Nicotine-Induced Neuroprotection in Rotenone In Vivo and In Vitro Models of Parkinson’s Disease: Evidences for the Involvement of the Labile Iron Pool Level as the Underlying Mechanism
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Parkinson’s disease (PD) is characterized by the degeneration of the dopaminergic neurons in the substantia nigra pars compacta (SNpc). Clinical and experimental evidence suggest that the activation of the nicotinic acetylcholine receptor (nAChR) could be protective for PD. In this study, we investigated the neuroprotective capacity of nicotine in a rat PD model. Considering that iron metabolism has been implicated in PD pathophysiology and nicotine has been described to chelate this metal, we also studied the effect of nicotine on the cellular labile iron pool (LIP) levels. Rotenone (1 μg) was unilaterally injected into the median forebrain bundle to induce the degeneration of the nigrostriatal pathway. Nicotine administration (1 mg/K, s.c. daily injection, starting 5 days before rotenone and continuing for 30 days) attenuated the dopaminergic cell loss in the SNpc and the degeneration of the dopaminergic terminals provoked by rotenone, as assessed by immunohistochemistry. Furthermore, nicotine partially prevented the reduction on dopamine levels in the striatum and improved the motor deficits, as determined by HPLC-ED and the forelimb use asymmetry test, respectively. Studies in primary mesencephalic cultures showed that pretreatment with nicotine (50 μM) improved the survival of tyrosine hydroxylase-positive neurons after rotenone (20 nM) exposure. Besides, nicotine induced a reduction in the LIP levels assessed by the calcein dequenching method only at the neuroprotective dose. These effects were prevented by addition of the nAChRs antagonist mecamylamine (100 μM). Overall, we demonstrate a neuroprotective effect of nicotine in a model of PD in rats and that a reduction in iron availability could be an underlying mechanism.
KeywordsParkinson’s disease Rotenone Nicotine Labile iron pool Neuroprotection
We thank to Prof. Prem Ponka for providing us with the iron quelator salicylaldehyde isonicotinoyl hydrazone. We also thank Prof. Cecilia Scorza and MSc. José P Prieto for helping with the behavioral experiments, Andrés Di Paolo for his technical assistance with the confocal microscopy, and Dr. Federico Dajas-Bailador for revising the manuscript.
This work was partially supported by the Agencia Nacional de Investigación e Innovación (ANII), Uruguay (FCE2007-517) and Programa de Desarrollo de las Ciencias Básicas (PEDECIBA), Uruguay.
Compliance with Ethical Standards
This study was approved by the Committee on Ethical Care and Use of Laboratory Animals of the IIBCE.
- Abin-Carriquiry JA, Costa G, Urbanavicius J, Cassels BK, Rebolledo-Fuentes M, Wonnacott S, Dajas F (2008) In vivo modulation of dopaminergic nigrostriatal pathways by cytisine derivatives: implications for Parkinson’s disease. Eur J Pharmacol 589:80–84. https://doi.org/10.1016/j.ejphar.2008.05.013 CrossRefPubMedGoogle Scholar
- Belluardo N, Olsson PA, Mudo’ G, Sommer WH, Amato G, Fuxe K (2005) Transcription factor gene expression profiling after acute intermittent nicotine treatment in the rat cerebral cortex. Neuroscience 133:787–796. https://doi.org/10.1016/j.neuroscience.2005.01.061 CrossRefPubMedGoogle Scholar
