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The Antidiabetic Drug Liraglutide Minimizes the Non-Cholinergic Neurotoxicity of the Pesticide Mipafox in SH-SY5Y Cells

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Abstract

Organophosphorus (OPs) compounds have been widely used in agriculture, industry, and household, and the neurotoxicity induced by them is still a cause of concern. The main toxic mechanism of OPs is the inhibition of acetylcholinesterase (AChE); however, the delayed neuropathy induced by OPs (OPIDN) is mediated by other mechanisms such as the irreversible inhibition of 70% of NTE activity (neuropathy target esterase) that leads to axonal degeneration. Liraglutide is a long-lasting GLP-1 analog clinically used as antidiabetic. Its neurotrophic and neuroprotective effects have been demonstrated in vitro and in experimental models of neurodegenerative diseases. As in OPIDN, axonal degeneration also plays a role in neurodegenerative diseases. Therefore, this study investigated the protective potential of liraglutide against the neurotoxicity of OPs by using mipafox as a neuropathic agent (at a concentration able to inhibit and age 70% of NTE activity) and a neuronal model with SH-SY5Y neuroblastoma cells, which express both esterases. Liraglutide protected cells against the neurotoxicity of mipafox by increasing neuritogenesis, the uptake of glucose, the levels of cytoskeleton proteins, and synaptic-plasticity modulators, besides decreasing the pro-inflammatory cytokine interleukin 1β and caspase-3 activity. This is the first study to suggest that liraglutide might induce beneficial effects against the delayed, non-cholinergic neurotoxicity of OPs.

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References

  • Abdollahi M, Donyavi M, Pournourmohammadi S, Saadat M (2004) Hyperglycemia associated with increased hepatic glycogen phosphorylase and phosphoenolpyruvate carboxykinase in rats following subchronic exposure to malathion. Comp Biochem Physiol C Toxicol Pharmacol 137:343–347

    Article  Google Scholar 

  • Abou-Donia MB (1993) The cytoskeleton as a target for organophosphorus ester-induced delayed neurotoxicity (OPIDN). Chem Biol Interact 87:383–393

    Article  CAS  Google Scholar 

  • Andreozzi F, Raciti GA, Nigro C, Mannino GC, Procopio T, Davalli AM, Beguinot F, Sesti G, Miele C, Folli F (2016) The GLP-1 receptor agonists exenatide and liraglutide activate glucose transport by an AMPK-dependent mechanism. J Transl Med 14:229

    Article  Google Scholar 

  • Androutsopoulos VP, Hernandez AF, Liesivuori J, Tsatsakis AM (2013) A mechanistic overview of health associated effects of low levels of organochlorine and organophosphorous pesticides. Toxicology 307:89–94

    Article  CAS  Google Scholar 

  • Arsenault AL, Gibson MA, Mader ME (1975) Hypoglycemia in malathion-treated chick embryos. Can J Zool 53:1055–1057

    Article  CAS  Google Scholar 

  • Athamneh AIM, He Y, Lamoureux P, Fix L, Suter DM, Miller KE (2017) Neurite elongation is highly correlated with bulk forward translocation of microtubules. Sci Rep 7:7292

    Article  Google Scholar 

  • Athauda D, Foltynie T (2016) The glucagon-like peptide 1 (GLP) receptor as a therapeutic target in Parkinson’s disease: mechanisms of action. Drug Discov Today 21:802–818

    Article  CAS  Google Scholar 

  • Banks CN, Lein PJ (2012) A review of experimental evidence linking neurotoxic organophosphorus compounds and inflammation. Neurotoxicology 33:575–584

    Article  CAS  Google Scholar 

  • Bauer S, Kerr BJ, Patterson PH (2007) The neuropoietic cytokine family in development, plasticity, disease and injury. Nat Rev Neurosci 8:221–232

    Article  CAS  Google Scholar 

  • Benomar Y, Naour N, Aubourg A, Bailleux V, Gertler A, Djiane J, Guerre-Millo ML, Taouis M (2006) Insulin and leptin induce Glut4 plasma membrane translocation and glucose uptake in a human neuronal cell line by a phosphatidylinositol 3-kinase- dependent mechanism. Endocrinology 147:2550–2556

    Article  CAS  Google Scholar 

  • Bissonnette CJ, Klegeris A, Mcgeer PL, Mcgeer EG (2004) Interleukin 1alpha and interleukin 6 protect human neuronal SH-SY5Y cells from oxidative damage. Neurosci Lett 361:40–43

