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Okadaik Asitle İndüklenen Alzheimer Sıçan Modelinde Betulin Tedavisi ile Çoklu Organ Hasarının COX Aracılığıyla Düzenlenmesi

Yıl 2024, Cilt: 9 Sayı: 1, 73 - 83, 11.03.2024
https://doi.org/10.26453/otjhs.1405878

Öz

Amaç: Alzheimer Hastalığı (AH) ilerleyici bir nörodejeneratif hastalıktır. Siklooksijenazlar (COX'ler), AH 'nin inflamatuar ve rejeneratif süreçlerinde gereklidir. Bu çalışma, doğal bir fitokimyasal (triterpen) olan Betulin'in, AH 'nin çoklu organ hasarının COX aracılı düzeltilmesi için aday olduğunu göstermeyi amaçlamaktadır.
Materyal ve Metod: Bu çalışmada okadaik asit ile indüklenen sıçan AH modelinde betulin'in böbrek, kalp ve ince bağırsak dokusundaki genetik ve histolojik bağlamdaki etkilerini ve tedavi potansiyeli araştırılmıştır. Çalışmaya 36 adet Wistar albino erkek sıçan dahil edildi. Böbrek, kalp ve ince bağırsak dokularında Cyclooxygenase 1 (COX1) ve Cyclooxygenase 2 (COX2) gen ekspresyonları kantitatif gerçek zamanlı PCR (qRT-PCR) ile araştırılmıştır. Dokulardaki COX-1 ve COX2 proteinleri immünohistokimya ile analiz edildi.
Bulgular: AH modelinde COX1 ve COX2 genlerinin aşırı eksprese edildiği tespit edildi. Her iki genin ekspresyonu AH modelinde artmış ve betulin tedavisinden sonra azalmıştır. Histolojik skorlar Betulin'in böbrek üzerinde güçlü bir olumlu etkisi olduğunu, kalp ve ince bağırsak dokusu üzerinde ise nispeten daha az etkili olduğunu gösterdi.
Sonuç: AH'de organ hasarının tedavisinde COX'lar betulin tarafından inhibe edilebilir ve fonksiyonel iyileşmede etkili olabilir.

