Effect of α-Ketoglutarate on Cyanide-induced Biochemical Alterations in Rat Brain and Liver

Objective To investigate the biochemical changes in rat brain and liver following acute exposure to a lethal dose of cyanide, and its response to treatment of α-ketoglutarate （α-KG） in the absence or presence of sodium thiosulfate （STS）. Methods Female rats were administered 2.0 LD50 potassium cyanide （KCN; oral） in the absence or presence of pre-treatment （-10 rain）, simultaneous treatment （0 rain） or post-treatment （＋2-3 min） of α-KG （2.0 g/kg, oral） and/or STS （1.0 g/kg, intraperitoneal, -15 min, 0 rain or ＋ 2-3 min）. At the time of onset of signs and symptoms of KCN toxicity （2-4 min） and at the time of death （5-15 min）, various parameters particularly akin to oxidative stress viz. cytochrome oxidase （CYTOX）, superoxide dismutase （SOD）, glutathione peroxidase （GPx）, reduced glutathione （GSH） and oxidized glutathione （GSSG） in brain, and CYTOX, sorbitol dehydrogenase （SDH）, alkaline phosphatase （ALP）, GSH and GSSG in liver homogenate were measured. Results At both time intervals brain CYTOX, SOD, GPx, and GSH significantly reduced （percent inhibition compared to control） to 24%, 56%, 77%, and 65%, and 44%, 46%, 78%, and 57%, respectively. At the corresponding time points liver CYTOX and GSH reduced to 74% and 63%, and 44% and 68%, respectively. The levels of GSSG in the brain and liver, and hepatic ALP and SDH were unchanged, Pre-treatment and simultaneous treatment of α-KG alone or with STS conferred significant protection on above variables. Post-treatment was effective in restoring the changes in liver but failed to normalize the changes in the brain. Conclusions Oral treatment with α-KG alone or in combination with STS has protective effects on cyanide-induced biochemical alterations in rat brain and liver.

Effect of Pre-treatment of α-Ketoglutarate on Cyanide-induced Toxicity and Alterations in Various Physiological Variables in Rodents

Objective To investigate the effects of pre-treatment of α-ketoglutarate （α-KG） on cyanide-induced lethality and changes in various physiological parameters in rodents. Methods The LD50 of potassium cyanide （KCN） given orally （po）, intraperitoneally （ip）, subcutaneously （sc） or intravenously （iv） was determined in male mice, in the presence or absence α-KG given po, ip or iv. α-KG was administered 10, 20 or 40 min prior to KCN at 0.50, 1.0 or 2.0 g/kg by po or ip route, and at 0.10, 0.20 or 0.40 g/kg by iv route. Protection index （PI） was calculated as the ratio of LD50 of KCN in the presence of α-KG （protected animals） and LD50 of KCN in the absence of α-KG （unprotected animals）. In a separate experiment, several physiological variables viz. mean arterial pressure （MAP）, heart rate （HR）, respiratory rate （RR）, neuromuscular transmission （NMT） and rectal temperature （RT） were measured in anesthetized female rats pre-treated （-10 rain） with po （2.0 g/kg） or iv （0.125 g/kg） α-KG and then administered sub-lethal （0.75 LD50） or lethal （2.0, 4.0 or 8.0 LD50） doses of KCN （po）. Results PI of 4.52, 6.40 and 7.60 at -10 min, 3.20, 5.40 and 6.40 at -20 min, and 1.40, 3.20 and 5.40 at -40 min of po administration with α-KG was observed for 0.50, 1.0 and 2.0 g/kg doses, respectively, against KCN given by po route. When KCN was given ip, a PI of 3.38, 4.79 and 5.70 was observed for 0.50, 1.0 and 2.0 g/kg α-KG given ip （-10 min）, respectively. A lower PI of 3.37, 2.83 and 2.38 was observed when KCN given sc was challenged by 2.0 g/kg α-KG given ip at -10, -20 or -40 min, respectively. Similarly, a PI of 3.37, 2.83 and 2.0 was noted when KCN given sc was antagonized by 2.0 g/kg α-KG given po at -10, -20 or -40 rain, respectively. No appreciable protection was observed when lower doses of α-KG （ip or po） challenged KCN given by sc route. Pre-treatment of iv or po administration of α-KG did not afford any protection against KCN given po or iv route. Oral treatment of 0.75 LD50 KCN caused significant decrease in MAP and HR after 15 min, RR after 30 min and NMT after 60 min. There was no effect on RT. No reduction in MAP, HR, RR and RT was observed when rats received 2.0 or 4.0 LD50 KCN after pre-treatment of α-KG （po; 2.0 g/kg）. However, no protection was observed on NMT. Protective efficacy of α-KG was not observed on MAP, HR, RR, and NMT decreased by 8.0 LD50 KCN. Decrease in MAP and NMT caused by 2.0 LD50 KCN （po） was resolved by iv administration of α-KG Conclusions Cyanide antagonism by α-KG is best exhibited when both α-KG and KCN are given by po route. The protective effect of α-KG on cyanide-induced changes in several physiological parameters also indicates a promising role of α-KG as an alternative cyanide antidote.