Avaliação de neurotoxicidade de formas enantioméricas de praguicidas organifosforados: estudos in vitro, in vivo e de neuroproteção
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Data
2012-03-02
Autores
Emerick, Guilherme Luz [UNESP]
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Editor
Universidade Estadual Paulista (Unesp)
Resumo
Clinicamente, os sintomas da intoxicação por organofosforados (OPs) são divididos em quatro categorias: síndrome colinérgica, síndrome intermediária, transtornos neuropsiquiátricos crônicos induzidos por OPs e neuropatia retardada induzida por OPs (NRIOP). Há estudos que comprovam a ocorrência de casos de NRIOP em seres humanos após intoxicação por metamidofós, porém existe grande dificuldade de estudar esta neuropatia no modelo experimental (galinha), devido à forte crise colinérgica que ocorre após a inibição da acetilcolinesterase (AChE). Uma possível explicação para tal diferença de efeito entre a espécie humana e a galinha é o fato de que os OPs possuem centros assimétricos e, assim sendo, se apresentam sob formas enantioméricas que podem apresentar diferenças de inibição da AChE e da esterase susceptível à neuropatia (ESNp). Assim, o objetivo deste trabalho foi avaliar, em sangue de galinhas e de seres humanos, em cérebro de galinhas (in vitro e in vivo) e em células da linhagem SH-SY5Y de neuroblastoma humano, a neurotoxicidade de formas enantioméricas de compostos organofosforados utilizados como praguicidas, tendo o metamidofós como protótipo e utilizando a AChE, butirilcolinesterase (BChE), ESNp e a calpaína como biomarcadores. Inicialmente, foi feita a separação dos enantiômeros do metamidofós utilizando a técnica de cromatografia líquida de alta eficiência (CLAE) com emprego de fases estacionárias quirais de polissacarídeos, onde se obteve resolução de até 1,56 para os enantiômeros avaliados. A forma (+)-metamidofós apresentou maior toxicidade in vitro para a BChE em galinhas e para ESNp...
Clinically, the symptoms of organophosphorus (OP) poisoning are divided into four categories: acute cholinergic syndrome, intermediate syndrome, chronic organophosphorus-induced neuropsychiatric disorders (COPIND) and organophosphorus-induced delayed neuropathy (OPIDN). There are studies that prove the occurrence of OPIDN in humans after methamidophos poisoning, but there is great difficulty in studying this neuropathy in the experimental model (hen), due to strong cholinergic crisis that occurs after inhibition of acetylcholinesterase (AChE). One possible explanation for this difference in effect between humans and hens is the fact that the OPs have asymmetric centers and therefore, are presented as enantiomeric forms that may exhibit differences in inhibition of AChE and neuropathy target esterase (NTE). Thus, the objective of this study was to evaluate, in the blood of hens and humans, in the brains of chickens (in vitro and in vivo) and in the SH-SY5Y human neuroblastoma cells, the neurotoxicity of enantiomeric forms of OPs used as pesticides, having methamidophos as the prototype and using AChE, butyrylcholinesterase (BChE), NTE and calpain as biomarkers. Initially, the complete separation of the methamidophos enantiomers was obtained applying the technique of high performance liquid chromatography (HPLC) and using polysaccharide chiral stationary phases. A maximum resolution of 1.56 was gotten for the enantiomers evaluated. The form (+)-methamidophos presented higher in vitro toxicity than that of the (-)-methamidophos for BChE of hens and NTE of hens and humans... (Complete abstract click electronic access below)
Clinically, the symptoms of organophosphorus (OP) poisoning are divided into four categories: acute cholinergic syndrome, intermediate syndrome, chronic organophosphorus-induced neuropsychiatric disorders (COPIND) and organophosphorus-induced delayed neuropathy (OPIDN). There are studies that prove the occurrence of OPIDN in humans after methamidophos poisoning, but there is great difficulty in studying this neuropathy in the experimental model (hen), due to strong cholinergic crisis that occurs after inhibition of acetylcholinesterase (AChE). One possible explanation for this difference in effect between humans and hens is the fact that the OPs have asymmetric centers and therefore, are presented as enantiomeric forms that may exhibit differences in inhibition of AChE and neuropathy target esterase (NTE). Thus, the objective of this study was to evaluate, in the blood of hens and humans, in the brains of chickens (in vitro and in vivo) and in the SH-SY5Y human neuroblastoma cells, the neurotoxicity of enantiomeric forms of OPs used as pesticides, having methamidophos as the prototype and using AChE, butyrylcholinesterase (BChE), NTE and calpain as biomarkers. Initially, the complete separation of the methamidophos enantiomers was obtained applying the technique of high performance liquid chromatography (HPLC) and using polysaccharide chiral stationary phases. A maximum resolution of 1.56 was gotten for the enantiomers evaluated. The form (+)-methamidophos presented higher in vitro toxicity than that of the (-)-methamidophos for BChE of hens and NTE of hens and humans... (Complete abstract click electronic access below)
Descrição
Palavras-chave
Intoxicação - Tratamento, Pesticidas - Toxicologia, Neuropathy target esterase (NTE)
Como citar
EMERICK, Guilherme Luz. Avaliação de neurotoxicidade de formas enantioméricas de praguicidas organifosforados: estudos in vitro, in vivo e de neuroproteção. 2012. 174 f. Tese (doutorado) - Universidade Estadual Paulista, Faculdade de Ciências Farmacêuticas, 2012.