Melatonin Yaşlı Sıçanlarda Postoperatif Kognitif Disfonksiyonu İyileştirir: Oksidatif Stres, PSD95 ve Ca2+/Kalmodulin Bağımlı Protein Kinazın Önemi

Abstract

Amaç: Postoperatif kognitif disfonksiyon (POCD) genellikle postoperatif dönemde yaşlı hastalarda görülmektedir. Bu çalışmada, yaşlı sıçanlarda abdominal cerrahi ile oluşturulan POCD modelinde melatoninin kognitif ve sinaptik disfonksiyon ve oksidatif stres üzerindeki etkilerini araştırmayı amaçladık. Gereç ve Yöntemler: Yirmi aylık erkek Wistar sıçanlar rastgele olarak kontrol grubu, melatonin uygulanan-kontrol grubu, cerrahi grubu ve melatonin uygulanan-cerrahi grubuna ayrıldı. Deneylerin sonunda sıçanların ameliyat sonrası bilişsel yeteneklerini değerlendirmek için yeni obje tanıma testi (NORT) kullanıldı. Hipokampüs sinaptozomlarında malondialdehit (MDA) ve indirgenmiş glutatyon (GSH) içerikleri spektrofotometrik yöntemlerle ölçüldü. kalsiyum-kalmodulin bağımlı protein kinaz II (CaMKII) ve postsinaptik dansite protein-95 (PSD95) protein seviyeleri ELISA kullanılarak ölçüldü. Bulgular: Cerrahi grubundaki hayvanlar NORT’ta yeni obje tanıma belleğinde önemli bir bozulma göstermiştir. Ayrıca cerrahi grubunda hipokampüste MDA içeriğinde (21,05±3,96) artış ve GSH (5,86±0,26) ve PSD95 (156,04±2,56) seviyelerinde azalma görülmüştür (sırasıyla p=0,012, p<0,001, p=0,004). PSD95 (193,08±4,14) ve CaMKII (2,82±0,25) düzeyleri (sırasıyla p=0,027, p=0,041) ve yeni obje tanıma belleği melatonin uygulaması ile iyileşmiştir. Sonuç: Melatonin, yaşlı hastalarda abdominal cerrahinin neden olduğu bilişsel işlev bozukluğuna karşı koruma sağlayabilecek potansiyel bir terapötik ajan olabilir.

Keywords

• Postoperatif kognitif disfonksiyon
• melatonin
• oksidatif stres
• PSD95
• CaMKII

Supporting Institution

Yok

Project Number

Yok

Thanks

Yok

Melatonin Improves Postoperative Cognitive Dysfunction in Aged Rats: Relevance of Oxidative Stress, PSD95 and Ca2+/Calmoduline Dependent Protein Kinase

Abstract

Aim: Postoperative cognitive dysfunction (POCD) is usually seen in the aged patients in postoperative period. In the present study, we aimed to investigate the effects of melatonin on cognitive and synaptic dysfunction and oxidative stress in POCD model constructed by abdominal surgery in aged rats. Material and Methods: Twenty months old male Wistar rats were randomly allocated into the control group, melatonin treated-control group, surgery group and melatonin treated-surgery group. The novel object recognition test (NORT) was used to assess the postoperative cognitive ability of rats at the end of the experiments. The contents of malondialdehyde (MDA) and reduced glutathione (GSH) were evaluated in the synaptosomes of hippocampus by spectrophotometric methods. The protein levels of calcium-calmodulin dependent protein kinase II (CaMKII) and postsynaptic density protein 95 (PSD95) were measured by using ELISA. . Results: Animals in surgery group showed significant an impairment of novel object recognition memory in NORT. Surgery group also exhibited increased content of MDA (21.05±3.96) and decreased levels of GSH (5.86±0.26) and PSD95 (156.04±2.56) in the hippocampus (respectively p=0.012, p<0.001, p=0.004) . The levels of PSD95 (193.08±4.14) and CaMKII (2.82±0.25) (respectively p=0.027, p=0.041) and novel object recognition memory was improved by melatonin treatment. Conclusion: Melatonin may be a potential therapeutic agent which can protect against abdominal surgery- induced cognitive dysfunction in elderly patients.