    Article  CAS  Google Scholar 

  • Burnette WN (1981) "Western blotting." Electrophoretic transfer of proteins from sodium dodecyl sulfate--polyacrylamide gels to unmodified nitrocellulose and radiographic detection with antibody and radioiodinated protein A. Anal Biochem 112:195–203

    Article  CAS  Google Scholar 

  • Carlson K, Ehrich M (2001) Organophosphorus compounds alter intracellular F-actin content in SH-SY5Y human neuroblastoma cells. Neurotoxicology 22:819–827

    Article  CAS  Google Scholar 

  • Caudle WM (2015) Chapter 14 - Occupational exposures and parkinsonism. In: Lotti M, Bleecker ML (eds) Handbook of clinical neurology. Elsevier

  • Chang PA, Wu YJ (2006) Effect of tri-o-cresyl phosphate on cytoskeleton in human neuroblastoma SK-N-SH cell. Mol Cell Biochem 290:145–151

    Article  CAS  Google Scholar 

  • Chen LN, Lyu J, Yang XF, Ji WJ, Yuan BX, Chen MX, Ma X, Wang B (2013) Liraglutide ameliorates glycometabolism and insulin resistance through the upregulation of GLUT4 in diabetic KKAy mice. Int J Mol Med 32:892–900

    Article  CAS  Google Scholar 

  • CHO T, Tiffany-Castiglioni E (2004) Neurofilament 200 as an indicator of differences between mipafox and paraoxon sensitivity in Sy5Y neuroblastoma cells. J Toxicol Environ Health A 67:987–1000

    Article  CAS  Google Scholar 

  • Cogulu D, Onay H, Ozdemir Y, Aslan GI, Ozkinay F, Kutukculer N, Eronat C (2015) Associations of interleukin (IL)-1beta, IL-1 receptor antagonist, and IL-10 with dental caries. J Oral Sci 57:31–36

    Article  CAS  Google Scholar 

  • Das KP, Freudenrich TM, Mundy WR (2004) Assessment of PC12 cell differentiation and neurite growth: a comparison of morphological and neurochemical measures. Neurotoxicol Teratol 26:397–406

    Article  CAS  Google Scholar 

  • Ehrich M, Jortner BS (2001) Organophosphate-induced delayed neuropathy. In: Massaro EJ (ed) Handbook of Neurotoxicology. Humana Press Inc., Totowa

    Google Scholar 

  • Ehrich M, Correll L, Veronesi B (1997) Acetylcholinesterase and neuropathy target esterase inhibitions in neuroblastoma cells to distinguish organophosphorus compounds causing acute and delayed neurotoxicity. Fundam Appl Toxicol 38:55–63

    Article  CAS  Google Scholar 

  • el-Fawal HA, Correll L, Gay L, Ehrich M (1990) Protease activity in brain, nerve, and muscle of hens given neuropathy-inducing organophosphates and a calcium channel blocker. Toxicol Appl Pharmacol 103:133–142

    Article  CAS  Google Scholar 

  • Emerick GL, Deoliveira GH, dos Santos AC, Ehrich M (2012) Mechanisms for consideration for intervention in the development of organophosphorus-induced delayed neuropathy. Chem Biol Interact 199:177–184

    Article  CAS  Google Scholar 

  • Emerick GL, Fernandes LS, de Paula ES, Barbosa F Jr, dos Santos NA, dos Santos AC (2015) In vitro study of the neuropathic potential of the organophosphorus compounds fenamiphos and profenofos: comparison with mipafox and paraoxon. Toxicol in Vitro 29:1079–1087

    Article  CAS  Google Scholar 

  • Erta M, Quintana A, Hidalgo J (2012) Interleukin-6, a major cytokine in the central nervous system. Int J Biol Sci 8:1254–1266

    Article  CAS  Google Scholar 

  • Fernandes LS, Emerick GL, dos Santos NA, de Paula ES, Barbosa F Jr, dos Santos AC (2015) In vitro study of the neuropathic potential of the organophosphorus compounds trichlorfon and acephate. Toxicol in Vitro 29:522–528

    Article  CAS  Google Scholar 

  • Fernandes LS, dos Santos NAG, Emerick GL, Santos ACD (2017) L- and T-type calcium channel blockers protect against the inhibitory effects of mipafox on neurite outgrowth and plasticity-related proteins in SH-SY5Y cells. J Toxicol Environ Health A 80:1086–1097

    Article  CAS  Google Scholar 

  • Gill KD, Flora G, Pachauri V, Flora SJS (2010) Neurotoxicity of organophosphates and carbamates. In: Satoh T, Gupta RC (eds) Anticholinesterase pesticides. Metabolism, neurotoxicity, and epidemiology. Wiley, New Jersey

