THE EFFECTS OF MELATONIN, FLUOXETINE AND THEIR COMBINATIONS ON STRESS INDUCED BEHAVIORAL AND COGNITIVE IMPAIRMENTS IN MICE

Öz

Objective: Melatonin (Mel) is a hormone with anti-depressant and anti-oxidant features. It is well known that melatonin protects brain cells from reactive oxygen species and that the brain's high oxygen consumption and lipid content make it particularly vulnerable to oxidative stress caused by prolonged stress. This study aims to investigate the effects of melatonin, fluoxetine and their combinations on emotional memory, depression, and anxiety-like behavioral changes induced by immobilization (Imb) stress. Material and Method: 48 male Balb/c mice were divided into eight groups: Cnt (control), Imb, Imb+Mlt, Imb+Flx (fluoxetine), Imb+Mlt+Flx, Mlt, Flx and Mlt+Flx. For seven days in a row, the mice underwent daily immobilization stress for 6 hours. Mice were treated with Mlt (10 mg/kg) and Flx (20 mg/kg). All animals were subjected to the behavioral tests; forced swimming test (FST), open field test (OFT), elevated plus maze (EPM), passive avoidance test (PAT) and hot plate (HP) test. After all behavioral tests, brain tissues were obtained for malondialdehyde level analysis. Result and Discussion: OFT test data showed the time spent in the central zone and the number of entrances to the central area were significantly lower in the Imb group compared to the Cnt group, these were higher in the Imb+Flx, Imb+Mlt, Imb+Mlt+Flx groups compared to the Imb group. Also, according to the data obtained from FST, immobile time was significantly higher in the Imb group compared to the Cnt group, it was lower in the Imb+Flx, Imb+Mlt, Imb+Mlt+Flx groups compared to the Imb group. Besides, it was demonstrated that the emotional memory index was statistically higher in the Imb group compared to the Cnt group, and the increasing of memory index returned to normal in the Imb+Mlt and Imb+Mlt+Flx groups with PAT. And also, lipid peroxidation level, which increased in the Imb group, decreased significantly in the Imb+Flx, Imb+Mlt, and Imb+Mlt+Flx groups. As a result, it was observed that melatonin has anti-depressant, anxiolytic, antioxidant effects and normalized emotional memory. Also, melatonin, fluoxetine and their combinations exert similar effects in the present study.

