A novel approach to medical countermeasures against organophosphorus compound toxicity

The toxicity of organophosphorus compounds (OPs) results primarily from the irreversible inhibition of acetylcholinesterase (AChE). Huperzine A (HupA) is a reversible inhibitor of AChE and HupA sustained-release microspheres (HSMs) steadily release HupA, resulting in the continual inhibition of AChE activity for 14 days in mice. The present study aimed to investigate the preventive effects of HSMs on the toxicity of methyl parathion (MP). The mice were pretreated with HSMs followed by MP exposure. Subsequently, the median lethal dose (LD₅₀) and survival of the mice were determined. A histopathological examination of the brain, liver, lungs, heart, kidneys and intercostal muscles was also performed. The results revealed that the LD₅₀ was 51.4 mg/kg in the control group and 70.0, 67.5, 63.4 and 53.5 mg/kg at 2 h, 5, 10 and 15 days after pretreatment with HSMs, respectively. Pretreatment with HSMs at 2 h, 5 days and 10 days prior to an acute challenge with 1.2 × LD₅₀ MP was sufficient to counteract the lethality and acute toxicity of MP. HSM pretreatment also attenuated the pulmonary edema induced by MP. The results demonstrated that pretreatment with HSMs may be an effective method to counteract MP poisoning. To the best of our knowledge, the present study was the first to demonstrate that pretreatment with an AChE reversible inhibitor sustained-release agent may be a novel approach to effective protection against OP toxicity.