Banks CN, Lein PJ. A review of experimental evidence linking neurotoxic organophosphorus compounds and inflammation

Department of Molecular Biosciences, UC Davis School of Veterinary Medicine, One Shields Ave., Davis, CA 95616, USA.
NeuroToxicology (Impact Factor: 3.38). 02/2012; 33(3):575-84. DOI: 10.1016/j.neuro.2012.02.002
Source: PubMed


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.

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Available from: Pamela J Lein
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    • "While AChE inhibition is clearly an important mechanism of the toxicity of OPs, it may not account for all of the long term-neurological alterations associated with these chemicals. Deleterious effects of OPs that may be additive (or unrelated) to AChE inhibition include oxidative stress, impairments of mitochondrial function, neuroinflammation, and altered neurotrophin responses, etc. (Soltaninejad and Abdollahi, 2009; Banks and Lein, 2012; Terry, 2012). For several years our laboratory has been investigating the possibility that OPs impair axonal transport, a potentially significant issue given the fundamental importance of axonal transport to neuronal maintenance and function. "
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    ABSTRACT: The extensive use of organophosphates (OPs) is an ongoing environmental health concern due to multiple reports of OP-related neurological abnormalities. While the mechanism of the acute toxicity of OPs is attributed to inhibition of acetylcholinesterase (AChE), there is growing evidence that this may not account for all of the long term neurotoxic effects of OPs. In previous experiments (using ex vivo and in vitro model systems) we observed that the insecticide OP chlorpyrifos impaired the movements of vesicles and mitochondria in axons. Here, using a time-lapse imaging technique, we evaluated the OP-nerve agent, diisopropylfluorophosphate (DFP) across a wide range of concentrations (subnanomolar to micromolar) for effects on fast axonal transport of membrane bound organelles (MBOs) that contained the amyloid precursor protein (APP) tagged with the fluorescent marker, Dendra2 (APPDendra2). Both 1 and 24 hours of exposure to DFP and a positive control compound, colchicine, resulted in a decrease in the velocity of anterograde and retrograde movements of MBOs and an increase in the number of stationary MBOs. These effects occurred at picomolar (100 pM) to low nanomolar (0.1 nM) concentrations that were not associated with compromised cell viability or cytoskeletal damage. Moreover, the effects of DFP on axonal transport occurred at concentrations that did not inhibit AChE activity and they were not blocked by cholinergic receptor antagonists. Given the fundamental importance of axonal transport to neuronal function, these observations may explain some of the long term neurological deficits that have been observed in humans who have been exposed to organophosphates.
    Full-text · Article · Dec 2015 · Journal of Pharmacology and Experimental Therapeutics
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    • "But the multiple pharmacological action of PROM is indeed a factor for the survival whether by prompting spontaneous reactivation , centrally mediated anti-nicotinic or antimuscarinic action or by altering the detoxifying enzyme as found by Welch and Coon[5]. Petroianu et al.[22,30,31]investigated tiapride for acute paraoxon poisoning against rats and found very improved survival, though tion[17,19]. Cowan et al.[32]concluded that non-cholinergic mechanism of OP poisoning often includes anaphylactic shock which is prompted by autocoids such as histamine. "
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    ABSTRACT: Organophosphorus compound poisoning (OPC) is a global issue. The problem is aggravated with the threats of terrorist use, unintentional use and irresponsible practice as happened recently in turmoil countries. The purpose of the current study was to investigate the old-generation antihistamine promethazine (PROM), a drug with multi pharmacological actions, as an antidote to extremely and highly toxic (WHO’s class IA and IB) OPC poisoning in experimental animal models conducted on adult male wistar rats. Experimental groups were treated intraperitoneal (i.p.) with LD70 of methyl paraoxon (MPOX), class IA and dicrotophos (DCP), class IB alone and a combination of simultaneously i.p. injection of PROM. Mortality was recorded at 30 minutes, 1, 2, 3, 4, 24, 48 hours post injections. RBC-AChE was measured in survivals. MPOX was chosen for further studies with atropine (ATR) and pralidoxime (PAM). In addition to Kaplan-Meir survival analysis, serum lactate dehydrogenase (LDH) and creatinine kinase (CK) from serum were measured in all experimental groups with MPOX. The results revealed significant protection by PROM in both MPOX and DCP intoxicated rats, though the inhibition of RBC-AChE was high. The observed results show that groups treated with a combination of MPOX and PROM or MPOX, PROM, and PAM were protected higher than those treated with MPOX and ATR or MPOX, ATR, and PAM though statistically not significantly different (P ≤ 0.05). No effect was observed on the activity of LDH and CK. The study concludes that PROM may be effectively used in OPC poisoning. However, risk/benefits trials and further studies with different doses and other OPC groups are warranted.
    Full-text · Article · Oct 2015 · International Journal of Clinical and Experimental Medicine
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    • "(A) Oxidative stress and related mechanisms and (B) inhibition of esterases. ", increase; Th2, T helper 2. cancer and certain infections would be functional consequences of chronic OP poisoning (Banks & Lein, 2012; Tarkowski et al., 2004) (Figure 1B). "
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    ABSTRACT: Nowadays, in many communities, there is a growing concern about possible adverse effects of pesticides on human health. Reports indicate that during environmental or occupational exposure, pesticides can exert some intense adverse effects on human health through transient or permanent alteration of the immune system. There is evidence on the relation between pesticide-induced immune alteration and prevalence of diseases associated with alterations of the immune response. In the present study, direct immunotoxicity, endocrine disruption and antigenicity have been introduced as the main mechanisms working with pesticides-induced immune dysregulation. Moreover, the evidence on the relationship between pesticide exposure, dysregulation of the immune system and predisposition to different types of psychiatric disorders, cancers, allergies, autoimmune and infectious diseases are criticized.
    Full-text · Article · Mar 2015 · Toxicology Mechanisms and Methods
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