Mechanisms of organophosphate toxicity and the role of acetylcholinesterase inhibition Original paper

What was reviewed?

This narrative review synthesizes current evidence on organophosphate-toxicity mechanisms, focusing on how organophosphorus compounds (agricultural pesticides, industrial agents, and nerve agents) cause acute lethality and longer-term neurologic injury. The authors center the discussion on acetylcholinesterase (AChE) inhibition as the shared initiating event, then trace downstream pathways leading to respiratory depression, seizures, and status epilepticus (SE), and finally outline SE-driven neurodegeneration through excitotoxic calcium overload, oxidative stress, and neuroinflammation. The review also summarizes emerging mechanisms from low-dose, chronic exposure that may occur without SE and may not strictly depend on AChE inhibition, including persistent calcium dyshomeostasis and inflammatory signaling in neural and glial cells.

Who was reviewed?

Rather than a single patient cohort, the review integrates data from multiple experimental systems and exposure scenarios. These include mammalian animal models of acute nerve agent intoxication (notably soman and sarin), with a mechanistic emphasis on limbic circuitry (especially the basolateral amygdala) as a seizure trigger zone, as well as brain-slice electrophysiology studies that demonstrate region-specific epileptiform activity. It also draws on occupational and environmental exposure studies in humans (e.g., pesticide workers) to discuss chronic, low-dose neurobehavioral outcomes and biomarker relationships (such as blood cholinesterase activity), plus in vitro work in human astrocytes to illustrate inflammatory effects that are unlikely to be purely cholinergic. Importantly for clinicians building microbiome signature databases, the review does not evaluate gut, oral, or other microbiome profiles, and it does not report microbial taxa, microbial metabolites, or host–microbiome associations as exposures, mediators, or biomarkers.

Most important findings

Acute organophosphate poisoning begins with AChE phosphorylation, producing a surge of acetylcholine that hyperstimulates muscarinic and nicotinic receptors. The most immediate life threats are centrally mediated respiratory depression (with muscarinic signaling in brainstem respiratory networks implicated) and peripheral “cholinergic crisis” effects such as bronchorrhea/bronchoconstriction and neuromuscular weakness. In the brain, excess cholinergic drive rapidly precipitates seizures and SE, with strong evidence that the basolateral amygdala is a key initiation site; animals exposed to soman that fail to develop SE show little to no neurodegeneration despite AChE inhibition elsewhere, supporting SE as the main driver of lasting neuropathology. Early SE appears heavily muscarinic (notably M1 receptor–linked facilitation of glutamatergic excitation), but once established, SE becomes increasingly sustained by glutamate-mediated hyperexcitation. Neurotoxicity then follows classic excitotoxic cascades: calcium influx through AMPA/kainate/NMDA receptors, mitochondrial dysfunction, reactive oxygen species generation, blood–brain barrier disruption, and a self-amplifying neuroinflammatory response involving astrocytes and microglia. For chronic low-dose exposure, the review highlights persistent neuronal calcium elevations, oxidative stress, and inflammation that can occur without SE and may show inconsistent correlations with blood cholinesterase suppression. Microbiome-related findings are absent; no microbial biomarkers are proposed.

Key implications

Clinically, the review argues that survival and neuroprotection in acute organophosphate intoxication hinge on rapid seizure control, not only reversal of cholinergic symptoms. Benzodiazepines are most effective early, while delayed presentations may require anti-glutamatergic strategies to stop SE and prevent downstream excitotoxic and inflammatory injury; adjunct anti-inflammatory approaches may be necessary when SE-driven cascades are already active. For chronic exposures, clinicians should recognize that neurocognitive and mood sequelae may reflect calcium and inflammatory dysregulation even when cholinesterase measures are near-normal. From a microbiome-signature perspective, this paper contributes to mechanistic toxicology but provides no microbial associations; any microbiome database entry should explicitly mark “no microbiome data” to avoid false linkage.

Citation

Aroniadou-Anderjaska V, Figueiredo TH, de Araujo Furtado M, Pidoplichko VI, Braga MFM. Mechanisms of organophosphate toxicity and the role of acetylcholinesterase inhibition. Toxics. 2023;11(10):866. doi:10.3390/toxics11100866