Neurotoxicity Research

, Volume 36, Issue 4, pp 653–668 | Cite as

Not Just from Ethanol. Tetrahydroisoquinolinic (TIQ) Derivatives: from Neurotoxicity to Neuroprotection

  • Alessandra T. PeanaEmail author
  • Valentina Bassareo
  • Elio AcquasEmail author
Review Article


The 1,2,3,4-tetrahydroisoquinolines (TIQs) are compounds frequently described as alkaloids that can be found in the human body fluids and/or tissues including the brain. In most circumstances, TIQs may be originated as a consequence of reactions, known as Pictet-Spengler condensations, between biogenic amines and electrophilic carbonyl compounds, including ethanol’s main metabolite, acetaldehyde. Several TIQs may also be synthesized enzymatically whilst others may be formed in the body as by-products of other compounds including TIQs themselves. The biological actions of TIQs appear critically dependent on their metabolism, and nowadays, among TIQs, 1-methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline (salsolinol), N-methyl-1-methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline (N-methyl-(R)-salsolinol), 1-[(3,4-dihydroxyphenyl)methyl]-1,2,3,4-tetrahydroisoquinoline-6,7-diol (norlaudanosoline or tetrahydropapaveroline or THP) and 1-benzyl-1,2,3,4-tetrahydroisoquinoline (1BnTIQ) are considered as those endowed with the most potent neurotoxic actions. However, it remains to be established whether a continuous exposure to TIQs or to their metabolites might carry toxicological consequences in the short- or long-term period. Remarkably, recent findings suggest that some TIQs such as (1-[(4-hydroxyphenyl)methyl]-1,2,3,4-tetrahydroisoquinoline-6,7-diol) (higenamine) and 1-methyl-1,2,3,4-tetrahydroisoquinoline (1-MeTIQ) as well as N-methyl-tetrahydroisoquinoline (N-methyl-TIQ) exert unique neuroprotective and neurorestorative actions. The present review article provides an overview on these aspects of TIQs and summarizes those that presently appear the most significant highlights on this puzzling topic.


Tetrahydroisoquinolines Ethanol Neurotoxicity Neuroprotection 



  1. Abe K, Saitoh T, Horiguchi Y, Utsunomiya I, Taguchi K (2005) Synthesis and neurotoxicity of tetrahydroisoquinoline derivatives for studying Parkinnson’s disease. Biol Pharm Bull 28:1355–1362PubMedGoogle Scholar
  2. Ahmad W, Jantan I, Bukhari SN (2016) Tinospora crispa (L.) Hook. F. & Thomson: a review of its ethnobotanical, phytochemical, and pharmacological aspects. Front Pharmacol 7:59PubMedPubMedCentralGoogle Scholar
  3. Amit Z, Brown ZW, Rockman GE (1977) Possible involvement of acetaldehyde, norepinephrine and their tetrahydroisoquinoline derivatives in the regulation of ethanol self-administration. Drug Alcohol Depend 2(5–6):495–500PubMedGoogle Scholar
  4. Antkiewicz-Michaluk L (2002) Endogenous risk factors in Parkinson’s disease: dopamine and tetrahydroisoquinolines. Pol J Pharmacol 54:567–572PubMedGoogle Scholar
  5. Antkiewicz-Michaluk L, Michaluk J, Mokrosz M, Romanska I, Lorenc-Koci E, Ohta S, Vetulani J (2001) Different action on dopamine catabolic pathways of two endogenous 1,2,3,4-tetrahydroisoquinolines with similar antidopaminergc properties. J Neurochem 78:100–108PubMedGoogle Scholar
  6. Antkiewicz-Michaluk L, Karolewicz B, Romañska I, Michaluk J, Bojarski A, Vetulani J (2003) 1-Methyl-1,2,3,4-tetrahydroisoquinoline protects against rotenone-induced mortality and biochemical changes in rat brain. Eur J Pharmacol 466:263–269PubMedGoogle Scholar
  7. Antkiewicz-Michaluk L, Wardas J, Michaluk J, Romañska I, Bojarski A, Vetulani J (2004) Protective effect of 1-methyl-1,2,3,4-tetrahydroisoquinoline against dopaminergic neurodegeneration in the extrapyramidal structures produced by intracerebral injection of rotenone. Int J Neuropsychopharmacol 7:155–163PubMedGoogle Scholar
  8. Antkiewicz-Michaluk L, Wąsik A, Michaluk J (2014) 1-Methyl-1,2,3,4-tetrahydroisoquinoline, an endogenous amine with unexpected mechanism of action: new vistas of therapeutic application. Neurotox Res 25(1):1–12PubMedGoogle Scholar