    Google Scholar 

  • Hans VH, Kossmann T, Lenzlinger PM, Probstmeier R, Imhof HG, Trentz O, Morganti-Kossmann MC (1999) Experimental axonal injury triggers interleukin-6 mRNA, protein synthesis and release into cerebrospinal fluid. J Cereb Blood Flow Metab 19:184–194

    Article  CAS  Google Scholar 

  • Husain K (2014) Delayed neurotoxicity of organophosphorus Compounds. J Environ Immunol Toxicol 1:7

    Google Scholar 

  • Jiang Y, Liu X, Li S, Zhang Y, piao F, Sun X (2014) Identification of differentially expressed proteins related to organophosphorus-induced delayed neuropathy in the brains of hens. J Appl Toxicol 34:1352–1360

    Article  CAS  Google Scholar 

  • Johnson MK (1974) The primary biochemical lesion leading to the delayed neurotoxic effects of some organophosphorus esters. J Neurochem 23:785–789

    Article  CAS  Google Scholar 

  • Johnson MK (1982) The target site for the initiation of delayed neurotoxicity by organophosphorous esters: biochemical studies and toxicological applications. In: Hodgson JR, Philpot RM (eds) Rev Biochem Toxicol

  • Kanaan NM, Pigino GF, Brady ST, Lazarov O, Binder LI, Morfini GA (2013) Axonal degeneration in Alzheimer’s disease: when signaling abnormalities meet the axonal transport system. Exp Neurol 246:44–53

    Article  CAS  Google Scholar 

  • Karami-Mohajeri S, Abdollahi M (2011) Toxic influence of organophosphate, carbamate, and organochlorine pesticides on cellular metabolism of lipids, proteins, and carbohydrates: a systematic review. Hum Exp Toxicol 30:1119–1140

    Article  CAS  Google Scholar 

  • Kevenaar JT, Hoogenraad CC (2015) The axonal cytoskeleton: from organization to function. Front Mol Neurosci 8

  • Laemmli UK (1970) Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature 227:680–685

    Article  CAS  Google Scholar 

  • L'episcopo F, Serapide MF, Tirolo C, Testa N, Caniglia S, Morale MC, Pluchino S, Marchetti B (2011) A Wnt1 regulated frizzled-1/beta-catenin signaling pathway as a candidate regulatory circuit controlling mesencephalic dopaminergic neuron-astrocyte crosstalk: therapeutical relevance for neuron survival and neuroprotection. Mol Neurodegener 6:49

    Article  CAS  Google Scholar 

  • Li Z, Ni CL, Yao Z, Chen LM, Niu WY (2014) Liraglutide enhances glucose transporter 4 translocation via regulation of AMP-activated protein kinase signaling pathways in mouse skeletal muscle cells. Metabolism 63:1022–1030

    Article  CAS  Google Scholar 

  • Li M, Li S, Li Y (2015a) Liraglutide promotes cortical neurite outgrowth via the MEK-ERK pathway. Cell Mol Neurobiol 35:987–993

    Article  CAS  Google Scholar 

  • Li Y, Bader M, Tamargo I, Rubovitch V, Tweedie D, Pick CG, Greig NH (2015b) Liraglutide is neurotrophic and neuroprotective in neuronal cultures and mitigates mild traumatic brain injury in mice. J Neurochem 135:1203–1217

    Article  CAS  Google Scholar 

  • Long-Smith CM, Manning S, McClean PL, Coakley MF, O'Halloran DJ, Holscher C, O'Neill C (2013) The diabetes drug liraglutide ameliorates aberrant insulin receptor localisation and signalling in parallel with decreasing both amyloid-beta plaque and glial pathology in a mouse model of Alzheimer’s disease. NeuroMolecular Med 15:102–114

    Article  CAS  Google Scholar 

  • Lotti M (1991) The pathogenesis of organophosphate polyneuropathy. Crit Rev Toxicol 21:465–487

    Article  CAS  Google Scholar 

  • Lotti M, Moretto A, Capodicasa E, Bertolazzi M, Peraica M, Scapellato ML (1993) Interactions between neuropathy target esterase and its inhibitors and the development of polyneuropathy. Toxicol Appl Pharmacol 122:165–171

    Article  CAS  Google Scholar 

  • Mahmood T, Yang PC (2012) Western blot: technique, theory, and trouble shooting. N Am J Med Sci 4:429–434

    Article  Google Scholar 

  • Mainardi M, Fusco S, Grassi C (2015) Modulation of hippocampal neural plasticity by glucose-related signaling. Neural Plast 2015:657928

