Mechanisms of Organophosphorus Ester-Induced Delayed Neurotoxicity: Type I and Type II

Abstract

Some organophosphorus compounds produce neurologic dysfunctions, known as OPIDN, after a delay period that is accompanied by neuropathic damage in the central and peripheral nervous systems. This group of chemicals may be divided into two classes, Type I and II, based on chemical structure, species selectivity, age sensitivity, the length of latent period, clinical signs, morphology and distribution of neuropathologic lesions, protection with phenylmethyl sulfonyl fluoride, inhibition of neurotoxic esterase, and effect on catecholamine secretion from bovine adrenome-dullary chromaffin cells. The importance of this effect is underlined by the fact that incidents involving more than 40,000 cases of OPIDN in humans have been documented from 1899 to 1989. Most of these compounds are direct or indirect inhibitors of AChE, and produce acute cholinergic effects. Neurologic deficits are characterized by three phases: progressive, stationary, and improvement. Prognosis of OPIDN depends on the extent of damage of the nervous system. Improvement or even recovery of functions may follow mild cases, whereas severe toxicity results in long-lasting neurologic dysfunctions reflecting spinal cord damage. Recent studies have shown that delayed neurotoxic organophosphorus compounds interact with Ca2+/calmodulin kinase II (CaM kinase II), an enzyme responsible for the endogenous phosphorylation of cytoskeletal proteins, i.e. microtubules, neurofilaments, and MAP-2. This leads to an increased activity of CaM kinase II and enhanced phosphorylation of cytoskeletal elements, and eventually in the disassembly of cytoskeletal proteins. The dissociation of cytoskeletal proteins causes increased fast axonal transport in the treated animals resulting in the accumulation of altered cytoskeletal elements in the distal portions of the axon. Abnormal tubulin and neurofilaments are transformed into filamentous polymers and undergo condensation and dissolution. Concomitantly, proliferated endoplasmic reticulum and accumulated mitochondria degenerate and release Ca2+ ions. This leads to Ca2(+)-activated proteolysis of the cytoskeleton and interruption of ionic balance across the axonal membrane resulting in the uptake of water and axonal swelling, which subsequently degenerates. A similar mechanism may cause secondary myelin degeneration.

Time-dependent changes of lipid peroxidation and antioxidative status in nerve tissues of hens treated with tri-ortho-cresyl phosphate (TOCP)

“…In 1930, thousands of cases of paralysis occurred in the United States due to a consumption of Jamaica ginger extract ("Jake") contaminated with TOCP, also known as "Ginger Jake paralysis" (Nanda and Tapaswi, 1995). Since then, similar epidemics have been reported in other countries (Abou-Donia and Lapadula, 1990). In China, in the early 1990s, there were two outbreaks of OPIDN due to eating the flour contaminated by TOCP (Lu et al, 1992;Wang et al, 1996;Lei et al, 1998).…”

“…TOCP has been the archetype of a class of organophosphates inducing OPIDN, and adult hens are usually the animal model for experimental studies of OPIDN (Abou-Donia and Lapadula, 1990). Although a large number of toxicology studies have been done attempting to reveal the actual mechanism of OPIDN, it remains unclear.…”

Impaired Mitochondrial Functions in Organophosphate Induced Delayed Neuropathy in Rats

“…Organophosphate induced delayed neuropathy (OPIDN) is a well-recognized complication of acute organophosphate (OP) poisoning (Abou-Donia and Lapadula 1990;Marrs 1993;Karalliedde 1999), which becomes evident 2-3 weeks after acute exposure to certain OP and is characterized by distal degeneration of some long and large diameter axons in peripheral nerves and spinal cord (Lotti 1992). Axonal swellings containing aggregation of neurofilaments (NFs), microtubules, proliferation of endoplasmic reticulum and multivesicular vesicles have been shown in early stage, which is followed by disappearance of NFs from swollen axons after appearance of clinical signs of OPIDN (Abou-Donia 1981; Xie et al 2002).…”

Critical care requirements after mass toxic agent release

“…The third stage of clinical presentation of OP intoxication is organophosphate-induced delayed neuropathy, which develops over a long period postexposure This is thought to be an action of the OP on the neurotoxic esterase enzyme system and is not related to the anticholinesterase properties of the compound (21).…”