Dopamine-induced apoptosis is inhibited in PC12 cells expressing Bcl-2.
1. Degeneration of nigrostriatal dopaminergic neurons is the major pathogenic substrate of Parkinson's disease (PD). It is assumed that the lethal trigger is the accumulation of oxidative reactive species generated during metabolism of the natural neurotransmitter dopamine. 2. We have recently shown that dopamine is capable of inducing programmed cell death (PCD) or apoptosis in cultured postmitotic chick sympathetic neurons and rat PC12 pheochromocytoma cells. 3. The bcl-2 gene encodes a protein which blocks physiological PCD in many mammalian cells. In an attempt to elucidate further the mechanism of dopamine toxicity, we examined the potential protective effect of bcl-2 in PC12 cells which were transfected with the protooncogene. 4. In our experiments, Bcl-2 producing cells showed a marked resistance to dopamine toxicity. The percentage of nuclear condensation and DNA fragmentation visualized by the end-labeling method following dopamine treatment was significantly lower in bcl-2 expressing cells. Bcl-2 did not protect PC12 cells against toxicity induced by exposure to dopamine-melanin. Extracts of PC12 cells containing Bcl-2 inhibited dopamine autooxidation and formation of dopamine-melanin. Furthermore, the presence of Bcl-2 protected cells from thiol imbalance and prevented thiol loss following exposure to dopamine. 5. The protective effects of Bcl-2 against dopamine toxicity may be explained, in part, by its action as an antioxidant and by its interference in the production of toxic agents. The possible protection by Bcl-2 against neuronal degeneration caused by dopamine may play a role in the pathogenesis of PD and may provide a new direction for the development of neuroprotective therapies.
Offen
D
D
Department of Neurology, Beilinson Medical Center, Petah-Tiqva, Israel.
Ziv
I
I
Panet
H
H
Wasserman
L
L
Stein
R
R
Melamed
E
E
Barzilai
A
A
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D002457:Cell Extracts / Q000502:physiology; D002470:Cell Survival; D016895:Culture Media, Serum-Free; D004249:DNA Damage / Q000187:drug effects; D004298:Dopamine / Q000633:toxicity*; D017403:In Situ Hybridization; D008543:Melanins / Q000378:metabolism / Q000633:toxicity; D051379:Mice; D016716:PC12 Cells / Q000187:drug effects / Q000502:physiology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis* / Q000502:physiology; D051381:Rats; D013438:Sulfhydryl Compounds / Q000378:metabolism; D013936:Thymidine / Q000378:metabolism / Q000493:pharmacokinetics
D000975:Antioxidants; D002457:Cell Extracts; D016895:Culture Media, Serum-Free; D008543:Melanins; D019253:Proto-Oncogene Proteins c-bcl-2; D013438:Sulfhydryl Compounds; D013936:Thymidine; D004298:Dopamine