Research Article
Omurilik Hasarı Oluşturulan Sıçan Modelinde Riboflavin Tedavisi Apoptozu ve Oksidan DNA Hasarını Azaltır
Abstract
Amaç: Omurilik hasarı inflamatuar yanıta ve oksidatif strese yol açarak çeşitli organ sistemlerinde zararlı etkiler oluşturur. Riboflavin insan ve hayvanda sağlığın sürdürülmesinde önemli role sahip olan ve kolayca absorbe edilen mikrobesindir. Bu çalışma omurilik yaralanmasına bağlı omurilik ve böbrek dokusunda riboflavinin koruyucu etkilerini araştırmak üzere planlandı.
Yöntemler: Omurilik hasarı oluşturmak için anestezi altındaki sıçanlara T10 seviyesinde 100 g/cm şiddetinde ağırlık düşürme metodu uygulandı. Hasarlı hayvanlara riboflavin 25 mg/kg dozunda ya da taşıyıcı çözelti tedavisi hasardan 15 dakika sonra verildi ve 7 gün süreyle devam edildi. Hasardan sonra 7.günde nörolojik testin arkasından hayvanlar dekapite edilerek spinal ve böbrek dokuları alındı. Dokularda histolojik tayinler yapıldı ve malondialdehit (MDA), glutatyon (GSH), 8-hidroksi-2-deoksiguanozin (8-OHdG) düzeyleri ile myeloperoksidaz (MPO), süperoksid dismutaz (SOD) ve katalaz aktiviteleri tayin edildi.
Bulgular: Omurilik hasarı dokularda GSH düzeylerinde ve SOD aktivitesinde azalamaya, MDA düzeyinde ve MPO ve kaspaz aktivitelerinde artışa neden oldu. Riboflavin tedavisi bu parametreleri geri çevirdi ve histolojik bulgularda düzelme gösterdi.
Sonuç: Çalışmamızda Omurilik hasarı, dokuya nötrofil göçüne ve oksidan strese yol açarken, antiapoptotik ve nöroprotektif özellikleri ile riboflavin lipid peroksidasyonunu ve nötrofillerin dokuya infiltrasyonunu inhibe etti. Ayrıca, çalışmamız riboflavinin antiapoptotik ve antioksidan etkisinin sadece omurilikte değil omurilik hasarında ikincil olarak ortaya çıkan böbrek hasarında da önemli faydaları olduğunu gösterdi.
Keywords
References
- 1. Cristante AF, Barros Filho TE, Marcon RM, Letaif OB, Rocha ID. Therapeutic approaches for spinal cord injury. Clinics (Sao Paulo) 2012; 67: 1219-24. [CrossRef] 2. Boulenguez P, Vinay L. Strategies to restore motor functions after spinal cord injury. Curr Opin Neurobiol 2009; 19: 587-600. [CrossRef] 3. Hulsebosch CE. Recent advances in pathophysiology and treatment of spinal cord injury. Adv Physiol Educ 2002; 26: 238-55. [CrossRef] 4. Azbill RD, Mu X, Bruce-Keller AJ, Mattson MP, Springer JE. Impaired mitochondrial function, oxidative stress and altered antioxidant enzyme activities following traumatic spinal cord injury. Brain Res 1997; 765: 283- 90. [CrossRef] 5. Park E, Velumian AA, Fehlings MG. The role of excitotoxicity in secondary mechanisms of spinal cord injury: a review with an emphasis on the implications for white matter degeneration. J Neurotrauma 2004; 21: 754- 74. [CrossRef] 6. Hall ED. Antioxidant therapies for acute spinal cord injury. Neurotherapeutics 2011; 8: 152-67. [CrossRef] 7. Bastani NE, Kostovski E, Sakhi AK, Karlsen A, Carlsen MH, Hjeltnes N, et al. Reduced antioxidant defense and increased oxidative stress in spinal cord injured patients. Arch Phys Med Rehabil 2012; 93: 2223-8. [CrossRef] 8. Powers HJ. Riboflavin (vitamin B-2) and health. Am J Clin Nutr 2003; 77: 1352-60. 