5-s-Cysteinyl-conjugates of catecholamines induce cell damage,extensive DNA base modification and increases in caspase-3 activity in neurons |
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Authors: | Spencer Jeremy P E Whiteman Matthew Jenner Peter Halliwell Barry |
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Institution: | Wolfson Centre for Age-Related Diseases, GKT School of Biomedical Sciences, King's College London. jeremy.spencer@kcl.ac.uk |
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Abstract: | A decrease in reduced glutathione levels in dopamine containing nigral cells in Parkinson's disease may result from the formation of cysteinyl-adducts of catecholamines, which in turn exert toxicity on nigral cells. We show that exposure of neurons (CSM 14.1) to 5-S-cysteinyl conjugates of dopamine, L-DOPA, DOPAC or DHMA causes neuronal damage, increases in oxidative DNA base modification and an elevation of caspase-3 activity in cells. Damage to neurons was apparent 12-48 h of post-exposure and there were increases in caspase-3 activity in neurons after 6 h. These changes were paralleled by large increases in pyrimidine and purine base oxidation products, such as 8-OH-guanine suggesting that 5-S-cysteinyl conjugates of catecholamines are capable of diffusing into cells and stimulating the formation of reactive oxygen species (ROS), which may then lead to a mechanism of cell damage involving caspase-3. Indeed, intracellular ROS were observed to rise sharply on exposure to the conjugates. These results suggest one mechanism by which oxidative stress may occur in the substantia nigra in Parkinson's disease. |
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Keywords: | caspase-3 DNA base modification 5-S-cysteinyl-dopamine Parkinson's disease neurodegenerative disease |
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