- Bridge MH, Williams E, Lyons MEG, Tipton KF, Linert W (2004) 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 - Mol Basis Dis 1690:77–84. https://doi.org/10.1016/j.bbadis.2004.05.007 CrossRefGoogle Scholar
- Fine JM, Forsberg AC, Renner DB, Faltesek KA, Mohan KG, Wong JC, Arneson LC, Crow JM, Frey WH 2nd, Hanson LR (2014) Intranasally-administered deferoxamine mitigates toxicity of 6-OHDA in a rat model of Parkinson’s disease. Brain Res 1574:96–104. https://doi.org/10.1016/j.brainres.2014.05.048 CrossRefPubMedGoogle Scholar
- Finkelstein DI, Billings JL, Adlard PA, Ayton S, Sedjahtera A, Masters CL, Wilkins S, Shackleford DM, Charman SA, Bal W, Zawisza IA, Kurowska E, Gundlach AL, Ma S, Bush AI, Hare DJ, Doble PA, Crawford S, Gautier ECL, Parsons J, Huggins P, Barnham KJ, Cherny RA (2017) The novel compound PBT434 prevents iron mediated neurodegeneration and alpha-synuclein toxicity in multiple models of Parkinson’s disease. Acta Neuropathol Commun 5:53. https://doi.org/10.1186/s40478-017-0456-2 CrossRefPubMedPubMedCentralGoogle Scholar
- Guo C, Hao LJ, Yang ZH, Chai R, Zhang S, Gu Y, Gao HL, Zhong ML, Wang T, Li JY, Wang ZY (2016) Deferoxamine-mediated up-regulation of HIF-1α prevents dopaminergic neuronal death via the activation of MAPK family proteins in MPTP-treated mice. Exp Neurol 280:13–23. https://doi.org/10.1016/j.expneurol.2016.03.016 CrossRefPubMedGoogle Scholar
- Kaur D, Yantiri F, Rajagopalan S, Kumar J, Mo JQ, Boonplueang R, Viswanath V, Jacobs R, Yang L, Beal MF, DiMonte D, Volitaskis I, Ellerby L, Cherny RA, Bush AI, Andersen JK (2003) Genetic or pharmacological iron chelation prevents MPTP-induced neurotoxicity in vivo: a novel therapy for Parkinson’s disease. Neuron 37:899–909. https://doi.org/10.1016/S0896-6273(03)00126-0 CrossRefPubMedGoogle Scholar
- Lee S, Woo J, Kim YS, Im HI (2015) Integrated miRNA-mRNA analysis in the habenula nuclei of mice intravenously self-administering nicotine. Sci Rep 5. https://doi.org/10.1038/srep12909
- Linert W, Bridge MH, Huber M, Bjugstad KB, Grossman S, Arendash GW (1999) In vitro and in vivo studies investigating possible antioxidant actions of nicotine: relevance to Parkinson’s and Alzheimer’s diseases. Biochim Biophys Acta - Mol Basis Dis 1454:143–152. https://doi.org/10.1016/S0925-4439(99)00029-0 CrossRefGoogle Scholar
- Marshall DL, Redfern PH, Wonnacott S (1997) Presynaptic nicotinic modulation of dopamine release in the three ascending pathways studied by in vivo microdialysis: comparison of naive and chronic nicotine-treated rats. J Neurochem 68:1511–1519. https://doi.org/10.1046/j.1471-4159.1997.68041511.x CrossRefPubMedGoogle Scholar
- Napolitano A, Pezzella A, Prota G (1999) New reaction pathways of dopamine under oxidative stress conditions: nonenzymatic iron-assisted conversion to norepinephrine and the neurotoxins 6-hydroxydopamine and 6,7-dihydroxytetrahydroisoquinoline. Chem Res Toxicol 12:1090–1097. https://doi.org/10.1021/tx990079p CrossRefPubMedGoogle Scholar
- Oakley AE, Collingwood JF, Dobson J, Love G, Perrott HR, Edwardson JA, Elstner M, Morris CM (2007) Individual dopaminergic neurons show raised iron levels in Parkinson disease. Neurology 68:1820–1825. https://doi.org/10.1212/01.wnl.0000262033.01945.9a CrossRefPubMedGoogle Scholar