9. Depeint F, Bruce WR, Shangari N, Mehta R, O'Brien PJ. Mitochondrial function and toxicity: role of the B vitamin family on mitochondrial energy metabolism. Chem Biol Interact 2006; 163: 94-112. [CrossRef ] 10. Bodiga VL, Bodiga S, Surampudi S, Boindala S, Putcha U, Nagalla B, et al. Effect of vitamin supplementation on cisplatin-induced intestinal epithelial cell apoptosis in Wistar/NIN rats. Nutrition 2012; 28: 572-80. [CrossRef] 11. Al-Harbi NO, Imam F, Nadeem A, Al-Harbi MM, Korashy HM, SayedAhmed MM, et al. Riboflavin attenuates lipopolysaccharide-induced lung injury in rats. Toxicol Mech Methods 2015; 25: 417-23. [CrossRef] 12. Yu Z, Morimoto K, Yu J, Bao W, Okita Y, Okada K. Endogenous superoxide dismutase activation by oral administration of riboflavin reduces abdominal aortic aneurysm formation in rats. J Vasc Surg 2016; 64: 737-45. [CrossRef] 13. Bertollo CM, Oliveira AC, Rocha LT, Costa KA, Nascimento EB Jr, Coelho MM. Characterization of the antinociceptive and anti-inflammatory activities of riboflavin in different experimental models. Eur J Pharmacol 2006; 547: 184-91. [CrossRef] 14. Granados-Soto V, Terán-Rosales F, Rocha-González HI, Reyes-García G, Medina-Santillán R, Rodríguez-Silverio J, et al. Riboflavin reduces hyperalgesia and inflammation but not tactile allodynia in the rat. Eur J Pharmacol 2004; 492: 35-40. [CrossRef] 15. Allen AR. Surgery of experimental lesion of spinal cord equivalent to crush injury of fracture dislocation of spinal column. A preliminary report. JAMA 1911; 57: 878-80. [CrossRef] 16. Gale K, Kerasidis H, Wrathall JR. Spinal cord contusion in the rat: behavioral analysis of functional neurologic impairment. Exp Neurol 1985; 88: 123-34. [CrossRef] 17. Hillegass LM, Griswold DE, Brickson B, Albrightson-Winslow C. Assesment of myeloperoxidase activity in whole rat kidney. J Pharmacol Methods 1990; 24: 285-95. [CrossRef] 18. Beuge JA, Aust SD. Microsomal lipid peroxidation. Methods Enzymol 1978; 52: 302-10. [CrossRef] 19. Beutler E. Glutathione in red blood cell metabolism. A manuel of biochemical methods. Grune&Stratton, NewYork, 1975, p. 112-4. 20. Mylroie AA, Collins H, Umbles C, Kyle J. Erythrocyte superoxide dismutase activity and other parameters of copper status in rats ingesting lead acetate. Toxicol Appl Pharmacol 1986; 82: 512-20. [CrossRef] 21. Tavukçu HH, Sener TE, Tinay I. Akbal C, Erşahin M, Cevik O, et al. Melatonin and tadalafil treatment improves erectile dysfunction after spinal cord injury in rats. Clin Exp Pharmacol Physiol 2014; 41: 309-16. [CrossRef ] 22. Bradford, MM. A rapid and sensitive method for the quantitation of microgram quantitites of protein utilizing the principle of protein-dye binding. Anal Biochem 1976; 72: 248-54. [CrossRef] 23. McCormick DB, Innis WSA, Merrill AH Jr, Bowers-Komro DM, Oka M, Chastain JL. An update on flavin metabolism in rats and humans. In: Edmondson DE, McCormick DB, (Eds.), Flavin and flavoproteins. New York: Walter de Gruyter, 1988. p.459-71. 24. Bosch AM, Abeling NG, Ijlst L, Knoester H, van der Pol WL, Stroomer AE, et al. Brown-Vialetto-Van Laere and Fazio Londe syndrome is associated with a riboflavin transporter defect mimicking mild MADD: a new inborn error of metabolism with potential treatment. J Inherit Metab Dis 2011; 34: 159-64. [CrossRef] 25. McEwen ML, Sullivan PG, Rabchevsky AG, Springer JE. Targeting mitochondrial function for the treatment of acute spinal cord injury. Neurotherapeutics 2011; 8: 168-79. [CrossRef] 26. Mishra J, Kumar A. Improvement of mitochondrial NAD(+)/FAD(+)-linked state-3 respiration by caffeine attenuates quinolinic acid induced motor impairment in rats: implications in