氟马西尼联合肾上腺素对钩吻中毒的解救作用

doi:10.11843/j.issn.0366-6964.2022.03.026

Abstract

Abstract: This study aimed to assessment the detoxification of flumazenil combined with epinephrine on Gelsemium elegans Benth (G. elegans) poisoning rats, providing reference for G. elegans toxic mechanism and poisoning cases. G. elegans poisoning rat model was constructed, and 60 rats were randomly divided into 4 groups:control group, flumazenil rescue group, epinephrine rescue group and combined drug (flumazenil + epinephrine) rescue group. The poisoning and death of the groups' rats were recorded; the blood pressure and heart rate were monitored. Then evaluate the rescue effect of drugs in each group. Molecular docking and whole cell patch clamp technique were used to predict the target sites of gelsenicine (main toxic substance of G. elegans) and rescue drugs, and elucidate their possible detoxification mechanisms. We found that the LD₅₀ of G. elegans was 0.25 g·kg^-1 by gavage in rats; flumazenil combined with epinephrine had a significant detoxification effect on G. elegans poisoning rats; the survival rate increased from 25% to 92% (P<0.01), and the mean time to poisoning symptoms was extended from 16.56 to 25.98 min (P<0.01); the mean time to death was prolonged from 40.13 to 58.05 min (P<0.01); the rescue effect was significantly higher than that of the flumazenil and epinephrine alone rescue group. The combination of flumazenil and epinephrine significantly alleviated the clinical manifestations of decreased blood pressure and heart rate in poisoning rats. The results of molecular docking computer simulation showed that both flumazenil and gelsenicine had better binding effect to the same active site of GABA_A receptor. The binding energy of flumazenil was stronger than gelsenicine (-85.47 vs -77.15 kJ·mol^-1), which could reverse the toxicity effect of G. elegans. The whole cell patch clamp results showed that gelsenicine significantly prolonged the opening time of GABA_A receptor ion channels, and this effect was antagonized by flumazenil. In conclusion, the combination of flumazenil and epinephrine had a significant detoxification effect in G. elegans poisoning rats. The target of G. elegans neurotoxicity may relate to the GABA_A receptor that flumazenil action in the CNS; epinephrine was essential to prevent the decrease of blood pressure and heart rate caused by poisoning. Combination of drugs could use a therapy for both the causes and symptoms.

Key words: Gelsemium elegans, flumazenil, epinephrine, toxicity mechanism, GABA_A receptor

CLC Number:

S859.87

LI Yujuan, XIAO Ning, JIA Wendan, LI Xiarong, ZHENG Xiaofeng, SUN Zhiliang. The Effectiveness of Flumazenil-Epinephrine Combination on Treatment for Acute Gelsemium elegans Poisoning[J]. Acta Veterinaria et Zootechnica Sinica, 2022, 53(3): 938-946.

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The Effectiveness of Flumazenil-Epinephrine Combination on Treatment for Acute Gelsemium elegans Poisoning

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