{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T20:24:31Z","timestamp":1791404671244,"version":"4.3.3"},"reference-count":30,"publisher":"IMR Press","issue":"2","license":[{"start":{"date-parts":[[2022,3,23]],"date-time":"2022-03-23T00:00:00Z","timestamp":1647993600000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["J. Integr. Neurosci."],"abstract":"<jats:p>As a catechol isoquinoline, salsolinol (Sal) is widely distributed in mammalian brains, and is increased in the cerebrospinal fluid (CSF) and urine of Parkinsonian patients. Sal can be metabolized to N-methyl-salsolinol (NM-Sal), an MPP+-like neurotoxin, and impairs the function of dopaminergic neurons, causing the clinical symptoms of Parkinson\u2019s disease (PD). Sal synthase, which catalyzes the production of Sal from dopamine and acetaldehyde, may be the important enzyme in the metabolism of catechol isoquinolines (CTIQs). Previously, our work demonstrated the existence of Sal synthase in rat brain and identified its amino acid sequence. However, the biological function of Sal synthase has not been thoroughly explored, especially its role in dopaminergic neuronal degeneration. In this study, we tried to clarify the catalytic role of Sal synthase in the formation of CTIQs which are endogenous neurotoxins in the mammalian brain. Furthermore, the cytotoxicity of Sal synthase was also observed in dopaminergic PC12 cells. The results demonstrated that Sal synthase overexpression can increase the level of Sal and NM-Sal, and ultimately cause mitochondria damage and apoptosis.<\/jats:p>","DOI":"10.31083\/j.jin2102071","type":"journal-article","created":{"date-parts":[[2022,4,1]],"date-time":"2022-04-01T07:59:22Z","timestamp":1648799962000},"source":"Crossref","is-referenced-by-count":3,"title":["Sal synthase induced cytotoxicity of PC12 cells through production of the dopamine metabolites salsolinol and N-methyl-salsolinol"],"prefix":"10.31083","volume":"21","author":[{"given":"Qianqian","family":"Xiong","sequence":"first","affiliation":[{"name":"Beijing Key Laboratory of Environmental and Viral Oncology, Beijing International Science and Technology Cooperation Base for Antiviral Drugs, Faculty of Environment and Life, Beijing University of Technology, 100124 Beijing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaotong","family":"Zheng","sequence":"first","affiliation":[{"name":"Beijing Key Laboratory of Environmental and Viral Oncology, Beijing International Science and Technology Cooperation Base for Antiviral Drugs, Faculty of Environment and Life, Beijing University of Technology, 100124 Beijing, China"},{"name":"Beijing Institute of Biological Products Company Limited, 100176 Beijing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianan","family":"Wang","sequence":"first","affiliation":[{"name":"Beijing Key Laboratory of Environmental and Viral Oncology, Beijing International Science and Technology Cooperation Base for Antiviral Drugs, Faculty of Environment and Life, Beijing University of Technology, 100124 Beijing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zixuan","family":"Chen","sequence":"first","affiliation":[{"name":"School of Life Science, Beijing Institute of Technology, 100081 Beijing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yulin","family":"Deng","sequence":"first","affiliation":[{"name":"School of Life Science, Beijing Institute of Technology, 