Planta Med 2022; 88(07): 548-558
DOI: 10.1055/a-1527-1390
Biological and Pharmacological Activity
Original Papers

The Reassessed Impact of Nicotine against Neurotoxicity in Mesencephalic Dopaminergic Cell Cultures and Neuroblastoma N18TG2 Cells

1   Department of Pharmacology, Faculty of Medical Sciences in Zabrze, Medical University of Silesia, Katowice, Poland
,
2   Department of Pathology, Faculty of Veterinary Medicine, Assiut University, Assiut, Egypt
,
Christopher Krewenka
3   Institute of Medical Biochemistry, Department of Biomedical Sciences, University of Veterinary Medicine, Vienna, Austria
,
Barbara Kranner
3   Institute of Medical Biochemistry, Department of Biomedical Sciences, University of Veterinary Medicine, Vienna, Austria
,
Rudolf Moldzio
3   Institute of Medical Biochemistry, Department of Biomedical Sciences, University of Veterinary Medicine, Vienna, Austria
› Author Affiliations

Abstract

Neuroprotective effects of nicotine are still under debate, so further studies on its effectiveness against Parkinsonʼs disease are required. In our present study, we used primary dopaminergic cell cultures and N18TG2 neuroblastoma cells to investigate the effect of nicotine and its neuroprotective potential against rotenone toxicity. Nicotine protected dopaminergic (tyrosine hydroxylase immunoreactive) neurons against rotenone. This effect was not nAChR receptor-dependent. Moreover, the alkaloid at a concentration of 5 µM caused an increase in neurite length, and at a concentration of 500 µM, it caused an increase in neurite count in dopaminergic cells exposed to rotenone. Nicotine alone was not toxic in either cell culture model, while the highest tested concentration of nicotine (500 µM) caused growth inhibition of N18TG2 neuroblastoma cells. Nicotine alone increased the level of glutathione in both cell cultures and also in rotenone-treated neuroblastoma cells. The obtained results may be helpful to explain the potential neuroprotective action of nicotine on neural cell cultures.

Highlights
  1. Nicotine increases the neurite length and the neurite count in cells exposed to rotenone

  2. Nicotine increases the level of glutathione in cells

  3. Neuroprotection of nicotine against complex I inibition does not target mitochondria



Publication History

Received: 22 December 2020

Accepted after revision: 05 June 2021

Article published online:
06 July 2021

© 2021. Thieme. All rights reserved.