Keywords

• Postoperative cognitive dysfunction
• melatonin
• oxidative stress
• PSD95
• CaMKII

Project Number

Yok

References

1. 1. Cai L, Lu K, Chen X, Huang JY, Zhang BP, Zhang H. Auricular vagus nerve stimulation protects against postoperative cognitive dysfunction by attenuating neuroinflammation and neurodegeneration in aged rats. Neurosci Lett. 2019 Jun 11;703:104-110.
2. 2. Xu Z, Qian B. Sevoflurane anesthesia-mediated oxidative stress and cognitive impairment in hippocampal neurons of old rats can be ameliorated by expression of brain derived neurotrophic factor. Neurosci Lett. 2020 Mar 16;721:134785.
3. 3. Lin X, Chen Y, Zhang P, Chen G, Zhou Y, Yu X. The potential mechanism of postoperative cognitive dysfunction in older people. Exp Gerontol. 2020 Feb;130:110791.
4. 4. Liu Y, Ni C, Li Z, Yang N, Zhou Y, Rong X, Qian M, Chui D, Guo X. Prophylactic Melatonin Attenuates Isoflurane-Induced Cognitive Impairment in Aged Rats through Hippocampal Melatonin Receptor 2 - cAMP Response Element Binding Signalling. Basic Clin Pharmacol Toxicol 2017;120(3):219-226.
5. 5. Liang R, Ou S, Han Y, Xu J, Zhou S. Plasma amyloid beta level changes in aged mice with cognitive dysfunction following sevoflurane exposure. Exp Gerontol 2020;129:110737
6. 6. Jiang Y, Gao H, Yuan H, Xu H, Tian M, Du G, Xie W. Amelioration of postoperative cognitive dysfunction in mice by mesenchymal stem cell-conditioned medium treatments is associated with reduced inflammation, oxidative stress and increased BDNF expression in brain tissues. Neurosci Lett 2019;709:134372.
7. 7. Wang WX, Wu Q, Liang SS, Zhang XK, Hu Q, Chen QH, Huang HJ, Xu L, Lou FQ. Dexmedetomidine promotes the recovery of neurogenesis in aged mouse with postoperative cognitive dysfunction. Neurosci Lett 2018;677:110-116.
8. 8. Song J, Chu S, Cui Y, Qian Y, Li X, Xu F, Shao X, Ma Z, Xia T, Gu X. Circadian rhythm resynchronization improved isofluraneinduced cognitive dysfunction in aged mice. Exp Neurol 2018;306:45-54.

