Targeting the Glutamate Amino Acid by Alpha-Ketoisocaproic Acid and L-2-Oxothiazolidine-4-Carboxylic Acid as a Neuroprotective Approach in Rat Model of Cerebral Ischemia

Asmaa E El-Rakhawy, Vivian Bos


Background: Neuronal death following ischemic stroke is primarily attributed to glutamate excitotoxicity. Objective: The aim of the present study is to attenuate the glutamate excitotoxic effect in rat model of transient focal cerebral ischemia via two approaches. First by using alpha-ketoisocaproate (αKIC), a ketoacid of leucine that reacts with glutamate in glutamate/branched chain amino acid cycle. Second by using l-2-oxothiazolidine-4-carboxylate (OTC), a prodrug of cysteine and an oxoproline analog which is involved in gamma-glutamyl cycle of glutathione (GSH) biosynthesis. Method: Immediately after induction of transient left MCAO for 90 min. in rats, αKIC (300mg/kg) or OTC (8 mmol/kg) was injected intraperitoneally. Quantification of plasma glutamate, glycine, cysteine and leucine amino acids and reduced GSH was done 150 min after reperfusion. The post-infarct behavioral functioning and the infarction size were detected 24 hours after reperfusion. Results:The infarction caused by tMCAO was associated with significant increase in the plasma glutamate, glycine and cysteine and significant decrease in the plasma leucine and reduced GSH levels. Either αKIC or OTC caused significant decrease in the infarct size and improvement of the neurological outcome with significant decrease in the plasma glutamate level. OTC also had a significant anti-oxidant effect via increasing cysteine and GSH plasma levels. Conclusion: the use of these neuroprotective agents to prolong time window prior to reperfusion or to prevent reperfusion injury may represent a future therapeutic clinical application in ischemic stroke.

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