Neurology and Therapeutics

Biography

Biography: G. Nagesh

Abstract

It is well known that the neurotoxicity effects of Glutamate (L-Glu) involve the activation of glutamate receptors. However, during periods of cerebral ischemia there is also an activation of the Kyneurinine (KYN) pathway of tryptophan metabolism, which generates the NMDA receptor-glycine site antagonist Kyneurinic Acid (KYNA). We studied the effects of pretreatment of peripheral KYN on acute-L-Glu-induced neurotoxicity. NMDA receptors are supposed to play a crucial role in Glutamate (L-Glu) neurotoxicity.To evaluate the effects of the astrocyte-derived tryptophan metabolite KYNA, on L-Glu neurotoxicity, adult male rats were pretreated with KYN which is a precursor of KYNA, at a dose of 30 mg or 300 mg/kg bw i.p., 2 h before administration of a stereotactic L-Glu bolus (1µmole/1µl) administration into the cerebral cortex. Key oxidant and anti-oxidant parameters were estimated in both brain homogenates and isolated cortical neurons. To obtain individual neurons, finely chopped cerebral cortex tissue was treated with dispase (1000 protease units/ml) for 45 min at 370C. Viability test was done by trypan blue and 90% viable population of neurons was obtained. Acute L-Glu administration increased the rate of lipid peroxidation, nitric oxide and decreased key antioxidant parameters such as SOD, catalase, total glutathione and glutathione reductase in brain homogenates. In isolated cortical neurons, we observed increased levels of reactive oxygen species, calcium along with decreased mitochondrial membrane potential. Peripheral loading of 30 mg/kg dose of KYN had no protective effects on L-Glu induced neurotoxicity, but a dose of 300 mg/kg dose prevented the toxic effects following intracortical L-Glu.