Huntington's disease. Pharmacol Rep 2014; 66: 1148-55. [CrossRef] 27. Cevik O, Erşahin M, Sener TE, Tinay I, Tarcan T, Çetinel S, et al. Beneficial effects of quercetin on rat urinary bladder after spinal cord injury. J Surg Res 2013; 183: 695-703. [CrossRef] 28. Kubota K, Saiwai H, Kumamaru H, Maeda T, Ohkawa Y, Aratani Y, et al. Myeloperoxidase exacerbates secondary injury by generating highly reactive oxygen species and mediating neutrophil recruitment in experimental spinal cord injury. Spine (Phila Pa 1976) 2012; 37: 1363-9. [CrossRef] 29. Heinzelmann M, Mercer-Jones MA, Passmore JC. Neutrophils and renal failure. Am J Kidney Dis 1999; 34: 384-99. [CrossRef] 30. Shou-Shi W, Ting-Ting S, Ji-Shun N, Hai-Chen C. Preclinical efficacy of Dexmedetomidine on spinal cord injury provoked oxidative renal damage. Ren Fail 2015; 37: 1190-7. 31. Kannan K, Jain SK. Oxidative stress and apoptosis. Pathophysiology 2000; 7: 153-63. [CrossRef] 32. Hausmann ON. Post-traumatic inflammation following spinal cord injury. Spinal Cord 2003; 41: 369-78. [CrossRef] Sakarcan et al. Riboflavin Treatment in Spinal Cord Injury Clin Exp Health Sci 2017; 7: 55-63 62 Clin Exp Health Sci 2017; 7: 55-63 Sakarcan et al. Riboflavin Treatment in Spinal Cord Injury 63 33. Wang JL, Zhang QS, Zhu KD, Sun JF, Zhang ZP, Sun JW, et al. Hydrogen-rich saline injection into the subarachnoid cavity within 2 weeks promotes recovery after acute spinal cord injury. Neural Regen Res 2015; 10: 958-64. [CrossRef] 34. Gürer B, Kertmen H, Kasim E, Yilmaz ER, Kanat BH, Sargon MF et al. Neuroprotective effects of testosterone on ischemia/reperfusion injury of the rabbit spinal cord. Injury 2015; 46: 240-8. [CrossRef] 35. Ríos C, Orozco-Suarez S, Salgado-Ceballos H, Mendez-Armenta M, Nava-Ruiz C, Santander I, et al. Anti-apoptotic effects of dapsone after spinal cord ınjury in rats. Neurochem Res 2015; 40: 1243-51. [CrossRef] 36. Erşahin M, Çevik Ö, Akakın D, Şener A, Özbay L, Yegen BC, et al. Montelukast inhibits caspase-3 activity and ameliorates oxidative damage in the spinal cord and urinary bladder of rats with spinal cord injury. Prostaglandins Other Lipid Mediat 2012; 99: 131-9. [CrossRef] 37. Sener TE, Tinay I, Akbal C, Erşahin M, Çevik Ö, Cadırcı S, et al. Tadalafil attenuates spinal cord injury induced oxidative organ damage in rats. Marmara Pharm J 2014; 18: 49-55. [CrossRef] 38. Shunmugavel A, Khan M, Te Chou PC, Dhindsa RK, Martin MM, Copay AG, et al. Simvastatin protects bladder and renal functions following spinal cord injury in rats. J Inflamm (Lond) 2010; 7: 17. [CrossRef] 39. Wu G, Fang YZ, Yang S, Lupton JR, Turner ND. Glutathione metabolism and its implications for health. J Nutr 2004; 134: 489-92. 40. Al-Harbi NO, Imam F, Nadeem A, Al-Harbi MM, Iqbal M, Ahmad SF. Carbon tetrachloride-induced hepatotoxicity in rat is reversed by treatment with riboflavin. Int Immunopharmacol 2014; 21: 383-8. [CrossRef]
Year 2017,
Volume: 7 Issue: 2, 55 - 63, 15.06.2017
Abstract
Objective: Spinal cord injury (SCI) leads to an inflammatory response and results in oxidative stress, which has deleterious effects on several organ systems. Riboflavin is an easily absorbed micronutrient that plays an important role in maintaining health in humans and animals. The present study was designed to investigate the putative protective effect of riboflavin against SCI-induced spinal cord and kidney damage.
