Neuropathy target esterase inhibitors

Wu, S.Y., Casida, J.E. (1996). Subacute neurotoxicity induced in mice by potent organophosphoras neuropathy target esterase inhibitors. Toxicol. Appl. Pharmacol. 139 195-202. 

Li, W. W.. and Casida, J. E. (1998). Organopho.sphoru.s neuropathy target esterase inhibitors selectively block outgrowth of neurite-like and cell processes in cultured cells. To.r.iail. Leu. 98, 139-146-... 

Li. W., iind Casida, J. E. (1997). Actions of two highly potent organophosphonis neuropathy target esterase inhibitors in mammalian cell lines. Toxical. Lett. 92, 123-130. 

Exposure to some organophosphate cholinesterase inhibitors results in a delayed neuropathy characterized by degeneration of axons and myelin. This effect is not associated with the inhibition of acetylcholinesterase, but rather with the inhibition of an enzyme described as neuropathy target esterase (NTE) however, the exact mechanism of toxicity is not yet fully understood (Munro et al., 1994). For some organophosphate compounds, delayed neuropathy can be induced in experimental animals at relatively low exposure levels, whereas for others the effect is only seen following exposure to supralethal doses when the animal is protected from the acute toxic effects caused by cholinesterase inhibition. 

FIGURE 57.5. Subclasses of neuropathy target esterase (NTE) inhibitors. Type A inhibitors include phosphates, phosphonates, and phosphoramidates these are neuropathic and capable of aging. T pe B inhibitors include phosphinates, sulfonates, and carbamates these are nonneuropathic and not capable of aging. However, inhibition of NTE with a type B inhibitor will protect against organophosphorus compound-induced delayed neurotoxicity (OPIDN) from subsequently administered type A inhibitors. Reproduced with permission from Richardson (2005). 

DEF is a relatively weak inhibitor of acetylcholinesterase. The compound is hydrolyzed to a large extent in the intestine to -butyl mercaptan, which is responsible for the late acute effects of DEF. The putative molecular target in neural tissue for initiation of delayed neuropathy is neurotoxic esterase or neuropathy target esterase (NTE). 

Ehrich, M., Jortner, B.S., and Padilla, S., Comparison of the relative inhibition of acetylcholinesterase and neuropathy target esterase in rats and hens given cholinesterase inhibitors, Fundam. Appl. Toxicol.,24,94-101,1995... 

Makhaeva G., and Malygin V., Different specificity of acethylcholinesterase and neuropathy target esterase to organophosphorus inhibitors. The 12th ESN Meeting, St.-Petersburg, Abstracts, J. Neurochem., 71 (Suppl.), S21, 1998. 

Wu, S. Y., and Casida, J.E., Ethyl octylphosphonofluoridate and analogs Optimized inhibitors of neuropathy target esterase, Chem. Res. Toxicol. 8,1070-1075,1995. 

Lotti, M., Moretto, A, Capodicasa. E., Bertolazzi, M., Peraica, M., and Scapellato, M. L. (1993). Interactions between neuropathy target esterase and its inhibitors and the development of polyneuropathy. Toxicol. Appl. Pharmacol. 122, 16. -171. 

Qui.stad, G, B., Sparks, S. E,. Segall, Y Nomura, D. K., and Casida, J. E, (2002b). Selective inhibitors of fatty acid amide hydrola.se relative to neuropathy target esterase and acetylcholinesterase Toxicological implications. Tu.ckol Appl. Pharmacol, 179, 57-63. 

Certain organophosphates may also induce delayed polyneuropathy, usually 2-3 weeks after a single exposure. The symptoms are tingling of hands and feet, sensory loss, progressive muscle weakness, and ataxia. Also, certain organophosphorus compounds are poor inhibitors of AChE but may, however, bind to another esterase, known as neuropathy target esterase (NTE) and induce delayed neuropathy. 

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