Abstract
Beside the key inhibition of acetylcholinesterase (AChE), involvement of oxidative stress in organophosphate (OP)-induced toxicity has been supported by experimental and human studies. On the other hand, according to our best knowledge, possible antioxidant properties of oximes, the only causal antidotes to OP-inhibited AChE, have been examined only by a few studies. Thus, we have determined the effect of four conventional (obidoxime, trimedoxime, pralidoxime, asoxime) and two promising experimental oximes (K027, K203) on dichlorvos (DDVP)-induced oxidative changes in vivo. Wistar rats (5/group) were treated with oxime (5% LD50 i.m) immediately after DDVP challenge (75% LD50 s.c). Oxidative stress biomarkers were determined in plasma and brain 60 min after the treatment: prooxidative—superoxide anion (O2 ·−) and total oxidative status (TOS); antioxidative—superoxide dismutase (SOD), total thiol (SH) groups, total antioxidant status (TAS) and paraoxonase (PON1); tissue oxidative stress burden—prooxidative–antioxidative balance (PAB) and oxidative stress index (OSI); oxidative tissue damage—malondialdehyde (MDA) and advanced oxidation protein products (AOPP). All oximes were able to attenuate DDVP-induced oxidative stress in rat plasma and brain. Changes of determined parameters in brain were not as prominent as it was seen in plasma. Based on OSI, better abilities of oxime K027, K203 and obidoxime to maintain DDVP-induced oxidative stress in rat brain were shown as compared to trimedoxime, pralidoxime and asoxime. Oximes can influence the complex in vivo redox processes that might contribute to their overall therapeutic efficacy. Further research is needed to understand the underlying molecular mechanisms involved in this phenomenon.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Abdollahi M, Ranjbar A, Shadnia S et al (2004) Pesticides and oxidative stress: a review. Med Sci Rev 10:141–147
Alamdari DH, Paletas K, Pegiou T et al (2007) A novel assay for the evaluation of the prooxidant–antioxidant balance, before and after antioxidant vitamin administration in type II diabetes patients. Clin Biochem 40:248–254. https://doi.org/10.1016/j.clinbiochem.2006.10.017
Antonijevic B, Stojiljkovic MP (2007) Unequal efficacy of pyridinium oximes in acute organophosphate poisoning. Clin Med Res 5:71–82. https://doi.org/10.3121/cmr.2007.701
Antonijevic E, Musilek K, Kuca K et al (2016) Therapeutic and reactivating efficacy of oximes K027 and K203 against a direct acetylcholinesterase inhibitor. Neurotoxicology 55:33–39. https://doi.org/10.1016/j.neuro.2016.05.006
Auclair C, Voisin E (1985) Nitroblue tetrazolium reduction. Handbook of methods for oxygen radical research, Greenwald RA. CRC, Boca Raton, pp 123–132
Aycicek A, Erel O (2007) Total oxidant/antioxidant status in jaundiced newborns before and after phototherapy. J Pediatr (Rio J) 83:319–322. https://doi.org/10.1590/S0021-75572007000500006
Berend S, Lucić Vrdoljak A, Musilek K et al (2012) Effects of oxime K203 and oxidative stress in plasma of tabun poisoned rats. Croat Chem Acta 85:193–199
Bradford MM (1976) A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 72:248–254. https://doi.org/10.1016/0003-2697(76)90527-3
Burtis CA, Ashwood ER, Bruns DE (2012) Tietz textbook of clinical chemistry and molecular diagnostics. Elsevier, St. Louis, Missouri
Cankayali L, Demirag K, Eris O et al (2005) The effects of N-acetylcysteine on oxidative stress in organophosphate poisoning model. Adv Ther 22:107–116. https://doi.org/10.1007/BF02849882
