Elsevier

NeuroToxicology

Volume 33, Issue 3, June 2012, Pages 575-584
NeuroToxicology

Review
A review of experimental evidence linking neurotoxic organophosphorus compounds and inflammation

https://doi.org/10.1016/j.neuro.2012.02.002Get rights and content

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.

Introduction

Organophosphorus (OP) nerve agents and pesticides inhibit acetylcholinesterase (AChE), and this activity is widely accepted as a primary mechanism underlying the neurotoxicity of these compounds. AChE inhibition increases acetylcholine in cholinergic synapses resulting initially in overstimulation of nicotinic and muscarinic receptors followed by receptor downregulation. Acute cholinergic toxicity (OP poisoning) is thought to be mediated by overstimulation of receptors secondary to AChE inhibition, resulting in peripheral parasympathomimetic effects as well as seizures and respiratory arrest; whereas it is hypothesized that chronic OP neurotoxicity is mediated in part by receptor downregulation (Costa, 2006, Echbichon and Joy, 1995). However, a number of observations suggest that OP neurotoxicity is not due entirely to perturbations of cholinergic systems. For example, different OPs have different effects despite similar changes in AChE activity and other cholinergic markers (Bushnell and Moser, 2006, Jett and Lein, 2006, Pope et al., 2005, Pope, 1999), and AChE knockout mice exhibit symptoms of neurotoxicity comparable to those observed in wildtype mice following OP exposure (Duysen et al., 2001). There are also reports in the human and animal literature that OP neurotoxicity, particularly in response to chronic OP exposure, occurs in the absence of cholinesterase (ChE) inhibition (Abou-Donia, 2003, Costa, 2006, Kamel and Hoppin, 2004). For example, studies of humans with occupational exposures to OPs have consistently failed to find a significant association between blood cholinesterase activity and neurobehavioral deficits (Rohlman et al., 2011). A review of the animal literature presents a more complicated picture. In general, the most significant and prolonged motor effects are obtained following OP exposures that markedly inhibit brain ChE activity; however, cognitive deficits are not as clearly correlated with ChE inhibition (Bushnell and Moser, 2006). Considered together, these observations suggest that mechanisms in addition to or other than AChE inhibition mediate OP neurotoxicity. This conclusion has significant implications for the development of effective medical countermeasures for OP neurotoxicity and the use of AChE inhibition as a predictive or diagnostic biomarker of OP-induced neurotoxicity.

Of the various alternative molecular targets and mechanisms proposed to mediate OP-neurotoxicity (Casida and Quistad, 2005, Hernandez et al., 2004, Jett and Lein, 2006, Lockridge and Schopfer, 2010, Pancetti et al., 2007, Soltaninejad and Abdollahi, 2009), inflammation is of interest because of evidence suggesting that anti-inflammatory agents are neuroprotective following acute intoxication with OP nerve agents (Amitai et al., 2006) and because of the availability of experimentally validated quantitative peripheral biomarkers of inflammation that correlate well with neurobehavioral deficits observed consequent to neurodegenerative disease (Dziedzic, 2006, Mrak and Griffin, 2005). In this review, we will provide an overview of experimental evidence that links inflammation to acute and chronic OP intoxication, discuss mechanisms by which OPs may elicit inflammatory response and the potential pathophysiologic consequences of inflammation in the context of OP toxicity, and finally suggest how information regarding OP-induced inflammation may provide insight regarding novel therapeutic strategies for mitigating the neural damage consequent to OP intoxication.

Section snippets

Overview of inflammation

Inflammation is the natural response of the immune system to injury or infection. The inflammatory response is initiated via activation of macrophages in the periphery and microglia and/or astrocytes in the central nervous system (CNS), which leads to the release of proinflammatory mediators, such as cytokines. These compounds induce the dilation of blood vessels to promote migration of leukocytes, typically neutrophils, to the area of injury. Neutrophils and macrophages induce apoptosis of

Acute OP intoxication is associated with increased inflammation

One of the initial indicators that OPs may initiate an inflammatory response was evidence linking acute OP intoxication to the activation of microglia and astrocytes. Microglia are considered the immune cells of the brain in that they have the capability to respond to infection or injury in the CNS (Hanisch and Kettenmann, 2007, Kreutzberg, 1996). Microglial activation in response to neuronal insult is quite rapid (Stence et al., 2001), and activated microglia are characterized by cellular

Chronic OP exposures and inflammation

While there is clear and compelling evidence that acute OP intoxication is associated with inflammatory responses, there is still a question as to whether chronic OP exposures that have been linked to neurobehavioral deficits (Bouchard et al., 2011, Engel et al., 2011, Rohlman et al., 2011) are also associated with inflammation. Certainly traditional biomarkers of OP exposure (urinary OP metabolites and blood cholinesterase inhibition) have not been reliably associated with changes in cognitive

Mechanisms contributing to OP-induced inflammation

A key question is whether inflammatory responses to OP intoxication are mechanistically related to AChE inhibition. As indicated earlier, AChE inhibition is a hallmark characteristic of acute OP intoxication, that can result in cholinergic crisis and seizure onset. Experimental evidence indicates that OP-induced seizures are associated with neuronal damage and the induction of inflammation. OP-induced seizures are coincident with cytokine and chemokine elevation, glial activation, increases in

OP-induced inflammation: neurotoxic or neuroprotective?

The general assumption has been that OP-induced inflammation contributes to the pathology associated with OP neurotoxicity, and in particular, the delayed neuronal cell death and persistent neurobehavioral deficits observed following acute OP intoxication (Collombet, 2011). This assumption is based on the observation that many of the therapeutic agents currently used to treat OP poisoning possess anti-inflammatory properties. For example, benzodiazepines attenuate seizures and convulsions by

Conclusions

It is quite clear that acute OP intoxication leads to an inflammatory response that appears to be both neurotoxic and neuroprotective. Based on studies of the therapeutic efficacy of anti-inflammatory compounds and growth factors known to be secreted by activated astrocytes following acute OP intoxication, a model emerges in which inflammation is initially detrimental but may then serve to promote repair at later stages in at least some brain regions. An intriguing possibility that warrants

Conflict of interest

The authors have no conflict of interest to declare.

Acknowledgements

This work is supported by research grants from the National Institute of Neurological Disease and Stroke (NINDS CounterACT Program, R21 NS072094, Lein and Rogawski, MPI) and the National Institute of Environmental Health Sciences (NIEHS R01 ES016308, Anger and Lein, MPI), and an NIEHS postdoctoral fellowship to Banks (T32 ES007059-33). The content is solely the authors’ responsibility and does not necessarily represent official views of the NINDS or NIEHS.

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