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 
  • References

  • 1 World Health Organization. Tobacco Fact sheet N°339, updated May 2020, World Health Organization, Geneva. Accessed December 4, 2020 at: http://www.who.int/mediacentre/factsheets/fs339/en/
  • 2 Morens DM, Grandinetti A, Reed D, White LR, Ross GW. Cigarette smoking and protection from Parkinsonʼs disease: false association or etiologic clue?. Neurology 1995; 45: 1041-1051
  • 3 Fratiglioni L, Wang HX. Smoking and Parkinsonʼs and Alzheimerʼs disease: review of the epidemiological studies. Behav Brain Res 2000; 113: 117-120
  • 4 Checkoway H, Powers K, Smith-Weller T, Franklin GM, Longstreth WT, Swanson PD. Parkinsonʼs disease risks associated with cigarette smoking, alcohol consumption, and caffeine intake. Am J Epidemiol 2002; 155: 732-738
  • 5 De Reuck J, De Weweire M, Van Maele G, Santens P. Comparison of the age of onset and development of motor complications between smokers and non-smokers in Parkinsonʼs disease. J Neurol Sci 2005; 231: 35-39
  • 6 Talhout R, Opperhuizen A, van Amsterdam JG. Role of acetaldehyde in tobacco smoke addiction. Eur Neuropsychopharmacol 2007; 17: 627-636
  • 7 Perfetti TA, Rodgman A. The complexity of tobacco and tobacco smoke. Beitr Tabakforsch Int 2011; 24: 215-232
  • 8 Wang D, Gao T, Zhao Y, Mao Y, Sheng Z, Lan Q. Nicotine exerts neuroprotective effects by attenuating local inflammatory cytokine production following crush injury to rat sciatic nerves. Eur Cytokine Netw 2019; 30: 59-66
  • 9 Gandelman JA, Newhouse P, Taylor WD. Nicotine and networks: potential for enhancement of mood and cognition in late-life depression. Neurosci Biobehav Rev 2018; 84: 289-298
  • 10 Williams E, Linert W. In vitro evidence supporting the therapeutic role of nicotine against neurodegeneration. In Vivo 2004; 18: 391-399
  • 11 Takeuchi H, Yanagida T, Inden M, Takata K, Kitamura Y, Yamakawa K, Sawada H, Izumi Y, Yamamoto N, Kihara T, Uemura K, Inoue H, Taniguchi T, Akaike A, Takahashi R, Shimohama S. Nicotinic receptor stimulation protects nigral dopaminergic neurons in rotenone-induced Parkinsonʼs disease models. J Neurosci Res 2009; 87: 576-585
  • 12 Dunnett SB, Bjorklund A. Prospects for new restorative and neuroprotective treatments in Parkinsonʼs disease. Nature 1999; 399: 32-39
  • 13 Shimohama S, Sawada H, Kitamura Y, Taniguchi T. Disease model: Parkinsonʼs disease. Trends Mol Med 2003; 9: 360-365
  • 14 Sherer TB, Betarbet R, Greenamyre JT. Environment, mitochondria, and Parkinsonʼs disease. Neuroscientist 2002; 8: 192-197
  • 15 Olanow CW, Agid Y, Mizuno Y, Albanese A, Bonuccelli U, Damier P, De Yebenes J, Gershanik O, Guttman M, Grandas F, Hallett M, Hornykiewicz O, Jenner P, Katzenschlager R, Langston WJ, LeWitt P, Melamed E, Mena MA, Michel PP, Mytilineou C, Obeso JA, Poewe W, Quinn N, Raisman-Vozari R, Rajput AH, Rascol O, Sampaio C, Stocchi F. Levodopa in the treatment of Parkinsonʼs disease: current controversies. Mov Disord 2004; 19: 997-1005
  • 16 Betarbet R, Sherer TB, MacKenzie G, Garcia-Osuna M, Panov AV, Greenamyre JT. Chronic systemic pesticide exposure reproduces features of Parkinsonʼs disease. Nat Neurosci 2000; 3: 1301-1306
  • 17 Radad K, Rausch WD, Gille G. Rotenone induces cell death in primary dopaminergic culture by increasing ROS production and inhibiting mitochondrial respiration. Neurochem Int 2006; 49: 379-386
