PROTECTIVE EFFECTTS OF DANTROLENE AGAINST SPINAL CORD INJURY INDUCED EARLY OXIDATIVE DAMAGEIN RABBIT BLADDER

Yıl 2019, Cilt: 20 Sayı: 1, 195 - 200, 27.08.2019

İbrahim Keleş , Mehmet Fatih Bozkurt , Abdurrahman Fatih Fidan , Mustafa Karalar , Soner Çoban , Barış Denk

https://doi.org/10.18229/kocatepetip.586526

Öz

OBJECTIVE: To investigate the effects of early dantrolene treatment of changes in bladder characteristics after spinal cord injury (SCI).

MATERIAL AND METHODS: We studied the possible protective effects of dantrolene on SCI-induced oxidative damage in bladder tissues of rabbit. We devided 38 rabbits into five groups; the control group (1), spinal cord injury (SCI) (2.group), SCI+dantrolene 0. Hour (3.group), SCI+dantrolene 1. Hour (4.group), SCI+dantrolene 4. Hour (5.group). After a 24 hour euthanasia the urinary bladder was removed for gross, histological and biochemical evaluation. Bladder tissues were investigated by light microscopy. Furthermore blood and tissue malondialdehyde (MDA), glutathione (GSH) and nitric oxide (NO) were also determined.

RESULTS: Significant increase in congestion and edema was observed in the early period spinal trauma (SCI) group compared to control group. In groups 3 and 4, dantrolene was more effective in preventing edema and inflammation, whereas in groups 3, 4 and 5, dantrolene did not reduce congestion. MDA levels and NO levels increased and GSH levels were decreased in SCI group compared to controls. Dantrolene was not effective in all three treatment groups to normalize decreased GSH levels after trauma. It was seen that dantrolene was not effective in all three treatment groups to normalize the decreased GSH level after trauma. Increased levels of MDA after spinal trauma were found to be the lowest in group 5 given at the 4th hour of dantrolene.

CONCLUSIONS: It can be concluded that dantrolene given in the early period is effective in reducing inflammation and edema in the bladder and not effective in decreasing post-traumatic GSH levels to normal. As a result; dantrolene may be helpful in correcting impaired bladder morphology.

Anahtar Kelimeler

Spinal cord injury, Dantrolene, Anti-inflammatory, Antioxidant

TAVŞANDA SPİNAL KORD TRAVMASININ NEDEN OLDUĞU ERKEN OXİDATİF STRESE KARŞI DANTROLENİN MESANE ÜZERİNE KORUYUCU ETKİLERİ

Öz

AMAÇ: Spinal kord travmasından sonra mesanede görülen değişiklikler üzerine erken dönem dantrolen tedavisinin ekinliğinin araştırılması.

GEREÇ VE YÖNTEM: Spinal kord travmasının neden olduğu tavşan mesanesindeki oksidatif hasara karşı dantrolenin erken dönemdeki olası koruyucu etkileri araştırıldı. Toplam 38 hayvan 5 gruba ayrıldı,1. grup kontrol, 2. grup spinal travma (ST), 3. grup ST+dantrolen 0. saat, 4. grup ST+dantrolen 1. Saat ve 5. grup ta ST+dantrolen 4. saat olarak belirlendi. Travmadan 24 saat sonra histopatolojik ve biyokimyasal inceleme yapılmak üzere anestezi altında tavşanların mesaneleri operasyonla çıkartıldı. Mesane dokusu ışık mikroskobunda incelendi. Ayrıca kan ve mesane dokusunda malondialdehid (MDA), glutatyon (GSH) and nitrik oxid (NO) düzeylerine bakıldı.

