N-acetylcysteine and reduced glutathione reverse flupirtine-induced liver injury and pro-duce other beneficial effects in combination with flupirtine / 中国药理学与毒理学杂志

ABSTRACT

OBJECTIVE To assess whether N-acetylcysteine(NAC)and reduced glutathione(GSH)are effective in reversing flupirtine-induced hepatotoxicity and whether they have other bene-ficial effects when combined with flupirtine.METHODS The analgesic effects of NAC and flupirtine were first evaluated in carrageenan-induced inflammatory pain and paclitaxel-induced neuropathic pain.The combination subthreshold-ing approach was then used to determine whether the combination of NAC and flupirtine produced synergistic analgesic effects.Hepatotoxicity markers and histopathological examination of the liver were used to assess the efficacy of NAC and GSH in reversing flupirtine-induced hepato-toxicity.Finally,the effect of GSH on the safe range of flupirtine was assessed in an acute tox-icity assay.RESULTS Flupirtine and NAC pro-duced dose-dependent antiallodynic effects evoked by carrageenan and paclitaxel in mice.In the above model,the combination of NAC and flupirtine produced an unexpected synergistic analgesic effect.There were no significant differ-ences observed in the hepatotoxicity markers and liver histopathology between the experimen-tal group and the control group under NAC and GSH treatment.Finally,GSH(200 mg·kg-1)expanded the therapeutic index of flupirtine by 1.77 times.CONCLUSION NAC and GSH are effective in preventing liver damage caused by long-term flupirtine use,which provides a solu-tion for the safe and effective treatment of chronic pain with flupirtine.In addition,the other benefi-cial effects of NAC and GSH when combined with flupirtine may provide the basis for the devel-opment of a new therapy with minimal side-effects and good efficacy.