100081 Beijing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rugang","family":"Zhong","sequence":"first","affiliation":[{"name":"Beijing Key Laboratory of Environmental and Viral Oncology, Beijing International Science and Technology Cooperation Base for Antiviral Drugs, Faculty of Environment and Life, Beijing University of Technology, 100124 Beijing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan","family":"Wang","sequence":"first","affiliation":[{"name":"Beijing Key Laboratory of Environmental and Viral Oncology, Beijing International Science and Technology Cooperation Base for Antiviral Drugs, Faculty of Environment and Life, Beijing University of Technology, 100124 Beijing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuechai","family":"Chen","sequence":"first","affiliation":[{"name":"Beijing Key Laboratory of Environmental and Viral Oncology, Beijing International Science and Technology Cooperation Base for Antiviral Drugs, Faculty of Environment and Life, Beijing University of Technology, 100124 Beijing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"16242","published-online":{"date-parts":[[2022,3,23]]},"reference":[{"key":"ref1","doi-asserted-by":"crossref","unstructured":"Cacabelos R. Parkinson\u2019s disease: from pathogenesis to pharmacogenomics. International Journal of Molecular Sciences. 2017; 18: 551.","DOI":"10.3390\/ijms18030551"},{"key":"ref2","doi-asserted-by":"crossref","unstructured":"Kalia LV, Lang AE. Parkinson\u2019s disease. Lancet. 2015; 386: 896\u2013912.","DOI":"10.1016\/S0140-6736(14)61393-3"},{"key":"ref3","doi-asserted-by":"crossref","unstructured":"Hu Z, Mao C, Wang H, Zhang Z, Zhang S, Luo H, et al. CHIP protects against MPP(+)\/MPTP-induced damage by regulating Drp1 in two models of Parkinson\u2019s disease. Aging. 2021; 13: 1458\u20131472.","DOI":"10.18632\/aging.202389"},{"key":"ref4","doi-asserted-by":"crossref","unstructured":"Nagatsu T. Isoquinoline neurotoxins in the brain and Parkinson\u2019s disease. Neuroscience Research. 1997; 29: 99\u2013111.","DOI":"10.1016\/S0168-0102(97)00083-7"},{"key":"ref5","doi-asserted-by":"crossref","unstructured":"Hipolito L, Sanchez-Catalan MJ, Zornoza T, Polache A, Granero L. Locomotor stimulant effects of acute and repeated intrategmental injections of salsolinol in rats: role of mu-opioid receptors. Psychopharmacology. 2010; 209: 1\u201311.","DOI":"10.1007\/s00213-009-1751-9"},{"key":"ref6","doi-asserted-by":"crossref","unstructured":"Zhang Y, Wang L, Mu X, Duan J, Zhu Y, Qing H, et al. Assessment of salsolinol N-methyltransferase activity in rat peripheral lymphocytes by liquid chromatography-electrospray time-of-flight mass spectrometry. Analytical and Bioanalytical Chemistry. 2011; 399: 3541\u20133545.","DOI":"10.1007\/s00216-011-4683-2"},{"key":"ref7","doi-asserted-by":"crossref","unstructured":"Carmo-Goncalves P, Romao L, Follmer C. In vitro protective action of monomeric and fibrillar alpha-synuclein on neuronal cells exposed to the dopaminergic toxins salsolinol and DOPAL. ACS Chemical Neuroscience. 2020; 11: 3541\u20133548.","DOI":"10.1021\/acschemneuro.0c00527"},{"key":"ref8","doi-asserted-by":"crossref","unstructured":"Naoi M, Maruyama W, Akao Y, Zhang J, Parvez H. Apoptosis induced by an endogenous neurotoxin, N-methyl(R)salsolinol, in dopamine neurons. Toxicology. 