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Treatment of cyanide poisoning generally includes methemoglobin forming agents, like amyl nitrite and/or sodium nitrite (SN), in combination with sodium thiosulphate (STS). However, in many instances of cyanide poisoning, use of nitrites are contraindicated due to their strong vasoactive properties. alpha-Ketoglutarate (alpha-KG) antagonises cyanide by cyanohydrin formation and is considered a promising antidote for cyanide poisoning. In the present study, pre-treatment (30 min) and simultaneous treatment (0 min) of alpha-KG (5 mM) was found to confer significant protection against 5 mM potassium cyanide (KCN) induced cytotoxicity in rat thymocytes as measured by eosin Y exclusion and leakage of intracellular lactate dehydrogenase (LDH), but could not prevent the mitochondrial dysfunction (MTT assay), depletion of cellular GSH (reduced glutathione) and DNA damage. The post-treatment (5 or 30 min) of alpha-KG did not offer any protection on any of the above parameters. Results of in vitro studies were also supported by in vivo data. Pre-treatment of peroral (p.o.) alpha-KG (0.125-2.0 g/kg) exhibited dose and time dependent effects and was found to be effective even when given upto 60 min prior to KCN (p.o.). Addition of STS significantly enhanced the protective efficacy of alpha-KG at all the doses and time intervals. A 10 min pre-treatment of alpha-KG increased the LD(50) of KCN 7.6-fold, which was further increased to 25.6-fold by the addition of both SN and STS. Simultaneous treatment of alpha-KG (2.0 g/kg) increased the LD50 of KCN 5.4-fold which was increased to 18.1-fold by the addition of STS. However, addition of SN did not confer any additional protection. In the presence of SN+STS, a decrease in the dose of alpha-KG exhibited a dose-dependent decrease in protection, but still a >10-fold protection could be observed at 1.0 g/kg dose of alpha-KG. 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 individual situation.

The effect of melatonin on potassium cyanide-induced neurotoxicity was investigated in vivo. The ED50 value of potassium cyanide, as measured by induction of tonic and clonic seizures, was significantly increased by 1.5- or 1.8-fold by s.c. preinjection of melatonin (20, 100 or 345 mg/kg) in mice. The preventive effect of melatonin against potassium cyanide-induced seizures was dose dependent. The LD50 value of potassium cyanide, based on 24-h mortality, was also significantly increased by 1.3-fold by preinjection of melatonin. Potassium cyanide (8 mg/kg, s.c.) increased lipid peroxidation in whole brain of mice, and the increased lipid peroxidation was completely abolished when cyanide-induced seizures were stopped by preadministration of melatonin. These results suggest that melatonin, a pineal hormone, may protect against cyanide-induced neurotoxicity with its free radical scavenging effects in mice.

The effects of atropine on acute lethality induced by cyanide were investigated in mice. The LD50 value of cyanide (s.c. injection) was 8.4 (7.6-9.3) mg/kg. However, the LD50 value of cyanide (s.c.) was significantly increased by 1.5-fold when atropine (32 mg/kg) was injected s.c. in mice. Furthermore, the combined administration of atropine (32 mg/kg), Ca2+ (500 mg/kg) and sodium thiosulfate (1 g/kg) tremendously increased the LD50 value by 5.6-fold in mice although sodium thiosulfate or Ca2+ alone increased the LD50 2.5- or 1.5-fold. On the other hand, although the LD50 value of cyanide (intracerebroventricular injection (i.v.t.)) was 52.0 (47.4-57.0) micrograms/brain, the LD50 value of cyanide (i.v.t.) was significantly increased by 1.3- or 1.61-fold in mice 10 min after s.c. injection of atropine (32 mg/kg) or Ca2+ (500 mg/kg). Furthermore, the combined administration of atropine and Ca2+ increased the LD50 value of cyanide by 2.1-fold. These results suggest that atropine inhibits cyanide-induced acute lethality and promotes the antagonistic effect of thiosulfate and Ca2+ in mice.