  9. Antkiewicz-Michaluk L, Romańska I, Wąsik A, Michaluk J (2017) Antidepressant-like effect of the endogenous neuroprotective amine, 1MeTIQ in clonidine-induced depression: behavioral and neurochemical studies in rats. Neurotox Res 32(1):94–106. CrossRefPubMedPubMedCentralGoogle Scholar
  10. Bai G, Yang Y, Shi Q, Liu Z, Zhang Q, Zhu YY (2008) Identification of higenamine in Radix Aconiti Lateralis Preparata as a beta2-adrenergic receptor agonist. Acta Pharmacol Sin 29:1187–1194PubMedGoogle Scholar
  11. Berger T, French ED, Siggins GR, Shier WT, Bloom FE (1982) Ethanol and some tetrahydroisoquinolines alter the discharge of cortical and hippocampal neurons: relationship to endogenous opioids. Pharmacol Biochem Behav 17(4):813–821PubMedGoogle Scholar
  12. Berríos-Cárcamo P, Quintanilla ME, Herrera-Marschitz M, Vasiliou V, Zapata-Torres G, Rivera-Meza M (2017) Racemic salsolinol and its enantiomers act as agonists of the μ-opioid receptor by activating the Gi protein-adenylate cyclase pathway. Front Behav Neurosci 10:253PubMedPubMedCentralGoogle Scholar
  13. Betarbet R, Sherer TB, Di Monte DA, Greenamyre JT (2002) Mechanistic approaches to Parkinson’s disease pathogenesis. Brain Pathol 12:499–510PubMedGoogle Scholar
  14. Blum K (1988) Narcotic antagonism of seizures induced by a dopamine-derived tetrahydroisoquinoline alkaloid. Experientia 44(9):751–753PubMedGoogle Scholar
  15. Brochmann-Hanssen E (1984) A second pathway for the terminal steps in the biosynthesis of morphine. Planta Med 50(4):343–345PubMedGoogle Scholar
  16. Cashaw JL (1993) Tetrahydropapaveroline in brain regions of rats after acute ethanol administration. Alcohol 10:133–138PubMedGoogle Scholar
  17. Chen X, Zheng X, Ali S, Guo M, Zhong R, Chen Z, Zhang Y, Qing H, Deng Y (2018) Isolation and sequencing of salsolinol synthase, an enzyme catalyzing salsolinol biosynthesis. ACS Chem Neurosci 30:1388–1398. CrossRefGoogle Scholar
  18. Chiba H, Sato H, Abe K, Saito T, Horiguchi Y, Nojima H, Taguchi K (2015) Effects of 1,2,3,4-tetrahydroisoquinoline derivatives on dopaminergic spontaneous discharge in substantia nigra neurons in rats. Pharmacology 95:87e94Google Scholar
  19. Chiueh CC, Markey SP, Burns RS, Johannessen JN, Jacobowitz DM, Kopin IJ (1984) Neurochemical and behavioral effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in rat, guinea pig, and monkey. Psychopharmacol Bull 20(3):548–553PubMedGoogle Scholar
  20. Cohen G, Collins M (1970) Alkaloids from catecholamines in adrenal tissue: possible role in alcoholism. Science 167(3926):1749–1751PubMedGoogle Scholar
  21. Cohen PA, Travis JC, Keizers PHJ, Boyer FE, Venhuis BJ (2019) The stimulant higenamine in weight loss and sports supplements. Clin Toxicol (Phila) 57(2):125–130. CrossRefGoogle Scholar
  22. Collins MA (2004) Tetrahydropapaveroline in Parkinson’s disease and alcoholism: a look back in honor of Merton Sandler. Neurotoxicology 25:117–120PubMedGoogle Scholar
  23. Collins MA, Bigdeli MG (1975) Tetrahydroisoquinolines in vivo. I. Rat brain formation of salsolinol, a condensation product of dopamine and acetaldehyde, under certain conditions during ethanol intoxication. Life Sci 16(4):585–601PubMedGoogle Scholar
  24. Collins MA, Neafsey EJ (2002) Potential neurotoxic “agents provocateurs” in Parkinson’s disease. Neurotoxicol Teratol 24:571–577PubMedGoogle Scholar
  25. Collins MA, Nijm WP, Borge GF, Teas G, Goldfarb C (1979) Dopamine-related tetrahydroisoquinolines: significant urinary excretion by alcoholics after alcohol consumption. Science 206(4423):1184–1186PubMedGoogle Scholar
  26. Collins MA, Ung-Chhun N, Cheng BY, Pronger D (1990) Brain and plasma tetrahydroisoquinolines in rats: effects of chronic ethanol intake and diet. J Neurochem 55(5):1507–1514PubMedGoogle Scholar
  27. Collins MA, Neafsey EJ, Mukamal KJ, Gray MO, Parks DA, Das DK, Korthuis RJ (2009) Alcohol in moderation, cardioprotection, and neuroprotection: epidemiological considerations and mechanistic studies. Alcohol Clin Exp Res 33:206–219PubMedGoogle Scholar