  • 18 Ferrante RJ, Schulz JB, Kowall NW, Beal MF. Systemic administration of rotenone produces selective damage in the striatum and globus pallidus, but not in the substantia nigra. Brain Res 1997; 753: 157-162
  • 19 Alam M, Schmidt WJ. Rotenone destroys dopaminergic neurons and induces parkinsonian symptoms in rats. Behav Brain Res 2002; 136: 317-324
  • 20 Moldzio R, Piskernik C, Radad K, Rausch WD. Rotenone damages striatal organotypic slice culture. Ann N Y Acad Sci 2008; 1148: 530-535
  • 21 Moldzio R, Pacher T, Krewenka C, Kranner B, Novak J, Duvigneau JC, Rausch WD. Effects of cannabinoids Δ(9)-tetrahydrocannabinol, Δ(9)-tetrahydrocannabinolic acid and cannabidiol in MPP+ affected murine mesencephalic cultures. Phytomedicine 2012; 19: 819-824
  • 22 Gille G, Rausch WD, Hung ST, Moldzio R, Janetzky B, Hundemer HP, Kolter T, Reichmann H. Pergolide protects dopaminergic neurons in primary culture under stress conditions. J Neural Transm 2002; 109: 633-643
  • 23 Shimohama S. Nicotinic receptor-mediated neuroprotection in neurodegenerative disease models. Biol Pharm Bull 2009; 32: 332-336
  • 24 Changeux JP. Nicotinic receptors and nicotine addiction. C R Biol 2009; 332: 421-425
  • 25 Ryan RE, Ross SA, Drago J, Loiacono RE. Dose-related neuroprotective effects of chronic nicotine in 6-hydroxydopamine treated rats, and loss of neuroprotection in alpha4 nicotinic receptor subunit knockout mice. Br J Pharmacol 2001; 132: 1650-1656
  • 26 Nourse jr. JB, Harshefi G, Marom A, Karmi A, Cohen Ben-Ami H, Caldwell KA, Caldwell GA, Treinin M. Conserved nicotine-activated neuroprotective pathways involve mitochondrial stress. iScience 2021; 24: 102140
  • 27 Dong Y, Bi W, Zheng K, Zhu E, Wang S, Xiong Y, Chang J, Jiang J, Liu B, Lu Z, Cheng Y. Nicotine prevents oxidative stress-induced hippocampal neuronal injury through α7-nAChR/Erk1/2 signaling pathway. Front Mol Neurosci 2020; 13: 557647
  • 28 Kaur J, Rauti R, Nistri A. Nicotine-mediated neuroprotection of rat spinal networks against excitotoxicity. Eur J Neurosci 2018; 47: 1353-1374
  • 29 Nicholatos JW, Francisco AB, Bender CA, Yeh T, Lugay FJ, Salazar JE, Glorioso C, Libert S. Nicotine promotes neuron survival and partially protects from Parkinsonʼs disease by suppressing SIRT6. Acta Neuropathol Commun 2018; 6: 120
  • 30 Sherer TB, Betarbet R, Stout AK, Lund S, Baptista M, Panov AV, Cookson MR, Greenamyre JT. An in vitro model of Parkinsonʼs disease: linking mitochondrial impairment to altered alpha-synuclein metabolism and oxidative damage. J Neurosci 2002; 22: 7006-7015
  • 31 Ritz B, Lee PC, Lassen CF, Arah OA. Parkinson disease and smoking revisited: ease of quitting is an early sign of the disease. Neurology 2014; 83: 1396-1402
  • 32 Grandinetti A, Morens DM, Reed D, MacEachern D. Prospective study of cigarette smoking and the risk of developing idiopathic Parkinsonʼs disease. Am J Epidemiol 1994; 139: 1129-1138
  • 33 Gorell JM, Rybicki BA, Cole Johnson C, Peterson EL. Occupational metal exposures and the risk of Parkinsonʼs disease. Neuroepidemiology 1999; 18: 303-308
  • 34 Shastry P, Basu A, Rajadhyaksha MS. Neuroblastoma cell lines–a versatile in vitro model in neurobiology. Int J Neurosci 2001; 108: 109-126
  • 35 JanssenDuijghuijsen LM, Grefte S, de Boer VCJ, Zeper L, van Dartel DAM, van der Stelt I, Bekkenkamp-Grovenstein M, van Norren K, Wichers HJ, Keijer J. Mitochondrial ATP depletion disrupts Caco-2 monolayer integrity and internalizes claudin 7. Front Physiol 2007; 8: 794
  • 36 Quik M, Jeyarasasingam G. Nicotinic receptors and Parkinsonʼs disease. Eur J Pharmacol 2000; 393: 223-230