    Article  Google Scholar 

  • McClean PL, Parthsarathy V, Faivre E, Holscher C (2011) The diabetes drug liraglutide prevents degenerative processes in a mouse model of Alzheimer’s disease. J Neurosci 31:6587–6594

    Article  CAS  Google Scholar 

  • Meredith C, Johnson MK (1988) Neuropathy target esterase: rates of turnover in vivo following covalent inhibition with phenyl di-n-pentylphosphinate. J Neurochem 51:1097–1101

    Article  CAS  Google Scholar 

  • Murphy PG, Grondin J, Altares M, Richardson PM (1995) Induction of interleukin-6 in axotomized sensory neurons. J Neurosci 15:5130–5138

    Article  CAS  Google Scholar 

  • Narayan S, Liew Z, Paul K, Lee P-C, Sinsheimer JS, Bronstein JM, Ritz B (2013) Household organophosphorus pesticide use and Parkinson’s disease. Int J Epidemiol 42:1476–1485

    Article  Google Scholar 

  • Parthsarathy V, Holscher C (2013a) Chronic treatment with the GLP1 analogue liraglutide increases cell proliferation and differentiation into neurons in an AD mouse model. PLoS One 8:e58784

    Article  CAS  Google Scholar 

  • Perry T, Lahiri DK, Chen D, Zhou J, Shaw KT, Egan JM, Greig NH (2002) A novel neurotrophic property of glucagon-like peptide 1: a promoter of nerve growth factor-mediated differentiation in PC12 cells. J Pharmacol Exp Ther 300:958–966

    Article  CAS  Google Scholar 

  • Porseva VV, Smirnova VP, Korzina MB, Emanuilov AI, Masliukov PM (2013) Age-associated changes in sympathetic neurons containing neurofilament 200 kDa during chemical deafferentation. Bull Exp Biol Med 155:268–271

    Article  CAS  Google Scholar 

  • Postuma RB, Saez-Valero J, Small DH (1999) Inhibition of neurite outgrowth from chick sympathetic neurons by cholinesterase inhibitors is not mediated by binding to cholinesterases. Neurosci Lett 266:77–80

    Article  CAS  Google Scholar 

  • Pournourmohammadi S, Farzami B, Ostad SN, Azizi E, Abdollahi M (2005) Effects of malathion subchronic exposure on rat skeletal muscle glucose metabolism. Environ Toxicol Pharmacol 19:191–196

    Article  CAS  Google Scholar 

  • Raghunath M, Patti R, Bannerman P, Lee CM, Baker S, Sutton LN, Phillips PC, Damodar Reddy C (2000) A novel kinase, AATYK induces and promotes neuronal differentiation in a human neuroblastoma (SH-SY5Y) cell line. Brain Res Mol Brain Res 77:151–162

    Article  CAS  Google Scholar 

  • Rasband WS 1997-2014. ImageJ, U. S. National Institutes of Health. Bethesda, Maryland, USA http://imagej.nih.gov/ij/

  • Ren K, Torres R (2009) Role of interleukin-1β during pain and inflammation. Brain Res Rev 60:57–64

    Article  CAS  Google Scholar 

  • Richardson RJ, Worden RM, Wijeyesakere SJ, Hein ND, Fink JK, Makhaeva GF (2015) Chapter 63 - Neuropathy target esterase as a biomarker and biosensor of delayed neuropathic agents A2. In: Gupta RC (ed) Handbook of toxicology of chemical warfare agents, 2nd edn. Academic Press, Boston

    Google Scholar 

  • Rohlman DS, Anger WK, Lein PJ (2011) Correlating neurobehavioral performance with biomarkers of organophosphorous pesticide exposure. Neurotoxicology 32:268–276

    Article  CAS  Google Scholar 

  • Romero-Navarro G, Lopez-Aceves T, Rojas-Ochoa A, Fernandez Mejia C (2006) Effect of dichlorvos on hepatic and pancreatic glucokinase activity and gene expression, and on insulin mRNA levels. Life Sci 78:1015–1020

    Article  CAS  Google Scholar 

  • Russo VC, Kobayashi K, Najdovska S, Baker NL, Werther GA (2004) Neuronal protection from glucose deprivation via modulation of glucose transport and inhibition of apoptosis: a role for the insulin-like growth factor system. Brain Res 1009:40–53

    Article  CAS  Google Scholar 

  • Sachana M, Flaskos J, Alexaki E, Hargreaves AJ (2003) Inhibition of neurite outgrowth in N2a cells by leptophos and carbaryl: effects on neurofilament heavy chain, GAP-43 and HSP-70. Toxicol in Vitro 17:115–120

