroisoquinoline, in organotypic slice co-culture of mesencephalon and striatum. Neuroscience 117:63–70

    Article  PubMed  CAS  Google Scholar 

  • Lorenc-Koci E, Śmiałowska M, Antkiewicz-Michaluk L, Gołembiowska K, Bajkowska M, Wolfarth S (2000) Effect of acute and chronic administration of 1,2,3,4-tetrahydroisoquinoline on muscle tone, metabolism of dopamine in the striatum and tyrosine hydroxylase immunocytochemistry in the substantia nigra in rats. Neuroscience 95:1049–1059

    Article  PubMed  CAS  Google Scholar 

  • Maruyama W, Takahashi T, Minami M, Takahashi A, Dostert P, Nagatsu T, Naoi M (1993) Cytotoxicity of dopamine-derived 6,7-dihydroxy-1,2,3,4-tetrahydroisoquinolines. Adv Neurol 60:224–230

    Article  PubMed  CAS  Google Scholar 

  • Maruyama W, Naoi M, Kasamatsu T, Hashizume Y et al (1997) An endogenous dopaminergic neurotoxin, N-methyl-(R )-salsolinol, induces DNA damage in human dopaminergic neuroblastoma SH-SY5Y cells. J Neurochem 69:322–329

    Article  PubMed  CAS  Google Scholar 

  • Michaluk J, Krygowska-Wajs A, Karolewicz B, Antkiewicz-Michaluk L (2002) Role of noradrenergic system in the mechanism of action of endogenous neurotoxin 1,2,3,4-tetrahydroisoquinoline: biochemical and functional studies. Pol J Pharmacol 54:19–25

    PubMed  CAS  Google Scholar 

  • Miller J, Selhub J, Joseph J (1996) Oxidative damage caused by free radicals produced during catecholamine autoxidation: protective effects of O-methylation and melatonin. Free Radic Biol Med 21:241–249

    Article  PubMed  CAS  Google Scholar 

  • Morikawa N, Nakagawa-Hattori Y, Mizuno Y (1996) Effects of dopamine, dimethoxyphenylamine, papaverine, and related compounds on mitochondrial respiration and complex I activity. J Neurochem 66:1174–1181

    Article  PubMed  CAS  Google Scholar 

  • Morikawa N, Naoi M, Maruyama W, Ohta S et al (1998) Effects of various tetrahydroisoquinoline derivatives on mitochondrial respiration and the electron transfer complexes. J Neural Transm 105:677–688

    Article  PubMed  CAS  Google Scholar 

  • Moser A, Kompf D (1992) Presence of methyl-6,7-dihydroxy-1,2,3,6-tetrahydroisoquinolines, derivatives of the neurotoxin isoquinoline, in parkinsonian lumbar CSF. Life Sci 50:1885–1891

    Article  PubMed  CAS  Google Scholar 

  • Nagatsu T, Yoshida M (1988) An endogenous substance of the brain, tetrahydroisoquinoline, produces parkinsonism in primates with decreased dopamine, tyrosine hydroxilase and biopterin in the nigrostriatal regions. Neurosci Lett 87:178–182

    Article  PubMed  CAS  Google Scholar 

  • Naoi M, Matsuura S, Parvez H, Takahashi T et al (1989a) Oxidation of N-methyl-1,2,3,4-tetrahydroisoquinoline into the N-methylisoquinolinium ion by monoamine oxidase. J Neurochem 52:653–655

    Article  PubMed  CAS  Google Scholar 

  • Naoi M, Matsuura S, Takahashi T, Nagatsu T (1989b) An N-methyltransferase in human brain catalyses N-methylation of 1,2,3,4-tetrahydroisoquinoline into N-methyl-1,2,3,4-tetrahydroisoquinoline, a precursor of a dopaminergic neurotoxin N-methylisoquinolinium ion. Bioche Biopys Res Commun 161:1213–1219

    Article  CAS  Google Scholar 

  • Naoi M, Maruyama W, Niwa T, Nagatsu T (1994) Novel toxins and Parkinson’s disease: N-methylation and oxidation as metabolic bioactivation of neurotoxin. J Neural Transm Suppl 41:197–205

    Article  CAS  Google Scholar 

  • Naoi M, Maruyama W, Dostert P, Kohda K et al (1996) A novel enzyme enantio-selectively synthesizes (R )salsolinol a precursor of the dopaminergic neurotoxin, N-methyl(R) sal-solinol. Neurosci Lett 212:183–186

    Article  PubMed  CAS  Google Scholar 

  • Naoi M, Maruyama W, Nagy GM (2004) Dopamine-derived salsolinol derivatives as endogenous monoamine oxidase inhibitors: occurrence, metabolism and function in human brains. Neurotoxicology 2591–2:193–204