  28. Correa M, Salamone JD, Segovia KN, Pardo M, Longoni R, Spina L, Peana AT, Vinci S, Acquas E (2012) Piecing together the puzzle of acetaldehyde as a neuroactive agent. Neurosci Biobehav Rev 36(1):404–430. CrossRefPubMedGoogle Scholar
  29. Davis V, Walsh MJ (1970) Alcohol, amines, and alkaloids: a possible biochemical basis for alcohol addiction. Science 167:1005–1007PubMedGoogle Scholar
  30. Diamond A, Desgagné-Penix I (2016) Metabolic engineering for the production of plant isoquinoline alkaloids. Plant Biotechnol J 14(6):1319–1328. CrossRefPubMedGoogle Scholar
  31. Diamond I, Yao L (2015) From ancient Chinese medicine to a novel approach to treat cocaine addiction. CNS Neurol Disord Drug Targets 14(6):716–726PubMedGoogle Scholar
  32. Dostert P, Strolin Benedetti M, Dordain G (1988) Dopamine-derived alkaloids in alcoholism and in Parkinson’s and Huntington’s diseases. J Neural Transm 74:61–74PubMedGoogle Scholar
  33. ffrench-Mullen JM, Rogawski MA (1989) Interaction of phencyclidine with voltage-dependent potassium channels in cultured rat hippocampal neurons: comparison with block of the NMDA receptor-ionophore complex. J Neurosci 9(11):4051–4061PubMedPubMedCentralGoogle Scholar
  34. Ghirga F, Quaglio D, Ghirga P, Berardozzi S, Zappia G, Botta B, Mori M, D'Acquarica I (2016) Occurrence of enantioselectivity in nature: the case of (S)-norcoclaurine. Chirality 28(3):169–180. CrossRefPubMedGoogle Scholar
  35. 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(1):79–78PubMedGoogle Scholar
  36. Greenberg RS, Cohen G (1973) Tetrahydroisoquinoline alkaloids: stimulated secretion from the adrenal medulla. J Pharmacol Exp Ther 184(1):119–128PubMedGoogle Scholar
  37. Grobe N, Lamshöft M, Orth RG, Dräger B, Kutchan TM, Zenk MH, Spiteller M (2010) Urinary excretion of morphine and biosynthetic precursors in mice. Proc Natl Acad Sci U S A 107(18):8147–8152. CrossRefPubMedPubMedCentralGoogle Scholar
  38. Grucza K, Kwiatkowska D, Kowalczyk K, Wicka M, Szutowski M, Chołbiński P (2017) Analysis for higenamine in urine by means of ultra-high-performance liquid chromatography-tandem mass spectrometry: interpretation of results. Drug Test Anal 30:1017–1024. CrossRefGoogle Scholar
  39. Haber H, Roske I, Rottmann M, Georgi M, Melzig MF (1997) Alcohol induces formation of morphine precursors in the striatum of rats. Life Sci 60(2):79–89PubMedGoogle Scholar
  40. Hagel JM, Facchini PJ (2013) Benzylisoquinoline alkaloid metabolism: a century of discovery and a brave new world. Plant Cell Physiol 54:647–672PubMedGoogle Scholar
  41. Herraiz T (2016) N-methyltetrahydropyridines and pyridinium cations as toxins and comparison with naturally-occurring alkaloids. Food Chem Toxicol 97:23–39PubMedGoogle Scholar
  42. Hipólito L, Sánchez-Catalán MJ, Granero L, Polache A (2009) Local salsolinol modulates dopamine extracellular levels from rat nucleus accumbens: shell/core differences. Neurochem Int 55(4):187–192. CrossRefPubMedGoogle Scholar
  43. Hipólito L, Sánchez-Catalán MJ, Zornoza T, Polache A, Granero L (2010) Locomotor stimulant effects of acute and repeated intrategmental injections of salsolinol in rats: role of mu-opioid receptors. Psychopharmacology 209(1):1–11. CrossRefPubMedGoogle Scholar
  44. Hipólito L, Sánchez-Catalán MJ, Martí-Prats L, Granero L, Polache A (2012) Revisiting the controversial role of salsolinol in the neurobiological effects of ethanol: old and new vistas. Neurosci Biobehav Rev 36(1):362–378PubMedGoogle Scholar
  45. Israel Y, Karahanian E, Ezquer F, Morales P, Ezquer M, Rivera-Meza M, Herrera-Marschitz M, Quintanilla ME (2017) Acquisition, maintenance and relapse-like alcohol drinking: lessons from the UChB rat line. Front Behav Neurosci 11:57PubMedPubMedCentralGoogle Scholar
  46. Jackson-Lewis V, Przedborski S (2007) Protocol for the MPTP mouse model of Parkinson’s disease. Nat Protoc 2(1):141–151PubMedGoogle Scholar
  47. Jellinger KA (2017) Dementia with Lewy bodies and Parkinson’s disease-dementia: current concepts and controversies. J Neural Transm 8:615–650. CrossRefGoogle Scholar
