Dissertation

Organophosphorus ester-induced delayed neuropathy: The possible role of calcium

Wisler, John Arden

1988

Overview

Organophosphorus ester-induced delayed neuropathy (OPIDN) is a distal axonopathy induced by only some of the organophosphorus (OP) compounds: tri-ortho-cresyl phosphate (TOCP) and diisopropyl fluorophosphate (DFP) both induce OPIDN, whereas paraoxon does not. Although inhibition of neuropathy target esterase (NTE) has been correlated with the development of OPIDN, the actual biochemical mechanism remains unresolved. These studies were undertaken to evaluate whether OP-induced changes in intracellular calcium ( (Ca$\\sp{2+}$) $\\sb{\\rm i}$) predictably presage development of the axonopathy. Naive hens were pretreated with atropine sulfate (10 mg/kg, i.v.) and then dosed with either TOCP (750 mg/kg, p.o.), paraoxon (10 mg/kg, p.o.) or corn oil (control) and sacrificed after 24, 48, or 72 hours. NTE activity was significantly inhibited by TOCP (p $<$ 0.05) at all time points. Synaptosomes prepared from spinal cords of TOCP-treated hens exhibited significantly elevated (Ca$\\sp{2+}$) $\\sb{\\rm i}$ at 48 and 72 hours compared to (Ca$\\sp{2+}$) $\\sb{\\rm i}$ in controls, as measured by the fluorescent dye FURA-2. (Ca$\\sp{2+}$) $\\sb{\\rm i}$ was not elevated by paraoxon. Ca$\\sp{2+}$/K$\\sp+$-ATPase (CKA) and Na$\\sp+$/K$\\sp+$-ATPase (NKA) have been reported to be inhibited by some OP's and, if inhibited, could alter (Ca$\\sp{2+}$) $\\sb{\\rm i}$. DFP in vitro had no effect on NKA activity in synaptosomes from hen spinal cord. TOCP in vivo had no inhibitory effect on CKA or NKA activities in microsomes from hen spinal cord or brain. TOCP also had no effect on conjugated diene formation, an indication of lipid peroxidation, in hen spinal cord preparations. Ca$\\sp{2+}$ channel antagonists have been reported to be partially effective in preventing the early development of OPIDN. DFP in vitro had no effect on Ca$\\sp{2+}$ uptake into rat brain synaptosomes. In a separate series of experiments, NTE activity was found to be positively correlated with CKA activity in cardiac sarcoplasmic membrane reticular vesicles and their subfractions isolated from naive mongrel dogs. These data suggested that the OPIDN marker NTE may be associated with sarcoplasmic reticulum, an organelle central to (Ca$\\sp{2+}$) $\\sb{\\rm i}$ regulation. These findings suggest that intracellular calcium is elevated during the early development of OPIDN. This could be consistent with a calcium mediated neurotoxicity. The mechanism(s) for this alteration of calcium homeostasis remains unknown.

• Publisher: ProQuest Dissertations & Theses
• Subject: Neurology / Neurosciences / Pharmacology
• ISBN: 9798206892048