    Article  Google Scholar 

  • Okada T, Shimada S, Sato K, Kotake Y, Kawai H, Ohta S, Tohyama M, Nishimura T (1998) Tetrahydropapaveroline and its derivatives inhibit dopamine uptake through dopamine transporter expressed in HEK293 cells. Neurosci Res 30:87–90

    Article  Google Scholar 

  • Patsenka A, Antkiewicz-Michaluk L (2004) Inhibition of rodent brain monoamine oxidase and tyrosine hydroxylase by endogenous compounds - 1,2,3,4-tetrahydro-isoquinoline alkaloids. Pol J Pharmacol 56(6):727–734

    PubMed  CAS  Google Scholar 

  • Sandler M, Carter SB, Hunter KR, Stern GM (1973) Tetrahydroisoquinoline alkaloids: in vivo metabolites of L-DOPA in man. Nature 241:439–443

    Article  PubMed  CAS  Google Scholar 

  • Schapira AH, Mann VM, Cooper JM, Dexter D et al (1990) Anatomic and disease specificity of NADH CoQ1 reductase (complex I) deficiency in Parkinson’s disease. J Neurochem 55:2142–2145

    Article  PubMed  CAS  Google Scholar 

  • Shavali S, Ebadi M (2003) 1-Benzyl-1,2,3,4-tetrahydroisoquinoline (1BnTIQ), an endogenous neurotoxin, induces dopaminergic cell death through apoptosis. Neurotoxicology 24:417–424

    Article  PubMed  CAS  Google Scholar 

  • Shavali S, Carlson EC, Swinscoe JC, Ebadi M (2004) 1-Benzyl-1,2,3,4-tetrahydroisoquinoline, a Parkinsonism-inducing endogenous toxin, increases α-synuclein expression and causes nuclear damage in human dopaminergic cells. J Neurosci Res 76:563–572

    Article  PubMed  CAS  Google Scholar 

  • Storch A, Kaftan A, Burkhardt K, Schwarz J (2000) 1-Methyl-6,7,-dihydroxy-1,2,3,4-tetrahydroisoquinoline (salsolinol) is toxic to dopaminergic neuroblastoma SH-SY5Y cells via impairment of cellular energy metabolism. Brain Res 855:67–75

    Article  PubMed  CAS  Google Scholar 

  • Vetulani J, Nalepa I, Antkiewicz-Michaluk L, Sansone M (2001) Opposite effect of simple tetrahydroisoquinolines on amphetamine- and morphine-stimulated locomotor activity in mice. J Neural Transm 108:513–526

    Article  PubMed  CAS  Google Scholar 

  • Vinogradov AD, Goloveshkina VG, Gavrikova EV (1976) Regulation of succinate dehydrogenase: does the membrane environment change the catalytic activity of the enzyme? Adv Enzyme Regul 15:23–31

    Article  PubMed  CAS  Google Scholar 

  • Wąsik A, Romańska I, Antkiewicz-Michaluk L (2009) 1-Benzyl-1,2,3,4-tetrahydroisoquinoline, an endogenous parkinsonism-inducing toxin, strongly potentiates MAO-dependent dopamine oxidation and impairs dopamine release: ex vivo and in vivo neurochemical studies. Neurotox Res 15:15–23

    Article  PubMed  Google Scholar 

  • Whaley WM, Govindachari TR (1951) The Pictet-Spengler synthesis of tetrahydroisoquinolines and related compounds. Org React 6:74

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

Thanks are due to Dr Jan Boksa (Department of Medicinal Chemistry, Institute of Pharmacology PAS, Krakow, Poland) for the synthesis of 1BnTIQ. The study was supported by the statutory funds of the Institute of Pharmacology, Polish Academy of Sciences, Krakow, Poland.

Author information

Authors and Affiliations

  1. Department of Neurochemistry, Institute of Pharmacology Polish Academy of Sciences, 31-343, Kraków, Poland

    Agnieszka Wąsik & Lucyna Antkiewicz-Michaluk

Authors
  1. Agnieszka Wąsik
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Lucyna Antkiewicz-Michaluk
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Agnieszka Wąsik .

Editor information

Editors and Affiliations

  1. Smetna 12, Krakow, 31-343, Poland

    Lucyna Antkiewicz-Michaluk

  2. , Departments of Psychiatry, Charité-University Medicine, Berlin, 10117, Germany

    Hans Rommelspacher

Rights and permissions

Reprints and permissions

Copyright information

© 2012 Springer Science+Business Media, LLC

About this chapter

Cite this chapter

Wąsik, A., Antkiewicz-Michaluk, L. (2012). Isoquinolines as Neurotoxins: Action and Molecular Mechanism. In: Antkiewicz-Michaluk, L., Rommelspacher, H. (eds) Isoquinolines And Beta-Carbolines As Neurotoxins And Neuroprotectants. Current Topics in Neurotoxicity, vol 1. Springer, Boston, MA. https://doi.org/10.1007/978-1-4614-1542-8_2

Download citation

Publish with us

Policies and ethics

Search

Navigation