Comparison of the Protective Effect of Indole Beta-carbolines and R-(-)-deprenyl Against Nitrogen Species-Induced Cell Death in Experimental Culture Model of Parkinson's Disease

Overview

Journal J Clin Neurol

Specialty Neurology

Date 2010 Apr 17

PMID 20396475

Citations 2

Authors

Young-Su Han

Jung-Mee Kim

Jeong-Seon Cho

Chung Soo Lee

Doo-Eung Kim

Affiliations

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Abstract

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 beta-carbolines may be neurotoxic, these compounds provide a protective effect against cytotoxicity of other neurotoxins. In addition, the effect of indole beta-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 beta-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. beta-Carbolines and R-(-)-deprenyl attenuated the SNAP-induced cell death and GSH depletion concentration dependently with a maximal inhibitory effect at 25-50 microM. 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. beta-Carbolines and R-(-)-deprenyl attenuated the H(2)O(2)-induced cell death and depletion of GSH.

Conclusions: The results suggest that indole beta-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 beta-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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References

Airaksinen M, Kari I . Beta-carbolines, psychoactive compounds in the mammalian body. Part I: Occurrence, origin and metabolism. Med Biol. 1981; 59(1):21-34. View

Polster B, Fiskum G . Mitochondrial mechanisms of neural cell apoptosis. J Neurochem. 2004; 90(6):1281-9. DOI: 10.1111/j.1471-4159.2004.02572.x. View

van Klaveren R, Hoet P, Pype J, Demedts M, Nemery B . Increase in gamma-glutamyltransferase by glutathione depletion in rat type II pneumocytes. Free Radic Biol Med. 1997; 22(3):525-34. DOI: 10.1016/s0891-5849(96)00375-9. View

Jenner P . Oxidative stress in Parkinson's disease. Ann Neurol. 2003; 53 Suppl 3:S26-36; discussion S36-8. DOI: 10.1002/ana.10483. View

Jurma O, Hom D, Andersen J . Decreased glutathione results in calcium-mediated cell death in PC12. Free Radic Biol Med. 1997; 23(7):1055-66. DOI: 10.1016/s0891-5849(97)00134-2. View

Cobuzzi Jr R, Neafsey E, Collins M . Differential cytotoxicities of N-methyl-beta-carbolinium analogues of MPP+ in PC12 cells: insights into potential neurotoxicants in Parkinson's disease. J Neurochem. 1994; 62(4):1503-10. DOI: 10.1046/j.1471-4159.1994.62041503.x. View

Kadota T, Yamaai T, Saito Y, Akita Y, Kawashima S, Moroi K . Expression of dopamine transporter at the tips of growing neurites of PC12 cells. J Histochem Cytochem. 1996; 44(9):989-96. DOI: 10.1177/44.9.8773564. View

Hantraye P, Brouillet E, Ferrante R, Palfi S, Dolan R, Matthews R . Inhibition of neuronal nitric oxide synthase prevents MPTP-induced parkinsonism in baboons. Nat Med. 1996; 2(9):1017-21. DOI: 10.1038/nm0996-1017. View

Lee C, Song E, Park S, Han E . Combined effect of dopamine and MPP+ on membrane permeability in mitochondria and cell viability in PC12 cells. Neurochem Int. 2003; 43(2):147-54. DOI: 10.1016/s0197-0186(02)00214-0. View

10.

Birkmayer W, Knoll J, Riederer P, Youdim M, Hars V, Marton J . Increased life expectancy resulting from addition of L-deprenyl to Madopar treatment in Parkinson's disease: a longterm study. J Neural Transm. 1985; 64(2):113-27. DOI: 10.1007/BF01245973. View

11.

Pari K, Sundari C, Chandani S, Balasubramanian D . beta-carbolines that accumulate in human tissues may serve a protective role against oxidative stress. J Biol Chem. 2000; 275(4):2455-62. DOI: 10.1074/jbc.275.4.2455. View

12.

Maher P, Davis J . The role of monoamine metabolism in oxidative glutamate toxicity. J Neurosci. 1996; 16(20):6394-401. PMC: 6578906. View

13.

Fu W, Luo H, Parthasarathy S, Mattson M . Catecholamines potentiate amyloid beta-peptide neurotoxicity: involvement of oxidative stress, mitochondrial dysfunction, and perturbed calcium homeostasis. Neurobiol Dis. 1998; 5(4):229-43. DOI: 10.1006/nbdi.1998.0192. View

14.

Tatton W, Chalmers-Redman R, Ju W, Mammen M, Carlile G, Pong A . Propargylamines induce antiapoptotic new protein synthesis in serum- and nerve growth factor (NGF)-withdrawn, NGF-differentiated PC-12 cells. J Pharmacol Exp Ther. 2002; 301(2):753-64. DOI: 10.1124/jpet.301.2.753. View

15.

Pryor W, Squadrito G . The chemistry of peroxynitrite: a product from the reaction of nitric oxide with superoxide. Am J Physiol. 1995; 268(5 Pt 1):L699-722. DOI: 10.1152/ajplung.1995.268.5.L699. View

16.

Beck O, Faull K . Concentrations of the enantiomers of 5-hydroxymethtryptoline in mammalian urine: implications for in vivo biosynthesis. Biochem Pharmacol. 1986; 35(15):2636-9. DOI: 10.1016/0006-2952(86)90067-5. View

17.

Fernandez de Arriba A, Lizcano J, Balsa M, Unzeta M . Inhibition of monoamine oxidase from bovine retina by beta-carbolines. J Pharm Pharmacol. 1994; 46(10):809-13. DOI: 10.1111/j.2042-7158.1994.tb03735.x. View

18.

Ogawa Y, Adachi J, Tatsuno Y . Accumulation of 1-methyl-tetrahydro-beta-carboline-3-carboxylic acid in blood and organs of rat. A possible causative substance of eosinophilia-myalgia syndrome associated with ingestion of L-tryptophan. Arch Toxicol. 1993; 67(4):290-3. DOI: 10.1007/BF01974349. View

19.

Tatton W, Chalmers-Redman R . Modulation of gene expression rather than monoamine oxidase inhibition: (-)-deprenyl-related compounds in controlling neurodegeneration. Neurology. 1996; 47(6 Suppl 3):S171-83. DOI: 10.1212/wnl.47.6_suppl_3.171s. View

20.

Gearhart D, Toole P, Beach J . Identification of brain proteins that interact with 2-methylnorharman. An analog of the parkinsonian-inducing toxin, MPP+. Neurosci Res. 2002; 44(3):255-65. DOI: 10.1016/s0168-0102(02)00133-5. View