Study of the potential toxicity of adrenaline to neurons, using the SH-SY5Y human cellular model
DOI:
https://doi.org/10.1590/s2175-97902023e20467Keywords:
Neurotoxicity, Adrenaline, N-acetyl-cysteine, Tiron, Reactive speciesAbstract
Prolonged overexposure to catecholamines causes toxicity, usually credited to continuous adrenoceptor stimulation, autoxidation, and the formation of reactive pro-oxidant species. Non-differentiated SH-SY5Y cells were used to study the possible contribution of oxidative stress in adrenaline (ADR)-induced neurotoxicity, as a model to predict the toxicity of this catecholamine to peripheral nerves. Cells were exposed to several concentrations of ADR (0.1, 0.25, 0.5 and 1mM) and two cytotoxicity assays [lactate dehydrogenase (LDH) release and 3-(4,5-dimethylthiazol-2yl)-2,5-diphenyl tetrazolium bromide (MTT) reduction] were performed at several time-points (24, 48, and 96h). The cytotoxicity of ADR was concentration- and time-dependent in both assays, since the lowest concentration tested (0.1mM) also caused significant cytotoxicity at 96h. N-acetyl-cysteine (1mM), a precursor of glutathione synthesis, prevented ADR-induced toxicity elicited by 0.5mM and 0.25mM ADR following a 96-h exposure, while the antioxidant Tiron (100µM) was non-protective. In conclusion, ADR led to mitochondrial distress and ultimately cell death in non-differentiated SH-SY5Y cells, possibly because of ADR oxidation products. The involvement of such processes in the catecholamine-induced peripheral neuropathy requires further analysis.
Downloads
References
Adeghate E, Ponery AS, Sheen R. Streptozotocin-Induced diabetes mellitus is associated with increased pancreatic tissue levels of noradrenaline and adrenaline in the rat. Pancreas. 2001;22(3):311-6.
Aldini G, Altomare A, Baron G, Vistoli G, Carini M, Borsani L, et al. N-Acetylcysteine as an antioxidant and disulphide breaking agent: the reasons why. Free Radic Res. 2018;52(7):751-62.
Almeida D, Pinho R, Correia V, Soares J, Bastos ML, Carvalho F, et al. Mitoxantrone is more toxic than doxorubicin in SH-SY5Y human cells: a ‘chemobrain’ in vitro study. Pharmaceuticals (Basel). 2018;11(2):41
Aruoma OI, Halliwell B, Hoey BM, Butler J. The antioxidant action of N-acetylcysteine: its reaction with hydrogen peroxide, hydroxyl radical, superoxide, and hypochlorous acid. Free Radic Biol Med. 1989;6(6):593-7.
Asanuma M, Miyazaki I, Ogawa N. Dopamine- or L-DOPA- induced neurotoxicity: the role of dopamine quinone formation and tyrosinase in a model of Parkinson’s disease. Neurotox Res. 2003;5(3):165-76.
Capela JP, Carmo H, Remião F, Bastos ML, Meisel A, Carvalho F. Molecular and cellular mechanisms of ecstasy-induced neurotoxicity: an overview. Mol Neurobiol. 2009;39(3):210-71.
Capela JP, da Costa Araujo S, Costa VM, Ruscher K, Fernandes E, Bastos ML, et al. The neurotoxicity of hallucinogenic amphetamines in primary cultures of hippocampal neurons. Neurotoxicology. 2013;34:254-63.
Capela JP, Meisel A, Abreu AR, Branco PS, Ferreira LM, Lobo AM, et al. Neurotoxicity of ecstasy metabolites in rat cortical neurons, and influence of hyperthermia. J Pharmacol Exp Ther. 2006a;316(1):53-61.
Capela JP, Ruscher K, Lautenschlager M, Freyer D, Dirnagl U, Gaio AR, et al. Ecstasy-induced cell death in cortical neuronal cultures is serotonin 2A-receptor-dependent and potentiated under hyperthermia. Neuroscience. 2006b;139(3):1069-81.
