Biochemical changes in sciatic nerve of hens treated with tri-o-cresyl phosphate: increased phosphorylation of cytoskeletal proteins

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Abstract

Calcium- and calmodulin-regulated protein phosphorylation has been suggested to play a role in the pathogenesis of organophosphorus compound-induced delayed neurotoxicity (OPIDN). This condition is characterized by ataxia that progresses to paralysis concurrent with a central-peripheral distal axonopathy after a delay period of 1–2 weeks following exposure to an organophosphorus compound causing delayed neurotoxicity, such as tri-o-cresyl phosphate (TOCP). Calcium/calmodulin (CaM) kinase II is involved in the increased phosphorylation of brain microtubule and spinal cord neurofilament triplet proteins following treatment of animals with organophosphorus compounds that are capable of producing OPIDN. In this study, chickens were given a single oral neurotoxic dose of 750 mg TOCP/kg body weight and killed after 1, 6, 14 or 21 days following treatment. Protein kinase-mediated phosphorylation of cytoskeletal proteins was studied in proximal and distal parts of sciatic nerves of control and treated hens. Peripheral nerve proteins were phosphorylated in vitro using [γ-32P]ATP as a phosphoryl group donor. Phosphorylated proteins were separated by one- and two-dimensional sodium dodecyl sulfate polyacrylamide gel electrophoresis. Protein phosphorylation was detected by autoradiography and quantified by laser microdensitometry. The extent of Ca2+-calmodulin dependent phosphorylation of five cytoskeletal proteins was significantly increased in TOCP treated animals, particularly at 1 and 6 days after treatment, in both the proximal and distal portion of the nerve. The identity of these proteins was confirmed by 2-D PAGE as tubulin, the neurofilament triplet proteins and microtubule associated protein-2 (MAP-2). These results confirm earlier observation of the close temporal relationship between increased cytoskeletal protein phosphorylation and the development and OPIDN.

References (43)

  • M.B. Abou-Donia

    Organosphosphorus ester-induced delayed neurotoxicity

    A. Rev. Pharmac. Toxicol.

    (1981)
  • M.B. Abou-Donia et al.

    Studies on the molecular pathogenesis of organophosphorus compound-induced delayed neurotoxicity (OPIDN)

  • M.B. Abou-Donia et al.

    Mechanism of organophosphorus ester induced delayed neurotoxicity: Type I and Type II

    A. Rev. Pharmac. Toxicol.

    (1990)
  • M.B. Abou-Donia et al.

    Possible role of endogenous protein phosphorylation in organophosphorus compound-induced delayed neurotoxicity

  • W.N. Aldridge

    Tricresyl phosphate and cholinesterase

    Biochem. J.

    (1954)
  • W.N. Aldridge et al.

    Further observations on the neurotoxicity of organophosphorus compounds

    Biochem. Pharmac.

    (1966)
  • H. Bloch et al.

    Uber dic spezifitat der cholinesterase-hemmung durch tri-o-kresyl phosphat

    Z. Vitaminforsch.

    (1943)
  • S.L. Brenner et al.

    Tubulin antibody: a practical guide for immunization, purification and indirect immunofluorescence

  • J.B. Cavanagh

    The significance of the “dying back” process in experimental animals and human neurological disease

    Int. Rev. Exp. Path.

    (1964)
  • F.-C. Chiu et al.

    Bulk preparation of CNS cytoskeleton and the separation of individual neurofilament proteins by gel filtration: dyebinding characteristics and amino acid composition

    J. Neurochem.

    (1982)
  • R.J. Colbran et al.

    Calcium/calmodulin protein kinase II

    Biochem. J.

    (1989)
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