Abstract
Parkinson’s disease (PD) remarks its pathology by affecting the patient’s movements and postural instability by dopaminergic loss in the substantia nigra of midbrain. The disease is characterized by the accumulation of alpha-synuclein protein followed by dementia symptoms. Moreover, the pathology enhances the production of monoamine oxidases A and B (MAO A and B), leucine-rich repeat kinase 2 (LRRK2), phosphate and tensin homolog (PTEN), PTEN-induced putative kinase 1 (PINK1), and PARK7 (deglycase 1 (DJ-1)). Hinokitiol (HIN), a tropolone-related compound, has widely been reported as an antioxidant, antineuralgic as well as a neuroprotective agent. Hence, in this study, we have examined the effect of hinokitol to act as a neuroprotective agent against 6-OHDA-induced toxicity in SH-SY5Y neuroblastoma cells through downregulation of the mRNA expression of PD pathological proteins like alpha-synuclein, MAO A and B, LRRK2, PTEN, PINK1, and PARK7 (deglycase 1 (DJ-1)). The study revealed that the 6-OHDA-induced elevation in the mRNA expression of the pathology marker proteins was subsequently downregulated by the treatment with HIN and was referenced with the positive control, amantadine (AMA), widely used nowadays as a treatment drug for PD symptoms. Thus, the study suggests that hinokitiol could be a drug of choice against 6-OHDA-induced neurotoxicity in SH-SY5Y neuroblastoma cells.
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References
Bonifati V, Rizzu P, van Baren MJ, Schaap O, Breedveld GJ, Krieger E, Dekker MC, Squitieri F, Ibanez P, Joosse M, van Dongen JW, Vanacore N, van Swieten JC, Brice A, Meco G, van Duijn CM, Oostra BA, Heutink P (2003) Mutations in the DJ-1 gene associated with autosomal recessive early-onset parkinsonism. Sci 299(5604):256–259. https://doi.org/10.1126/science.1077209
Cheng F, Li X, Li Y, Wang C, Wang T, Liu G, Baskys A, Uéda K, Chan P, Yu S (2011) α-Synuclein promotes clathrin-mediated NMDA receptor endocytosis and attenuates NMDA-induced dopaminergic cell death. J Neurochem 119:815–825. https://doi.org/10.1111/j.1471-4159.2011.07460.x
Deng H, Le W, Guo Y, Hunter CB, Xie W, Huang M, Jankovic J (2006) Heterogeneous phenotype in a family with compound heterozygous parkin gene mutations. Arch Neurol 63:273–277. https://doi.org/10.1001/archneur.63.2.273
Dias V, Junn E, Mouradian MM (2013) The role of oxidative stress in Parkinson’s disease. J Parkinsons Dis 3:461–491. https://doi.org/10.3233/JPD-130230
Drechsel DA, Patel M (2008) Role of reactive oxygen species in the neurotoxicity of environmental agents implicated in Parkinson’s disease. Free Radic Biol Med 44:1873–1886. https://doi.org/10.1016/j.freeradbiomed.2008.02.008
Fathima MZ, Mohamed N, Somasundaram I, Shanmugarajan TS (2018) Hinokitiol-ameliorated diethylnitrosamine-induced hepatocarcinogenesis through antioxidant mechanism in rats: in vitro and in vivo study. Asian J Pharm Clin Res 11(6):232–237. https://doi.org/10.22159/ajpcr.2018.v11i6.21950
Fukui H, Moraes CT (2008) The mitochondrial impairment, oxidative stress and neurodegeneration connection: reality or just an attractive hypothesis? Trends Neurosci 31:251–256. https://doi.org/10.1016/j.tins.2008.02.008
Glinka Y, Gassen M, Youdim MB (1997) Mechanism of 6-hydroxydopamine neurotoxicity. J Neural Transm Suppl 50:55–66. https://www.ncbi.nlm.nih.gov/pubmed/9120425. Accessed 17 July 2018
Gonzalez-Hernandez T, Barroso-Chinea P, De La Cruz Muros I, Perez-Delgado DMM, Rodriguez M (2004) Expression of dopamine and vesicular monoamine transporters and differential vulnerability of mesostriatal dopaminergic neurons. J Comp Neurol 479:198–215. https://doi.org/10.1002/cne.20323