Cohen BH (2008) Explaining psychological statistics, 3rd edn. Wiley, New York
da Silva AP, Farina M, Franco JL et al (2008) Temporal effects of newly developed oximes (K027, K048) on malathion-induced acetylcholinesterase inhibition and lipid peroxidation in mouse prefrontal cortex. Neurotoxicology 29:184–189
de Lima Portella R, Barcelos RP, de Bem AF et al (2008) Oximes as inhibitors of low density lipoprotein oxidation. Life Sci 83:878–885. https://doi.org/10.1016/j.lfs.2008.10.005
de Lima WEA, Pereira AF, de Castro AA et al (2016) Flexibility in the molecular design of acetylcholinesterase reactivators: probing representative conformations by chemometric techniques and docking/QM calculations. Lett Drug Des Discov 13:360–371
dos Santos AA, dos Santos DB, Ribeiro RP et al (2011) Effects of K074 and pralidoxime on antioxidant and acetylcholinesterase response in malathion-poisoned mice. Neurotoxicology 32:888–895. https://doi.org/10.1016/j.neuro.2011.05.008
Duarte T, Martin C, Baud FJ et al (2012) Follow up studies on the respiratory pattern and total cholinesterase activities in dichlorvos-poisoned rats. Toxicol Lett 213:142–150. https://doi.org/10.1016/j.toxlet.2012.06.010
Ellman GL (1959) Tissue sulfhydryl groups. Arch Biochem Biophys 82:70–77. https://doi.org/10.1016/0003-9861(59)90090-6
Erel O (2004) A novel automated direct measurement method for total antioxidant capacity using a new generation, more stable ABTS radical cation. Clin Biochem 37:277–285. https://doi.org/10.1016/j.clinbiochem.2003.11.015
Erel O (2005) A new automated colorimetric method for measuring total oxidant status. Clin Biochem 38:1103–1111. https://doi.org/10.1016/j.clinbiochem.2005.08.008
Eyer P (2003) The role of oximes in the management of organophosphorus pesticide poisoning. Toxicol Rev 22:165–190. https://doi.org/10.2165/00139709-200322030-00004
Floyd RA (1996) The protective action of nitrone-based free radical traps in neurodegenerative diseases. In: Neurodegenerative Diseases. Springer, p 235–245
Giacoppo JOS, França TCC, Kuča K et al (2014) Molecular modeling and in vitro reactivation study between the oxime BI-6 and acetylcholinesterase inhibited by different nerve agents. J Biomol Struct Dyn 33:2048–2058
Girotti M, Khan N, McLellan B (1991) Early measurement of systemic lipid peroxidation products in plasma of major blunt trauma patients. J Trauma Acute Care Surg 31:32–35
Gorecki L, Korabecny J, Musilek K et al (2016) SAR study to find optimal cholinesterase reactivator against organophosphorous nerve agents and pesticides. Arch Toxicol 90:2831–2859. https://doi.org/10.1007/s00204-016-1827-3
Gupta RC, Goad JT, Milatovic D, Dettbarn W-D (2000) Cholinergic and noncholinergic brain biomarkers of insecticide exposure and effects. Hum Exp Toxicol 19:297–308. https://doi.org/10.1191/096032700678815927
Gupta RC, Milatovic D, Dettbarn W-D (2001) Depletion of energy metabolites following acetylcholinesterase inhibitor-induced status epilepticus: protection by antioxidants. Neurotoxicology 22:271–282. https://doi.org/10.1016/S0161-813X(01)00013-4
Gupta SC, Siddique HR, Saxena DK, Chowdhuri DK (2005) Hazardous effect of organophosphate compound, dichlorvos in transgenic Drosophila melanogaster (hsp70-lacZ): induction of hsp70, anti-oxidant enzymes and inhibition of acetylcholinesterase. Biochim Biophys Acta BBA 1725:81–92. https://doi.org/10.1016/j.bbagen.2005.04.033