Methods: In order to induce SCI, the standard weight-drop method was used to induce a moderately severe injury (100 g/cm force) at the T10 vertebral level. Injured animals were given either 25 mg/kg riboflavin or carboxymethyl cellulose 15 min after injury, and this regimen was repeated twice daily for 7 days. On the 7th post-injury day, a neurological examination was performed and rats were sacrificed. Spinal cord and kidney samples were harvested and prepared for a histological examination. Tissue levels of malondialdehyde (MDA), glutathione (GSH), and 8-hydroxy-2′-deoxyguanosine (8-OHdG) and activities of myeloperoxidase (MPO), superoxide dismutase (SOD), and caspase-3 were determined.
Results: SCI caused a significant decrease in tissue GSH levels and SOD activities, which were accompanied by significant increases in MDA and 8-OHdG levels and MPO and caspase-3 activities. However, riboflavin treatment reversed these parameters and improved histological findings.
Conclusion: SCI caused tissue injury through oxidative stress and neutrophil infiltration into tissues. Riboflavin inhibited tissue injury through its neuroprotective and antiapoptotic effects. Moreover, our study demonstrated that riboflavin not only exerts antioxidant and antiapoptotic effects on the spinal cord but also has a significant impact on preventing kidney damage secondary to SCI.
Keywords
References
- 1. Cristante AF, Barros Filho TE, Marcon RM, Letaif OB, Rocha ID. Therapeutic approaches for spinal cord injury. Clinics (Sao Paulo) 2012; 67: 1219-24. [CrossRef] 2. Boulenguez P, Vinay L. Strategies to restore motor functions after spinal cord injury. Curr Opin Neurobiol 2009; 19: 587-600. [CrossRef] 3. Hulsebosch CE. Recent advances in pathophysiology and treatment of spinal cord injury. Adv Physiol Educ 2002; 26: 238-55. [CrossRef] 4. Azbill RD, Mu X, Bruce-Keller AJ, Mattson MP, Springer JE. Impaired mitochondrial function, oxidative stress and altered antioxidant enzyme activities following traumatic spinal cord injury. Brain Res 1997; 765: 283- 90. [CrossRef] 5. Park E, Velumian AA, Fehlings MG. The role of excitotoxicity in secondary mechanisms of spinal cord injury: a review with an emphasis on the implications for white matter degeneration. J Neurotrauma 2004; 21: 754- 74. [CrossRef] 6. Hall ED. Antioxidant therapies for acute spinal cord injury. Neurotherapeutics 2011; 8: 152-67. [CrossRef] 7. Bastani NE, Kostovski E, Sakhi AK, Karlsen A, Carlsen MH, Hjeltnes N, et al. Reduced antioxidant defense and increased oxidative stress in spinal cord injured patients. Arch Phys Med Rehabil 2012; 93: 2223-8. [CrossRef] 8. Powers HJ. Riboflavin (vitamin B-2) and health. Am J Clin Nutr 2003; 77: 1352-60. 9. Depeint F, Bruce WR, Shangari N, Mehta R, O'Brien PJ. Mitochondrial function and toxicity: role of the B vitamin family on mitochondrial energy metabolism. Chem Biol Interact 2006; 163: 94-112. [CrossRef ] 10. Bodiga VL, Bodiga S, Surampudi S, Boindala S, Putcha U, Nagalla B, et al. Effect of vitamin supplementation on cisplatin-induced intestinal epithelial cell apoptosis in Wistar/NIN rats. Nutrition 2012; 28: 572-80. [CrossRef] 11. Al-Harbi NO, Imam F, Nadeem A, Al-Harbi MM, Korashy HM, SayedAhmed