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KMID : 1130620050010010081
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Journal of Clinical Neurology
2005 Volume.1 No. 1 p.81 ~ p.91
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Comparison of the Protective Effect of Indole β-carbolines and R-(-)-deprenyl Against Nitrogen Species-Induced Cell Death in Experimental Culture Model of Parkinson’s Disease
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Han Young-Su
Lee Chung-Soo
Cho Jeong-Seon
Kim Jung-Mee
Kim Doo-Eung
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Abstract
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Background: The membrane permeability transition of mitochondria has been suggested to be involved in toxic and oxidative forms of cell injury. Mitochondrial dysfunction is considered to play a critical role in neurodegeneration in Parkinson’s disease. Despite the suggestion that indole β-carbolines may be neurotoxic, these compounds provide a protective effect against cytotoxicity of other neurotoxins. In addition, the effect of indole β-carbolines on change in the mitochondrial membrane permeability due to reactive nitrogen species (RNS), which may lead to cell death, has not been clarified.
Methods: Differentiated PC12 cells were used as the experimental culture model for the investigation of neuronal cell injury, which occurs in Parkinson’s disease. The effect of indole β-carbolines (harmalol and harmine) on differentiated PC12 cells against toxicity of S-nitroso-N-acetyl-DL-penicillamine (SNAP) was determined by measuring the effect on the change in transmembrane potential, cytochrome c release, formation of ROS, GSH contents, caspase-3 activity and cell viability, and was compared to that of R-(-)-deprenyl.
Results: Specific inhibitors of caspases (z-LEHD.fmk, z-DQMD.fmk) and antioxidants (N-acetylcysteine, dithiothreitol, melatonin, carboxy-PTIO and uric acid) depressed cell death in PC12 cells due to SNAP. β- Carbolines and R-(-)-deprenyl attenuated the SNAP-induced cell death and GSH depletion concentration dependently with a maximal inhibitory effect at 25-50 μM. The compounds inhibited the nuclear damage, decrease in mitochondrial transmembrane potential, cytochrome c release and formation of reactive oxygen species caused by SNAP in PC12 cells. β-Carbolines and R-(-)-deprenyl attenuated the H2O2-induced cell death and depletion of GSH.
Conclusions: The results suggest that indole β-carbolines attenuate the SNAP-induced viability loss in PC12 cells by inhibition of change in the mitochondrial membrane permeability, which may be caused by free radicals. Indole β-carbolines appear to exert a protective effect against the nitrogen species-mediated neuronal cell injury in Parkinson’s disease comparable to R-(-)-deprenyl
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KEYWORD
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Indole β-carbolines, Nitrogen Species, Mitochondrial membrane permeability, Cell death, Differentiated PC12 cells
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