    Article  CAS  Google Scholar 

  • Scheller J, Chalaris A, Schmidt-Arras D, Rose-John S (2011) The pro- and anti-inflammatory properties of the cytokine interleukin-6. Biochim Biophys Acta 1813:878–888

    Article  CAS  Google Scholar 

  • Schimmelpfeng J, Weibezahn KF, Dertinger H (2004) Quantification of NGF-dependent neuronal differentiation of PC-12 cells by means of neurofilament-L mRNA expression and neuronal outgrowth. J Neurosci Methods 139:299–306

    Article  CAS  Google Scholar 

  • Schneider L, Giordano S, Zelickson BR, Johnson SM, Bernavides AG, Ouyang X, Fineberg N, Darley-Usmar VM, Zhang J (2011) Differentiation of SH-SY5Y cells to a neuronal phenotype changes cellular bioenergetics and the response to oxidative stress. Free Radic Biol Med 51:2007–2017

    Article  CAS  Google Scholar 

  • Sharma MK, Jalewa J, Holscher C (2014) Neuroprotective and anti-apoptotic effects of liraglutide on SH-SY5Y cells exposed to methylglyoxal stress. J Neurochem 128:459–471

    Article  CAS  Google Scholar 

  • Sharma AN, Ligade SS, Sharma JN, Shukla P, Elased KM, Lucot JB (2015) GLP-1 receptor agonist liraglutide reverses long-term atypical antipsychotic treatment associated behavioral depression and metabolic abnormalities in rats. Metab Brain Dis 30:519–527

    Article  CAS  Google Scholar 

  • Tagliaferro P, Burke RE (2016) Retrograde axonal degeneration in Parkinson disease. J Parkinsons Dis 6:1–15

    Article  Google Scholar 

  • Tagliati M (2017) A phase II, randomized, double-blinded, placebo-controlled trial of liraglutide in Parkinson’s disease [Online]. https://clinicaltrials.gov/ct2/show/study/NCT02953665

  • Terry AV Jr (2012) Functional consequences of repeated organophosphate exposure: potential non-cholinergic mechanisms. Pharmacol Ther 134:355–365

    Article  CAS  Google Scholar 

  • Thorens B, Mueckler M (2010) Glucose transporters in the 21st century. Am J Physiol Endocrinol Metab 298:E141–E145

    Article  CAS  Google Scholar 

  • Towbin H, Staehelin T, Gordon J (1979) Electrophoretic transfer of proteins from polyacrylamide gels to nitrocellulose sheets: procedure and some applications. Proc Natl Acad Sci U S A 76:4350–4354

    Article  CAS  Google Scholar 

  • Vester A, Caudle WM (2016) The synapse as a central target for neurodevelopmental susceptibility to pesticides. Toxics 4

  • Voorhees JR, Rohlman DS, Lein PJ, Pieper AA (2017) Neurotoxicity in preclinical models of occupational exposure to organophosphorus compounds. Front Neurosci 10

  • Xiong H, Zheng C, Wang J, Song J, Zhao G, Shen H, Deng Y (2013) The neuroprotection of liraglutide on Alzheimer-like learning and memory impairment by modulating the hyperphosphorylation of tau and neurofilament proteins and insulin signaling pathways in mice. J Alzheimers Dis 37:623–635

    Article  Google Scholar 

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Funding

This study received financial support from Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq, Grants 307657/2016-7 and 140105/2015-8) and Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP, Grants 2012/00168-6, 2012/16319-3 and 2013/26906-6).

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  1. Departamento de Análises Clínicas, Toxicológicas e Bromatológicas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto—FCFRP, Universidade de São Paulo, USP, Avenida do Café s/n, Ribeirão Preto, SP, 14040-903, Brazil

    Laís Silva Fernandes, Neife Aparecida G. dos Santos & Antonio Cardozo dos Santos

  2. Instituto de Ciências da Saúde, Universidade Federal de Mato Grosso—ICS/UFMT/CUS, Sinop, MT, Brazil

    Guilherme Luz Emerick

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  1. Laís Silva Fernandes
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  2. Neife Aparecida G. dos Santos
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  4. Antonio Cardozo dos Santos
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Correspondence to Antonio Cardozo dos Santos.

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Fernandes, L.S., dos Santos, N.A.G., Emerick, G.L. et al. The Antidiabetic Drug Liraglutide Minimizes the Non-Cholinergic Neurotoxicity of the Pesticide Mipafox in SH-SY5Y Cells. Neurotox Res 35, 150–159 (2019). https://doi.org/10.1007/s12640-018-9941-z

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