  48. Kashiwada Y, Aoshima A, Ikeshiro Y, Chen YP, Furukawa H, Itoigawa M, Fujioka T, Mihashi K, Cosentino LM, Morris-Natschke SL, Lee KH (2005) Anti-HIV benzylisoquinoline alkaloids and flavonoids from the leaves of Nelumbo nucifera, and structure-activity correlations with related alkaloids. Bioorg Med Chem 13(2):443–448PubMedGoogle Scholar
  49. Katagiri N, Chida S, Abe K, Nojima H, Kitabatake M, Hoshi K, Horiguchi Y, Taguchi K (2010) Preventative effects of 1,3-dimethyl- and 1,3-dimethyl-N-propargyl-1,2,3,4-tetrahydroisoquinoline on MPTP-induced Parkinson's disease-like symptoms in mice. Brain Res 1321:133–142PubMedGoogle Scholar
  50. Kato E, Kimura S, Kawabata J (2017) Ability of higenamine and related compounds to enhance glucose uptake in L6 cells. Bioorg Med Chem 25(24):6412–6416. CrossRefPubMedGoogle Scholar
  51. Kaut O, Schmitt I, Wüllner U (2012) Genome-scale methylation analysis of Parkinson’s disease patients’ brains reveals DNA hypomethylation and increased mRNA expression of cytochrome P450 2E1. Neurogenetics 13:87–91. CrossRefPubMedGoogle Scholar
  52. Kennedy J (2008) Mutasynthesis, chemobiosynthesis, and back to semi-synthesis: combining synthetic chemistry and biosynthetic engineering for diversifying natural products. Nat Prod Rep 25(1):25–34PubMedGoogle Scholar
  53. Kohta R, Kotake Y, Hosoya T, Hiramatsu T, Otsubo Y, Koyama H, Hirokane Y, Yokoyama Y, Ikeshoji H, Oofusa K, Suzuki M, Ohta S (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. CrossRefPubMedGoogle Scholar
  54. Kosuge T, Yokota M (1976) Letter: studies on cardiac principle of aconite root. Chem Pharm Bull 24(1):176–178PubMedGoogle Scholar
  55. Kotake Y, Tasaki Y, Makino Y, Ohta 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 65:2633–2638PubMedGoogle Scholar
  56. Kotake Y, Sekiya Y, Okuda K, Ohta S (2014) Detection of a novel neurotoxic metabolite of Parkinson’s disease-related neurotoxin, 1-benzyl-1,2,3,4-tetrahydroisoquinoline. J Toxicol Sci 39(5):749–754PubMedGoogle Scholar
  57. Krygowska-Wajs A, Szczudlik A, Antkiewicz-Michaluk L, Romańska I, Vetulani J (1997) Salsolinol, 3-O-methyl-dopa and homovanillic acid in the cerebrospinal fluid of Parkinson patients. Neurol Neurochir Pol 31(5):875–885PubMedGoogle Scholar
  58. Kukula-Koch W, Kruk-Słomka M, Stępnik K, Szalak R, Biała G (2017) The evaluation of pro-cognitive and antiamnestic properties of berberine and magnoflorine isolated from barberry species by centrifugal partition chromatography (CPC), in relation to QSAR modelling. Int J Mol Sci 18(12)PubMedCentralGoogle Scholar
  59. Kurnik-Łucka M, Panula P, Bugajski A, Gil K (2018) Salsolinol: an unintelligible and double-faced molecule-lessons learned from in vivo and in vitro experiments. Neurotox Res 33(2):485–514. CrossRefPubMedGoogle Scholar
  60. Lee J, Ramchandani VA, Hamazaki K, Engleman EA, McBride WJ, Li TK, Kim HY (2010) A critical evaluation of influence of ethanol and diet on salsolinol enantiomers in humans and rats. Alcohol Clin Exp Res 34(2):242–250. CrossRefPubMedGoogle Scholar
  61. Libondi T, Ragone R, Vincenli D, Stiuso P, Auricchio G, Collona G (1994) In vitro cross-linking of calf lens alpha-crystallin by malondialdehyde. Int J Pept Protein Res 44:342–347PubMedGoogle Scholar
  62. Lorenc-Koci E, Antkiewicz-Michaluk L, Wardas J, Zapa M, Wieroñska J (2004) Effect of 1,2,3,4-tetrahyd-roisoquinoline administration under conditions of CYP2D inhibition on dopamine metabolism, level of tyrosine hydroxylase protein and the binding of [H] GBR 12 935 to dopamine transporter in the rat nigrostriatal dopaminergic system. Brain Res 1009:67–81PubMedGoogle Scholar
  63. Makino Y, Ohta S, Tachikawa O, Hirobe M (1988) Presence of tetrahydroisoquinoline and 1-methyl-tetrahydro-isoquinoline in foods. Compounds related to Parkinson’s disease. Life Sci 43:373–378PubMedGoogle Scholar
  64. Makino Y, Tasaki Y, Ohta S, Hirobe M (1990) Confirmation of the enantiomers of 1-methyl-1,2,3,4-tetrahydroisoquinoline in the mouse brain and foods applying gas chromatography/mass spectrometry with negative ion chemical ionization. Biomed Environ Mass Spectrom 19:415–419PubMedGoogle Scholar