Gupta SC, Siddique HR, Mathur N et al (2007) Induction of hsp70, alterations in oxidative stress markers and apoptosis against dichlorvos exposure in transgenic Drosophila melanogaster: modulation by reactive oxygen species. Biochim Biophys Acta BBA 1770:1382–1394. https://doi.org/10.1016/j.bbagen.2007.05.010
Hai D, Varga S, Matkovics B (1997) Organophosphate effects on antioxidant system of carp (Cyprinus carpio) and catfish (Ictalurus nebulosus). Comp Biochem Physiol C 117:83–88
Hasan M, Ali S (1981) Organophosphate pesticide dichlorvos-induced increase in the rate of lipid peroxidation in the different regions of the rat brain: supporting ultrastructural findings. Neurotoxicology 2:43–52
Jordanova E, Docovsky D, Miskova R (1974) Hematologic and enzyme examinations in agricultural workers with acute intrathion poisoning. Vatrechni Boles 13:59–62
Karami-Mohajeri S, Abdollahi M (2013) Mitochondrial dysfunction and organophosphorus compounds. Toxicol Appl Pharmacol 270:39–44. https://doi.org/10.1016/j.taap.2013.04.001
Kotur-Stevuljevic J, Spasic S, Jelic-Ivanovic Z et al (2008) PON1 status is influenced by oxidative stress and inflammation in coronary heart disease patients. Clin Biochem 41:1067–1073. https://doi.org/10.1016/j.clinbiochem.2008.06.009
Kotur-Stevuljevic J, Bogavac-Stanojevic N, Jelic-Ivanovic Z et al (2015) Oxidative stress and paraoxonase 1 status in acute ischemic stroke patients. Atherosclerosis 241:192–198. https://doi.org/10.1016/j.atherosclerosis.2015.05.016
Lukaszewicz-Hussain A (2010) Role of oxidative stress in organophosphate insecticide toxicity—short review. Pestic Biochem Physiol 98:145–150. https://doi.org/10.1016/j.pestbp.2010.07.006
Masoud A, Kiran R, Sandhir R (2009) Impaired mitochondrial functions in organophosphate induced delayed neuropathy in rats. Cell Mol Neurobiol 29:1245–1255. https://doi.org/10.1007/s10571-009-9420-4
Milatovic D, Gupta RC, Aschner M (2006) Anticholinesterase toxicity and oxidative stress. Sci World J 6:295–310. https://doi.org/10.1100/tsw.2006.38
Mileson BE, Chambers JE, Chen WL et al (1998) Common mechanism of toxicity: a case study of organophosphorus pesticides. Toxicol Sci 41:8–20. https://doi.org/10.1093/toxsci/41.1.8
Misra HP, Fridovich I (1972) The role of superoxide anion in the autoxidation of epinephrine and a simple assay for superoxide dismutase. J Biol Chem 247:3170–3175
Nurulain SM, Szegi P, Tekes K, Naqvi SN (2013) Antioxidants in organophosphorus compounds poisoning. Arh Hig Rada Toksikol 64:169–176. https://doi.org/10.2478/10004-1254-64-2013-2294
Özen T, Taş M (2009) Screening and evaluation of antioxidant activity of some amido-carbonyl oxime derivatives and their radical scavenging activities. J Enzyme Inhib Med Chem 24:1141–1147. https://doi.org/10.1080/14756360802669981
Pachecka J, Królewska B (1977) The effects of dichlorvos and trichlorphon on catalase induction, respiration and growth of yeast, saccharomyces cerevisiae. Bull Environ Contam Toxicol 17:342–348. https://doi.org/10.1007/BF01686088
Peña-Llopis S, Ferrando MD, Peña JB (2003) Fish tolerance to organophosphate-induced oxidative stress is dependent on the glutathione metabolism and enhanced by N-acetylcysteine. Aquat Toxicol 65:337–360. https://doi.org/10.1016/S0166-445X(03)00148-6
Pohanka M, Karasova JZ, Musilek K et al (2009) Effect of five acetylcholinesterase reactivators on tabun-intoxicated rats: induction of oxidative stress versus reactivation efficacy. J Appl Toxicol 29:483–488. https://doi.org/10.1002/jat.1432