Proje Numarası

TF.HZP.23.43

Kaynakça

  • 1. Ma C, Long H. Protective effect of betulin on cognitive decline in streptozotocin (STZ)-induced diabetic rats. Neurotoxicology. 2016;57:104-111. doi:10.1016/j.neuro.2016.09.009
  • 2. Kamat PK, Rai S, Nath C. Okadaic acid induced neurotoxicity: an emerging tool to study Alzheimer's disease pathology. Neurotoxicology. 2013;37:163-172. doi:10.1016/j.neuro.2013.05.002
  • 3. Kamat PK, Tota S, Saxena G, et al. Okadaic acid (ICV) induced memory impairment in rats: a suitable experimental model to test anti-dementia activity. Brain Res. 2010;1309:66-74. doi:10.1016/j.brainres.2009.10.064
  • 4. Adepoju FO, Duru KC, Li E, Kovaleya EG, Tsurkan MV. Pharmacological potential of betulin as a multitarget compound. Biomolecules. 2023;13(7):1105. doi:10.3390/biom13071105
  • 5. Amiri S, Dastghaib S, Ahmadi M, et al. Betulin and its derivatives as novel compounds with different pharmacological effects. Biotechnol Adv. 2020;38:107409. doi:10.1016/j.biotechadv.2019.06.008
  • 6. Takibayeva AT, Zhumabayeva GK, Bakibaev AA, et al. Methods of analysis and identification of betulin and its derivatives. Molecules. 2023;28(16):5946. doi:10.3390/molecules28165946
  • 7. Faki Y, Er A. Different chemical structures and physiological/pathological roles of cyclooxygenases. Rambam Maimonides Med J. 2021;12(1):1-13. doi:10.5041/RMMJ.10426
  • 8. Adelizzi RA. COX-1 and COX-2 in health and disease. J Am Osteopath Assoc. 1999;99(11):7-12. doi:10.7556/jaoa.1999.03
  • 9. Takeuchi K, Tanaka A, Kato S, Amagase K, Satoh H. Roles of COX inhibition in pathogenesis of NSAID-induced small intestinal damage. Clin Chim Acta. 2010;411(7-8):459-466. doi:10.1016/j.cca.2009.12.026
  • 10. Rio DC, Ares M, Hannon GJ, Nilsen TW. Purification of RNA using TRIzol (TRI reagent). Cold Spring Harb Protoc. 2010;2010(6):534. doi:10.1101/pdb.prot5439
  • 11. Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2−ΔΔCT method. Methods. 2001;25(4):402-408. doi:10.1006/meth.2001.1262
  • 12. Moro MG, Sánchez PKV, Lupepsa AC, Baller EM, Franco GCN. Cyclooxygenase biology in renal function-literature review. Revista Colombiana de Nefrología. 2017;4(1):27-37. doi:10.22265/acnef.4.1.263
  • 13. Gu M, Tan M, Zhou L, et al. Protein phosphatase 2Acα modulates fatty acid oxidation and glycolysis to determine tubular cell fate and kidney injury. Kidney Int. 2022;102(2):321-336. doi:10.1016/j.kint.2022.03.024
  • 14. Shao L, Ma Y, Fang Q, et al. Role of protein phosphatase 2A in kidney disease. Exp Ther Med. 2021;22(5):1-10. doi:10.3892/etm.2021.10671
  • 15. Nogueira A, Pires MJ, Oliveira PA. Pathophysiological mechanisms of renal fibrosis: a review of animal models and therapeutic strategies. In vivo. 2017;31(1):1-22. doi:10.21873/invivo.11019
  • 16. Troncone L, Luciani M, Coggins M, et al. Aβ amyloid pathology affects the hearts of patients with Alzheimer’s disease: mind the heart. Am J Cardiol. 2016;68(22):2395-2407. doi:10.1016/j.jacc.2016.08.073
  • 17. Walker KA, Le Page LM, Terrando N, et al. The role of peripheral inflammatory insults in Alzheimer’s disease: a review and research roadmap. Mol Neurodegener. 2023;18(1):1-19. doi:10.1186/s13024-023-00627-2
  • 18. Megha KB, Joseph X, Akhil V, Mohanan PV. Cascade of immune mechanism and consequences of inflammatory disorders. Phytomedicine. 2021;91:153712. doi:10.1016/j.phymed.2021.153712
  • 19. Yang C, Yang Y, DeMars KM, Rosenberg GA, Candelario JE. Genetic deletion or pharmacological inhibition of cyclooxygenase-2 reduces blood-brain barrier damage in experimental ischemic stroke. Front Neurol. 2020;11:887. doi:10.3389/fneur.2020.00887
  • 20. Choi SH, Aid S, Bosetti F. The distinct roles of cyclooxygenase-1 and-2 in neuroinflammation: implications for translational research. Trends Pharmacol Sci. 2009; 30(4):174-181. doi:10.1016/j.tips.2009.01.002
  • 21. Sun Y, Koyama Y, Shimada S. Inflammation from peripheral organs to the brain: how does systemic inflammation cause neuroinflammation. Front Aging Neurosci. 2022;14:903455. doi:10.3389/fnagi.2022.903455
  • 22. Immanuel J, Yun S. Vascular Inflammatory Diseases and Endothelial Phenotypes. Cells. 2023;12(12):1640. doi:10.3390/cells12121640
  • 23. Tiwari PC, Pal R. The potential role of neuroinflammation and transcription factors in Parkinson disease. Dialogues Clin Neurosci. 2017;19(1):71-80. doi:10.31887/DCNS.2017.19.1/rpal
  • 24. Villaseñor R, Lampe J, Schwaninger M, Collin L. Intracellular transport and regulation of transcytosis across the blood–brain barrier. Cell Mol Life Sci. 2019;76:1081-1092. doi:10.1007/s00018-018-2982-x
  • 25. Wang L, Gao F, Wang Z, et al. Transcutaneous auricular vagus nerve stimulation in the treatment of disorders of consciousness: mechanisms and applications. Front Neuroenergetics. 2023;17:1286267. doi:10.3389/fnins.2023.1286267
  • 26. Gasparotto J, Girardi CS, Somensi N, et al. Receptor for advanced glycation end products mediates sepsis-triggered amyloid-β accumulation, Tau phosphorylation, and cognitive impairment. J Biol Chem. 2018;293(1):226-244. doi:10.1074/jbc.M117.786756
  • 27. Nelson, Amy R. Peripheral pathways to neurovascular unit dysfunction, cognitive impairment, and Alzheimer’s Disease. Frontiers in aging neuroscience. 2022;14:858429. doi:10.3389/fnagi.2022.858429

COX-mediated Regulation of Multiple Organ Damage by Betulin Treatment in Okadaic Acid-induced Alzheimer Rat Model

Yıl 2024, Cilt: 9 Sayı: 1, 73 - 83, 11.03.2024
https://doi.org/10.26453/otjhs.1405878