9. 9. Jia M, Liu WX, Sun HL, Chang YQ, Yang JJ, Ji MH, Yang JJ, Feng CZ. Suberoylanilide hydroxamic acid, a histone deacetylase inhibitor, attenuates postoperative cognitive dysfunction in aging mice. Front Mol Neurosci 2015;8:52.
10. 10. Mu S, Wu Y, Wu A. Relationship among melatonin, postoperative delirium, and postoperative cognitive dysfunction. Ann Palliat Med 2021;10(9):9443-9452.
11. 11. Yuan H, Wu G, Zhai X, Lu B, Meng B, Chen J. Melatonin and rapamycin attenuate isoflurane-induced cognitive impairment through inhibition of neuroinflammation by suppressing the mTOR signaling in the hippocampus of aged mice. Front Aging Neurosci 2019;11:314.
12. 12. Ali T, Kim MO. Melatonin ameliorates amyloid betainduced memory deficits, tau hyperphosphorylation and neurodegeneration via PI3/Akt/GSk3β pathway in the mouse hippocampus. J Pineal Res 2015;59(1):47-59.
13. 13. Rehman SU, Ikram M, Ullah N, Alam SI, Park HY, Badshah H, Choe K, Kim MO. Neurological enhancement effects of melatonin against brain injury-induced oxidative stress, neuroinflammation, and neurodegeneration via AMPK/CREB signaling. Cells 2019;8(7):760.
14. 14. Muhammad T, Ali T, Ikram M, Khan A, Alam SI, Kim MO. Melatonin rescue oxidative stress-mediated neuroinflammation/ neurodegeneration and memory impairment in scopolamineinduced amnesia mice model. J Neuroimmune Pharmacol 2019;14(2):278-294.
15. 15. Song TY, Lin HC, Chen CL, Wu JH, Liao JW, Hu ML. Ergothioneine and melatonin attenuate oxidative stress and protect against learning and memory deficits in C57BL/6J mice treated with D-galactose. Free Radic Res 2014;48(9):1049- 1060.
16. 16. Shigeta H, Yasui A, Nimura Y, Machida N, Kageyama M, Miura M, Menjo M, Ikeda K. Postoperative delirium and melatonin levels in elderly patients. Am J Surg 2001;182(5):449-454.
17. 17. Fan Y, Yuan L, Ji M, Yang J, Gao D. The effect of melatonin on early postoperative cognitive decline in elderly patients undergoing hip arthroplasty: A randomized controlled trial. J Clin Anesth 2017;39:77-81.
18. 18. Ergenc M, Ozacmak HS, Turan I, Ozacmak VH. 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. Arch Physiol Biochem 2022;128(2):402-410.
19. 19. Muscat SM, Deems NP, D’Angelo H, Kitt MM, Grace PM, Andersen ND, Silverman SN, Rice KC, Watkins LR, Maier SF, Barrientos RM. Postoperative cognitive dysfunction is made persistent with morphine treatment in aged rats. Neurobiol Aging 2021;98:214-224.
20. 20. Kawano T, Iwata H, Aoyama B, Nishigaki A, Yamanaka D, Tateiwa H, Eguchi S, Locatelli FM, Yokoyama M. The role of hippocampal insulin signaling on postoperative cognitive dysfunction in an aged rat model of abdominal surgery. Life Sci 2016;162:87-94.
21. 21. Grayson B, Leger M, Piercy C, Adamson L, Harte M, Neill JC. Assessment of disease-related cognitive impairments using the novel object recognition (NOR) task in rodents. Behav Brain Res 2015;285:176-193.
22. 22. Dos Santos AC, Castro MA, Jose EA, Delattre AM, Dombrowski PA, Da Cunha C, Ferraz AC, Lima MM. REM sleep deprivation generates cognitive and neurochemical disruptions in the intranigral rotenone model of Parkinson’s disease. J Neurosci Res 2013;91(11):1508-1516.
23. 23. Turunc Bayrakdar E, Uyanikgil Y, Kanit L, Koylu E, Yalcin A. Nicotinamide treatment reduces the levels of oxidative stress, apoptosis, and PARP-1 activity in Aβ(1-42)-induced rat model of Alzheimer’s disease. Free Radic Res 2014;48(2):146-158.
24. 24. Draper HH, Hadley M. Malondialdehyde determination as index of lipid peroxidation. Methods Enzymol 1990;186:421-431.
25. 25. Aykaç G, Uysal M, Yalçin AS, Koçak-Toker N, Sivas A, Oz H. The effect of chronic ethanol ingestion on hepatic lipid peroxide, glutathione, glutathione peroxidase and glutathione transferase in rats. Toxicology 1985;36(1):71-76.
26. 26. Cohen SJ, Stackman RW Jr. Assessing rodent hippocampal involvement in the novel object recognition task. A review. Behav Brain Res 2015;285:105-117.
27. 27. Yabuki Y, Ohizumi Y, Yokosuka A, Mimaki Y, Fukunaga K. Nobiletin treatment improves motor and cognitive deficits seen in MPTP-induced Parkinson model mice. Neuroscience 2014;259:126-141.
28. 28. Amirazodi F, Mehrabi A, Amirazodi M, Parsania S, Rajizadeh MA, Esmaeilpour K. The combination effects of resveratrol and swimming HIIT exercise on novel object recognition and openfield tasks in aged rats. Exp Aging Res 2020;46(4):336-358.
29. 29. Hosseini L, Farokhi-Sisakht F, Badalzadeh R, Khabbaz A, Mahmoudi J, Sadigh-Eteghad S. Nicotinamide Mononucleotide and Melatonin Alleviate Aging-induced Cognitive Impairment via Modulation of Mitochondrial Function and Apoptosis in the Prefrontal Cortex and Hippocampus. Neuroscience 2019;423:29-37.
30. 30. Xu J, Gao H, Zhang L, Rong S, Yang W, Ma C, Chen M, Huang Q, Deng Q, Huang F. Melatonin alleviates cognition impairment by antagonizing brain insulin resistance in aged rats fed a highfat diet. J Pineal Res 2019;67(2):e12584.
31. 31. Liu Y, Ni C, Tang Y, Tian X, Zhou Y, Qian M, Li Z, Chui D, Guo X. Melatonin attenuates isoflurane-induced acute memory impairments in aged rats. Basic Clin Pharmacol Toxicol 2013;113(4):215-220.
32. 32. Shen QH, Li HF, Zhou XY, Lu YP, Yuan XZ. Relation of serum melatonin levels to postoperative delirium in older patients undergoing major abdominal surgery. J Int Med Res 2020;48(3):300060520910642.
33. 33. Gao M, Ji S, Li J, Zhang S. DL-3-n-butylphthalide (NBP) ameliorates cognitive deficits and CaMKII-mediated long-term potentiation impairment in the hippocampus of diabetic db/db mice. Neurol Res 2019;41(11):1024-1033.
34. 34. Singhakumar R, Boontem P, Ekthuwapranee K, Sotthibundhu A, Mukda S, Chetsawang B, Govitrapong P. Melatonin attenuates methamphetamine-induced inhibition of neurogenesis in the adult mouse hippocampus: An in vivo study. Neurosci Lett 2015;606:209-214.
35. 35. Zhang L, Zhang HQ, Liang XY, Zhang HF, Zhang T, Liu FE. Melatonin ameliorates cognitive impairment induced by sleep deprivation in rats: role of oxidative stress, BDNF and CaMKII. Behav Brain Res 2013;256:72-81.
36. 36. Rosales-Corral SA, Acuña-Castroviejo D, Coto-Montes A, Boga JA, Manchester LC, Fuentes-Broto L, Korkmaz A, Ma S, Tan DX, Reiter RJ. Alzheimer’s disease: pathological mechanisms and the beneficial role of melatonin. J Pineal Res 2012;52(2):167-202