Pohanka M, Karasova JZ, Musilek K et al (2011) Changes of rat plasma total low molecular weight antioxidant level after tabun exposure and consequent treatment by acetylcholinesterase reactivators. J Enzyme Inhib Med Chem 26:93–97
Pope C, Karanth S, Liu J (2005) Pharmacology and toxicology of cholinesterase inhibitors: uses and misuses of a common mechanism of action. Environ Toxicol Pharmacol 19:433–446. https://doi.org/10.1016/j.etap.2004.12.048
Puntel GO, Gubert P, Peres GL et al (2008) Antioxidant properties of oxime 3-(phenylhydrazono) butan-2-one. Arch Toxicol 82:755–762. https://doi.org/10.1007/s00204-008-0298-6
Puntel GO, de Carvalho NR, Gubert P et al (2009) Butane-2,3-dionethiosemicarbazone: an oxime with antioxidant properties. Chem Biol Interact 177:153–160. https://doi.org/10.1016/j.cbi.2008.09.028
Ramalho TC, França TCC, Rennó MN et al (2010) Development of new acetylcholinesterase reactivators: molecular modeling versus in vitro data. Chem Biol Interact 187:436–440. https://doi.org/10.1016/j.cbi.2010.05.016
Ramalho TC, de Castro AA, Silva DR et al (2016) Computational enzymology and organophosphorus degrading enzymes: promising approaches toward remediation technologies of warfare agents and pesticides. Curr Med Chem 23:1041–1061
Richter R, Furlong C, Clement E (1999) Determination of paraoxonase (PON1) status requires more than genotyping. Pharmacogenet Genom 9:745–753
Simonian N, Coyle J (1996) Oxidative stress in neurodegenerative diseases. Annu Rev Pharmacol Toxicol 36:83–106
Soltaninejad K, Abdollahi M (2009) Current opinion on the science of organophosphate pesticides and toxic stress: a systematic review. Med Sci Rev 15:RA75–RA90
Vadhva P, Hasan M (1986) Organophosphate dichlorvos induced dose-related differential alterations in lipid levels and lipid peroxidation in various regions of the fish brain and spinal cord. J Environ Sci Health Part B 21:413–424
Varó I, Navarro JC, Nunes B, Guilhermino L (2007) Effects of dichlorvos aquaculture treatments on selected biomarkers of gilthead sea bream (Sparus aurata L.) fingerlings. Aquaculture 266:87–96. https://doi.org/10.1016/j.aquaculture.2007.02.045
Witko-Sarsat V, Friedlander M, Capeillère-Blandin C et al (1996) Advanced oxidation protein products as a novel marker of oxidative stress in uremia. Kidney Int 49:1304–1313. https://doi.org/10.1038/ki.1996.186
Worek F, Thiermann H (2013) The value of novel oximes for treatment of poisoning by organophosphorus compounds. Pharmacol Ther 139:249–259. https://doi.org/10.1016/j.pharmthera.2013.04.009
Worek F, Thiermann H, Wille T (2016) Oximes in organophosphate poisoning: 60 years of hope and despair. Chem Biol Interact 259:93–98. https://doi.org/10.1016/j.cbi.2016.04.032
Acknowledgements
This study was supported by a grant from the Ministry of Education, Science and Technological Development of the Republic of Serbia (Project no. III46009 and OI 175035), Specific Research Project of Faculty of Science, University of Hradec Kralove (no. 2110–2016) and Ministry of Education, Youth and Sports (no. 8F17004).
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that they have no conflict of interest.
Rights and permissions
About this article
Cite this article
Antonijevic, E., Kotur-Stevuljevic, J., Musilek, K. et al. Effect of six oximes on acutely anticholinesterase inhibitor-induced oxidative stress in rat plasma and brain. Arch Toxicol 92, 745–757 (2018). https://doi.org/10.1007/s00204-017-2101-z
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00204-017-2101-z