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

Abstract

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. a-Ketoglutarate (a-KG) antagonizes cyanide poisoning by cyanohydrin formation. Protective efficacy of graded doses of a-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 a-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 a-KG at all the doses and time intervals. A 10-min pretreatment with a-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 a-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 a 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 a-KG and STS. Considering the efficacy and safety of peroral a-KG, a promising treatment regimen consisting of a-KG +STS or a-KG+SN+STS is proposed depending upon the situation.