Duloksetinin Rat Beyin Dokularındaki Oksidan-Antioksidan Sistem Üzerine Etkisi

Öz

Amaç: Oksidatif stres (OS) ve depresyon arasındaki ilişki gösterildikten sonra antidepresanların OS üzerine etkisi önemli hale gelmiştir. Bu çalışmanın amacı duloksetinin rat beyin dokularındaki katalaz (CAT), süperoksit dismutaz (SOD), adenozin deaminaz (ADA), ksantin oksidaz (XO) ve glutatyon peroksidaz (GSH-Px) enzim aktiviteleri ile nitrik oksit (NO) ve malondialdehid (MDA) düzeylerine etkilerini araştırmaktır. Gereç ve Yöntem: Çalışmaya birinci grup kontrol grubu (n=10) ve ikinci grup duloksetin grubu (n=10) olmak üzere toplam yirmi tane Sprague-Dawley cinsi erkek rat alındı. Duloksetin grubuna günde bir defa 10 mg/kg dozunda intragastrik yoldan iki hafta süreyle duloksetin verildi. Kontrol grubuna da günde bir defa iki hafta süreyle intragastrik olarak su verildi. On beşinci günde tüm ratlar sakrifiye edilerek beyin dokuları çıkarıldı ve incelemeler yapıldı. Bulgular: Çalışmamızda duloksetinin rat beyin dokularında kontrol grubuna kıyasla SOD (P=0,026) enzim aktivitesini anlamlı düzeyde artırdığını ve XO (P=0,034), ADA (P=0,041) ve CAT (P=0,006) enzim aktivitelerini anlamlı düzeyde azalttığını saptadık. Ayrıca GSH-Px enzim aktivitesini anlamlı olmayan düzeyde artma ve MDA ile NO düzeylerinde ise anlamlı olmayan düzeyde azalma saptadık. Sonuç: Çalışmamızda antioksidan bir enzim olan SOD enzim aktivitesinin anlamlı düzeyde artması, organizmada reaktif oksijen ürünleri oluşumuna neden olabilen XO ve ADA enzim aktivitelerinin anlamlı düzeyde azalması ve LP göstergesi olan MDA’nın artmayıp, anlamlı düzeyde olmasa da azalması duloksetinin antioksidan durumu olumlu yönde değiştirebileceğini düşündürmektedir.

Anahtar Kelimeler

• Duloksetin
• Adenozin deaminaz
• Ksantin oksidaz
• Süperoksit dismutaz
• Katalaz
• Malondialdehit

Effects of Duloxetine on Oxidant-Antioxidant System in Rat Brain Tissues

Öz

Objective: After the relationship between depression and oxidative stress (OS) was demonstrated, the effect of antidepressant drugs on OS has become important. In this study, we aimed to determine the effects of the antidepressant duloxetine on the activities of the superoxide dismutase (SOD), catalase (CAT), adenosine deaminase (ADA), xanthine oxidase (XO) and glutathione peroxidase (GSH-Px) enzymes as well as the lipid peroxidation (LP) product malondialdehyde (MDA) and nitric oxide (NO) levels in rat brains. Material and Method: Twenty male Sprague-Dawley rats were used for the study. The first group was the control group (n=10) and the second group was the duloxetine group (n=10). Duloxetine was administered intragastrically once a day at a dose of 10 mg/kg for two weeks in the second group. Water was administered intragastrically once a day for two weeks in the first group. Rats were sacrificed at the end of the fourteenth day. The brain tissues were collected and then analyzes were performed. Results: As a result of this study, we found that duloxetine increased the SOD (P=0.026) activity and decreased the ADA (P=0.041), XO (P=0.034) and CAT (P=0.006) activities significantly compared to the control group. We also found an increase in the GSH-Px enzyme activity and decrease in the NO and MDA levels at non-significant rates in the duloxetine group brain tissues. Conclusion: The significant increase in the activity of the antioxidant enzyme SOD, the significant decrease in the activities of the XO and ADA enzymes, which can cause the formation of reactive oxygen products in the organism, and the insignificant decrease in the LP indicator MDA suggest that duloxetine can positively change the antioxidant status in rat brain tissues.