Öz

Objective: Alzheimer's Disease (AD) is a progressive neurodegenerative disease. Cyclooxygenases (COXs) are essential in the inflammatory and regenerative processes of AD. This study aims to show that Betulin, a natural phytochemical (triterpene), is a candidate for COX-mediated correction of multiple organ damage of AD.
Materials and Methods: In this study, the effects and treatment potential of Betulin were investigated in the kidney, heart, and small intestine tissue in genetic, and histological contexts in an okadaic acid-induced rat AD model. A total of 36 Wistar albino male rats were included in the study. Cyclooxygenase 1 (COX-1) and Cyclooxygenase 2 (COX2) gene expressions were investigated by quantitative real-time PCR (qRT-PCR) in kidney, heart, and small intestine tissues. COX-1 and COX-2 proteins in tissues were analyzed by immunohistochemistry.
Results: COX-1 and COX-2 genes were detected to be overexpressed in the AD model. The expression of both genes was increased in the AD model and decreased after betulin treatment. Histological scores showed a strong positive effect of Betulin on the kidney, while it was relatively less effective on the heart and small intestine tissue.
Conclusion: In treating organ damage in AD, COXs can be inhibited by Betulin and may be effective in functional recovery.

Etik Beyan

The work described in this article has been carried out by the Gaziantep University Experimental Animals Local Ethics Committee (decision number 2023/29, protocol number: 323).