Anahtar Kelimeler

• Anxiety
• depression
• emotional memory
• melatonin
• stress

Proje Numarası

TIP.16.011

Kaynakça

1. 1. Sahin, E., Gumuslu, S. (2007). Immobilization stress in rat tissues: alterations in protein oxidation, lipid peroxidation and antioxidant defense system. Comparative Biochemistry and Physiology Part C: Toxicology&Pharmacology, 144(4), 342-347. [CrossRef]
2. 2. Kang, Y. J., Sim, Y. B., Park, S. H., Sharma, N., Suh, H. W. (2015). Involvement of alpha(2)-adrenergic receptor in the regulation of the blood glucose level induced by immobilization stress. Archives of Pharmacal Research, 38(5), 921-929. [CrossRef]
3. 3. Chiba, S., Numakawa, T., Ninomiya, M., Richards, M. C., Wakabayashi, C., Kunugi, H. (2012). Chronic restraint stress causes anxiety- and depression-like behaviors, downregulates glucocorticoid receptor expression, and attenuates glutamate release induced by brain-derived neurotrophic factor in the prefrontal cortex. Progress in Neuropsychopharmacology and Biological Psychiatry, 39(1), 112-119. [CrossRef]
4. 4. Samarghandian, S., Azimi-Nezhad, M., Farkhondeh, T., Samini, F. (2017). Anti-oxidative effects of curcumin on immobilization-induced oxidative stress in rat brain, liver and kidney. Biomedicine & Pharmacotherapy, 87, 223-229. [CrossRef]
5. 5. Azouzi, S., Santuz, H., Morandat, S., Pereira, C., Cote, F., Hermine, O., El Kirat, K., Colin, Y., Le Van Kim, C., Etchebest, C., Amireault, P. (2017). Antioxidant and membrane binding properties of serotonin protect lipids from oxidation. Biophysical Journal, 112(9), 1863-1873. [CrossRef]
6. 6. Li, K., Shen, S., Ji, Y. T., Li, X. Y., Zhang, L. S., Wang, X. D. (2018). Melatonin augments the effects of fluoxetine on depression-like behavior and hippocampal BDNF-TrkB signaling. Neuroscience Bulletin, 34(2), 303-311. [CrossRef]
7. 7. Avitsur, R., Grinshpahet, R., Goren, N., Weinstein, I., Kirshenboim, O., Chlebowski, N. (2016). Prenatal SSRI alters the hormonal and behavioral responses to stress in female mice: Possible role for glucocorticoid resistance. Hormones and Behavior, 84, 41-49. [CrossRef]
8. 8. Tchekalarova, J., Stoynova, T., Ilieva, K., Mitreva, R., Atanasova, M. (2018). Agomelatine treatment corrects symptoms of depression and anxiety by restoring the disrupted melatonin circadian rhythms of rats exposed to chronic constant light. Pharmacology Biochemistry and Behavior, 171, 1-9. [CrossRef]