Anahtar Kelimeler

• Adenosine deaminase
• Xanthine oxidase
• Superoxide dismutase
• Catalase
• Malondialdehyde
• Duloxetine

Kaynakça

1. Adam-Vizi V, Chinopoulos C. Bioenergetics and the formation of mitochondrial reactive oxygen species. Trends Pharmacol Sci. 2006;27(12):639-645. doi:10.1016/j.tips.2006.10.005
2. Halliwell B. Biochemistry of oxidative stress. Biochem Soc Trans. 2007;35(Pt 5):1147-1150. doi:10.1042/BST0351147
3. Valko M, Leibfritz D, Moncol J, Cronin MTD, Mazur M, Telser J. Free radicals and antioxidants in normal physiological functions and human disease. Int J Biochem Cell Biol. 2007;39(1):44-84. doi:10.1016/j.biocel.2006.07.001
4. Hulbert AJ, Pamplona R, Buffenstein R, Buttemer WA. Life and Death: Metabolic Rate, Membrane Composition, and Life Span of Animals. Physiol Rev. 2007;87(4):1175-1213. doi:10.1152/physrev.00047.2006
5. Bhatt S, Nagappa AN, Patil CR. Role of oxidative stress in depression. Drug Discov Today. 2020;25(7):1270-1276. doi:10.1016/j.drudis.2020.05.001
6. Michel TM, Camara S, Tatschner T, et al. Increased xanthine oxidase in the thalamus and putamen in depression. The World Journal of Biological Psychiatry. 2010;11(2-2):314-320. doi:10.3109/15622970802123695
7. Michel TM, Frangou S, Thiemeyer D, et al. Evidence for oxidative stress in the frontal cortex in patients with recurrent depressive disorder—a postmortem study. Psychiatry Res. 2007;151(1-2):145-150. doi:10.1016/j.psychres.2006.04.013
8. Castrén E. Is mood chemistry? Nat Rev Neurosci. 2005;6(3):241-246. doi:10.1038/nrn1629