Destekleyen Kurum

Gaziantep University Scientific Research Projects Unit

Proje Numarası

TF.HZP.23.43

Teşekkür

Gaziantep University Scientific Research Projects Unit

Kaynakça

  • 1. Ma C, Long H. Protective effect of betulin on cognitive decline in streptozotocin (STZ)-induced diabetic rats. Neurotoxicology. 2016;57:104-111. doi:10.1016/j.neuro.2016.09.009
  • 2. Kamat PK, Rai S, Nath C. Okadaic acid induced neurotoxicity: an emerging tool to study Alzheimer's disease pathology. Neurotoxicology. 2013;37:163-172. doi:10.1016/j.neuro.2013.05.002
  • 3. Kamat PK, Tota S, Saxena G, et al. Okadaic acid (ICV) induced memory impairment in rats: a suitable experimental model to test anti-dementia activity. Brain Res. 2010;1309:66-74. doi:10.1016/j.brainres.2009.10.064
  • 4. Adepoju FO, Duru KC, Li E, Kovaleya EG, Tsurkan MV. Pharmacological potential of betulin as a multitarget compound. Biomolecules. 2023;13(7):1105. doi:10.3390/biom13071105
  • 5. Amiri S, Dastghaib S, Ahmadi M, et al. Betulin and its derivatives as novel compounds with different pharmacological effects. Biotechnol Adv. 2020;38:107409. doi:10.1016/j.biotechadv.2019.06.008
  • 6. Takibayeva AT, Zhumabayeva GK, Bakibaev AA, et al. Methods of analysis and identification of betulin and its derivatives. Molecules. 2023;28(16):5946. doi:10.3390/molecules28165946
  • 7. Faki Y, Er A. Different chemical structures and physiological/pathological roles of cyclooxygenases. Rambam Maimonides Med J. 2021;12(1):1-13. doi:10.5041/RMMJ.10426
  • 8. Adelizzi RA. COX-1 and COX-2 in health and disease. J Am Osteopath Assoc. 1999;99(11):7-12. doi:10.7556/jaoa.1999.03
  • 9. Takeuchi K, Tanaka A, Kato S, Amagase K, Satoh H. Roles of COX inhibition in pathogenesis of NSAID-induced small intestinal damage. Clin Chim Acta. 2010;411(7-8):459-466. doi:10.1016/j.cca.2009.12.026
  • 10. Rio DC, Ares M, Hannon GJ, Nilsen TW. Purification of RNA using TRIzol (TRI reagent). Cold Spring Harb Protoc. 2010;2010(6):534. doi:10.1101/pdb.prot5439
  • 11. Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2−ΔΔCT method. Methods. 2001;25(4):402-408. doi:10.1006/meth.2001.1262
  • 12. Moro MG, Sánchez PKV, Lupepsa AC, Baller EM, Franco GCN. Cyclooxygenase biology in renal function-literature review. Revista Colombiana de Nefrología. 2017;4(1):27-37. doi:10.22265/acnef.4.1.263
  • 13. Gu M, Tan M, Zhou L, et al. Protein phosphatase 2Acα modulates fatty acid oxidation and glycolysis to determine tubular cell fate and kidney injury. Kidney Int. 2022;102(2):321-336. doi:10.1016/j.kint.2022.03.024
  • 14. Shao L, Ma Y, Fang Q, et al. Role of protein phosphatase 2A in kidney disease. Exp Ther Med. 2021;22(5):1-10. doi:10.3892/etm.2021.10671
  • 15. Nogueira A, Pires MJ, Oliveira PA. Pathophysiological mechanisms of renal fibrosis: a review of animal models and therapeutic strategies. In vivo. 2017;31(1):1-22. doi:10.21873/invivo.11019
  • 16. Troncone L, Luciani M, Coggins M, et al. Aβ amyloid pathology affects the hearts of patients with Alzheimer’s disease: mind the heart. Am J Cardiol. 2016;68(22):2395-2407. doi:10.1016/j.jacc.2016.08.073
  • 17. Walker KA, Le Page LM, Terrando N, et al. The role of peripheral inflammatory insults in Alzheimer’s disease: a review and research roadmap. Mol Neurodegener. 2023;18(1):1-19. doi:10.1186/s13024-023-00627-2
  • 18. Megha KB, Joseph X, Akhil V, Mohanan PV. Cascade of immune mechanism and consequences of inflammatory disorders. Phytomedicine. 2021;91:153712. doi:10.1016/j.phymed.2021.153712
  • 19. Yang C, Yang Y, DeMars KM, Rosenberg GA, Candelario JE. Genetic deletion or pharmacological inhibition of cyclooxygenase-2 reduces blood-brain barrier damage in experimental ischemic stroke. Front Neurol. 2020;11:887. doi:10.3389/fneur.2020.00887
  • 20. Choi SH, Aid S, Bosetti F. The distinct roles of cyclooxygenase-1 and-2 in neuroinflammation: implications for translational research. Trends Pharmacol Sci. 2009; 30(4):174-181. doi:10.1016/j.tips.2009.01.002
  • 21. Sun Y, Koyama Y, Shimada S. Inflammation from peripheral organs to the brain: how does systemic inflammation cause neuroinflammation. Front Aging Neurosci. 2022;14:903455. doi:10.3389/fnagi.2022.903455
  • 22. Immanuel J, Yun S. Vascular Inflammatory Diseases and Endothelial Phenotypes. Cells. 2023;12(12):1640. doi:10.3390/cells12121640
  • 23. Tiwari PC, Pal R. The potential role of neuroinflammation and transcription factors in Parkinson disease. Dialogues Clin Neurosci. 2017;19(1):71-80. doi:10.31887/DCNS.2017.19.1/rpal
  • 24. Villaseñor R, Lampe J, Schwaninger M, Collin L. Intracellular transport and regulation of transcytosis across the blood–brain barrier. Cell Mol Life Sci. 2019;76:1081-1092. doi:10.1007/s00018-018-2982-x
  • 25. Wang L, Gao F, Wang Z, et al. Transcutaneous auricular vagus nerve stimulation in the treatment of disorders of consciousness: mechanisms and applications. Front Neuroenergetics. 2023;17:1286267. doi:10.3389/fnins.2023.1286267
  • 26. Gasparotto J, Girardi CS, Somensi N, et al. Receptor for advanced glycation end products mediates sepsis-triggered amyloid-β accumulation, Tau phosphorylation, and cognitive impairment. J Biol Chem. 2018;293(1):226-244. doi:10.1074/jbc.M117.786756
  • 27. Nelson, Amy R. Peripheral pathways to neurovascular unit dysfunction, cognitive impairment, and Alzheimer’s Disease. Frontiers in aging neuroscience. 2022;14:858429. doi:10.3389/fnagi.2022.858429
Toplam 27 adet kaynakça vardır.

Ayrıntılar

Birincil Dil İngilizce
Konular Tıbbi Fizyoloji (Diğer)
Bölüm Araştırma Makalesi
Yazarlar

Ahmet Sarper Bozkurt 0000-0002-7293-0974

Şenay Görücü Yılmaz 0000-0003-0523-7819

Proje Numarası TF.HZP.23.43
Yayımlanma Tarihi 11 Mart 2024
Gönderilme Tarihi 16 Aralık 2023
Kabul Tarihi 23 Şubat 2024
Yayımlandığı Sayı Yıl 2024 Cilt: 9 Sayı: 1

Kaynak Göster

AMA Bozkurt AS, Görücü Yılmaz Ş. COX-mediated Regulation of Multiple Organ Damage by Betulin Treatment in Okadaic Acid-induced Alzheimer Rat Model. OTSBD. Mart 2024;9(1):73-83. doi:10.26453/otjhs.1405878

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