- Parain K, Hapdey C, Rousselet E, Marchand V, Dumery B, Hirsch EC (2003) Cigarette smoke and nicotine protect dopaminergic neurons against the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine Parkinsonian toxin. Brain Res 984:224–232. https://doi.org/10.1016/S0006-8993(03)03195-0 CrossRefPubMedGoogle Scholar
- Paris I, Martinez-Alvarado P, Perez-Pastene C, Vieira MNN, Olea-Azar C, Raisman-Vozari R, Cardenas S, Graumann R, Caviedes P, Segura-Aguilar J (2005) Monoamine transporter inhibitors and norepinephrine reduce dopamine-dependent iron toxicity in cells derived from the substantia nigra. J Neurochem 92:1021–1032. https://doi.org/10.1111/j.1471-4159.2004.02931.x CrossRefPubMedGoogle Scholar
- Paxinos G, Watson C (1997) The rat brain in stereotaxic coordinates, 3rd (edn). Academic Press, San DiegoGoogle Scholar
- Ryan RE, Ross SA, Drago J, Loiacono RE (2001) 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 132:1650–1656. https://doi.org/10.1038/sj.bjp.0703989 CrossRefPubMedPubMedCentralGoogle Scholar
- Schallert T, Fleming SM, Leasure JL, Tillerson JL, Bland ST (2000) CNS plasticity and assessment of forelimb sensorimotor outcome in unilateral rat models of stroke, cortical ablation, parkinsonism and spinal cord injury. Neuropharmacology 39:777–787. https://doi.org/10.1016/S0028-3908(00)00005-8 CrossRefPubMedGoogle Scholar
- Singh K, Singh S, Singhal NK, Sharma A, Parmar D, Singh MP (2010) Nicotine- and caffeine-mediated changes in gene expression patterns of MPTP-lesioned mouse striatum: implications in neuroprotection mechanism. Chem Biol Interact 185:81–93. https://doi.org/10.1016/j.cbi.2010.03.015 CrossRefPubMedGoogle Scholar
- Soto-Otero R, Méndez-Álvarez E, Hermida-Ameijeiras Á et al (2002) Effects of (-)-nicotine and (-)-cotinine on 6-hydroxydopamine-induced oxidative stress and neurotoxicity: relevance for Parkinson’s disease. Biochem Pharmacol 64:125–135. https://doi.org/10.1016/S0006-2952(02)01070-5 CrossRefPubMedGoogle Scholar
- 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 (2009) Nicotinic receptor stimulation protects nigral dopaminergic neurons in rotenone-induced Parkinson’s disease models. J Neurosci Res 87:576–585. https://doi.org/10.1002/jnr.21869 CrossRefPubMedGoogle Scholar
- Tiwari MN, Agarwal S, Bhatnagar P, Singhal NK, Tiwari SK, Kumar P, Chauhan LKS, Patel DK, Chaturvedi RK, Singh MP, Gupta KC (2013) Nicotine-encapsulated poly(lactic-co-glycolic) acid nanoparticles improve neuroprotective efficacy against MPTP-induced parkinsonism. Free Radic Biol Med 65:704–718. https://doi.org/10.1016/j.freeradbiomed.2013.07.042 CrossRefPubMedGoogle Scholar
- Visanji NP, O’Neill MJ, Duty S (2006) Nicotine, but neither the α4β2 ligand RJR2403 nor an α7 nAChR subtype selective agonist, protects against a partial 6-hydroxydopamine lesion of the rat median forebrain bundle. Neuropharmacology 51:506–516. https://doi.org/10.1016/j.neuropharm.2006.04.015 CrossRefPubMedGoogle Scholar
- Zhang L, Yagnik G, Jiang D, Shi S, Chang P, Zhou F (2012) Separation of intermediates of iron-catalyzed dopamine oxidation reactions using reversed-phase ion-pairing chromatography coupled in tandem with UV-visible and ESI-MS detections. J Chromatogr B Anal Technol Biomed Life Sci 911:55–58. https://doi.org/10.1016/j.jchromb.2012.10.026 CrossRefGoogle Scholar