MELATONIN PREVENTS APOPTOSIS INDUCED BY 6-HYDROXYDOPAMINE IN NEURONALCELLS - IMPLICATIONS FOR PARKINSONS-DISEASE

It was recently reported that low doses of 6-hydroxydopamine (6-OHDA) induce apoptosis of naive (undifferentiated) and neuronal (differentia ted) PC12 cells, and this system has been proposed as an adequate expe rimental model for the study of Parkinson's disease. The mechanism by which this neurotoxin damages cells is via the production of free radi cals. Given that the neurohormone melatonin has been reported 1) to be a highly effective endogenous free radical scavenger, 2) to increase the mRNA levels and the activity of several antioxidant enzymes, and 3 ) to inhibit apoptosis in other tissues, we have studied the ability o f melatonin to prevent the programmed cell death induced by 6-OHDA in PC12 cells. We found that melatonin prevents the apoptosis caused by 6 -OHDA in naive and neuronal PC12 cells as estimated by 1) cell viabili ty assays, 2) counting of the number of apoptotic cells, and 3) analys is and quantification of DNA fragmentation. Exploration of the mechani sms used by melatonin to reduce programmed cell death revealed that th is chemical mediator prevents the 6-OHDA induced reduction of mRNAs fo r several antioxidant enzymes. The possibility that melatonin utilized additional mechanisms to prevent apoptosis of these cells is also dis cussed. Since this endogenous agent has no known side effects and read ily crosses the blood brain-barrier, we consider melatonin to have a h igh clinical potential in the treatment of Parkinson's disease and pos sibly other neurodegenerative diseases, although more research on the mechanisms is yet to be done.