MM, et al. Riboflavin attenuates lipopolysaccharide-induced lung injury in rats. Toxicol Mech Methods 2015; 25: 417-23. [CrossRef] 12. Yu Z, Morimoto K, Yu J, Bao W, Okita Y, Okada K. Endogenous superoxide dismutase activation by oral administration of riboflavin reduces abdominal aortic aneurysm formation in rats. J Vasc Surg 2016; 64: 737-45. [CrossRef] 13. Bertollo CM, Oliveira AC, Rocha LT, Costa KA, Nascimento EB Jr, Coelho MM. Characterization of the antinociceptive and anti-inflammatory activities of riboflavin in different experimental models. Eur J Pharmacol 2006; 547: 184-91. [CrossRef] 14. Granados-Soto V, Terán-Rosales F, Rocha-González HI, Reyes-García G, Medina-Santillán R, Rodríguez-Silverio J, et al. Riboflavin reduces hyperalgesia and inflammation but not tactile allodynia in the rat. Eur J Pharmacol 2004; 492: 35-40. [CrossRef] 15. Allen AR. Surgery of experimental lesion of spinal cord equivalent to crush injury of fracture dislocation of spinal column. A preliminary report. JAMA 1911; 57: 878-80. [CrossRef] 16. Gale K, Kerasidis H, Wrathall JR. Spinal cord contusion in the rat: behavioral analysis of functional neurologic impairment. Exp Neurol 1985; 88: 123-34. [CrossRef] 17. Hillegass LM, Griswold DE, Brickson B, Albrightson-Winslow C. Assesment of myeloperoxidase activity in whole rat kidney. J Pharmacol Methods 1990; 24: 285-95. [CrossRef] 18. Beuge JA, Aust SD. Microsomal lipid peroxidation. Methods Enzymol 1978; 52: 302-10. [CrossRef] 19. Beutler E. Glutathione in red blood cell metabolism. A manuel of biochemical methods. Grune&Stratton, NewYork, 1975, p. 112-4. 20. Mylroie AA, Collins H, Umbles C, Kyle J. Erythrocyte superoxide dismutase activity and other parameters of copper status in rats ingesting lead acetate. Toxicol Appl Pharmacol 1986; 82: 512-20. [CrossRef] 21. Tavukçu HH, Sener TE, Tinay I. Akbal C, Erşahin M, Cevik O, et al. Melatonin and tadalafil treatment improves erectile dysfunction after spinal cord injury in rats. Clin Exp Pharmacol Physiol 2014; 41: 309-16. [CrossRef ] 22. Bradford, MM. A rapid and sensitive method for the quantitation of microgram quantitites of protein utilizing the principle of protein-dye binding. Anal Biochem 1976; 72: 248-54. [CrossRef] 23. McCormick DB, Innis WSA, Merrill AH Jr, Bowers-Komro DM, Oka M, Chastain JL. An update on flavin metabolism in rats and humans. In: Edmondson DE, McCormick DB, (Eds.), Flavin and flavoproteins. New York: Walter de Gruyter, 1988. p.459-71. 24. Bosch AM, Abeling NG, Ijlst L, Knoester H, van der Pol WL, Stroomer AE, et al. Brown-Vialetto-Van Laere and Fazio Londe syndrome is associated with a riboflavin transporter defect mimicking mild MADD: a new inborn error of metabolism with potential treatment. J Inherit Metab Dis 2011; 34: 159-64. [CrossRef] 25. McEwen ML, Sullivan PG, Rabchevsky AG, Springer JE. Targeting mitochondrial function for the treatment of acute spinal cord injury. Neurotherapeutics 2011; 8: 168-79. [CrossRef] 26. Mishra J, Kumar A. Improvement of mitochondrial NAD(+)/FAD(+)-linked state-3 respiration by caffeine attenuates quinolinic acid induced motor impairment in rats: implications in Huntington's disease. Pharmacol Rep 2014; 66: 1148-55. [CrossRef] 