Gourie-Devi M (2014) Epidemiology of neurological disorders in India: review of background, prevalence and incidence of epilepsy, stroke, Parkinson’s disease and tremors. Neurol India 62(6):588–598. https://doi.org/10.4103/0028-3886.149365
Guo S, Bezard E, Zhao B (2005) Protective effect of green tea polyphenols on the SH-SY5Y cells against 6-OHDA induced apoptosis through ROS–NO pathway. Free Radic Biol Med 39:682–695. https://doi.org/10.1016/j.freeradbiomed.2005.04.022
Hideyuki S, Tomoko O, Sadako K, Masahiro N, Kenji Y, Mitsutoshi Y, Kinya H, Takashi K (2010) Amantadine for dyskinesis in Parkinson’s disease: a randomized controlled trial. PLoS One 5(12):e15298. https://doi.org/10.1371/journal.pone.0015298
Huang C, Jayakumar T, Chang C, Fong TH, Lu SH, Philip AT, Cheuk-Sing C, Joen-Rong S (2015) Hinokitiol exerts anticancer activity through downregulation of MMPs 9/2 and enhancement of catalase and SOD enzymes: in vivo augmentation of lung histoarchitecture. Mole 20:17720–17734. https://doi.org/10.3390/molecules201017720
Huang X, Huihui W, Mark RM, Xinghu Q, Jingchuan M, Xiongbing T, Guangchun C, Guangjun W, Xiangqun N, Zehua Z (2016) Quantitative analysis of diet structure by real-time PCR, reveals different feeding patterns by two dominant grasshopper species. Sci Rep 6:32166. https://doi.org/10.1038/srep32166
Jayakumar T, Wen-Hsien H, Ting-Lin Y, Jun-Yun L, Yu-Cheng K, Tsorng-Harn F, Joen-Rong S (2013) Hinokitiol, a natural tropolone derivative, offers neuroprotection from thromboembolic stroke in vivo. Evid Based Complement Alternat Med. Article number: 840487. https://doi.org/10.1155/2013/840487
Jayakumar T, Chao-Hong L, Guan-Yi W, Tzu-Yin L, Manjunath M, Cheng-Ying H, Chih-Hao J-RS (2018) Hinokitiol inhibits migration of A549 lung cancer cells via suppression of MMPs and induction of antioxidant enzymes and apoptosis. Int J Mol Sci 19(4):939. https://doi.org/10.3390/ijms19040939
Lan-Hui L, Ping W, Jen-Yi L, Pei-Rong L, Wan-Yu H, Chao-Chi H, Chen-LH, Wan-Jiun C, Chien-Chun W, Muh-Yong Y, Shun-Min Y, Huei-Wen C (2014) Hinokitiol induces DNA damage and autophagy followed by cell cycle arrest and senescence in gefitinib-resistant lung adenocarcinoma cells. PLoS One 9(8):e104203
Larsen J, Ambrosi G, Mullett SJ, Berman SB Hinkle DA (2011) DJ-1 knock-down impairs astrocyte mitochondrial function. Neuroscience 196:251–264. https://doi.org/10.1016/j.neuroscience.2011.08.016
Mitsumoto A, Nakagawa Y (2001) DJ-1 is an indicator for endogenous reactive oxygen species elicited by endotoxin. Free Radic Res 35(6):885–893. https://www.ncbi.nlm.nih.gov/pubmed/11811539. Accessed 17 July 2018
Mullett SJ, Hamilton RL, Hinkle DA (2009) DJ-1 immunoreactivity in human brain astrocytes is dependent on infarct presence and infarct age. Neuropathology 29(2):125–131. https://doi.org/10.1111/j.1440-1789.2008.00955.x
O’Carroll AM, Fowler CJ, Phillips J, Tobbia I, Tipton KF (1983) The deamination of dopamine by human brain monoamine oxidase. Specificity for the two enzyme forms in seven brain regions. Naunyn Schmiedeberg's Arch Pharmacol 198–202(1983):322. https://www.ncbi.nlm.nih.gov/pubmed/6408492. Accessed 17 July 2018
Ouyang WC, Liao YW, Chen PN, Lu KH, Yu CC, Hsieh PL (2017) Hinokitiol suppresses cancer stemness and oncogenicity in glioma stem cells by Nrf2 regulation. Cancer Chemother Pharmacol 80:411–419. https://doi.org/10.1007/s00280-017-3381-y
Paquette MA, Martinez AA, Macheda T, Meshul CK, Johnson SW, Berger SP, Giuffrida A (2012) Anti-dyskinetic mechanisms of amantadine and dextromethorphan in the 6-OHDA rat model of Parkinson’s disease: role of NMDA vs. 5-HT1A receptors. Eur J Neurosci 36(9):3224–3234. https://doi.org/10.1111/j.1460-9568.2012.08243.x
Raszewski G, Lemieszek MK, Łukawski K (2016) Cytotoxicity induced by cypermethrin in human neuroblastoma cell line SH-SY5Y. Ann Agric Environ Med 23(1):106–110. https://doi.org/10.5604/12321966.1196863.
