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5‐S‐Cysteinyl‐conjugates of catecholamines induce cell damage, extensive DNA base modification and increases in caspase‐3 activity in neurons
Author(s) -
Spencer Jeremy P. E.,
Whiteman Matthew,
Jenner Peter,
Halliwell Barry
Publication year - 2002
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1046/j.1471-4159.2002.00808.x
Subject(s) - substantia nigra , dopamine , dna damage , reactive oxygen species , oxidative stress , chemistry , glutathione , intracellular , guanine , biochemistry , microbiology and biotechnology , cell damage , dopaminergic , biology , dna , endocrinology , enzyme , nucleotide , gene
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.