In vitro and in vivo evaluation of various carbonyl compounds against cyanide toxicity with particular reference to alpha-ketoglutaric acid.
Cyanide is a rapidly acting neurotoxin that necessitates immediate, vigorous therapy. The commonly used treatment regimen for cyanide includes the intravenous administration of sodium nitrite (SN) and sodium thiosulphate (STS). Due to many limitations of these antidotes, a search for more effective, safer molecules continues. Cyanide is known to react with carbonyl compounds to form the cyanohydrin complex. The present study addresses the efficacy of several carbonyl compounds and their metabolites or nutrients with alpha-ketoglutaric acid (A-KG), citric acid, succinic acid, maleic acid, malic acid, fumaric and oxaloacetic acid, glucose, sucrose, fructose, mannitol, sorbitol, dihydroxyacetone, and glyoxal (5 or 10 mM; -10 min) against toxicity of potassium cyanide (KCN; 10 mM) in rat thymocytes in vitro. Six hours after KCN, cell viability measured by MTT assay and crystal violet dye exclusion revealed maximum cytoprotection by A-KG, followed by oxaloacetic acid. A-KG also resolved the leakage of intracellular lactate dehydrogenase, loss in nuclear integrity (propidium iodide staining), and altered mitochondrial membrane potential (rhodamine 123 assay) as a result of cyanide toxicity. Protection Index (ratio of LD(50) of KCN in protected and unprotected animals; PI) of all the compounds (oral; 1.0 g/kg; -10 min) determined in male mice, revealed that maximum protection was afforded by A-KG (7.6 PI), followed by oxaloacetic acid (6.4 PI). Comparative evaluation of various salts of A-KG alone or with STS (intraperitoneal; 1.0 g/kg; -15 min) showed that maximum protection was conferred by disodium anhydrous salt of A-KG, which also significantly prevented the inhibition of brain cytochrome oxidase caused by 0.75 LD(50) KCN. This study indicates the potential of A-KG as alternative cyanide antidote.
Bhattacharya
Rahul
R
Defence Research and Development Establishment, Division of Pharmacology and Toxicology, Gwalior, India. rbhattacharya41@rediffmail.com
Tulsawani
Rajkumar
R
D000284:Administration, Oral; D000818:Animals; D000931:Antidotes / Q000008:administration & dosage / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects* / Q000201:enzymology; D002467:Cell Nucleus / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D019610:Cytoprotection; D004305:Dose-Response Relationship, Drug; D003576:Electron Transport Complex IV / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000506:poisoning*; D007656:Ketoglutaric Acids / Q000008:administration & dosage / Q000494:pharmacology*; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D007928:Lethal Dose 50; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D011041:Poisoning / Q000517:prevention & control; D011190:Potassium Cyanide / Q000506:poisoning*; D051381:Rats; D017208:Rats, Wistar; D013950:Thymus Gland / Q000187:drug effects* / Q000473:pathology
D000931:Antidotes; D004791:Enzyme Inhibitors; D007656:Ketoglutaric Acids; D007770:L-Lactate Dehydrogenase; D003576:Electron Transport Complex IV; D011190:Potassium Cyanide