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Mechanisms of Organophosphate Neurotoxicity

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Mechanisms of Organophosphate Neurotoxicity UC Davis UC Davis Previously Published Works Title Mechanisms of organophosphate neurotoxicity. Permalink https://escholarship.org/uc/item/9w96f916 Authors Tsai, Yi-Hua Lein, Pamela J Publication Date 2021-06-01 DOI 10.1016/j.cotox.2021.04.002 Peer reviewed eScholarship.org Powered by the California Digital Library University of California Available online at www.sciencedirect.com Current Opinion in ScienceDirect Toxicology Mechanisms of organophosphate neurotoxicity Yi-Hua Tsai and Pamela J. Lein Abstract nicotinic cholinergic receptors in the peripheral and The canonical mechanism of organophosphate (OP) neuro- central nervous systems. Acute inhibition of AChE by toxicity is the inhibition of acetylcholinesterase (AChE). How- 60e70% causes ‘cholinergic crisis’, a clinical toxidrome ever, multiple lines of evidence suggest that mechanisms in characterized by muscle fasciculations and weakness, addition to or other than AChE inhibition contribute to the parasympathomimetic signs, depression of respiratory neurotoxic effects associated with acute and chronic OP ex- control centers in the brainstem, seizures, and death posures. Characterizing the role(s) of AChE inhibition versus [1,2]. Clinical and experimental evidence supports noncholinergic mechanisms in OP neurotoxicity remains an AChE inhibition as the mechanism triggering acute active area of research with significant diagnostic and thera- neurotoxic effects of OPs [1,2], although AChE peutic implications. Here, we review recently published studies knockout mice exhibit signs of acute neurotoxicity that provide mechanistic insights regarding (1) OP-induced similar to those observed in wild-type mice after acute status epilepticus, (2) long-term neurologic consequences of OP poisoning [3]. Persistent epileptiform discharges, acute OP exposures, and (3) neurotoxic effects associated cognitive deficits, and anxious/depressive behavior with repeated low-level OP exposures. Key data gaps and manifest in acutely intoxicated humans [4,5] and challenges are also discussed. experimental animals [1,6,7] well after AChE activity has recovered to pre-exposure levels. These observa- Addresses Department of Molecular Sciences, University of California, Davis tions suggest that acute and long-term effects of acute School of Veterinary Medicine, 1089 Veterinary Medicine Drive, Davis, OP intoxication are mediated by mechanisms in addition CA, 95616, USA to or other than AChE inhibition. Corresponding author: Lein, Pamela J ([email protected]) Occupational [8,9] and early-life [10] OP exposures that do not cause cholinergic crisis are also associated with Current Opinion in Toxicology 2021, 26:49–60 neurotoxic outcomes, but there is little evidence This review comes from a themed issue on Mechanistic Toxicology supporting an association between AChE activity and neurobehavioral outcomes. The hypothesis that non- Edited by Monica Neagu and Ayse Basak Engin cholinergic mechanisms contribute to the neurotoxicity Available online 30 April 2021 of repeated low-level OP exposures is largely supported For a complete overview see the Issue and the Editorial by preclinical literature [10,11]. Although the most https://doi.org/10.1016/j.cotox.2021.04.002 significant and prolonged motor effects in animals are 2468-2020/© 2021 Elsevier B.V. All rights reserved. observed after OP exposures that markedly inhibit AChE activity, deficits in cognitive [12] and social [13] behavior are not as clearly correlated with AChE Keywords Calcium homeostasis, Cannabinoid signaling, Glutamatergic signaling, inhibition. Neuroinflammation, Oxidative stress, Synaptotoxicity. Abbreviations Characterization of noncholinergic mechanisms of OP 2+ AChE, acetylcholinesterase; AMPAR, AMPA receptors; [Ca ]i, intra- 2+ neurotoxicity remains an area of active research. Here, cellular Ca concentrations; CB1R, endocannabinoid type 1 receptors; we review selected studies published from late 2018 CPF, chlorpyrifos; DFP, diisopropyl fluorophosphate; GABAAR, GABAA receptors; GluK1R, kainate receptors containing the GluK1 subunit; through early 2021 that provide mechanistic insights IP3R, inositol triphosphate receptor; mAChR, muscarinic cholinergic into (1) OP-induced status epilepticus (SE), (2) long- receptor; NMDAR, NMDA receptor; OP(s), organophosphate(s); qRT- term neurologic consequences of acute OP exposures, PCR, quantitative reverse transcription–polymerase chain reaction; and (3) neurotoxicity of repeated low-level OP RNS, reactive nitrogen species; ROS, reactive oxygen species; SE, status epilepticus; RyR, ryanodine receptors; TSPO, 18 kDa mito- exposures. chondrial translocator protein. Mechanisms contributing to OP-induced SE Introduction