Onset rate and intensity of signs of organophosphate poisoning related to paraoxon dose and survival in rats

Abstract

Introduction: Oganophosphorus compounds (OP) bind to acetylcholinesterase (AChE) and inactivate it. In the synaptic cleft, undestroyed and accumulated acetylcholine produce the acute cholinergic effects. The aim of this study was to determine the frequency, speed of onset and intensity of certain signs of paraoxon poisoning depending on dose and outcome of poisoning. Methods: The study was conducted in adult Wistar rats. The median lethal dose (LD50) of paraoxon as well as protective ratio (PR) of atropine (10 mg/kg intramuscularly) was determined. Clinical signs of poisoning were observed: fasciculations, tremor, seizures, ataxia, piloerection, lacrimation, exophthalmos, bizzare/stereotypic behaviour and dyspnoea. The time from paraoxon injection to the first appearance of the sign of poisoning was recorded as well as the intensity of poisoning with evaluation at 10 time intervals throughout the 4 h observational period. Results: The LD50 of paraoxon was 0.33 mg/kg (subcutaneously) and PR of atropine was 2.73. Dose-dependent, piloerection occurred more often (p = 0.009) and at higher intensity (p = 0.016) at higher doses. Fasciculations, tremor, seizures and ataxia occurred significantly earlier at higher doses of paraoxon (p = 0.015, 0.002, 0.021 and 0.016, respectively), as well as the intensity of seizure, tremor and fasciculation. Piloerection (p = 0.002) and seizures occurred more frequently (p = 0.009) in non-survivors. Fasciculations, tremor, seizures and ataxia occurred significantly earlier and at higher intensity in non-survivors (p < 0.001, for all parameters), as well as dyspnoea (p = 0.009 and p = 0.048). In atropine-protected rats, nicotinic effects persevered, so they were the prognostic parameter of the severity of the poisoning. Conclusion: Seizures and fasciculations followed by tremor were strong prognostic parameters of the probability of lethal outcome of paraoxon poisoning. Also, the mentioned poisoning signs were with their intensity and speed of occurrence in a clear positive correlation with the administered dose of paraoxon. Even at high doses of paraoxon, atropine blocked the muscarinic (but not nicotinic) effects and somewhat mitigated the CNS toxic effects.

Toxicological Evaluation and In Silico Identification of Acetylcholinesterase Inhibitors in a Commercial Polyherbal Formulation (KWAPF01)

“…e choice of studying acetylcholinesterase inhibitory potential of the identi ed metabolites was informed because of the piloerection, tremor, and lacrimation observed following administration of KWAPF01. ese observations are some of the clinical signs of acetylcholinesterase inhibition, as reported by Maksimović et al [27]. AChE is a cholinergic enzyme found primarily at postsynaptic neuromuscular junctions in muscles and nerves [28].…”

Dose-Dependency of Toxic Signs and Outcomes of Paraoxon Poisoning in Rats

“…No clear relationship was found between the intensity of dyspnoea and the dose of paraoxon. However, in the recent study, a clear relationship was found between the onset rate of dyspnoea, as well as the overall intensity of dyspnoea and lethal outcome of poisoning (29). Respiratory failure is a consequence of both peripheral and central cholinergic effects (30).…”

Preparing a rat brain tissue samples for acetylcholinesterase activity measurement: The MM method

“…Paraoxon (diethyl (4-nitrophenyl) phosphate) is the active metabolite of the OP insecticide parathion. 13 The phosphorothioates (P=S) (eg, diazinon, parathion) are more lipophilic than phosphates (P=O) (eg, dichlorvos, paraoxon). Spontaneous reactivation of dimethyl-phosphorylated AChE often occurs rapidly even without oxime therapy.…”