  65. Mao J, Ma H, Xu Y, Su Y, Zhu H, Wang R, Lin F, Qing H, Deng Y (2013) Increased levels of monoamine-derived potential neurotoxins in fetal rat brain exposed to ethanol. Neurochem Res 38(2):356–363. CrossRefPubMedGoogle Scholar
  66. Maruyama W, Strolin-Benedetti M, Naoi M (2000) N-methyl(R)salsolinol and a neutral N-methyltransferase as pathogenic factors in Parkinson’s disease. Neurobiology 8:55–68PubMedGoogle Scholar
  67. Matsubara K, Fukushima S, Akane A, Kobayashi S, Shiono H (1992) Increased urinary morphine, codeine and tetrahydropapaveroline in parkinsonian patient undergoing L-3,4-dihydroxyphenylalanine therapy: a possible biosynthetic pathway of morphine from L-3,4-dihydroxyphenylalanine in humans. J Pharmacol Exp Ther 260(3):974–978PubMedGoogle Scholar
  68. Matsuzawa S, Suzuki T, Misawa M (2000) Involvement of mu-opioid receptor in the salsolinol-associated place preference in rats exposed to conditioned fear stress. Alcohol Clin Exp Res 24:366–372PubMedGoogle Scholar
  69. McCoy JG, Strawbridge C, McMurtrey KD, Kane VB, Ward CP (2003) A re-evaluation of the role of tetrahydropapaveroline in ethanol consumption in rats. Brain Res Bull 60(1-2):59–65PubMedGoogle Scholar
  70. McNaught KS, Carrupt PA, Altomare C, Cellamare S, Carotti A, Testa B, Jenner P, Marsden CD (1998) Isoquinoline derivatives as endogenous neurotoxins in the aetiology of Parkinson’s disease. Biochem Pharmacol 56(8):921–933PubMedGoogle Scholar
  71. Melis M, Carboni E, Caboni P, Acquas E (2015) Key role of salsolinol in ethanol actions on dopamine neuronal activity of the posterior ventral tegmental area. Addict Biol 20:182–193PubMedGoogle Scholar
  72. Morikawa N, Nakagawa-Hattori Y, Mizuno Y (1996) Effect of dopamine, dimethoxyphenylethylamine, papaverine, and related compounds on mitochondrial respiration and complex I activity. J Neurochem 66(3):1174–1181PubMedGoogle Scholar
  73. Morikawa N, Naoi M, Maruyama W, Ohta S, Kotake Y, Kawai H, Niwa T, Dostert P, Mizuno Y (1998) Effects of various tetrahydroisoquinoline derivatives on mitochondrial respiration and the electron transfer complexes. J Neural Transm 105(6–7):677–688PubMedGoogle Scholar
  74. Müller T, Sällström Baum S, Häussermann P, Przuntek H, Rommelspacher H, Kuhn W (1999) R- and S-salsolinol are not increased in cerebrospinal fluid of parkinsonian patients. J Neurol Sci 164(2):158–162PubMedGoogle Scholar
  75. Myers WD, Ng KT, Singer G, Smythe GA, Duncan MW (1985) Dopamine and salsolinol levels in rat hypothalami and striatum after schedule-induced self-injection (SISI) of ethanol and acetaldehyde. Brain Res 358(1-2):122–128PubMedGoogle Scholar
  76. Nagatsu T (1997) Isoquinoline neurotoxins in the brain and Parkinson’s disease. Neurosci Res 29:99–111PubMedGoogle Scholar
  77. Naoi M, Maruyama W, Dostert P, Kohda K, Kaiya T (1996) A novel enzyme enantio-selectively synthesizes (R) salsolinol, a precursor of a dopaminergic neurotoxin, N-methyl(R)salsolinol. Neurosci Lett 212(3):183–186PubMedGoogle Scholar
  78. Naoi M, Maruyama W, Akao Y, Yi H (2002) Dopamine-derived endogenous N-methyl-(R)-salsolinol: its role in Parkinson’s disease. Neurotoxicol Teratol 24:579–591PubMedGoogle Scholar
  79. Naoi M, Maruyama W, Nagy GM (2004) Dopamine-derived salsolinol derivatives as endogenous monoamine oxidase inhibitors: occurrence, metabolism and function in human brains. Neurotoxicology 25(1–2):193–204PubMedGoogle Scholar
  80. Nowicki M, Tran S, Chatterjee D, Gerlai R (2015) Inhibition of phosphorylated tyrosine hydroxylase attenuates ethanol-induced hyperactivity in adult zebrafish (Danio rerio). Pharmacol Biochem Behav 138:32–39PubMedPubMedCentralGoogle Scholar
  81. Olanow CW, Tatton WG (1999) Etiology and pathogenesis of Parkinson’s disease. Annu Rev Neurosci 22:123–144PubMedGoogle Scholar
  82. Origitano T, Hannigan J, Collins MA (1981) Rat brain salsolinol and blood-brain barrier. Brain Res 224:446–451PubMedGoogle Scholar