Seizures are generated by the initial hypercholinergic The canonical mechanism of organophosphate (OP) state, but are reinforced and sustained by glutamatergic (Box 1) neurotoxicity is inhibition of acetylcholines- activity [14]. The molecular mechanism(s) mediating terase (AChE), which results in hyperstimulation of the transition to SE are poorly understood. Recent muscarinic cholinergic receptors (mAChRs) and electrophysiological studies of acute rat brain slices www.sciencedirect.com Current Opinion in Toxicology 2021, 26:49–60 50 Mechanistic Toxicology Box 1. What are OPs? presynaptic glutamate release, the authors proposed that hyperstimulation of postsynaptic M1/M3 mAChRs The term “organophosphates” (OPs) refers to a group of synthetic triggered postsynaptic release of endocannabinoids that compounds that have in common a pentavalent phosphorus bound retrogradely diffused across the synapse to activate to sulfur or oxygen via a covalent double bond. OPs were first CB1Rs and reduce presynaptic release probability [16]. synthesized in the early 20th century as insecticides. The discovery The observation that presynaptic depression occurred in the 1930s that their insecticidal activity was primarily mediated before interictal bursting suggested that OP suppression by inhibition of acetylcholinesterase (AChE), an enzyme conserved of presynaptic glutamate release is an early compensa- across species, including humans, led to the development during tory response to excessive cholinergic signaling. In World War II of potent OP nerve agent, such as sarin, cyclosarin, support of this, pharmacologic antagonism of CB1Rs soman, tabun, VR and VX, that have been weaponized for use enhanced lethality in a mouse soman model [16]. against military and civilian targets. Since World War II, hundreds of OP compounds have been The neurotransmitter receptor subtypes involved in sus- developed for commercial applications, predominantly as in- taining OP-induced seizures have also been the focus of secticides, but also as plasticizers, fire retardants, and fuel additives. recent research (Ta bl e 1). Seizures result from imbal- Despite increasing regulatory restrictions on their use in the United anced excitatory to inhibitory signaling in the brain, and States and Europe, OPs remain the most commonly used group of prolonged seizure activity is associated with upregulated insecticides worldwide, with particularly heavy use in developing countries because of their lower cost compared to newer in- expression of all three ionotropic glutamate receptor secticides. As a result, human exposure to OPs is widespread, as subtypes - alpha-amino-3-hydroxy-5-methyl-4-isoxazole- evidenced by data indicating that OPs are among the most propionic acid (AMPA), kainate, and NMDA - and commonly detected anthropogenic contaminants in human tissues. downregulated expression of gamma aminobutyric acid (GABA) receptors (GABA R) at synapses in the hippo- Human and animal studies have established neurotoxicity as the A A primary endpoint of concern associated with OP exposures. There campus and amygdala, brain regions critically involved in are several “toxic scenarios” associated with OP exposure: acute OP-induced SE [14]. Downregulation of synaptic cholinergic crisis triggered by acute inhibition of AChE by more GABAAR is posited to mediate benzodiazepine refracto- than 60–70%, long-term effects associated with acute OP intoxi- riness, a characteristic feature of OP-induced SE [14,17]. cation, neurotoxicity associated with repeated low-level OP expo- Neurosteroids are positive allosteric modulators of not sures that may inhibit AChE, but do not cause signs of cholinergic only synaptic but also extrasynaptic GABAAR[17]. Post- crisis. exposure administration of neurosteroids significantly attenuated benzodiazepine-refractory seizures in rats found that paraoxon acutely enhanced the acutely intoxicated with sarin [18] or diisopropyl fluo- rophosphate (DFP) [19], suggesting that activity of hyperpolarization-activated cation current Ih in baso- lateral amygdala principal neurons [15]. The M1 extrasynaptic GABAAR influences seizure duration after mAChR antagonist, VU0255035, blocked this effect, acute OP intoxication. suggesting a mechanism by which cholinergic over- stimulation increases glutamatergic signaling in the Recent studies also support a causal role for AMPA and basolateral amygdala, a brain region critically involved in kainate receptor activity in sustaining OP-induced sei- seizure initiation by OP nerve agents [14]. In support of zures. Administration of LY293558, a relatively broad- this model, pretreatment with VU0255035 prevented spectrum antagonist of AMPA receptors (AMPARs) the development of SE for up to 40 min in rats acutely and kainate receptors containing the GluK1 subunit intoxicated with paraoxon or soman
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