A review on oxidative stress in organophosphate-induced neurotoxicity

Abstract

Acetylcholinesterase inhibition, the principal mechanism of acute organophosphorus compound toxicity, cannot explain neuropsychiatric symptoms occurring after exposure to low organophosphate concentrations causing no cholinergic symptoms. Organophosphate-triggered oxidative stress has increasingly come into focus, occurring when the action of reactive oxygen species, generated from free radicals, is not compensated by antioxidant free radical scavengers. Being nucleophilic, organophosphates can easily accept an electron, thereby generating free radicals. Organophosphates inhibit the antioxidant paraoxonase, and reactive oxygen species are produced during organophosphate metabolism. Organophosphates disrupt the function of mitochondria, the principal source of free radicals. Organophosphates also induce neuroinflammation, which generates reactive oxygen species, and reactive oxygen species in turn stimulate neuroinflammation. Markers of reactive oxygen species are elevated in vitro and in vivo after exposure to organophosphates and in individuals professionally exposed to organophosphates. This most probably contributes to the pathogenesis of the intermediate syndrome, chronic organophosphate-induced neuropsychiatric disorders and neurodegeneration occurring in patients after organophosphate exposure. Evidence for beneficial effects of antioxidants in organophosphate poisoning is discussed.

Keywords: Acetylcholinesterase inhibition; Antioxidants; Blood brain barrier; Enzyme reactivation; Free radicals; Microglia; N-acetylcysteine; Neurodegeneration; Neuroinflammation; Organophosphates; Oxidative stress; Paraoxonase; Pesticide; Reactive oxygen species.