Possible role of enhanced microtubule phosphorylation in dichlorvos induced delayed neurotoxicity in rat.
The effect of a single subcutaneous dose of 200 mg/kg body weight dichlorvos on neuronal microtubule phosphorylation has been studied in rat following the development of organophosphate induced delayed neurotoxicity (OPIDN). Microtubule associated Ca2+/calmodulin dependent as well as cAMP dependent protein kinases were assayed. Dichlorvos administration led to a consistent increase in the activity of both the kinases at all post exposure intervals (7th, 15th and 21st day) as compared to that of controls. After in vitro phosphorylation using [gamma-32P]ATP, various proteins were resolved on one-dimensional 8% SDS-PAGE, stained with Coomassie Blue and autoradiographed. The amount of 32P incorporated was quantified by microdensitometry. Dichlorvos enhanced the phosphorylation of 55- and 280-kDa proteins. These two proteins were identified as tubulin and microtubule associated protein-2 (MAP-2) by immunoblotting. This study showed that dichlorvos induced hyperphosphorylation of tubulin and MAP-2 which in turn destabilizes microtubule assembly, and may ultimately result in axonal degeneration leading to dichlorvos induced delayed neurotoxicity.
Department of Biochemistry, Postgraduate Institute of Medical Education and Research, - 160012, Chandigarh, India.
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Choudhary
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Joshi
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KD
Gill
D000818:Animals; D001792:Blood Platelets / Q000187:drug effects / Q000201:enzymology; D001923:Brain Chemistry / Q000187:drug effects; D002147:Calmodulin / Q000378:metabolism; D002265:Carboxylic Ester Hydrolases / Q000378:metabolism; D003402:Creatine Kinase / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004006:Dichlorvos / Q000633:toxicity*; D007306:Insecticides / Q000633:toxicity*; D008297:Male; D008854:Microscopy, Electron; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D008870:Microtubules / Q000378:metabolism* / Q000648:ultrastructure; D016472:Motor Neuron Disease / Q000139:chemically induced / Q000378:metabolism; D009410:Nerve Degeneration / Q000139:chemically induced / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000201:enzymology; D010766:Phosphorylation; D051381:Rats; D017208:Rats, Wistar
D002147:Calmodulin; D007306:Insecticides; D008869:Microtubule-Associated Proteins; D004006:Dichlorvos; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D003402:Creatine Kinase; D002265:Carboxylic Ester Hydrolases; C021859:neurotoxic esterase