Effect of Alpha-Ketoglutarate on Neurobehavioral, Neurochemical and Oxidative Changes Caused by Sub-Chronic Cyanide Poisoning in Rats

Abstract

Recent studies revealed that alpha-ketoglutarate (A-KG) alone or with sodium thiosulfate (STS) provide significant protection against acute and sub-acute cyanide poisoning in rodents. This study addresses the protective effect of A-KG and/or STS in sub-chronic (90 days) cyanide poisoning. Wistar rats were divided into seven groups (n = 10): Control animals, potassium cyanide (KCN) A-KG, STS, KCN ? A-KG, KCN ? STS and KCN ? A-KG ? STS. Spontaneous motor activity and motor coordination were recorded every 15th day. Lipid peroxidation (LPO), reduced glutathione (GSH), glutathione peroxidase (GPx), superoxide dismutase (SOD) and catalase (CAT) in blood, brain, liver and kidney, and glutamate, aspartate and dopamine in discrete regions of brain were measured following 90 days exposure. Cyanide significantly decreased motor coordination, accompanied by increase in LPO (blood, brain and liver) and dopamine (corpus striatum and cerebral cortex) levels, and depletion in GSH (blood, brain and liver), GPx (brain and liver), SOD (brain and liver), and CAT (blood and brain) levels. Although treatment of A-KG and STS alone significantly blunted the toxicity of KCN, concomitant use of both afforded the maximum protection. This study shows a promising role of A-KG and STS as treatment regime for long term cyanide exposure.

Alpha-ketoglutarate attenuates toxic effects of sodium nitroprusside and hydrogen peroxide in Drosophila melanogaster

“…Thus, the combined administration of AKG and SNP partially prevented antioxidant enzyme inactivation and oxidative damage of lipids which agrees with previous studies (Tulsawani et al, 2005;Bhattacharya et al, 200;Mathangi et al, 2011).…”

“…The protective effects of AKG are considered to be due to the capability of the carbonyl groups on AKG to interact with cyanide to yield less toxic cyanohydrin intermediates (Niknahad et al, 1994, Mitchell et al, 2013. In the line with this, the potential of AKG to prevent depletion of antioxidant defenses or counteract the increase in levels of oxidative stress markers during acute or sub-chronic cyanide poisoning was demonstrated (Tulsawani et al, 2005;Tulsawani and Bhattacharya, 2006;Bhattacharya et al, 2009;Mathangi et al, 2011). Furthermore, several studies reported that the protective effects of AKG against various toxic agents in vitro and in vivo could be related with its direct antioxidant action (Sokołowska et al, 1999;Murugesan and Subramanian, 2006;Kovalenko et al, 2011;Niemiec et al, 2011;Long and Halliwell, 2011).…”

“…Cyanide is a mitochondrial toxin that impairs cellular respiration due to inhibition of cytochrome oxidase, a terminal enzyme of mitochondrial electron transport chain (Pettersen and Cohen, 1992). Treatment with cyanide was found to inhibit multiple enzymes including antioxidant ones (particularly superoxide dismutase), and oxidative stress is one such event which has been frequently associated with cyanide toxicity (Ardelt et al, 1994;Tulsawani et al, 2005;Tulsawani and Bhattacharya, 2006;Mathangi et al, 2011). The protective effects of AKG are considered to be due to the capability of the carbonyl groups on AKG to interact with cyanide to yield less toxic cyanohydrin intermediates (Niknahad et al, 1994, Mitchell et al, 2013.…”

“…Several mechanisms may be implicated in SNP induction of oxidative stress, including inhibition of cytochrome oxidase by cyanide leading to increased ROS production by the mitochondrial electron transport chain (Pettersen and Cohen, 1992;Ardelt et al, 1994;Tulsawani and Bhattacharya, 2006;Mathangi et al, 2011). Iron cation and • NO released from SNP are also well known inducers of oxidative stress in many organisms (Gospogaryov, 1995;Lushchak and Lushchak, 2008;Semchuk et al, 2011;Lozinsky et al, 2012).…”

“…Iron cation and • NO released from SNP are also well known inducers of oxidative stress in many organisms (Gospogaryov, 1995;Lushchak and Lushchak, 2008;Semchuk et al, 2011;Lozinsky et al, 2012). In several studies, the ability of AKG to diminish the intensity of oxidative stress induced by cyanide was demonstrated and this was attributed to the cyanine-binding activity of AKG (Tulsawani et al, 2005;Bhattacharya et al, 200;Mathangi et al, 2011). At the same time, antioxidant properties of AKG both in vivo and in vitro were reported, and in particular AKG was found to be involved in the prevention of lipid peroxidation in rats under chronic ethanol administration (Velvizhi et al, 2002), sodium valproate treatment (Murugesan and Subramanian, 2006), H 2 O 2 -induced hemolysis of human erythrocytes (Sokołowska et al, 1999), or ischemia of the hippocampus (Kovalenko et al, 2011).…”