2000; 153: 123\u2013141.","DOI":"10.1016\/S0300-483X(00)00309-7"},{"key":"ref9","doi-asserted-by":"crossref","unstructured":"Arshad A, Chen X, Cong Z, Qing H, Deng Y. TRPC1 protects dopaminergic SH-SY5Y cells from MPP+, salsolinol, and N-methyl-(R)-salsolinol-induced cytotoxicity. Acta Biochimica et Biophysica Sinica. 2014; 46: 22\u201330.","DOI":"10.1093\/abbs\/gmt127"},{"key":"ref10","doi-asserted-by":"crossref","unstructured":"Naoi M, Maruyama W, Nagy GM. Dopamine-derived salsolinol derivatives as endogenous monoamine oxidase inhibitors: occurrence, metabolism and function in human brains. Neurotoxicology. 2004; 25: 193\u2013204.","DOI":"10.1016\/S0161-813X(03)00099-8"},{"key":"ref11","doi-asserted-by":"crossref","unstructured":"Naoi M, Maruyama W, Dostert P, Kohda K, Kaiya T. A novel enzyme enantio-selectively synthesizes (R)salsolinol, a precursor of a dopaminergic neurotoxin, N-methyl(R)salsolinol. Neuroscience Letters. 1996; 212: 183\u2013186.","DOI":"10.1016\/0304-3940(96)12807-X"},{"key":"ref12","doi-asserted-by":"crossref","unstructured":"Chen XC, Chen Y, Wu GS, Lu JQ, Iqbal J, Qing H, et al. Existence and characterization of Salsolinol synthase in neuronal cells and rat brain. Neurochemical Journal. 2013; 7: 192\u2013197.","DOI":"10.1134\/S1819712413030045"},{"key":"ref13","doi-asserted-by":"crossref","unstructured":"Chen X, Zheng X, Ali S, Guo M, Zhong R, Chen Z, et al. Isolation and sequencing of salsolinol synthase, an enzyme catalyzing salsolinol biosynthesis. ACS Chemical Neuroscience. 2018; 9: 1388\u20131398.","DOI":"10.1021\/acschemneuro.8b00023"},{"key":"ref14","doi-asserted-by":"crossref","unstructured":"Zhang Y, Ma H, Xie B, Han C, Wang C, Qing H, et al. Alpha-synuclein overexpression induced mitochondrial damage by the generation of endogenous neurotoxins in PC12 cells. Neuroscience Letters. 2013; 547: 65\u201369.","DOI":"10.1016\/j.neulet.2013.05.012"},{"key":"ref15","doi-asserted-by":"crossref","unstructured":"Shi Y, Wei Y, Qu S, Wang Y, Li Y, Li R. Arsenic induces apoptosis of human umbilical vein endothelial cells through mitochondrial pathways. Cardiovascular Toxicology. 2010; 10: 153\u2013160.","DOI":"10.1007\/s12012-010-9073-z"},{"key":"ref16","doi-asserted-by":"crossref","unstructured":"Zhang G, Buchler IP, DePasquale M, Wormald M, Liao G, Wei H, et al. Development of a PC12 cell based assay for screening catechol-O-methyltransferase inhibitors. ACS Chemical Neuroscience. 2019; 10: 4221\u20134226.","DOI":"10.1021\/acschemneuro.9b00395"},{"key":"ref17","doi-asserted-by":"crossref","unstructured":"Naoi M, Maruyama W, Akao Y, Yi H. Dopamine-derived endogenous N-methyl-(R)-salsolinol: its role in Parkinson\u2019s disease. Neurotoxicology & Teratology. 2002; 24: 579\u2013591.","DOI":"10.1016\/S0892-0362(02)00211-8"},{"key":"ref18","doi-asserted-by":"crossref","unstructured":"Wang F, Ni J, Wang X, Xie B, Feng C, Zhao S, et al. Salsolinol damaged neuroblastoma SH-SY5Y cells induce proliferation of human monocyte THP-1 cells through the mTOR pathway in a co-culture system. Neurochemical Research. 2015; 40: 932\u2013941.","DOI":"10.1007\/s11064-015-1547-8"},{"key":"ref19","doi-asserted-by":"crossref","unstructured":"Shukla A, Mohapatra TM, Agrawal AK, Parmar D, Seth K. Salsolinol induced apoptotic changes in neural stem cells: Amelioration by neurotrophin support. Neurotoxicology. 