Mechanisms for consideration for intervention in the development of organophosphorus-induced delayed neuropathy

Author(s)

Emerick, Guilherme L. ^{[1, 2]} ; DeOliveira, Georgino H. ^[1] ; dos Santos, Antonio C. ^[2] ; Ehrich, Marion ^[3]

Affiliation

^[1] Univ Estadual Paulista UNESP, Sch Pharmaceut Sci, Dept Nat Act Principles & Toxicol, BR-14801902 Araraquara, SP - Brazil

^[2] Fac Ciencias Farmaceut Ribeirao Preto USP, Dept Anal Clin Toxicol & Bromatol, Ribeirao Preto, SP - Brazil

^[3] Virginia Tech, Virginia Maryland Reg Coll Vet Med, Dept Biomed Sci & Pathobiol, Blacksburg, VA - USA

• Document type: Review article
• Source: Chemico-Biological Interactions; v. 199, n. 3, p. 177-184, SEP 30 2012.
• Web of Science Citations: 21

Abstract

Organophosphorus-induced delayed neuropathy (OPIDN) is a neurodegenerative disorder characterised by ataxia progressing to paralysis with concomitant central and peripheral distal axonopathy. Symptoms of OPIDN in people include tingling of the hands and feet. This tingling is followed by sensory loss, progressive muscle weakness and flaccidity of the distal skeletal muscles of the lower and upper extremities and ataxia, which appear about 8-14 days after exposure. Some organophosphorus compounds (OPs) that are still used in worldwide agriculture have potential to induce OPIDN, including methamidophos, trichlorfon, dichlorvos and chorpyrifos. This review summarizes experimental attempts to prevent and/or treat OPIDN and the different mechanisms involved in each approach. The initial mechanism associated with development of OPIDN is phosphorylation and inhibition of neuropathy target esterase (NTE). The phosphorylated enzyme undergoes a second reaction known as ``aging{''} that results in the loss of one of the ``R{''} groups bound to the phosphorus of the OP. A second mechanism involved in OPIDN is an imbalance in calcium homeostasis. This can lead to the activation of calcium-activated neutral protease and increases in calcium/calmodulin-dependent protein kinases. These events contribute to aberrant phosphorylation of cytoskeletal proteins and protein digestion in the terminal axon that can proceed similarly to Wallerian-type degeneration. Several experimental studies demonstrated alleviation of the signs and symptoms of OPIDN by restoring calcium balance. Other studies have used preadministration of NTE inhibitors, such as carbamates, thiocarbamates, sulfonyl fluorides and phosphinate to prevent OPIDN. Progress is being made, but there is yet no single specific treatment available for use in clinical practice to prevent or alleviate the severe effects of OPIDN. (C) 2012 Elsevier Ireland Ltd. All rights reserved. (AU)

• FAPESP's process: 12/00168-6 - Organophosphate-induced delayed neuropathy: in vitro studies of mechanisms of neurotoxicity and neuroprotection
• Grantee: Guilherme Luz Emerick
• Support Opportunities: Scholarships in Brazil - Post-Doctoral