Diwakar, L and Ravindranath, V (2007) Inhibition of cystathionine-gamma-lyase leads to loss of glutathione and aggravation of mitochondrial dysfunction mediated by excitatory amino acid in the CNS. Neurochem Int, 50 (2). pp. 418-426.

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Abstract

Oxidative stress has been implicated in the pathogenesis and progression of neurodegenerative disorders and antioxidants potentially have a major role in neuroprotection. Optimum levels of glutathione (gamma-glutamylcysteinyl glycine), an endogenous thiol antioxidant are required for the maintenance of the redox status of cells. Cystathionine gamma-lyase is the rate-limiting enzyme for the synthesis of cysteine from methionine and availability of cysteine is a critical factor in glutathione synthesis. In the present study, we have examined the role of cystathionine gamma-lyase in maintaining the redox homeostasis in brain, particularly with reference to mitochondrial function since the complex I of the electron transport chain is sensitive to redox perturbation. Inhibition of cystathionine gamma-lyase by l-propargylglycine caused loss of glutathione and decrease in complex I activity in the brain although the enzyme activity in mouse brain was 1% of the corresponding hepatic activity. We then examined the effect of this inhibition on the neurotoxicity mediated by the excitatory amino acid, l-beta-oxalyl amino-l-alanine, which is the causative factor of a type of motor neuron disease, neurolathyrism. l-beta-Oxalyl amino-l-alanine toxicity was exacerbated by l-propargylglycine measured as loss of complex I activity indicating the importance of cystathionine gamma-lyase in maintaining glutathione levels and in turn the mitochondrial function during excitotoxicity. Oxidative stress generated by l-beta-oxalyl amino-l-alanine itself inhibited cystathionine gamma-lyase, which could be prevented by prior treatment with thiol antioxidant. Thus, cystathionine gamma-lyase itself is susceptible to inactivation by oxidative stress and this can potentially exacerbate oxidant-induced damage. Cystathionine gamma-lyase is present in neuronal cells in human brain and its activity is several-fold higher compared to mouse brain. It could potentially play an important role in maintaining glutathione and protein thiol homeostasis in brain and hence afford neuroprotection.

Item Type:	Article
Subjects:	Neurodegenerative Disorders Neuro-Oncological Disorders Neurocognitive Processes Neuronal Development and Regeneration Informatics and Imaging Genetics and Molecular Biology
Depositing User:	Dr. D.D. Lal
Date Deposited:	10 Feb 2020 07:31
Last Modified:	10 Feb 2020 07:31
URI:	http://nbrc.sciencecentral.in/id/eprint/569

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