  83. Ortwine DF, Malone TC, Bigge CF, Drummond JT, Humblet C, Johnson G, Pinter GW (1992) Generation of N-methyl-D-aspartate agonist and competitive antagonist pharmacophore models. Design and synthesis of phosphonoalkyl-substituted tetrahydroisoquinolines as novel antagonists. J Med Chem 35(8):1345–1370PubMedGoogle Scholar
  84. Park JE, Kang YJ, Park KM, Lee YS, Kim HJ, Seo HG (2006) Enantiomers of higenamine inhibit LPS-induced iNOS in a macrophage cell line and improve the survival of mice with experimental endotoxemia. Int Immunopharmacol 6:226–233PubMedGoogle Scholar
  85. Patsenka A, Antkiewicz-Michaluk L (2004) Inhibition of rodent brain monoamine oxidase and tyrosine hydroxylase by endogenous compounds-1,2,3,4-tetrahydroisoquinoline alkaloids. Pol J Pharmacol 56:727–734PubMedGoogle Scholar
  86. Pavey L, Sparks P, Churchill S (2018) Proscriptive vs. prescriptive health recommendations to drink alcohol within recommended limits: effects on moral norms, reactance, attitudes, intentions and behaviour change. Alcohol Alcohol. PubMedGoogle Scholar
  87. Peana AT, Porcheddu V, Bennardini F, Carta A, Rosas M, Acquas E (2015) Role of ethanol-derived acetaldehyde in operant oral self-administration of ethanol in rats. Psychopharmacology 232(23):4269–4276PubMedGoogle Scholar
  88. Peana AT, Rosas M, Porru S, Acquas E (2016) From ethanol to salsolinol: role of ethanol metabolites in the effects of ethanol. J Exp Neurosci 10:137–146PubMedPubMedCentralGoogle Scholar
  89. Peana AT, Sánchez-Catalán MJ, Hipólito L, Rosas M, Porru S, Bennardini F, Romualdi P, Caputi FF, Candeletti S, Polache A, Granero L, Acquas E (2017) Mystic acetaldehyde: the never-ending story on alcoholism. Front Behav Neurosci 11:81PubMedPubMedCentralGoogle Scholar
  90. Perry TL, Jones K, Hansen S (1988) Tetrahydroisoquinoline lacks dopaminergic nigrostriatal neurotoxicity in mice. Neurosci Lett 85:101–110PubMedGoogle Scholar
  91. Pertel RH, Greenwald JE, Schwarz R, Wong L, Bianchine J (1980) Opiate receptor binding and analgesic effects of the tetrahydroisoquinolines salsolinol and tetrahydropapaveroline. Res Commun Chem Pathol Pharmacol 27:3–16Google Scholar
  92. Poli A, Marangoni F, Avogaro A, Barba G, Bellentani S, Bucci M, Cambieri R, Catapano AL, Costanzo S, Cricelli C, de Gaetano G, Di Castelnuovo A, Faggiano P, Fattirolli F, Fontana L, Forlani G, Frattini S, Giacco R, La Vecchia C, Lazzaretto L, Loffredo L, Lucchin L, Marelli G, Marrocco W, Minisola S, Musicco M, Novo S, Nozzoli C, Pelucchi C, Perri L, Pieralli F, Rizzoni D, Sterzi R, Vettor R, Violi F, Visioli F (2013) Moderate alcohol use and health: a consensus document. Nutr Metab Cardiovasc Dis 23(6):487–504. CrossRefPubMedGoogle Scholar
  93. Pyo MK, Lee D-H, Kim D-H, Lee J-H, Moon J-C, Chang KC, Yun-Choi HS (2008) Enantioselective synthesis of (R)-(+)- and (S)-(−)-higenamine and their analogues with effects on platelet aggregation and experimental animal model of disseminated intravascular coagulation. Bioorg Med Chem Lett 18:4110–4114PubMedGoogle Scholar
  94. Quintanilla ME, Rivera-Meza M, Berrios-Cárcamo PA, Bustamante D, Buscaglia M, Morales P, Karahanian E, Herrera-Marschitz M, Israel Y (2014) Salsolinol, free of isosalsolinol, exerts ethanol-like motivational/sensitization effects leading to increases in ethanol intake. Alcohol 48(6):551–559. CrossRefPubMedGoogle Scholar
  95. Samanani N, Facchini PJ (2001) Isolation and partial characterization of norcoclaurine synthase, the first committed step in benzylisoquinoline alkaloid biosynthesis, from opium poppy. Planta 213(6):898–906PubMedGoogle Scholar
  96. Sandler M, Carter SB, Hunter KR, Stern GM (1973) Tetrahydroisoquinoline alkaloids: in vivo metabolites of L-dopa in man. Nature 241(5390):439–443PubMedGoogle Scholar
  97. Sango K, Maruyama W, Matsubara K, Dostert P, Minami C, Kawai M, Naoi M (2000) Enantio-selective occurrence of (S)-tetrahydropapaveroline in human brain. Neurosci Lett 283:224–226PubMedGoogle Scholar