Carvalho M, Carmo H, Costa VM, Capela JP, Pontes H, Remiao F, et al. Toxicity of amphetamines: an update. Arch Toxicol. 2012;86(8):1167-231.
Cassagnes LE, Chhour M, Perio P, Sudor J, Gayon R, Ferry G, et al. Oxidative stress and neurodegeneration: The possible contribution of quinone reductase 2. Free Radic Biol Med . 2018;120:56-61.
Costa VM, Carvalho F, Bastos ML, Carvalho RA, Carvalho M, Remiao F. Contribution of catecholamine reactive intermediates and oxidative stress to the pathologic features of heart diseases. Curr Med Chem. 2011;18(15):2272-314.
Costa VM, Ferreira LM, Branco PS, Carvalho F, Bastos ML, Carvalho RA, et al. Cross-functioning between the extraneuronal monoamine transporter and multidrug resistance protein 1 in the uptake of adrenaline and export of 5-(glutathion-S-yl)adrenaline in rat cardiomyocytes. Chem Res Toxicol. 2009a;22(1):129-35.
Costa VM, Silva R, Ferreira LM, Branco PS, Carvalho F, Bastos ML, et al. Oxidation process of adrenaline in freshly isolated rat cardiomyocytes: formation of adrenochrome, quinoproteins, and GSH adduct. Chem Res Toxicol . 2007;20(8):1183-91.
Costa VM, Silva R, Ferreira R, Amado F, Carvalho F, Bastos ML, et al. Adrenaline in pro-oxidant conditions elicits intracellular survival pathways in isolated rat cardiomyocytes. Toxicology. 2009b;257(1-2):70-9.
Costa VM, Silva R, Tavares LC, Vitorino R, Amado F, Carvalho F, et al. Adrenaline and reactive oxygen species elicit proteome and energetic metabolism modifications in freshly isolated rat cardiomyocytes. Toxicology. 2009c;260(1-3):84-96.
Cryer PE, Silverberg AB, Santiago JV, Shah SD. Plasma catecholamines in diabetes. The syndromes of hypoadrenergic and hyperadrenergic postural hypotension. Am J Med. 1978;64(3):407-16.
Del Rio G, Carani C, Baldini A, Marrama P, Della Casa L. Chronobiology of catecholamine excretion in normal and diabetic men. J Endocrinol Invest. 1990;13(7):575-80.
Del Rio G, Marrama P, Della Casa L. High urinary excretion of adrenaline in insulin dependent diabetic subjects. Horm Metab Res Suppl. 1992;26:106-8.
Dong Y, Berners-Price SJ, Thorburn DR, Antalis T, Dickinson J, Hurst T, et al. Serine protease inhibition and mitochondrial dysfunction associated with cisplatin resistance in human tumor cell lines: targets for therapy. Biochem Pharmacol. 1997;53(11):1673-82.
Ferreira PS, Nogueira TB, Costa VM, Branco PS, Ferreira LM, Fernandes E, et al. Neurotoxicity of “ecstasy” and its metabolites in human dopaminergic differentiated SH-SY5Y cells. Toxicol Lett. 2013;216(2-3):159-70.
Fu W, Luo H, Parthasarathy S, Mattson MP. Catecholamines potentiate amyloid beta-peptide neurotoxicity: involvement of oxidative stress, mitochondrial dysfunction, and perturbed calcium homeostasis. Neurobiol Dis. 1998;5(4):229-43.
Gallego M, Setién R, Izquierdo MJ, Casis O, Casis E. Diabetes-induced biochemical changes in central and peripheral catecholaminergic systems. Physiol Res. 2003;52(6):735-41.
Gibson KR, Neilson IL, Barrett F, Winterburn TJ, Sharma S, MacRury SM, et al. Evaluation of the antioxidant properties of N-acetylcysteine in human platelets: prerequisite for bioconversion to glutathione for antioxidant and antiplatelet activity. J Cardiovasc Pharmacol. 2009;54(4):319-26.