9. Behr GA, Moreira JCF, Frey BN. Preclinical and Clinical Evidence of Antioxidant Effects of Antidepressant Agents: Implications for the Pathophysiology of Major Depressive Disorder. Oxid Med Cell Longev. 2012;2012:1-13. doi:10.1155/2012/609421
10. Anttila S, Leinonen E. Duloxetine Eli Lilly. Curr Opin Investig Drugs. 2002;3(8):1217-1221.
11. Akpinar A, Uğuz AC, Nazıroğlu M. Agomelatine and duloxetine synergistically modulates apoptotic pathway by inhibiting oxidative stress triggered intracellular calcium entry in neuronal PC12 cells: role of TRPM2 and voltage-gated calcium channels. J Membr Biol. 2014;247(5):451-459. doi:10.1007/s00232-014-9652-1
12. Demirdaş A, Nazıroğlu M, Övey İS. Duloxetine Reduces Oxidative Stress, Apoptosis, and Ca2+ Entry Through Modulation of TRPM2 and TRPV1 Channels in the Hippocampus and Dorsal Root Ganglion of Rats. Mol Neurobiol. 2017;54(6):4683-4695. doi:10.1007/s12035-016-9992-1
13. Tynan RJ, Weidenhofer J, Hinwood M, Cairns MJ, Day TA, Walker FR. A comparative examination of the anti-inflammatory effects of SSRI and SNRI antidepressants on LPS stimulated microglia. Brain Behav Immun. 2012;26(3):469-479. doi:10.1016/j.bbi.2011.12.011
14. Lee TK, Park JH, Ahn JH, et al. Pretreated duloxetine protects hippocampal CA1 pyramidal neurons from ischemia-reperfusion injury through decreases of glial activation and oxidative stress. J Neurol Sci. 2016;370:229-236. doi:10.1016/j.jns.2016.09.059
15. Meejuru GF, Somavarapu A, Danduga RCSR, Nissankara Roa LS, Kola PK. Protective effects of duloxetine against chronic immobilisation stress-induced anxiety, depression, cognitive impairment and neurodegeneration in mice. Journal of Pharmacy and Pharmacology. 2021;73(4):522-534. doi:10.1093/jpp/rgaa003
16. Borumand MR, MM, MM, GM. Duloxetine by modulating the Akt/GSK3 signaling pathways has neuroprotective effects against methamphetamine-induced neurodegeneration and cognition impairment in rats. Iran J Med Sci. 2019;44(2):146.
17. Doğan İ, Doğan N. Estimation of Sample Size with Resource Equation Method in Experimental Animal Studies. Turkiye Klinikleri Journal of Biostatistics. 2020;12(2):211-217. doi:10.5336/biostatic.2020-73726
18. Molteni R, Calabrese F, Cattaneo A, et al. Acute stress responsiveness of the neurotrophin BDNF in the rat hippocampus is modulated by chronic treatment with the antidepressant duloxetine. Neuropsychopharmacology. 2009;34(6):1523-1532. doi:10.1038/npp.2008.208
19. Aebi H. Catalase in vitro. Methods Enzymol . 1984;105:121-126.
20. Paglia DE, Valentine WN. Studies on the quantitative and qualitative characterization of erythrocyte glutathione peroxidase. J Lab Clin Med. 1967;70(1):158-169.
21. Sun Y, Oberley LW, Li Y. A simple method for clinical assay of superoxide dismutase. Clin Chem. 1988;34(3):497-500.
22. Giusti G, Castagnari L, Gakis C, Galanti B. [Evaluation of the efficacy of laboratory diagnosis of typhoid infection. (Latex test, conditioned hemagglutination, adenosine deaminase activity in the serum)]. G Mal Infett Parassit. 1972;24(4):296-299.
23. Prajda N, Weber G. Malignant transformation-linked imbalance: decreased xanthine oxidase activity in hepatomas. FEBS Lett. 1975;59(2):245-249. doi:10.1016/0014-5793(75)80385-1
24. Cortas NK, Wakid NW. Determination of inorganic nitrate in serum and urine by a kinetic cadmium-reduction method. Clin Chem. 1990;36(8 Pt 1):1440-1443.
25. Draper HH, Hadley M. Malondialdehyde determination as index of lipid peroxidation. Methods Enzymol. 1990;186:421-431. doi:10.1016/0076-6879(90)86135-i
26. Lowry OH, Rosebrough NJ, Farr AL, Randall RJ. Protein measurement with the Folin phenol reagent. J Biol Chem. 1951;193(1):265-275.
27. Bains JS, Shaw CA. Neurodegenerative disorders in humans: the role of glutathione in oxidative stress-mediated neuronal death. Brain Res Rev. 1997;25(3):335-358. doi:10.1016/S0165-0173(97)00045-3
28. Engel DF, de Oliveira J, Lieberknecht V, Rodrigues ALS, de Bem AF, Gabilan NH. Duloxetine Protects Human Neuroblastoma Cells from Oxidative Stress-Induced Cell Death Through Akt/Nrf-2/HO-1 Pathway. Neurochem Res. 2018;43(2):387-396. doi:10.1007/s11064-017-2433-3
29. Winters KC, Lee CYS. Likelihood of developing an alcohol and cannabis use disorder during youth: association with recent use and age. Drug Alcohol Depend. 2008;92(1-3):239-247. doi:10.1016/j.drugalcdep.2007.08.005
30. Halliwell B. Free radicals and antioxidants – quo vadis? Trends Pharmacol Sci. 2011;32(3):125-130. doi:10.1016/j.tips.2010.12.002
31. Santana-Coelho D, Souza-Monteiro JR, Paraense RSO, et al. Antidepressant drugs in convulsive seizures: Pre-clinical evaluation of duloxetine in mice. Neurochem Int. 2016;99:62-71. doi:10.1016/j.neuint.2016.06.001
32. Harrison R. Physiological Roles of Xanthine Oxidoreductase. Drug Metab Rev. 2004;36(2):363-375. doi:10.1081/DMR-120037569
33. Cristalli G, Costanzi S, Lambertucci C, et al. Adenosine deaminase: Functional implications and different classes of inhibitors. Med Res Rev. 2001;21(2):105-128. doi:10.1002/1098-1128(200103)21:2<105::AID-MED1002>3.0.CO;2-U
34. Herken H, Gurel A, Selek S, et al. Adenosine Deaminase, Nitric Oxide, Superoxide Dismutase, and Xanthine Oxidase in Patients with Major Depression: Impact of Antidepressant Treatment. Arch Med Res. 2007;38(2):247-252. doi:10.1016/j.arcmed.2006.10.005
35. Herken H, Akyol O, Yilmaz HR, et al. Nitric oxide, adenosine deaminase, xanthine oxidase and superoxide dismutase in patients with panic disorder: alterations by antidepressant treatment. Human Psychopharmacology: Clinical and Experimental. 2006;21(1):53-59. doi:10.1002/hup.742
36. Huie RE, Padmaja S. The Reaction of no With Superoxide. Free Radic Res Commun. 1993;18(4):195-199. doi:10.3109/10715769309145868
37. Álvarez-González I, Camacho-Cantera S, Gómez-González P, et al. Genotoxic and oxidative effect of duloxetine on mouse brain and liver tissues. Sci Rep. 2021;11(1):6897. doi:10.1038/s41598-021-86366-0