A review of experimental evidence linking neurotoxic organophosphorus compounds and inflammation

Abstract

Organophosphorus (OP) nerve agents and pesticides inhibit acetylcholinesterase (AChE), and this is thought to be a primary mechanism mediating the neurotoxicity of these compounds. However, a number of observations suggest that mechanisms other than or in addition to AChE inhibition contribute to OP neurotoxicity. There is significant experimental evidence that acute OP intoxication elicits a robust inflammatory response, and emerging evidence suggests that chronic repeated low-level OP exposure also upregulates inflammatory mediators. A critical question that is just beginning to be addressed experimentally is the pathophysiologic relevance of inflammation in either acute or chronic OP intoxication. The goal of this article is to provide a brief review of the current status of our knowledge linking inflammation to OP intoxication, and to discuss the implications of these findings in the context of therapeutic and diagnostic approaches to OP neurotoxicity.

Figure 1

Schematic diagram of the cholinergic anti-inflammatory pathway (CAP). Stimulation of the vagus nerve induces acetylcholine (ACh) release, which binds to a7-nicotinic acetylcholine receptors (nAChR) on macrophages. Activation of a7-nAChR initiates the Jak2- STAT3 signaling pathway, and inhibits NF-kB nuclear translocation, leading to the inhibition of pro-inflammatory cytokine release. OP exposure should activate CAP by inhibiting acetylcholinesterase (AChE), causing an increase in acetylcholine levels.

Figure 2

Schematic of the inflammatory response following acute exposure to organophosphate (OP) agents. Inhibition of acetylcholinesterase (AChE) induces cholinergic toxicity, leading to neuronal damage via the release of pro-inflammatory cytokines from activated microglia, astrocytes. Prostaglandin/isoprostanoid release and neuronal damage due to enhanced glutamatergic activity (excitotoxicity) are additional consequences of acute OP intoxication. Astrocytes secrete neurotrophic factors which lead to neurogenesis. The role of the cholinergic anti-inflammatory pathway in organophosphate toxicity is not currently known. Novel or unknown pathways are indicated with grey dashed arrows/bars.