MONOAMINE-INDUCED APOPTOTIC NEURONAL CELL-DEATH

1. The monoamines dopamine (DA), norepinephrine (NE), epinephrine (E), and serotonin (5-HT) serve as endogenous neurotransmitters in the ner vous system. We recently reported that the neurotransmitter DA can tri gger apoptosis (programmed cell death; PCD) in cultured, postmitotic c hick embryo sympathetic neurons, suggesting a role for apoptosis in de generative processes such as Parkinson's disease (PD). However, PD is also associated with involvement of other monoaminergic (MA) neuronal systems (noradrenergic and serotoninergic), though to a lesser extent. 2. We therefore tested the apoptosis-triggering potential of NE, E, a nd 5-HT in comparison to the DA effect, in cultured postmitotic nerve growth factor (NGF)-dependent chick embryo sympathetic neurons and mou se cerebellar granule cells. 3. In both model systems MA induced neuro nal attrition characteristic of apoptosis. MA caused marked morphologi cal alterations: severe neuronal soma shrinkage, membrane blebbing, nu clear condensation and fragmentation, and axonal disintegration. Flow- cytometric analysis of propidium iodide-stained cell nuclei revealed c haracteristic apoptotic nuclear fragmentation. MA-induced apoptosis co uld be blocked by SH-group containing antioxidants but not by inhibito rs of transcription and translation. 4. Comparison between the two mod el systems revealed that the cerebellar granule neurons were distinctl y more sensitive to the neurotoxic potential of the MA than sympatheti c neuronal cells. Significant differences in the dose dependencies and time course of the apoptotic effect were observed among the examined MA, graded as DA > NE approximate to E > 5-HT. 5. We conclude that the apoptosis triggering potential, probably mediated by oxidative metabo lites, is shared by all MA tested, but with differential time course a nd dose dependencies. A correlation can be drawn between the effects o f DA vs NE vs 5-HT and the relative involve ment of dopaminergic/norad renergic/serotoninergic pathways in PD, which may suggest a common mul tisystem underlying abnormality in neuronal apoptosis-control mechanis ms.