Isatin-3-N4 -benzilthiosemicarbazone, a non-toxic thiosemicarbazone derivative, protects and reactivates rat and human cholinesterases inhibited by methamidophos in vitro and in silico
Autor(a) principal: | |
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Data de Publicação: | 2012 |
Outros Autores: | , , , , , , , , |
Tipo de documento: | Artigo |
Idioma: | eng |
Título da fonte: | Repositório Institucional da FURG (RI FURG) |
Texto Completo: | http://repositorio.furg.br/handle/1/4613 |
Resumo: | Organophosphates (OPs), which are widely used as pesticides, are acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitors. The inactivation of AChE results in the accumulation of acetylcholine at cholinergic receptor sites, causing a cholinergic crisis that can lead to death. The classical treatment for OP poisoning is administration of oximes, but these compounds are ineffective in some cases. Here we determined whether the new compound isatin-3-N4-benzilthiosemicarbazone (IBTC), which in our previous study proved to be an antioxidant and antiatherogenic molecule, could protect and reactivate AChE and BChE. Toxicity of IBTC after subcutaneous injection in mice was measured using assays for oxidized diclorofluoresceine (DCF), thiobarbituric acid reactive substances (TBARS), non-protein thiol (NPSH) levels, and catalase (CAT), sodium potassium (Na+/K+) ATPase, delta-aminolevulinic acid dehydratase (ALA-D), and glutathione peroxidases (GPx) enzyme activities. The cytotoxicity was evaluated and the enzymatic activity of cholinesterase was measured in human blood samples. Molecular docking was used to predict the mechanism of IBTC interactions with the AChE active site. We found that IBTC did not increase the amount of DCF-RS or TBARS, did not reduce NPSH levels, and did not increase CAT, (Na+/K+) ATPase, ALA-D, or GPx activities. IBTC protected and reactivated both AChE and BChE activities. Molecular docking predicted that IBTC is positioned at the peripheral anionic site and in the acyl binding pocket of AChE and can interact with methamidophos, releasing the enzyme’s active site. Our results suggest that IBTC, besides being an antioxidant and a promising antiatherogenic agent, is a non-toxic molecule for methamidophos poisoning treatment. |
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Barcelos, Rômulo PillonPortella, Rafael de LimaLugokenski, Thiago HenriqueRosa, Edovando José Flores daAmaral, Guilherme PiresGarcia, Luiz Filipe MachadoBresolin, LeandroGervini, Vanessa CarratuSoares, Félix Alexandre AntunesBarbosa, Nilda Berenice de Vargas2014-09-23T23:38:28Z2014-09-23T23:38:28Z2012BARCELOS, Rômulo Pillon et al. Isatin-3-N4-benzilthiosemicarbazone, a non-toxic thiosemicarbazone derivative, protects and reactivates rat and human cholinesterases inhibited by methamidophos in vitro and in silico. Toxicology in Vitro, v.26, n. 6, p.1030–1039, 2012. Disponível em: <http://ac.els-cdn.com/S0887233312000975/1-s2.0-S0887233312000975-main.pdf?_tid=04a9ef38-2f0b-11e4-9e9c-00000aab0f26&acdnat=1409268689_0d7324cb6946b5ab68c8ad8d84ba80f9>. Acesso em: 23 set. 2014.0887-2333http://repositorio.furg.br/handle/1/461310.1016/j.tiv.2012.04.008Organophosphates (OPs), which are widely used as pesticides, are acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitors. The inactivation of AChE results in the accumulation of acetylcholine at cholinergic receptor sites, causing a cholinergic crisis that can lead to death. The classical treatment for OP poisoning is administration of oximes, but these compounds are ineffective in some cases. Here we determined whether the new compound isatin-3-N4-benzilthiosemicarbazone (IBTC), which in our previous study proved