BULGULAR: Spinal travma sonrası erken dönemde kontrol grubuyla karılaştırıldığında travma oluşturulan grupta ödem ve konjesyonda anlamlı artış vardı. Ödem ve inflamasyonu önlemede 3 ve 4. gruplarda dantrolen daha etkiliydi. Ancak 3, 4 ve 5. gruplarda dantrolenin konjesyonu azaltamadığı görüldü. Kontrol grubuyla karşılaştırıldığında MDA ve NO düzeylerinin yükseldiği GSH seviyesinin ise azaldığı görüldü. Travma sonrası azalan GSH seviyesini normale çekmede dantrolenin her 3 tedavi grubunun etkili olmadığı görüldü. Spinal travma sonrası artan MDA seviyesi 24 saat sonunda 5. grupta en düşük seviyelere indi.

SONUÇ: Erken dönemde verilen dantrolenin mesanede inflamasyon ve ödemi azaltmada etkili olduğu, travma sonrası azalan GSH seviyelerini normale yaklaştırmada ise etkin olmadığı söylenebilir. Sonuç olarak; dantrolen bozulmuş mesane morfolojisini düzeltmede yardımcı

Anahtar Kelimeler

Spinal kord travması, dantrolen, anti-inflamatuar

Kaynakça

• 1. 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;15;765(2):283-90.
• 2. Bao F, Brown A, Dekaban GA, Omana V, Weaver LC. CD11d integrin blockade reduces the systemic inflammatory response syndrome after spinal cord injury. Exp. Neurol. 2011;231(2):272-83.
• 3. Wrathall JR, Teng YD, Choiniere D. Amelioration of functional deficits from spinal cord trauma with systemically administered NBQX, an antagonist of non-N-methyl- D-aspartate receptors. Exp. Neurol. 1996;137(1):119-26.
• 4. Benevento BT, Sipski ML: Neurogenic bladder, neurogenic bowel, and sexual dysfunction in people with spinal cord injury. Phys. Ther. 2002;82:601–12.
• 5. S. Kobayashi, M.L. Bannister, J.P. Gangopadhyay, T. Hamada, J. Parness, N. Ikemoto, Dantrolene stabilizes domain interactions within the ryanodine receptor, J. Biol. Chem. 2005;280; 6580–7.
• 6. F. Zhao, P. Li, S.R. Chen, C.F. Louis, B.R. Fruen, Dantrolene inhibition of ryanodine receptor Ca2+ release channels. molecular mechanisms and isoform selectivity, J. Biol. Chem. 2001;276:13810–6.
• 7. G. Cherednichenko, C.W. Ward, F. Feng, et all. Enhanced excitation-coupled calcium entry in myotubes expressing malignant hyperthermia mutation R163c is attenuated by dantrolene, Mol. Pharmacol. 2008:73;1203–12.
• 8. A. Ward, M.O. Chaffman, E.M. Sorkin, Dantrolene. A review of its pharmacodynamic and pharmacokinetic properties and therapeutic use in malignant hyperthermia, the neuroleptic malignant syndrome and an update of its use in muscle spasticity, Drugs 1986:32;130–68.
• 9. T. Krause, M.U. Gerbershagen, M. Fiege, R. Weisshorn, F. Wappler, Dantrolene–a review of its pharmacology, therapeutic use and new developments, Anaesthesia 2004:59;364–73.
• 10. S. Muehlschlegel, J.R. Sims, Dantrolene: mechanisms of neuroprotection and possible clinical applications in the neurointensive care unit, Neurocrit. Care 2009:10;103–15.
• 11. H. Uc¸ üncü, S. Taysi, B. Aktan, M.E. Buyukokuroglu, M. Elmastas, Effect of dantrolene on lipid peroxidation, glutathione and glutathione-dependent enzyme activities in experimental otitis media with effusion in guinea pigs, Hum. Exp. Toxicol. 2005:24;567–71.
• 12. M.E. Büyükokuroglu, Anti-inflamatory and antinociceptive properties of dantrolene sodium in rats and mice, Pharmacol. Res. 2002:45;455–60.
