J Korean Neurol Assoc.  2004 Aug;22(4):352-359.

Increased Poly (ADP-ribose) Polymerase Activation in the 6-Hydroxydopamine Induced Dopaminergic Neuronal Cell Death

• Kang JH
• Kang SY
• Park SY
• Kang HK
• Park DB
• Lee YK
• Koh JY

Abstract

BACKGROUND
The pathological hallmark of Parkinson's disease (PD) is dopaminergic cell death in the substantia nigra (SN), but the cause of cell death is unknown. 6-Hydroxydopamine (6-OHDA) is one of the neurotoxins used in experimental models of PD, and its use has led to greater understanding of the pathogenesis of PD. The present study examined the role of poly(ADP-ribose) polymerase (PARP) in 6-OHDA toxicity. METHODS: An in-vitro study was performed using PC12 cells. After treatment with 6-OHDA, the poly(ADP-ribosyl) ation was monitored using a monoclonal antibody to poly(ADP-ribose) (PAR) to examine the PARP activity. To evaluate the effect of the PARP inhibition in 6-OHDA-induced cell death, 3-aminobenzamide or nicotinamide was administered 30 minutes before 6-OHDA treatment. An in-vivo study was performed using a Parkinson rat model. 6-OHDA was stereotactically injected into the unilateral SN of rats. PAR immunolabeling was used to examine the time-dependent activation of PARP. The dopaminergic cell death in the SN was quantified using apomorphine-induced rotations and tyrosine hydroxylase- immunoreactive cell numbers in the SN 2 weeks after lesioning. RESULTS: Poly(ADP-ribosyl)ation of nuclear proteins was maximal at 6 hr, and was still present 24 hr after 6-OHDA treatment. Pretreatment of 3-aminobenzamide or nicotinamide significantly attenuated the 6-OHDA-induced PC12 cell death. In 6-OHDA injected rats, PAR formation was seen 6 hr after 6-OHDA injection, peaked at 12 hr, and was still detectable at 24 hr. The dopaminergic cell death in the SN was significantly decreased by intraperitoneal injection of nicotinamide in 6-OHDA injected rats. CONCLUSIONS: These results provide evidence suggesting an involvement of the PARP in 6-OHDA-induced dopaminergic cell death, and inhibitors of PARP may have a protective benefit in PD.

Keyword

Parkinson's disease; PARP; 6-hydroxydopamine; PARP inhibitor

MeSH Terms

Animals
Cell Count
Cell Death*
Dopaminergic Neurons*
Injections, Intraperitoneal
Models, Animal
Models, Theoretical
Neurotoxins
Niacinamide
Nuclear Proteins
Oxidopamine*
Parkinson Disease
PC12 Cells
Poly Adenosine Diphosphate Ribose
Poly(ADP-ribose) Polymerases
Rats
Substantia Nigra
Tyrosine
Neurotoxins
Niacinamide
Nuclear Proteins
Oxidopamine
Poly Adenosine Diphosphate Ribose
Poly(ADP-ribose) Polymerases
Tyrosine