Hoyt KR, Reynolds IJ, Hastings TG. Mechanisms of dopamine-induced cell death in cultured rat forebrain neurons: interactions with and differences from glutamate-induced cell death. Exp Neurol. 1997;143(2):269-81.
Kovalevich J, Langford D. Considerations for the Use of SH-SY5Y Neuroblastoma cells in neurobiology. In: Amini S, White MK, editors. neuronal cell culture: Methods and protocols. Totowa, NJ: Humana Press; 2013. p. 9-21.
Krishna CM, Liebmann JE, Kaufman D, DeGraff W, Hahn SM, McMurry T, et al. The catecholic metal sequestering agent 1,2-dihydroxybenzene-3,5-disulfonate confers protection against oxidative cell damage. Arch Biochem Biophys. 1992;294(1):98-106.
Kumar H, Lim HW, More SV, Kim BW, Koppula S, Kim IS, et al. The role of free radicals in the aging brain and Parkinson’s Disease: convergence and parallelism. Int J Mol Sci. 2012;13(8):10478-504.
Lelkes E, Unsworth BR, Lelkes PI. Reactive oxygen species, apoptosis and altered NGF-induced signaling in PC12 pheochromocytoma cells cultured in elevated glucose: an in vitro cellular model for diabetic neuropathy. Neurotox Res . 2001;3(2):189-203.
Offen D, Ziv I, Sternin H, Melamed E, Hochman A. Prevention of dopamine-induced cell death by thiol antioxidants: possible implications for treatment of Parkinson’s disease. Exp Neurol . 1996;141(1):32-9.
Rossato LG, Costa VM, Vilas-Boas V, Bastos ML, Rolo A, Palmeira P, et al. Therapeutic concentrations of mitoxantrone elicit energetic imbalance in H9c2 cells: mitochondrionopathy as a key factor in the cytotoxicity. Cardiovasc Toxicol. 2013;13(4):413-25.
Rushworth GF, Megson IL. Existing and potential therapeutic uses for N-acetylcysteine: The need for conversion to intracellular glutathione for antioxidant benefits. Pharmacol Ther. 2014;141(2):150-9.
Shih AY, Erb H, Murphy TH. Dopamine activates Nrf2-regulated neuroprotective pathways in astrocytes and meningeal cells. J Neurochem. 2007;101(1):109-19.
Smythies J, Galzigna L. The oxidative metabolism of catecholamines in the brain: a review. Biochim Biophys Acta. 1998;1380(2):159-62.
Soares AS, Costa VM, Diniz C, Fresco P. Potentiation of cytotoxicity of paclitaxel in combination with Cl-IB-MECA in human C32 metastatic melanoma cells: A new possible therapeutic strategy for melanoma. Biomed Pharmacother. 2013;67(8):777-89.
Stewart JK, Campbell TG, Gbadebo TD, Narasimhachari N, Manning JW. Cardiovascular responses and central catecholamines in streptozocin-diabetic rats. Neurochem Int. 1994;24(2):183-9.
Tank AW, Lee Wong D. Peripheral and central effects of circulating catecholamines. Compr Physiol. 2015;5(1):1-15.
Verberne AJ, Korim WS, Sabetghadam A, Llewellyn-Smith IJ. Adrenaline: insights into its metabolic roles in hypoglycaemia and diabetes. Br J Pharmacol. 2016;173(9):1425-37.
Xicoy H, Wieringa B, Martens GJ. The SH-SY5Y cell line in Parkinson’s disease research: a systematic review. Mol Neurodegener. 2017;12(1):10.
Zhitkovich A. N-Acetylcysteine: Antioxidant, aldehyde scavenger, and more. Chem Res Toxicol . 2019;32(7):1318-9.
Downloads
Published
Issue
Section
License
This work is licensed under a Creative Commons Attribution 4.0 International License.
All content of the journal, except where identified, is licensed under a Creative Commons attribution-type BY.
The on-line journal has open and free access.