  • 37 Shen JX, Yakel JL. Functional alpha7 nicotinic ACh receptors on astrocytes in rat hippocampal CA1 slices. J Mol Neurosci 2012; 48: 14-21
  • 38 Malińska D, Więckowski M, Michalska B, Drabik K, Prill M, Patalas-Krawczyk P, Walczak J, Szymański J, Mathis C, Van der Toorn M, Luettich K, Hoeng J, Peitsch M, Duszyński J, Szczepanowska J. Mitochondria as a possible target for nicotine action. J Bioenerg Biomembr 2019; 51: 259-276
  • 39 Smeyne M, Smeyne RJ. Glutathione metabolism and Parkinsonʼs disease. Free Radic Biol Med 2013; 62: 13-25
  • 40 Aspera-Werz RH, Ehnert S, Heid D, Zhu S, Chen T, Braun B, Sreekumar V, Arnscheidt C, Nussler AK. Nicotine and cotinine inhibit catalase and glutathione reductase activity contributing to the impaired osteogenesis of SCP-1 cells exposed to cigarette smoke. Oxid Med Cell Longev 2018; e2018: 3172480
  • 41 Dringen R, Pfeiffer B, Hamprecht B. Synthesis of the antioxidant glutathione in neurons: supply by astrocytes of CysGly as precursor for neuronal glutathione. J Neurosci 1999; 19: 562-569
  • 42 Patel H, McIntire J, Ryan S, Dunah A, Loring R. Anti-inflammatory effects of astroglial alpha7 nicotinic acetylcholine receptors are mediated by inhibition of the NF-kappaB pathway and activation of the Nrf2 pathway. J Neuroinflammation 2017; 14: 192
  • 43 Cormier A, Morin C, Zini R, Tillement JP, Lagrue G. In vitro effects of nicotine on mitochondrial respiration and superoxide anion generation. Brain Res 2001; 900: 72-79
  • 44 Linert W, Bridge MH, Huber M, Bjugstad KB, Grossman S, Arendash GW. In vitro and in vivo studies investigating possible antioxidant actions of nicotine: relevance to Parkinsonʼs and Alzheimerʼs diseases. Biochim Biophys Acta 1999; 1454: 143-152
  • 45 Bridge MH, Williams E, Lyons ME, Tipton KF, Linert W. Electrochemical investigation into the redox activity of Fe(II)/Fe(III) in the presence of nicotine and possible relations to neurodegenerative diseases. Biochim Biophys Acta 2004; 1690: 77-84
  • 46 Mouhape C, Costa G, Ferreira M, Abin-Carriquiry JA, Dajas F, Prunell G. Nicotine-induced neuroprotection in rotenone in vivo and in vitro models of Parkinsonʼs disease: evidences for the involvement of the labile iron pool level as the underlying mechanism. Neurotox Res 2019; 35: 71-82
  • 47 Mayer B. How much nicotine kills a human? Tracing back the generally accepted lethal dose to dubious self-experiments in the nineteenth century. Arch Toxicol 2014; 88: 5-7
  • 48 Mari M, Colell A, Morales A, Montfort C, Garcia-Ruiz C, Fernandez-Checa JC. Redox control of liver function in health and disease. Antioxid Redox Signal 2010; 12: 1295-1331
  • 49 Delijewski M, Wrześniok D, Otręba M, Beberok A, Rok J, Buszman E. Nicotine impact on melanogenesis and antioxidant defense system in HEMn-DP melanocytes. Mol Cell Biochem 2014; 395: 109-116
  • 50 Ferrea S, Winterer G. Neuroprotective and neurotoxic effects of nicotine. Pharmacopsychiatry 2009; 42: 255-265
  • 51 Koutsilieri E, Chen TS, Kruzik P, Rausch WD. A morphometric analysis of bipolar and multipolar TH-IR neurons treated with the neurotoxin MPP+ in co-cultures from mesencephalon and striatum of embryonic C57BL/6 mice. J Neurosci Res 1995; 41: 197-205
  • 52 Rupprecht A, Sittner D, Smorodchenko A, Hilse KE, Goyn J, Moldzio R, Seiler AE, Brauer AU, Pohl EE. Uncoupling protein 2 and 4 expression pattern during stem cell differentiation provides new insight into their putative function. PLoS One 2014; 9: e88474