to be an antioxidant and antiatherogenic molecule, could protect and reactivate AChE and BChE. Toxicity of IBTC after subcutaneous injection in mice was measured using assays for oxidized diclorofluoresceine (DCF), thiobarbituric acid reactive substances (TBARS), non-protein thiol (NPSH) levels, and catalase (CAT), sodium potassium (Na+/K+) ATPase, delta-aminolevulinic acid dehydratase (ALA-D), and glutathione peroxidases (GPx) enzyme activities. The cytotoxicity was evaluated and the enzymatic activity of cholinesterase was measured in human blood samples. Molecular docking was used to predict the mechanism of IBTC interactions with the AChE active site. We found that IBTC did not increase the amount of DCF-RS or TBARS, did not reduce NPSH levels, and did not increase CAT, (Na+/K+) ATPase, ALA-D, or GPx activities. IBTC protected and reactivated both AChE and BChE activities. Molecular docking predicted that IBTC is positioned at the peripheral anionic site and in the acyl binding pocket of AChE and can interact with methamidophos, releasing the enzyme’s active site. Our results suggest that IBTC, besides being an antioxidant and a promising antiatherogenic agent, is a non-toxic molecule for methamidophos poisoning treatment.engElsevierAntioxidantCholinesterasesMolecular dockingThiosemicarbazonesMethamidophosIsatin-3-N4 -benzilthiosemicarbazone, a non-toxic thiosemicarbazone derivative, protects and reactivates rat and human cholinesterases inhibited by methamidophos in vitro and in silicoinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleinfo:eu-repo/semantics/openAccessreponame:Repositório Institucional da FURG (RI FURG)instname:Universidade Federal do Rio Grande (FURG)instacron:FURGORIGINAL3.pdf3.pdfapplication/pdf781905https://repositorio.furg.br/bitstream/1/4613/1/3.pdfc9044458976c112ded2ea385c71ce945MD51open accessLICENSElicense.txtlicense.txttext/plain; charset=utf-81748https://repositorio.furg.br/bitstream/1/4613/2/license.txt8a4605be74aa9ea9d79846c1fba20a33MD52open access1/46132019-11-13 21:04:34.011open accessoai:repositorio.furg.br:1/4613Tk9URTogUExBQ0UgWU9VUiBPV04gTElDRU5TRSBIRVJFClRoaXMgc2FtcGxlIGxpY2Vuc2UgaXMgcHJvdmlkZWQgZm9yIGluZm9ybWF0aW9uYWwgcHVycG9zZXMgb25seS4KCk5PTi1FWENMVVNJVkUgRElTVFJJQlVUSU9OIExJQ0VOU0UKCkJ5IHNpZ25pbmcgYW5kIHN1Ym1pdHRpbmcgdGhpcyBsaWNlbnNlLCB5b3UgKHRoZSBhdXRob3Iocykgb3IgY29weXJpZ2h0Cm93bmVyKSBncmFudHMgdG8gRFNwYWNlIFVuaXZlcnNpdHkgKERTVSkgdGhlIG5vbi1leGNsdXNpdmUgcmlnaHQgdG8gcmVwcm9kdWNlLAp0cmFuc2xhdGUgKGFzIGRlZmluZWQgYmVsb3cpLCBhbmQvb3IgZGlzdHJpYnV0ZSB5b3VyIHN1Ym1pc3Npb24gKGluY2x1ZGluZwp0aGUgYWJzdHJhY3QpIHdvcmxkd2lkZSBpbiBwcmludCBhbmQgZWxlY3Ryb25pYyBmb3JtYXQgYW5kIGluIGFueSBtZWRpdW0sCmluY2x1ZGluZyBidXQgbm90IGxpbWl0ZWQgdG8gYXVkaW8gb3IgdmlkZW8uCgpZb3UgYWdyZWUgdGhhdCBEU1UgbWF5LCB3aXRob3V0IGNoYW5naW5nIHRoZSBjb250ZW50LCB0cmFuc2xhdGUgdGhlCnN1Ym1pc3Npb24gdG8gYW55IG1lZGl1bSBvciBmb3JtYXQgZm9yIHRoZSBwdXJwb3NlIG9mIHByZXNlcnZhdGlvbi4KCllvdSBhbHNvIGFncmVlIHRoYXQgRFNVIG1heSBrZWVwIG1vcmUgdGhhbiBvbmUgY29weSBvZiB0aGlzIHN1Ym1pc3Npb24gZm9yCnB1cnBvc2VzIG9mIHNlY3VyaXR5LCBiYWNrLXVwIGFuZCBwcmVzZXJ2YXRpb24uCgpZb3UgcmVwcmVzZW50IHRoYXQgdGhlIHN1Ym1pc3Npb24gaXMgeW91ciBvcmlnaW5hbCB3b3JrLCBhbmQgdGhhdCB5b3UgaGF2ZQp0aGUgcmlnaHQgdG8gZ3JhbnQgdGhlIHJpZ2h0cyBjb250YWluZWQgaW4gdGhpcyBsaWNlbnNlLiBZb3UgYWxzbyByZXByZXNlbnQKdGhhdCB5b3VyIHN1Ym1pc3Npb24gZG9lcyBub3QsIHRvIHRoZSBiZXN0IG9mIHlvdXIga25vd2xlZGdlLCBpbmZyaW5nZSB1cG9uCmFueW9uZSdzIGNvcHlyaWdodC4KCklmIHRoZSBzdWJtaXNzaW9uIGNvbnRhaW5zIG1hdGVyaWFsIGZvciB3aGljaCB5b3UgZG8gbm90IGhvbGQgY29weXJpZ2h0LAp5b3UgcmVwcmVzZW50IHRoYXQgeW91IGhhdmUgb2J0YWluZWQgdGhlIHVucmVzdHJpY3RlZCBwZXJtaXNzaW9uIG9mIHRoZQpjb3B5cmlnaHQgb3duZXIgdG8gZ3JhbnQgRFNVIHRoZSByaWdodHMgcmVxdWlyZWQgYnkgdGhpcyBsaWNlbnNlLCBhbmQgdGhhdApzdWNoIHRoaXJkLXBhcnR5IG93bmVkIG1hdGVyaWFsIGlzIGNsZWFybHkgaWRlbnRpZmllZCBhbmQgYWNrbm93bGVkZ2VkCndpdGhpbiB0aGUgdGV4dCBvciBjb250ZW50IG9mIHRoZSBzdWJtaXNzaW9uLgoKSUYgVEhFIFNVQk1JU1NJT04gSVMgQkFTRUQgVVBPTiBXT1JLIFRIQVQgSEFTIEJFRU4gU1BPTlNPUkVEIE9SIFNVUFBPUlRFRApCWSBBTiBBR0VOQ1kgT1IgT1JHQU5JWkFUSU9OIE9USEVSIFRIQU4gRFNVLCBZT1UgUkVQUkVTRU5UIFRIQVQgWU9VIEhBVkUKRlVMRklMTEVEIEFOWSBSSUdIVCBPRiBSRVZJRVcgT1IgT1RIRVIgT0JMSUdBVElPTlMgUkVRVUlSRUQgQlkgU1VDSApDT05UUkFDVCBPUiBBR1JFRU1FTlQuCgpEU1Ugd2lsbCBjbGVhcmx5IGlkZW50aWZ5IHlvdXIgbmFtZShzKSBhcyB0aGUgYXV0aG9yKHMpIG9yIG93bmVyKHMpIG9mIHRoZQpzdWJtaXNzaW9uLCBhbmQgd2lsbCBub3QgbWFrZSBhbnkgYWx0ZXJhdGlvbiwgb3RoZXIgdGhhbiBhcyBhbGxvd2VkIGJ5IHRoaXMKbGljZW5zZSwgdG8geW91ciBzdWJtaXNzaW9uLgo=Repositório InstitucionalPUBhttps://repositorio.furg.br/oai/request || http://200.19.254.174/oai/requestopendoar:2019-11-14T00:04:34Repositório Institucional da FURG (RI FURG) - Universidade Federal do Rio Grande (FURG)false |
dc.title.pt_BR.fl_str_mv |
Isatin-3-N4 -benzilthiosemicarbazone, a non-toxic thiosemicarbazone derivative, protects and reactivates rat and human cholinesterases inhibited by methamidophos in vitro and in silico |
title |
Isatin-3-N4 -benzilthiosemicarbazone, a non-toxic thiosemicarbazone derivative, protects and reactivates rat and human cholinesterases inhibited by methamidophos in vitro and in silico |
spellingShingle |
Isatin-3-N4 -benzilthiosemicarbazone, a non-toxic thiosemicarbazone derivative, protects and reactivates rat and human cholinesterases inhibited by methamidophos in vitro and in silico Barcelos, Rômulo Pillon Antioxidant Cholinesterases Molecular docking Thiosemicarbazones Methamidophos |
title_short |
Isatin-3-N4 -benzilthiosemicarbazone, a non-toxic thiosemicarbazone derivative, protects and reactivates rat and human cholinesterases inhibited by methamidophos in vitro and in silico |
title_full |
Isatin-3-N4 -benzilthiosemicarbazone, a non-toxic thiosemicarbazone derivative, protects and reactivates rat and human cholinesterases inhibited by methamidophos in vitro and in silico |
title_fullStr |
Isatin-3-N4 -benzilthiosemicarbazone, a non-toxic thiosemicarbazone derivative, protects and reactivates rat and human cholinesterases inhibited by methamidophos in vitro and in silico |
title_full_unstemmed |
Isatin-3-N4 -benzilthiosemicarbazone, a non-toxic thiosemicarbazone derivative, protects and reactivates rat and human cholinesterases inhibited by methamidophos in vitro and in silico |
title_sort |
Isatin-3-N4 -benzilthiosemicarbazone, a non-toxic thiosemicarbazone derivative, protects and reactivates rat and human cholinesterases inhibited by methamidophos in vitro and in silico |
author |
Barcelos, Rômulo Pillon |
author_facet |
Barcelos, Rômulo Pillon Portella, Rafael de Lima Lugokenski, Thiago Henrique Rosa, Edovando José Flores da Amaral, Guilherme Pires Garcia, Luiz Filipe Machado Bresolin, Leandro Gervini, Vanessa Carratu Soares, Félix Alexandre Antunes Barbosa, Nilda Berenice de Vargas |
author_role |
author |
author2 |
Portella, Rafael de Lima Lugokenski, Thiago Henrique Rosa, Edovando José Flores da Amaral, Guilherme Pires Garcia, Luiz Filipe Machado Bresolin, Leandro Gervini, Vanessa Carratu Soares, Félix Alexandre Antunes Barbosa, Nilda Berenice de Vargas |
author2_role |
author author author author author author author author author |
dc.contributor.author.fl_str_mv |
Barcelos, Rômulo Pillon Portella, Rafael de Lima Lugokenski, Thiago Henrique Rosa, Edovando José Flores da Amaral, Guilherme Pires Garcia, Luiz Filipe Machado Bresolin, Leandro Gervini, Vanessa Carratu Soares, Félix Alexandre Antunes Barbosa, Nilda Berenice de Vargas |
dc.subject.por.fl_str_mv |