9. 9. Rebai, R., Jasmin, L., Boudah, A. (2017). The antidepressant effect of melatonin and fluoxetine in diabetic rats is associated with a reduction of the oxidative stress in the prefrontal and hippocampal cortices. Brain Research Bulletin, 134, 142-150. [CrossRef]
10. 10. Ergenc, M., Ozacmak, H. S., Turan, I., Ozacmak, V. H. (2019). Melatonin reverses depressive and anxiety like-behaviours induced by diabetes: involvement of oxidative stress, age, rage and S100B levels in the hippocampus and prefrontal cortex of rats. Archives of Physiology and Biochemistry, 1-9. [CrossRef]
11. 11. Roni MA, Rahman S. Effects of lobeline and reboxetine, fluoxetine, or bupropion combination on depression-like behaviors in mice. Pharmacology Biochemistry and Behavior. 2015;139(Pt A):1-6. [CrossRef]
12. 12. Dhir, A., Padi, S. S., Naidu, P. S., Kulkarni, S. K. (2006). Protective effect of naproxen (non-selective COX-inhibitor) or rofecoxib (selective COX-2 inhibitor) on immobilization stress-induced behavioral and biochemical alterations in mice. European Journal of Pharmacology, 535(1-3), 192-198. [CrossRef]
13. 13. Kumar, N., Singh, N., Jaggi, A. S. (2012). Anti-stress effects of cilnidipine and nimodipine in immobilization subjected mice. Physiology and Behavior, 105(5), 1148-1155. [CrossRef]
14. 14. Castagne, V., Moser, P., Roux, S., Porsolt, R. D. (2011). Rodent models of depression: forced swim and tail suspension behavioral despair tests in rats and mice. Current Protocols in Neuroscience, Chapter 8, Unit 8 10A. [CrossRef]
15. 15. McGaugh, J. L., Cahill, L., Roozendaal, B. (1996). Involvement of the amygdala in memory storage: interaction with other brain systems. Proceedings of the National Academy of Sciences of the United States of America, 93(24), 13508-13514. [CrossRef]
16. 16. Walf, A. A., Frye, C. A. (2007). The use of the elevated plus maze as an assay of anxiety-related behavior in rodents. Nature Protocols, 2(2), 322-328. [CrossRef]
17. 17. Pompella, A., Maellaro, E., Casini, A. F., Ferrali, M., Ciccoli, L., Comporti, M. (1987). Measurement of lipid peroxidation in vivo: a comparison of different procedures. Lipids, 22(3), 206-211. [CrossRef]
18. 18. Samad, N., Saleem, A., Yasmin, F., Shehzad, M. A. (2018). Quercetin protects against stress-induced anxiety- and depression-like behavior and improves memory in male mice. Physiological Research, 67(5), 795-808. [CrossRef]
19. 19. Kumar, A., Kaur, G., Rinwa, P. (2014). Buspirone along with melatonin attenuates oxidative damage and anxiety-like behavior in a mouse model of immobilization stress. Chinese Journal of Natural Medicines, 12(8), 582-589. [CrossRef]
20. 20. Sakhri, F. Z., Adachi, N., Zerizer, S., Ohashi, Y., Ikemoto, H., Tsukada, M., Kabouche, Z., Hisamitsu, T., Sunagawa, M. (2021). Behavioral and neurological improvement by Cydonia oblonga fruit extract in chronic immobilization stress rats. Phytotherapy Research, 35(4), 2074-2084. [CrossRef]
21. 21. Macedo, I. C., Rozisky, J. R., Oliveira, C., Oliveira, C. M., Laste, G., Nonose, Y., Santos, V.S., Marquez, P.R., Ribeiro, M.F.M., Caumo, W., Torres, I. L.S. (2015). Chronic stress associated with hypercaloric diet changes the hippocampal BDNF levels in male Wistar rats. Neuropeptides, 51, 75-81. [CrossRef]
22. 22. Faucher, P., Huguet, C., Mons, N., Micheau, J. (2022). Acute pre-learning stress selectively impairs hippocampus-dependent fear memory consolidation: Behavioral and molecular evidence. Neurobiology of Learning and Memory, 188, 107585. [CrossRef]
23. 23. Woo, H., Hong, C. J., Jung, S., Choe, S., Yu, S. W. (2018). Chronic restraint stress induces hippocampal memory deficits by impairing insulin signaling. Molecular Brain, 11(1), 37. [CrossRef]
24. 24. Kumar, R. S., Narayanan, S. N., Kumar, N., Nayak, S. (2018). Exposure to enriched environment restores altered passive avoidance learning and ameliorates hippocampal injury in male albino wistar rats subjected to chronic restraint stress. International Journal of Applied and Basic Medical Research, 8(4), 231-236. [CrossRef]
25. 25. Rajbhandari, A. K., Gonzalez, S. T., Fanselow, M. S. (2018). Stress-enhanced fear learning, a robust rodent model of post-traumatic stress disorder. Journal of Visiulized Experiments(140). [CrossRef]
