Effects of Sublethal Organophosphate Toxicity and Anti-cholinergics on Electroencephalogram and Respiratory Mechanics in Mice

Abstract

Organophosphates are used in agriculture as insecticides but are potentially toxic to humans when exposed at high concentrations. The mechanism of toxicity is through antagonism of acetylcholinesterase, which secondarily causes excess activation of cholinergic receptors leading to seizures, tremors, respiratory depression, and other physiological consequences. Here we investigated two of the major pathophysiological effects, seizures and respiratory depression, using subcutaneous injection into mice of the organophosphate diisopropylfluorophosphate (DFP) at sublethal concentrations (2.1 mg/Kg) alone and co-injected with current therapeutics atropine (50 mg/Kg) or acetylcholinesterase reactivator HI6 (3 mg/Kg). We also tested a non-specific cholinergic antagonist dequalinium chloride (2 mg/Kg) as a novel treatment for organophosphate toxicity. Electroencephalogram (EEG) recordings revealed that DFP causes focal delta frequency (average 1.4 Hz) tonic spikes in the parietal region that occur transiently (lasting an average of 171 ± 33 min) and a more sustained generalized theta frequency depression in both parietal and frontal electrode that did not recover the following 24 h. DFP also caused behavioral tremors that partially recovered the following 24 h. Using whole body plethysmography, DFP revealed acute respiratory depression, including reduced breathing rates and tidal volumes, that partially recover the following day. Among therapeutic treatments, dequalinium chloride had the most potent effect on all physiological parameters by reducing acute EEG abnormalities and promoting a full recovery after 24 h from tremors and respiratory depression. Atropine and HI6 had distinct effects on EEGs. Co-treatment with atropine converted the acute 1.4 Hz tonic spikes to 3 Hz tonic spikes in the parietal electrode and promoted a partial recovery after 24 h from theta frequency and respiratory depression. HI6 fully removed the parietal delta spike increase and promoted a full recovery in theta frequency and respiratory depression. In summary, while all anticholinergic treatments promoted survival and moderated symptoms of DFP toxicity, the non-selective anti-cholinergic dequalinium chloride had the most potent therapeutic effects in reducing EEG abnormalities, moderating tremors and reducing respiratory depression.

Modifiable contributing factors to COVID-19: A comprehensive review

“…High-fat-diet has been shown to impact diabetes ( da Cruz et al, 2022 ), hypertension ( Logvinov et al, 2021 ), obesity ( Kang et al, 2022 ), and respiratory diseases ( Li et al, 2021a ). Organophosphate pesticides (and pesticides in general) have been shown to impact diabetes ( Miranda et al, 2022 ), hypertension ( Ledda et al, 2015 ), obesity ( Miranda et al, 2022 ), and respiratory diseases ( Bugay et al, 2022 ), and heavy metals have been shown to impact diabetes ( Wang et al, 2022 ), hypertension ( Tang et al, 2022a ), obesity ( Duc et al, 2022 ), and respiratory diseases ( Yao et al, 2021 ). More data are required to state with confidence that there are strong overlaps between the CFs to COVID-19 and its comorbidities.…”

Cardiovascular responses of adult male Sprague–Dawley rats following acute organophosphate intoxication and post-exposure treatment with midazolam with or without allopregnanolone

“…Acute OP intoxication leads to accumulation of acetylcholine and hyperstimulation of the cholinergic pathway both in the peripheral and the central nervous system (CNS), resulting in cholinergic crisis (Hulse et al 2014 ). Without intervention, the primary cause of death from OP-induced cholinergic crisis is respiratory failure (Bugay et al 2022 ; Dube et al 1993 ; Gaspari and Paydarfar 2007 ; Hulse et al 2014 ). Cardiovascular collapse from direct effects of OP on the cardiovascular system also contribute to fatal outcomes (McFarland and Lacy 1968 ; Munidasa et al 2004 ).…”