27. Cevik O, Erşahin M, Sener TE, Tinay I, Tarcan T, Çetinel S, et al. Beneficial effects of quercetin on rat urinary bladder after spinal cord injury. J Surg Res 2013; 183: 695-703. [CrossRef] 28. Kubota K, Saiwai H, Kumamaru H, Maeda T, Ohkawa Y, Aratani Y, et al. Myeloperoxidase exacerbates secondary injury by generating highly reactive oxygen species and mediating neutrophil recruitment in experimental spinal cord injury. Spine (Phila Pa 1976) 2012; 37: 1363-9. [CrossRef] 29. Heinzelmann M, Mercer-Jones MA, Passmore JC. Neutrophils and renal failure. Am J Kidney Dis 1999; 34: 384-99. [CrossRef] 30. Shou-Shi W, Ting-Ting S, Ji-Shun N, Hai-Chen C. Preclinical efficacy of Dexmedetomidine on spinal cord injury provoked oxidative renal damage. Ren Fail 2015; 37: 1190-7. 31. Kannan K, Jain SK. Oxidative stress and apoptosis. Pathophysiology 2000; 7: 153-63. [CrossRef] 32. Hausmann ON. Post-traumatic inflammation following spinal cord injury. Spinal Cord 2003; 41: 369-78. [CrossRef] Sakarcan et al. Riboflavin Treatment in Spinal Cord Injury Clin Exp Health Sci 2017; 7: 55-63 62 Clin Exp Health Sci 2017; 7: 55-63 Sakarcan et al. Riboflavin Treatment in Spinal Cord Injury 63 33. Wang JL, Zhang QS, Zhu KD, Sun JF, Zhang ZP, Sun JW, et al. Hydrogen-rich saline injection into the subarachnoid cavity within 2 weeks promotes recovery after acute spinal cord injury. Neural Regen Res 2015; 10: 958-64. [CrossRef] 34. Gürer B, Kertmen H, Kasim E, Yilmaz ER, Kanat BH, Sargon MF et al. Neuroprotective effects of testosterone on ischemia/reperfusion injury of the rabbit spinal cord. Injury 2015; 46: 240-8. [CrossRef] 35. Ríos C, Orozco-Suarez S, Salgado-Ceballos H, Mendez-Armenta M, Nava-Ruiz C, Santander I, et al. Anti-apoptotic effects of dapsone after spinal cord ınjury in rats. Neurochem Res 2015; 40: 1243-51. [CrossRef] 36. Erşahin M, Çevik Ö, Akakın D, Şener A, Özbay L, Yegen BC, et al. Montelukast inhibits caspase-3 activity and ameliorates oxidative damage in the spinal cord and urinary bladder of rats with spinal cord injury. Prostaglandins Other Lipid Mediat 2012; 99: 131-9. [CrossRef] 37. Sener TE, Tinay I, Akbal C, Erşahin M, Çevik Ö, Cadırcı S, et al. Tadalafil attenuates spinal cord injury induced oxidative organ damage in rats. Marmara Pharm J 2014; 18: 49-55. [CrossRef] 38. Shunmugavel A, Khan M, Te Chou PC, Dhindsa RK, Martin MM, Copay AG, et al. Simvastatin protects bladder and renal functions following spinal cord injury in rats. J Inflamm (Lond) 2010; 7: 17. [CrossRef] 39. Wu G, Fang YZ, Yang S, Lupton JR, Turner ND. Glutathione metabolism and its implications for health. J Nutr 2004; 134: 489-92. 40. Al-Harbi NO, Imam F, Nadeem A, Al-Harbi MM, Iqbal M, Ahmad SF. Carbon tetrachloride-induced hepatotoxicity in rat is reversed by treatment with riboflavin. Int Immunopharmacol 2014; 21: 383-8. [CrossRef]
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Details
| Primary Language | English |
|---|---|
| Subjects | Health Care Administration |
| Journal Section | Articles |
| Authors | |
| Publication Date | June 15, 2017 |
| Submission Date | October 28, 2016 |
| Published in Issue | Year 2017 Volume: 7 Issue: 2 |
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