Promising role of alpha-ketoglutarate in protecting against the lethal effects of cyanide

Treatment of cyanide poisoning generally includes amyl nitrite and/or sodium nitrite (SN) in combination with sodium thiosulphate (STS). However, in many instances of cyanide poisoning, use of nitrites is contraindicated due to their strong vasoactive properties. alpha-Ketoglutarate (alpha-KG) antagonizes cyanide poisoning by cyanohydrin formation. Protective efficacy of graded doses of alpha-KG (p.o.) as pretreatment, simultaneous treatment or post-treatment was evaluated against acute potassium cyanide (KCN) poisoning (p.o.) in female rats. Pretreatment with alpha-KG (0.125-2.0 g/kg) exhibited dose- and time-dependent effects and was found to be effective even when given up to 60 min prior to KCN. Addition of STS significantly enhanced the protective efficacy of alpha-KG at all the doses and time intervals. A 10-min pretreatment with alpha-KG increased the LD50 of KCN by 7-fold, which was further increased 28-fold by the addition of both SN and STS. Simultaneous treatment with alpha-KG (2.0 g/kg) increased the LD50 of KCN by 7-fold, which was doubled by the addition of STS. However, addition of SN did not confer any additional protection. Post-treatment with alpha-KG + STS minimized the mortality by 50% but did not significantly extend the survival time in KCN (2 LD50)-administered rats. KCN (0.75 LD50) inhibited rat brain cytochrome oxidase, which was significantly protected by pretreatment or simultaneous treatment with alpha-KG and STS. Considering the efficacy and safety of peroral alpha-KG, a promising treatment regimen consisting of alpha-KG + STS or alpha-KG + SN + STS is proposed depending upon the situation.