2013; 35: 50\u201361.","DOI":"10.1016\/j.neuro.2012.12.005"},{"key":"ref20","doi-asserted-by":"crossref","unstructured":"Voon SM, Ng KY, Chye SM, Ling APK, Voon KGL, Yap YJ, et al. The mechanism of action of salsolinol in brain: implications in Parkinson\u2019s disease. CNS Neurol Disord Drug Targets. 2020; 19: 725\u2013740.","DOI":"10.2174\/1871527319666200902134129"},{"key":"ref21","doi-asserted-by":"crossref","unstructured":"Decuypere M, Lu Y, Miller DD, Ledoux MS. Regional distribution of tetrahydroisoquinoline derivatives in rodent, human, and Parkinson\u2019s disease brain. Journal of Neurochemistry. 2008; 107: 1398\u20131413.","DOI":"10.1111\/j.1471-4159.2008.05709.x"},{"key":"ref22","doi-asserted-by":"crossref","unstructured":"Kurnik-Lucka M, Panula P, Bugajski A, Gil K. Salsolinol: an unintelligible and double-faced molecule-lessons learned from in vivo and in vitro experiments. Neurotoxicity Research. 2018; 33: 485\u2013514.","DOI":"10.1007\/s12640-017-9818-6"},{"key":"ref23","doi-asserted-by":"crossref","unstructured":"Naoi M, Maruyama W. Cell death of dopamine neurons in aging and Parkinson\u2019s disease. Mechanisms of Ageing and Development. 1999; 111: 175\u2013188.","DOI":"10.1016\/S0047-6374(99)00064-0"},{"key":"ref24","doi-asserted-by":"crossref","unstructured":"Storch A, Ott S, Hwang YI, Ortmann R, Hein A, Frenzel S, et al. Selective dopaminergic neurotoxicity of isoquinoline derivatives related to Parkinson\u2019s disease: studies using heterologous expression systems of the dopamine transporter. Biochemical Pharmacology. 2002; 63: 909\u2013920.","DOI":"10.1016\/S0006-2952(01)00922-4"},{"key":"ref25","doi-asserted-by":"crossref","unstructured":"Quintanilla ME, Rivera-Meza M, Berrios-Carcamo P, Cassels BK, Herrera-Marschitz M, Israel Y. (R)-Salsolinol, a product of ethanol metabolism, stereospecifically induces behavioral sensitization and leads to excessive alcohol intake. Addiction Biology. 2016; 21: 1063\u20131071.","DOI":"10.1111\/adb.12268"},{"key":"ref26","doi-asserted-by":"crossref","unstructured":"Su Y, Duan J, Ying Z, Hou Y, Zhang Y, Wang R, et al. Increased vulnerability of parkin knock down PC12 cells to hydrogen peroxide toxicity: the role of salsolinol and NM-salsolinol. Neuroscience. 2013; 233: 72\u201385.","DOI":"10.1016\/j.neuroscience.2012.12.045"},{"key":"ref27","doi-asserted-by":"crossref","unstructured":"Deng Y, Luan Y, Qing H, Xie H, Lu J, Zhou J. The formation of catechol isoquinolines in PC12 cells exposed to manganese. Neuroscience Letters. 2008; 444: 122\u2013126.","DOI":"10.1016\/j.neulet.2008.07.096"},{"key":"ref28","doi-asserted-by":"crossref","unstructured":"Yi H, Maruyama W, Akao Y, Takahashi T, Iwasa K, Youdim MB, et al. N-Propargylamine protects SH-SY5Y cells from apoptosis induced by an endogenous neurotoxin, N-methyl(R)salsolinol, through stabilization of mitochondrial membrane and induction of anti-apoptotic Bcl-2. Journal of Neural Transmission. 2006; 113: 21\u201332.","DOI":"10.1007\/s00702-005-0299-z"},{"key":"ref29","doi-asserted-by":"crossref","unstructured":"Brown D, Tamas A, Regl\u00f6di D, Tizabi Y. PACAP protects against salsolinol-induced toxicity in dopaminergic SH-SY5Y cells: implication for Parkinson\u2019s disease. Journal of Molecular Neuroscience. 2013; 50: 600\u2013607.","DOI":"10.1007\/s12031-013-0015-7"},{"key":"ref30","doi-asserted-by":"crossref","unstructured":"Zhao J, Shi L, Zhang LR. Neuroprotective effect of carnosine against salsolinol-induced Parkinson\u2019s disease. 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