title: Biochemical, histopathological and clinical evaluation of delayed effects caused by methamidophos isoforms and TOCP in hens: ameliorative effects using control of calcium homeostasis.
abstract: This work evaluated the potential of the isoforms of methamidophos to cause organophosphorus-induced delayed neuropathy (OPIDN) in hens. In addition to inhibition of neuropathy target esterase (NTE) and acetylcholinesterase (AChE), calpain activation, spinal cord lesions and clinical signs were assessed. The isoforms (+)-, (±)- and (-)-methamidophos were administered at 50mg/kg orally; tri-ortho-cresyl phosphate (TOCP) was administered (500mg/kg, po) as positive control for delayed neuropathy. The TOCP hens showed greater than 80% and approximately 20% inhibition of NTE and AChE in hen brain, respectively. Among the isoforms of methamidophos, only the (+)-methamidophos was capable of inhibiting NTE activity (approximately 60%) with statistically significant difference compared to the control group. Calpain activity in brain increased by 40% in TOCP hens compared to the control group when measured 24h after dosing and remained high (18% over control) 21 days after dosing. Hens that received (+)-methamidophos had calpain activity 12% greater than controls. The histopathological findings and clinical signs corroborated the biochemical results that indicated the potential of the (+)-methamidophos to be the isoform responsible for OPIDN induction. Protection against OPIDN was examined using a treatment of 2 doses of nimodipine (1mg/kg, i.m.) and one dose of calcium gluconate (5mg/kg, i.v.). The treatment decreased the effect of OPIDN-inducing TOCP and (+)-methamidophos on calpain activity, spinal cord lesions and clinical signs.
authors.affiliation: Department of Natural Active Principles and Toxicology, School of Pharmaceutical Science, Univ Estadual Paulista - UNESP, Araraquara, SP, Brazil. glemerick@yahoo.com.br
authors.forename: Guilherme L
authors.initials: GL
authors.lastname: Emerick
authors.forename: Marion
authors.initials: M
authors.lastname: Ehrich
authors.forename: Bernard S
authors.initials: BS
authors.lastname: Jortner
authors.forename: Regina V
authors.initials: RV
authors.lastname: Oliveira
authors.forename: Georgino H
authors.initials: GH
authors.lastname: Deoliveira
mesh_terms: D000110:Acetylcholinesterase / Q000187:drug effects / Q000378:metabolism; D000284:Administration, Oral; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D002118:Calcium / Q000378:metabolism; D002125:Calcium Gluconate / Q000494:pharmacology; D002154:Calpain / Q000187:drug effects / Q000378:metabolism; D002265:Carboxylic Ester Hydrolases / Q000037:antagonists & inhibitors / Q000378:metabolism; D002645:Chickens; D005260:Female; D006706:Homeostasis; D007306:Insecticides / Q000633:toxicity*; D020258:Neurotoxicity Syndromes / Q000209:etiology* / Q000517:prevention & control; D009553:Nimodipine / Q000494:pharmacology; D009946:Organothiophosphorus Compounds / Q000633:toxicity*; D013116:Spinal Cord / Q000187:drug effects / Q000473:pathology; D013997:Time Factors; D014317:Tritolyl Phosphates / Q000633:toxicity*
chemical_list: D007306:Insecticides; D009946:Organothiophosphorus Compounds; D014317:Tritolyl Phosphates; D009553:Nimodipine; C014655:methamidophos; D002265:Carboxylic Ester Hydrolases; C021859:neurotoxic esterase; D000110:Acetylcholinesterase; D002154:Calpain; D002125:Calcium Gluconate; D002118:Calcium; C025541:tri-o-cresyl phosphate