  98. Schubert D, Behl C, Lesley R, Brack A, Dargusch R, Sagara Y, Kimua H (1995) Amyloid peptides are toxic via a common oxidative mechanism. Proc Natl Acad Sci U S A 92:1989–1993PubMedPubMedCentralGoogle Scholar
  99. Shea KM, Hewitt AJ, Olmstead MC, Brien JF, Reynolds JN (2012) Maternal ethanol consumption by pregnant Guinea pigs causes neurobehavioral deficits and increases ethanol preference in offspring. Behav Pharmacol 23:105–112PubMedGoogle Scholar
  100. Shin MH, Jang JH, Surh YJ (2004) Potential roles of NF-kappaB and ERK1/2 in cytoprotection against oxidative cell death induced by tetrahydropapaveroline. Free Radic Biol Med 36:1185–1194PubMedGoogle Scholar
  101. Singh IP, Shah P (2017) Tetrahydroisoquinolines in therapeutics: a patent review (2010-2015). Expert Opin Ther Pat 27(1):17–36PubMedGoogle Scholar
  102. Sjöquist B, Magnuson E (1980) Analysis of salsolinol and salsoline in biological samples using deuterium-labelled internal standards and gas chromatography-mass spectrometry. J Chromatogr 183:17–24PubMedGoogle Scholar
  103. Smargiassi A, Biagini C, Mutti A, Bergamaschi E, Bacchini A, Alinovi R, Cavazzini S (1994) Multiple interferences on catecholamine metabolism by tetrahydroisoquinolines (TIQs). Neurotoxicology 15(3):765–768PubMedGoogle Scholar
  104. Song Y, Feng Y, Leblanc MH, Castagloni N, Liu YM (2006) 1-Benzyl-1, 2,3,4-tetrahydroisoquinoline passes through the blood-brain barrier of rat brain: an in vivo microdialysis study. Neurosci Lett 395:63–66PubMedGoogle Scholar
  105. Sourkes TL (1971) Actions of levodopa and dopamine in the central nervous system. JAMA 218(13):1909–1911PubMedGoogle Scholar
  106. Stefano GB, Ptáček R, Kuželová H, Kream RM (2012) Endogenous morphine: up-to-date review 2011. Folia Biol (Praha) 58(2):49–56Google Scholar
  107. Storch A, Ott S, Hwang YI, Ortmann R, Hein A, Frenzel S, Matsubara K, Ohta S, Wolf HU, Schwarz J (2002) Selective dopaminergic neurotoxicity of isoquinoline derivatives related to Parkinson’s disease: studies using heterologous expression systems of the dopamine transporter. Biochem Pharmacol 63(5):909–920PubMedGoogle Scholar
  108. Surh YJ, Kim HJ (2010) Neurotoxic effects of tetrahydroisoquinolines and underlying mechanisms. Exp Neurobiol 19(2):63–70. CrossRefPubMedPubMedCentralGoogle Scholar
  109. Székács D, Bodnár I, Mravec B, Kvetnansky R, Vizi ES, Nagy GM, Fekete MI (2007) The peripheral noradrenergic terminal as possible site of action of salsolinol as prolactoliberin. Neurochem Int 50:427–434PubMedGoogle Scholar
  110. Turner AJ, Baker KM, Algeri S, Erigerio A, Garattini S (1974) Tetrahydropapaveroline: formation in vivo and in vitro in rat brain. Life Sci 14(11):2247–2257PubMedGoogle Scholar
  111. Vaglini F, Viaggi C, Piro V, Pardini C, Gerace C, Scarselli M, Corsini GU (2013) Acetaldehyde and parkinsonism: role of CYP450 2E1. Front Behav Neurosci 7:71. eCollection 2013CrossRefPubMedPubMedCentralGoogle Scholar
  112. Vimolmangkang S, Deng X, Owiti A, Meelaph T, Ogutu C, Han Y (2016) Evolutionary origin of the NCSI gene subfamily encoding norcoclaurine synthase is associated with the biosynthesis of benzylisoquinoline alkaloids in plants. Sci Rep 6:26323. CrossRefPubMedPubMedCentralGoogle Scholar
  113. von Bohlen und Halbach O, Schober A, Krieglstein K (2004) Genes, proteins, and neurotoxins involved in Parkinson’s disease. Prog Neurobiol 73:151–177Google Scholar
  114. Wang X, Li X, Jingfen W, Fei D, Mei P (2019a) Higenamine alleviates cerebral ischemia-reperfusion injury in rats. Front Biosci (Landmark Ed) 24:859–869Google Scholar
  115. Wang Y, Geng J, Jiang M, Li C, Han Y, Jiang J (2019b) The cardiac electrophysiology effects of higenamine in guinea pig heart. Biomed Pharmacother 109:2348–2356. CrossRefPubMedGoogle Scholar
  116. Wąsik A, Antkiewicz-Michaluk L (2017) The mechanism of neuroprotective action of natural compounds. Pharmacol Rep 69(5):851–860PubMedGoogle Scholar
  117. Wąsik A, Antkiewicz-Michulak L (2012) Isoquinolines as neurotoxins: action and molecular mechansim. In: Antkiewicz-Michaluk L, Rommeslpacher H (eds) Isoquinolines and β-carbolines as neurotoxins and neuroprotectants. New vistas in Parkinson’s disease therapy. Springer, Berlin, p 31e43Google Scholar
