5-s-Cysteinyl-conjugates of catecholamines induce cell damage, extensive DNA base modification and increases in caspase-3 activity in neurons.
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.
Spencer
Jeremy P E
JP
Wolfson Centre for Age-Related Diseases, GKT School of Biomedical Sciences, King's College London. jeremy.spencer@kcl.ac.uk
Whiteman
Matthew
M
Jenner
Peter
P
Halliwell
Barry
B
D015102:3,4-Dihydroxyphenylacetic Acid / Q000494:pharmacology; D000818:Animals; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002395:Catecholamines / Q000378:metabolism* / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003545:Cysteine / Q000378:metabolism*; D003548:Cysteinyldopa / Q000031:analogs & derivatives* / Q000494:pharmacology; D004247:DNA / Q000378:metabolism; D004298:Dopamine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D007424:Intracellular Fluid / Q000378:metabolism; D007980:Levodopa / Q000494:pharmacology; D008694:Methamphetamine / Q000031:analogs & derivatives / Q000494:pharmacology; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D011687:Purines / Q000378:metabolism; D011743:Pyrimidines / Q000378:metabolism; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism
D002395:Catecholamines; D011687:Purines; D011743:Pyrimidines; D017382:Reactive Oxygen Species; D015102:3,4-Dihydroxyphenylacetic Acid; C049277:5-S-cysteinyl-3,4-dihydroxyphenylacetic acid; D003548:Cysteinyldopa; D008694:Methamphetamine; D007980:Levodopa; D004247:DNA; C047408:5-S-cysteinyldopamine; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases; D003545:Cysteine; D004298:Dopamine