Toxicity assessment of gelsenicine and the search for effective antidotes

Abstract

Background Gelsenicine, one of the most toxic alkaloids of Gelsemium elegans Benth ( G. elegans), causes severe respiratory depression. However, its toxicity mechanisms are yet to be elucidated and no effective antidotes are available. Objective This study aimed to analyse the toxicity characteristics of gelsenicine. Methods Both acute and sub-acute toxicities were evaluated. Gelsenicine distribution and elimination in the central nervous system (CNS) and blood were observed. Effective antidotes for gelsenicine poisoning were screened. Results In the acute toxicity study, gelsenicine was highly toxic, and female rats exhibited greater sensitivity to gelsenicine than male rats (LD50 0.520 mg/kg vs 0.996 mg/kg, respectively). Death was primarily caused by respiratory failure. However, in the sub-acute toxicity study, no significant organ damage was observed. Gelsenicine was easily absorbed from the gastrointestinal tract and penetrated the blood–brain barrier, reaching peak concentrations in the CNS within 15 min and rapidly decreasing thereafter. Flumazenil or diazepam combined with epinephrine reversed gelsenicine toxicity and significantly improved survival rate in mice. Conclusions Gelsenicine is a highly toxic substance that affects nerve conduction without causing damage; the potential toxic mechanism is possibly associated with GABAA receptors. Our findings provide insights into the clinical treatment of gelsenicine -related poisoning and its toxicity mechanisms.

Sex Differences in the In Vivo Exposure Process of Multiple Components of Gelsemium elegans in Rats

“…This suggested that these toxic components were more highly exposed in female rats. In particular, compound H9 was the most toxic alkaloid in G. elegans [ 27 ], and it existed in higher concentrations in female rat plasma samples than in male rats, which was consistent with the published pharmacokinetic results of gelsenicine in male and female rats [ 28 ]. In previous studies on the toxicity of G. elegans in rats, a parenteral solution of crude alkaloidal extract was given to rats via intraperitoneal injection, and the LD 50 of female and male rats was 1.2 mg/kg and 1.5 mg/kg, respectively [ 1 ].…”

“…In previous studies on the toxicity of G. elegans in rats, a parenteral solution of crude alkaloidal extract was given to rats via intraperitoneal injection, and the LD 50 of female and male rats was 1.2 mg/kg and 1.5 mg/kg, respectively [ 1 ]. 14-(R)-hydroxy-gelsenicine was proven to have a significant gender difference with LD 50 values of 0.125 mg/kg and 0.295 mg/kg for female and male mice, respectively [ 28 ]. In Li et al’s acute toxicity study, gelsenicine was highly toxic, and female rats exhibited greater sensitivity to gelsenicine than male rats (LD 50 0.520 mg/kg vs. 0.996 mg/kg, respectively) [ 28 ].…”

“…14-(R)-hydroxy-gelsenicine was proven to have a significant gender difference with LD 50 values of 0.125 mg/kg and 0.295 mg/kg for female and male mice, respectively [ 28 ]. In Li et al’s acute toxicity study, gelsenicine was highly toxic, and female rats exhibited greater sensitivity to gelsenicine than male rats (LD 50 0.520 mg/kg vs. 0.996 mg/kg, respectively) [ 28 ]. These results indicated that female rats were more sensitive to the toxic components of G. elegans and there was significantly more toxic to female rats than male rats.…”

“…In addition to sex differences, there are significant species differences in G. elegans toxicity. The active ingredients of G. elegans mainly show pharmacological activity with less toxicity in pigs and goats, while it is highly toxic to rats and mice [ 20 , 28 ]. Multi-component metabolic studies of G. elegans in both goats and pigs indicated that the phase II metabolic reaction of glucuronidation was its most active metabolic way [ 20 , 28 ], while only one glucuronidated metabolite in rats.…”

“…The active ingredients of G. elegans mainly show pharmacological activity with less toxicity in pigs and goats, while it is highly toxic to rats and mice [ 20 , 28 ]. Multi-component metabolic studies of G. elegans in both goats and pigs indicated that the phase II metabolic reaction of glucuronidation was its most active metabolic way [ 20 , 28 ], while only one glucuronidated metabolite in rats. It was speculated that the difference in compound metabolism was one of the reasons leading to the difference in toxicity.…”