  118. Wąsik A, Romańska I, Michaluk J, Antkiewicz-Michaluk L (2012) Comparative behavioral and neurochemical studies of R- and S-1-methyl-1,2,3,4-tetrahydroisoquinoline stereoisomers in the rat. Pharmacol Rep 64(4):857–869PubMedGoogle Scholar
  119. Wąsik A, Romańska I, Michaluk J, Kajta M, Antkiewicz-Michaluk L (2014) 1-Benzyl-1,2,3,4-tetrahydroisoquinoline, an endogenous neurotoxic compound, disturbs the behavioral and biochemical effects of L-DOPA: in vivo and ex vivo studies in the rat. Neurotox Res 26(3):240–254PubMedPubMedCentralGoogle Scholar
  120. Wąsik A, Romańska I, Zelek-Molik A, Antkiewicz-Michaluk L (2018a) Multiple administration of endogenous amines TIQ and 1MeTIQ protects against a 6-OHDA-induced essential fall of dopamine release in the rat striatum: in vivo microdialysis study. Neurotox Res 33:523–531. CrossRefPubMedGoogle Scholar
  121. Wąsik A, Romańska I, Zelek-Molik A, Nalepa I, Antkiewicz-Michaluk L (2018b) The protective effect of repeated 1MeTIQ administration on the lactacystin-induced impairment of dopamine release and decline in TH level in the rat brain. Neurotox Res 34(3):706–716. CrossRefPubMedPubMedCentralGoogle Scholar
  122. Weitz CJ, Fauli KF, Goldstein A (1987) Synthesis of the skeleton of morphine molecule by mammalian liver. Nature 330:674–677PubMedGoogle Scholar
  123. Xie G, Krnjevic K, Ye JH (2013) Salsolinol modulation of dopamine neurons. Front Behav Neurosci 7:5Google Scholar
  124. Xie B, Lin F, Peng L, Ullah K, Wu H, Qing H, Deng Y (2014) Methylglyoxal increases dopamine level and leads to oxidative stress in SH-SY5Y cells. Acta Biochim Biophys Sin Shanghai 46(11):950–956. CrossRefPubMedGoogle Scholar
  125. Yamakawa T, Ohta S (1997) Isolation of 1-methyl-1,2,3,4-tetrahydroisoquinoline-synthesizing enzyme from rat brain: a possible Parkinson’s disease-preventing enzyme. Biochem Biophys Res Commun 236(3):676–668PubMedGoogle Scholar
  126. Yamakawa T, Ohta S (1999) Biosynthesis of a parkinsonism-preventing substance, 1-methyl-1,2,3,4-tetrahydroisoquinoline, is inhibited by parkinsonism-inducing compounds in rat brain mitochondrial fraction. Neurosci Lett 259:157–160PubMedGoogle Scholar
  127. Yoshida M, Ogawa M, Suzuki K, Nagatsu T (1993) Parkinsonism produced by tetrahydroisoquinoline (TIQ) or the analogues. Adv Neurol 60:207–211PubMedGoogle Scholar
  128. Yoshikawa T (1993) Free radicals and their scavengers in Parkinson’s disease. Eur Neurol 33(Suppl. 1):60–68PubMedGoogle Scholar
  129. Yun-Choi HS, Pyo MK, Chang KC, Lee DH (2002) The effects of higenamine on LPS-induced experimental disseminated intravascular coagulation (DIC) in rats. Planta Med 68:326–329PubMedGoogle Scholar
  130. Zhang N, Lian Z, Peng X, Li Z, Zhu H (2017) Applications of higenamine in pharmacology and medicine. J Ethnopharmacol 196:242–252PubMedGoogle Scholar
  131. Zhang N, Qu K, Wang M, Yin Q, Wang W, Xue L, Fu H, Zhu H, Li Z (2019) Identification of higenamine as a novel α1-adrenergic receptor antagonist. Phytother Res 15:708–717. CrossRefGoogle Scholar
  132. Zhao J, Shi L, Zhang LR (2017) Neuroprotective effect of carnosine against salsolinol-induced Parkinson’s disease. Exp Ther Med 14(1):664–670PubMedPubMedCentralGoogle Scholar
  133. Zuddas A, Vaglini F, Fornai F, Corsini GU (1992) Selective lesion of the nigrostriatali dopaminergic pathway by MPTP and acetaldehyde or diethyldithiocarbamate. Neurochem Int 20:287S–293S. CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Chemistry and PharmacyUniversity of SassariSassariItaly
  2. 2.Department of Biomedical Sciences, National Institute of Neuroscience, Cagliari section, Center of Excellence for the Study of Neurobiology of Addiction, University CampusUniversity of CagliariMonserrato (Cagliari)Italy
  3. 3.Department of Life and Environmental Sciences, Center of Excellence for the Study of Neurobiology of Addiction, University CampusUniversity of CagliariMonserrato (Cagliari)Italy

Personalised recommendations