26. 26. Das, A., Kapoor, K., Sayeepriyadarshini, A. T., Dikshit, M., Palit, G., Nath, C. (2000). Immobilization stress-induced changes in brain acetylcholinesterase activity and cognitive function in mice. Pharmacological Research, 42(3), 213-217. [CrossRef]
27. 27. Gomaa, A. M., Galal, H. M., Abou-Elgait, A. T. (2017). Neuroprotective effects of melatonin administration against chronic immobilization stress in rats. International Journal of Physiology, Pathophysiology and Pharmacology, 9(2), 16-27. Retrieved August 3, 2022, from ttp://www.europepmc.org/article/med/28533888
28. 28. Banagozar Mohammadi, A., Torbati, M., Farajdokht, F., Sadigh-Eteghad, S., Fazljou, S. M. B., Vatandoust, S. M., Golzari, S.E.J., Mahmoudi, J. (2019). Sericin alleviates restraint stress induced depressive- and anxiety-like behaviors via modulation of oxidative stress, neuroinflammation and apoptosis in the prefrontal cortex and hippocampus. Brain Research, 1715, 47-56. [CrossRef]
29. 29. Mendez-David, I., Tritschler, L., Ali, Z. E., Damiens, M. H., Pallardy, M., David, D. J., Kerdine-Römer, S., Gardier, A. M. (2015). Nrf2-signaling and BDNF: A new target for the antidepressant-like activity of chronic fluoxetine treatment in a mouse model of anxiety/depression. Neuroscience Letters, 597, 121-126. [CrossRef]
30. 30. Samanta, S. (2020). Physiological and pharmacological perspectives of melatonin. Archives of Physiology and Biochemistry, 1-22. [CrossRef]
31. 31. Nie, L., Wei, G., Peng, S., Qu, Z., Yang, Y., Yang, Q., Huang, X., Liu, J., Zhuang, Z., Yang, X. (2017). Melatonin ameliorates anxiety and depression-like behaviors and modulates proteomic changes in triple transgenic mice of Alzheimer's disease. Biofactors, 43(4), 593-611. [CrossRef]
32. 32. Tamura, I., Tamura, H., Kawamoto-Jozaki, M., Doi-Tanaka, Y., Takagi, H., Shirafuta, Y., Mihara, Y., Maekawa, R., Taketani, T., Sato, S., Sugino, N. (2021). Long-term melatonin treatment attenuates body weight gain with aging in female mice. Journal of Endocrinology, 251(1), 15-25. [CrossRef]
33. 33. Lamtai, M., Azirar, S., Zghari, O., Ouakki, S., El Hessni, A., Mesfioui, A., Ouichou, A. (2021). Melatonin ameliorates cadmium-induced affective and cognitive impairments and hippocampal oxidative stress in rat. Biological Trace Element Research, 199(4), 1445-1455. [CrossRef]
34. 34. Lin, C. H., Chiu, C. C., Lane, H. Y. (2021). Trough melatonin levels differ between early and late phases of Alzheimer Disease. Clinical Psychopharmacology and Neuroscience, 19(1), 135-144. [CrossRef]
35. 35. O'Neal-Moffitt, G., Pilli, J., Kumar, S. S., Olcese, J. (2014). Genetic deletion of MT(1)/MT(2) melatonin receptors enhances murine cognitive and motor performance. Neuroscience, 277, 506-521. [CrossRef]
36. 36. Stefanovic, B., Spasojevic, N., Jovanovic, P., Jasnic, N., Djordjevic, J., Dronjak, S. (2016). Melatonin mediated antidepressant-like effect in the hippocampus of chronic stress-induced depression rats: Regulating vesicular monoamine transporter 2 and monoamine oxidase A levels. European Neuropsychopharmacology, 26(10), 1629-1637. [CrossRef]
37. 37. Sun, X., Wang, M., Wang, Y., Lian, B., Sun, H., Wang, G., Li, Q., Sun, L. (2017). Melatonin produces a rapid onset and prolonged efficacy in reducing depression-like behaviors in adult rats exposed to chronic unpredictable mild stress. Neuroscience Letters, 642, 129-135. [CrossRef]
38. 38. Spasojevic, N., Stefanovic, B., Jovanovic, P., Dronjak, S. (2016). Anxiety and hyperlocomotion induced by chronic unpredictable mild stress can be moderated with melatonin treatment. Folia Biologica (Praha), 62(6), 250-257. Retrieved August 3, 2022, from ttp://www.fb.cuni.cz/file/5827/fb2016a0031.pdf
39. 39. Karimi, S. A., Salehi, I., Shykhi, T., Zare, S., Komaki, A. (2019). Effects of exposure to extremely low-frequency electromagnetic fields on spatial and passive avoidance learning and memory, anxiety-like behavior and oxidative stress in male rats. Behavioral Brain Research, 359, 630-638. [CrossRef]
40. 40. Pal, R., Gulati, K., Banerjee, B. D., Ray, A. (2016). Pharmacological and biochemical studies on the protective effects of melatonin during stress-induced behavioral and immunological changes in relation to oxidative stress in rats. Canadian Journal of Physiolology and Pharmacology, 94(3), 296-301. [CrossRef]