Feriha ÖZER, Sibel ÇETİN, Cemal ÖZCAN, Yusuf TÜRKÖZ, Eyüp ALTINÖZ, Handan Işın ÖZIŞIK, Sibel ALTINAYAR

Parkinson hastalarında L-Deprenilin nitrik oksit metabolitlerine etkisi

Amaç: L-deprenil, Parkinson hastalığı tedavisinde sıklıkla kullanılan, irreversibl bir mitokondriyal monoamin oksidaz tip-B (MAO-B) inhibitörüdür ve etkisini MAO-B enzim inhibisyonundan farklı bir mekanizma ile yaptığına inanılmaktadır. L-deprenilin serebral dokudaki nöroprotektif etkisini Nitrik oksit (NO) üretimi yoluyla yaptığını düşündüren, in vivo ve in vitro doku çalışmaları yayınlanmıştır. Bu çalışmanın amacı, Parkinson hastalığında L-Deprenil kullanımının NO metabolitlerine etkisini araştırmaktır. Gereç ve Yöntem: Bu çalışmaya L-deprenil kullanan (n=21) ve kullanmayan (n=16) olgular ile yaş ve cinsiyet açısından eşleştirilmiş sağlıklı kontrol grubu (n=24) dahil edildi. Serum total nitrit ve nitrat düzeyleri spektrofotometrik olarak belirlendi. Sonuçlar: L-Deprenil kullanmayan grupta; Total nitrit:62.6±16.2 µmol/L, Nitrat:59.5±16.2 µmol/L, L-Deprenil kullanan grupta; Total nitrit: 63.8±30.1 µmol/L, Nitrat: 67.3±29.0 µmol/L, kontrol grubunda; Total nitrit:66.2±21.8 µmol/L, Nitrat:62.4±21.2 µmol/L bulundu. Serum total nitrit ve nitrat düzeyleri üç grup arasında istatistiksel olarak farklı değildi. Tartışma: Bu bulgular, L-deprenilin serebral dokudaki nöroprotektif etkisinin NO üretimi yoluyla olduğunu ileri süren görüşü desteklememiştir. L-deprenilin serebral doku ve NO metabolizmasına etkisini anlayabilmek için in vivo ve in vitro farklı çalışmalara ihtiyaç vardır.

Effect of L-Deprenyl on nitric oxide metabolites in Parkinson’s disease patients

Objectives: L-deprenyl is an irreversible mitochondrial monoamine oxidase type-B (MAO-B) inhibitor and is mostly used in Parkinson’s Disease (PD) treatment. However, it is believed that the effect of L-deprenyl in PD is by a different mechanism than MAO-B enzyme inhibition and may be due to several factors. Neuroprotective effect of L-deprenyl on cerebral tissue achieved by NO production has been shown by in vivo and in vitro tissue studies. The purpose of this study was to determine the level of nitric oxide (NO) metabolites, nitrite and nitrate in human serum and to assess whether there is any relationship among serum nitrate–nitrite levels and L-deprenyl in PD. Patients and Methods: Twenty-one patients used L-Deprenile and 16 patients did not. Twenty-four healthy age- and sex matched control were included in the study. Serum total nitrite and nitrate levels were determined spectrophotometrically. Results: The levels of Total nitrite and Nitrate in L-Deprenil using and L-Deprenil not using, and control groups were found to be 63.8±30.1 $mu$mol/L and 67.3±29.0 $mu$mol/L, 62.6±16.2 $mu$mol/L and 59.5±16.2 $mu$mol/L, 66.2±21.8 $mu$mol/L and 62.4±21.2 $mu$mol/L, respectively. Serum total nitrite and nitrate levels were not significantly different among the three groups. Conclusion: These data do not support the concept that neuroprotective effect of L-deprenyl on cerebral tissue is achieved by NO production. Therefore, further in vivo and in vitro studies are needed to exactly clarify the cerebral effects of L-deprenyl and the role of NO in patients with PD.

