Fatty acids including alpha‐ketoglutarate, citrate, malate, fumarate, oxaloacetate, pyruvate, and succinate inhibit neurotoxicity induced by potassium cyanide in mice

When potassium cyanide (7mg/kg) was injected subcutaneously to mice, it was observed broad‐spectrum limbic and severe sustained seizures in 100 % of the treated mice. The seizures were abolished by an intraperitoneal pre‐injection at dose (1g/kg) of fatty acids such as alpha‐ketoglutarate, citrate, malate, fumarate, oxaroacetate, pyruvate and succinate, which all of those are substrates of enzymes in Krebs cycle. However, pre‐injection of another fatty acid including maleate (1g/kg) and malonate (1g/kg), which is not the substrate of enzymes in the Krebs cycle did not prevent against potassium cyanide‐induced seizures. In addition, in vivo exposure of potassium cyanide causeddamageto mitochondrial DNA (mtDNA) of brain frontal and central portion of cortex in mice. The damage of mtDNA was completely abolished by the intraperitoneal pre‐injection ofalpha‐ketoglutarate, citrate, fumarate, malate, oxaloacetate, pyruvate or succinate but not maleate or malonate. Furthermore, in vivo exposure of mouse brain to potassium cyanide elicited an increase in lipid peroxidation. However, the increased lipid peroxidation was completely inhibited by pre‐treatment with alpha‐ketoglutarate, citrate, fumarate, malate, oxaloacetate, pyruvate or succinate but not maleate or malonate. These results suggest that seizures and subsequent brain mtDNA damage induced by the neurotoxic agent, potassium cyanide, which may be produced by the induction of reactive oxygen species including hydroxyl radical, are protected by all substrates of enzymes in the Krebs cycle in mice.