Sakaguchi-Nakashima A, Meir JY, Jin Y, Matsumoto K, Hisamoto N (2007) LRK-1, a C. elegans PARK8-related kinase, regulates axonaldendritic polarity of SV proteins. Curr Biol 17(7):592–598. https://doi.org/10.1016/j.cub.2007.01.074
Sayre LM, Perry G, Smith MA (2008) Oxidative stress and neurotoxicity. Chem Res Toxicol 21:172–188. https://doi.org/10.1021/tx700210j
Settembre C, Fraldi A, Jahreiss L, Spampanato C, Venturi C, Medina D, de Pablo R, Tacchetti C, Rubinsztein DC, Ballabio A (2008) A block of autophagy in lysosomal storage disorders. Hum Mol Genet 17:119–129. https://doi.org/10.1093/hmg/ddm289
Song JX, Lu JH, Liu LF, Chen LL, Durairajan SS, Yue Z, Zhang HQ, Li M (2014) HMGB1 is involved in autophagy inhibition caused by SNCA/α-synuclein overexpression: a process modulated by the natural autophagy inducer corynoxine B. Autophagy 10:144–154. https://doi.org/10.4161/auto.26751
Soto-Otero R, Mendez-Alvarez E, Hermida-Ameijeiras A, Muñoz-Patiño AM, Labandeira-Garcia JL (2000) Autoxidation and neurotoxicity of 6-hydroxydopamine in the presence of some antioxidants: potential implication in relation to the pathogenesis of Parkinson’s disease. J Neurochem 74:1605–1612. https://www.ncbi.nlm.nih.gov/pubmed/10737618. Accessed 17 July 2018
Taira T, Saito Y, Niki T, Iguchi-Ariga SMM, Takahashi K, Ariga H (2004) DJ-1 has a role in antioxidative stress to prevent cell death. EMBO Rep 5(2):213–218. https://doi.org/10.1038/sj.embor.7400074
Wang Y, Wu C, Morrow WJW (2004) The apoptotic and necrotic effects of tomatine adjuvant. Vaccine 22:2316–2327. https://www.ncbi.nlm.nih.gov/pubmed/15149791. Accessed 17 July 2018
Wolff LF, Smith QT, Snyder WK, Bedrick JK, Liljemark WF, Aeppli DA, Bandt CL (1988) Relationship between lactate dehydrogenase and myeloperoxidase levels in human gingival crevicular fluid and clinical and microbial measurements. J Clin Periodontol 15(2):110–115. https://www.ncbi.nlm.nih.gov/pubmed/2831251. Accessed 17 July 2018
Wolozin B, Saha S, Guillily M, Ferree A, Riley M (2008) Investigating convergent actions of genes linked to familial Parkinson’s disease. Neurodegener Dis 5:182–185. https://doi.org/10.1159/000113697
Xu Y, Wang S, Miao Q, Jin K, Lou L, Ye X, Xi Y, Juan Y (2016) Protective role of Hinokitiol against H2O2-induced injury in human corneal epithelium. Curr Eye Res 42:1460–2202. https://doi.org/10.3109/02713683.2016.1151530
Yanagida T, Jun T, Yoshihisa K, Daijiro Y, Kazuyuki T, Tomonori S, Atsuko Y, Takashi T, Hiroyuki Y, Takahiro T, Shigehiro M, Toshihiro I, Ikuo T, Hiroyoshi A (2009) Oxidative stress induction of DJ-1 protein in reactive astrocytes scavenges free radicals and reduces cell injury. Oxidative Med Cell Longev 2(1):36–42. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2763229. Accessed 17 July 2018
Zhao DL, Zou LB, Lin S, Shi JG, Zhu HB (2007) Anti-apoptotic effect of esculin on dopamine-induced cytotoxicity in the human neuroblastoma SH-SY5Y cell line. Neuropharmacology 53:724–732. https://doi.org/10.1016/j.neuropharm.2007.07.017
Zhao DL, Zou LB, Lin S, Shi JG, Zhu HB (2008) 6,7-di-O-glucopyranosylesculetin protects SH-SY5Y cells from dopamine-induced cytotoxicity. Eur J Pharmacol 580:329–338. https://doi.org/10.1016/j.ejphar.2007.11.057
Acknowledgments
The authors wish to acknowledge Mr. Rajesh Ramachandran, Mr. Sumesh Soman, and Miss. Neenu GP, Biogenix Research Centre, Centre for Molecular Biology and Applied Science, Trivandrum, Kerala, for assisting us to carry out the cellular works. We would like to acknowledge Dr. A.K. Munirajan, Professor, Department of Genetics, Dr. A.L.M. Post Graduate Institute of Basic Medical Sciences, University of Madras, Taramani Campus, Chennai, to carry out real-time PCR works in Multidisciplinary Research Unit (MRU) of this institution.
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Varier, K.M., Sumathi, T. Hinokitiol Offers Neuroprotection Against 6-OHDA-Induced Toxicity in SH-SY5Y Neuroblastoma Cells by Downregulating mRNA Expression of MAO/α-Synuclein/LRRK2/PARK7/PINK1/PTEN Genes. Neurotox Res 35, 945–954 (2019). https://doi.org/10.1007/s12640-018-9988-x
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DOI: https://doi.org/10.1007/s12640-018-9988-x