PDF

___

1. Alexia T, Borlongand CV, Faullb RLM, Williamsa CE, Clarka RG, Gluckmana PD, Hughesc PE. Neuroprotective strategies for basal ganglia degeneration:Parkinson'sand Huntington's diseases. Progress in Neurobiology 2000;60:409-470.
2. Bonfoco E, Leist M, Zhivotovsky B, Orrenius S, Lipton SA, and Nicotera P. Cytoskeletal breakdown and apoptosis elicited by NO donors in cerebellar granulecells require NMDA receptor activation. J. Neurochem 1996;67:2484-2493.
3. Przedborski S, Jackson-Lewis V, Yokohama R, Shibata T, Dawson VL, and Dawlon TM. Role of neuronal nitric oxide inl-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced dopaminergic neurotoxicity. Proc. Nati. Acad Sci 1996;93:4565- 4571.
4. Hantraye P, Brouillet E, Ferrante R, Palfi S, Dolan R, Matthews R, and Beal MF.Inhibition of neuronal nitric oxide synthase prevents MPTP-induced parkinsonism in baboons. Nalure Med 1996;2:1017-1021.
5. Vallance P, Collier J. Biology and clinical relevance of nitric oxide. British Medical Journal 1994;Aug 13:453-462.
6. Dawson VL, Dawson TM. Nitric oxide in neurodegeneration. Prog Brain Res 1998;118:215-229.
7. Gerlach M, Desser H, Youdim MB, Riederer P. New horizons in molecular mechanisms underlying Parkinson's disease and in our understanding of the neuroprotective effects of L-Deprenile. J Neural Transm Suppl 1996;48:7-21.
8. Thomas T, McLendon C, Thomas G. L-deprenyl: nitric oxide production and dilation of cerebral blood vessels. Neuroreport 1998;Aug 3:9(11):2595-2600.
9. Naoi M, Maruyama W, Yagi K, Youdim M. Anti-apoptotic function of L-(-) deprenyl (L-Deprenile) and related compounds. Neurobiology (Bp) 2000;8(1):69-80.
10. Jungersten L, Edlund A, Petersson AS, Wennmalm A. Plasma nitrate as an index of nitric oxide formation in man: analyses of kinetics and confounding factors. Clin Physiol 1996;16:369–379.
11. Zeballos GA, Bernstein RD, Thompson CI, et al. Pharmacodynamics of plasma nitrate/nitrite as an indication of nitric oxide formation in conscious dogs. Circulation 1995;91:2982–2988.
12. Özbek E, Türkoz Y, Gökdeniz R, Davarcı M, Özügürlü F. Increased nitric oxide production in the spermatic vein of patients with varicocele. Eur Urol. 2000;37(2):172-175.
13. Marsden CD, Olanow CW. The causes of Parkinson's disease are being unraveled and rational neuroprotective therapy is close to reality. Ann Neurol 1998; Sep:44(3 Suppl1):S189-196.
14. Tatton WG, Greenwood CE. Rescue of dying neurons: a new action for deprenyl in MPTP parkinsonism. J Neurosci Res 1991; Dec:30(4):666-672.
15. Koller WC. Neuroprotective Therapy For Parkinson’s Disease. Experimental Neurology 1997;144:24–28.
16. Tatton BW, Chalmers-Redman R, and Tatton N. Neuroprotection by deprenyl and other propargylamines: glyceraldehyde-3-phosphate dehydrogenase rather than monoamine oxidase J Neural Transm 2003;110: 509–515.
17. Maruyama W, Takahashi T, Naoi M. (-)-Deprenyl protects human dopaminergic neuroblastoma SH-SY5Y cells from apoptosis induced by peroxynitrite and nitric oxide. J Neurochem 1998;Jun:70(6):2510-2515.
18. Kuiper MA, Visser JJ, Bergmans PLM, Scheltens P, Wolters EC. Decreased cerebral fluid nitrate levels in Parkinson’s disease, Alzheimer’s disease and multiple system atrophy patients. J Neurol Sci 1994;121:46 –49.
19. Thomas T. Monoamine oxidase-B inhibitors in the treatment of Alzheimers disease.Neurobiology of Aging 2000;21:343–348.
20. Beckman JS, Beckman TW, Chen J, Marshall PA, Freeman BA. Apparent hydroxyl radical production by peroxynitrite: MPP implications for endothelial injury from nitric oxide and superoxide, Proc. Natl. Acad Sci. 1990;87:1620–1624.
21. Dawson LV, Dawson TM. Physiologic and Toxicologic Actions of Nitric Oxide in the Central Nervous System. In: Ignarro L, Murad F (eds.). Nitric Oxide: Biochemistry, Molecular Biology and Therapeutic Implications. San Diago, California:Academic Pres Inc 1995:323-342.
22. Mandel S, Unblatt EGr, Riederer P, Gerlach M, Levites Y, and Youdim MBH. Neuroprotective Strategies in Parkinson’s Disease An Update on Progress. CNS Drugs 2003;17(10):729-762.