Antioxidant Cholinesterases Molecular docking Thiosemicarbazones Methamidophos |
topic |
Antioxidant Cholinesterases Molecular docking Thiosemicarbazones Methamidophos |
description |
Organophosphates (OPs), which are widely used as pesticides, are acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitors. The inactivation of AChE results in the accumulation of acetylcholine at cholinergic receptor sites, causing a cholinergic crisis that can lead to death. The classical treatment for OP poisoning is administration of oximes, but these compounds are ineffective in some cases. Here we determined whether the new compound isatin-3-N4-benzilthiosemicarbazone (IBTC), which in our previous study proved to be an antioxidant and antiatherogenic molecule, could protect and reactivate AChE and BChE. Toxicity of IBTC after subcutaneous injection in mice was measured using assays for oxidized diclorofluoresceine (DCF), thiobarbituric acid reactive substances (TBARS), non-protein thiol (NPSH) levels, and catalase (CAT), sodium potassium (Na+/K+) ATPase, delta-aminolevulinic acid dehydratase (ALA-D), and glutathione peroxidases (GPx) enzyme activities. The cytotoxicity was evaluated and the enzymatic activity of cholinesterase was measured in human blood samples. Molecular docking was used to predict the mechanism of IBTC interactions with the AChE active site. We found that IBTC did not increase the amount of DCF-RS or TBARS, did not reduce NPSH levels, and did not increase CAT, (Na+/K+) ATPase, ALA-D, or GPx activities. IBTC protected and reactivated both AChE and BChE activities. Molecular docking predicted that IBTC is positioned at the peripheral anionic site and in the acyl binding pocket of AChE and can interact with methamidophos, releasing the enzyme’s active site. Our results suggest that IBTC, besides being an antioxidant and a promising antiatherogenic agent, is a non-toxic molecule for methamidophos poisoning treatment. |
publishDate |
2012 |
dc.date.issued.fl_str_mv |
2012 |
dc.date.accessioned.fl_str_mv |
2014-09-23T23:38:28Z |
dc.date.available.fl_str_mv |
2014-09-23T23:38:28Z |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/article |
format |
article |
status_str |
publishedVersion |
dc.identifier.citation.fl_str_mv |
BARCELOS, Rômulo Pillon et al. Isatin-3-N4-benzilthiosemicarbazone, a non-toxic thiosemicarbazone derivative, protects and reactivates rat and human cholinesterases inhibited by methamidophos in vitro and in silico. Toxicology in Vitro, v.26, n. 6, p.1030–1039, 2012. Disponível em: <http://ac.els-cdn.com/S0887233312000975/1-s2.0-S0887233312000975-main.pdf?_tid=04a9ef38-2f0b-11e4-9e9c-00000aab0f26&acdnat=1409268689_0d7324cb6946b5ab68c8ad8d84ba80f9>. Acesso em: 23 set. 2014. |
dc.identifier.uri.fl_str_mv |
http://repositorio.furg.br/handle/1/4613 |
dc.identifier.issn.none.fl_str_mv |
0887-2333 |
dc.identifier.doi.pt_BR.fl_str_mv |
10.1016/j.tiv.2012.04.008 |
identifier_str_mv |
BARCELOS, Rômulo Pillon et al. Isatin-3-N4-benzilthiosemicarbazone, a non-toxic thiosemicarbazone derivative, protects and reactivates rat and human cholinesterases inhibited by methamidophos in vitro and in silico. Toxicology in Vitro, v.26, n. 6, p.1030–1039, 2012. Disponível em: <http://ac.els-cdn.com/S0887233312000975/1-s2.0-S0887233312000975-main.pdf?_tid=04a9ef38-2f0b-11e4-9e9c-00000aab0f26&acdnat=1409268689_0d7324cb6946b5ab68c8ad8d84ba80f9>. Acesso em: 23 set. 2014. 0887-2333 10.1016/j.tiv.2012.04.008 |
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http://repositorio.furg.br/handle/1/4613 |
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Elsevier |
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Elsevier |
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