• 13. R.S. Hotchkiss, D.F. Osborne, G.D. Lappas, I.E. Karl, Calcium antagonists decrease plasma and tissue concentrations of tumor necrosis factor-alpha, interleukin-1 beta, and interleukin-1 alpha in a mouse model of endotoxin, Shock 1995:3;337–42.
• 14. M. Gwak, P. Park, K. Kim, et all., The effects of dantrolene on hypoxic-ischemic injury in the neonatal rat brain, Anesth. Analg. 2008:106;227–33.
• 15. F. Li, T. Hayashi, G. Jin, et all. The protective effect of dantrolene on ischemic neuronal cell death is associated with reduced expression of endoplasmic reticulum stress markers, Brain Res. 2005:1048;59–68
• 16. R.H. Hackler, B.H. Broecker, F.A. Klein, S.M. Brady, A clinical experience with dantrolene sodium for external urinary sphincter hypertonicity in spinal cord injured patients, J. Urol. 1980:124;78–81.
• 17. M. Takeda, I. Araki, T. Mochizuki,et all., The forefront for novel therapeutic agents based on the pathophysiology of voiding dysfunction and pharmacological therapy, J. Pharmacol. Sci. 2010:112;121–7.
• 18. Ohkawa H, Ohishi N, Yagi K. Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Anal. Biochem. 1979;95:351-58.
• 19. Beutler E, Dubon OB, Kelly M. Improved method for the determination of blood glutathione. J Lab. Clin. Med. 1963;61:882-8.
• 20. Somogyi M. A method for the preparation of blood filtrates for the determination ofsugar. J Biol. Chem. 1930;86:55.
• 21. Miranda KM, Espey MG, Wink DA. A rapid, simple spectrophotometric method for simultaneous detection of nitrate and nitrite. Nitric Oxide 2001;5:62-71.
• 22. Lasfargues JE, Custis D, Morrone F, et al. A model for estimating spinal cord injury prevalence in the United States. Paraplegia 1995;33:62-8.
• 23. Sun X, Jones ZB, Chen XM, Zhou L, So KF, Ren Y. Multiple organ dysfunction and systemic inflammation after spinal cord injury: a complex relationship. J Neuroinflammation 2016;3(1):260.
• 24. Wu J, Yang H, Qiu Z, Zhang Q, Ding T, Geng D.Effect of Combined Treatment with Methylprednisolone and Nogo-A Monoclonal Antibody after Rat Spinal Cord Injury. J Int Med. Res. 2010;38(2):570-82.
• 25. Rosado IR, Lavor MSL, Alves EGL, Fukushima FB, Oliveira KM, Silva CMO, et al. Effects of methylprednisolone, dantrolene, and their combination on experimental spinal cord injury. Int. J Clin. Exp. Pathol. 2014;7(8):4617-26.
• 26. Torres B, Serakides R, Caldeira F, Gomes M, Melo E. The ameliorating effect of dantrolene on the morphology of urinary bladder in spinal cord injured rats. Pathol. Res. Pract. 2011:15;207(12):775-9.
• 27. Aslan A, Cemek M, Buyukokuroglu et all., Dantrolene can reduce secondary damage after spinal cord injury. Eur. Spine J 2009;18:1442-1451.
• 28. Ates O, Cayli S, Altinoz E, et all., Effects of resveratrol and methylprednisolone on biochemical, neurobehavioral and histopathological recovery after experimental spinal cord injury. Acta Pharmacologica Sinica 2006;27(10):1317-25.
• 29. Moncada S, Higgs A. The L-arginine-nitric oxide pathway. N Engl. J Med. 1993;329 (27):2002-12.
• 30. Taysi S, Koc M, Büyükokuroğlu ME, Altinkaynak K, Sahin YN. Melatonin reduces lipid peroxidation and nitric oxide during irradiation-induced oxidative injury in the rat liver. J Pineal Res. 2003;34(3):173-7.
• 31. Von Euler M, Akesson E, Samuelsson EB, Seiger A, Sundstrom E. Motor performance score: a new algorithm for accurate behavioral testing of spinal cord injury in rats. Exp. Neurol. 1996;137(2):242-54.