Involvement of calcium in organophosphorus-induced delayed neuropathy: A functional, morphological, and biochemical study

Organophosphorus compounds are widely used in agriculture as pesticides and in industry as petroleum additives and modifiers of plastics. Some of these compounds are capable of inducing an irreversible neuropathy developing weeks to months after exposure, yet there is no effective treatment. This may be due in part to the lack of knowledge of how this neuropathy develops.; In this dissertation it is proposed that as a consequence of a triggering event, peripheral nerves may be predisposed to an increase in calcium (Ca{dollar}sp{lcub}++{rcub}{dollar}) mobilization and the neuronal accumulation of this cation. This increase in Ca{dollar}sp{lcub}++{rcub}{dollar} could thereby initiate a cascade of events, in both nerve and muscle, that may account for some of the detrimental changes occurring during organophosphorus-induced delayed neuropathy (OPIDN).; The involvement of Ca{dollar}sp{lcub}++{rcub}{dollar} in the pathogenesis of OPIDN was tested using functional, morphological and biochemical techniques in the domestic hen, the recognized animal model of OPIDN.; The isolated biventer cervicis nerve-muscle preparation was developed for quick assessment of the time course of OPIDN deficits and validated by comparison to in vivo preparations. This preparation proved more sensitive by functional and morphological evaluation indicating early damage at 4 days following exposure and before appearance of clinical signs. Regeneration was detected after 21 days.; OPIDN was modified by using Ca{dollar}sp{lcub}++{rcub}{dollar} channel blockers, nifedipine and verapamil, in the presence of phenyl saligenin phosphate, an active neurotoxicant. Attenuation of OPIDN by these compounds was revealed by clinical assessment, by changes in nerve excitability denoted by strength-duration relationships in response to electrical stimulation, by denervation hypersensitivity to neurotransmitter and by morphology. These modifiers attenuated all degenerative responses.; Furthermore, it was revealed that the activity of Ca{dollar}sp{lcub}++{rcub}{dollar}-activated neutral protease (CANP), an enzyme responsible for neurofilament degradation, was increased in OPIDN. Such increases were ameliorated by modifiers of Ca{dollar}sp{lcub}++{rcub}{dollar} movement.; This study strongly suggests that Ca{dollar}sp{lcub}++{rcub}{dollar}, possibly through activation of CANP, may contribute to functional and morphological deficits of OPIDN.