Cilostazol, a Type III Phosphodiesterase Inhibitor, Reduces Ischemia/Reperfusion-Induced Spinal Cord Injury

Authors

  • Mehmet Ali Sahin
  • Burak Onan
  • Adem Guler
  • Emin Oztas
  • Bülent Uysal
  • Siddik Arslan
  • Ufuk Demirkilic
  • Harun Tatar

DOI:

https://doi.org/10.1532/HSF98.20101126

Abstract

Background: Spinal cord injury is still a devastating complication after surgical repair of thoracoabdominal aortic pathologies. In this study, we investigated the protective effect of cilostazol, a type III phosphodiesterase inhibitor, against ischemia/reperfusion (I/R)-induced spinal cord injury in rats.

Methods: Twenty-four rats were assigned to 3 experimental study groups: the control group (sham operation, n = 8); the ischemia group (nontreated, n = 8), which underwent aortic occlusion without pharmacologic intervention; and the cilostazol-treated group (n = 8), which received 20 mg/kg cilostazol per day orally for 3 days before spinal ischemia. All animals underwent a 45-minute period of spinal cord ischemia via clamping of the abdominal aorta between the left renal artery and the aortic bifurcation; removal of the aortic clamp was followed by reperfusion. Neurologic status was assessed before spinal ischemia and at 48 hours after the operation. All animals were sacrificed at 48 hours after the operation. Spinal cords were harvested for histopathologic examination and biochemical analyses for the malondialdehyde (MDA) level and superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activities.

Results: Tarlov scores at postoperative hour 48 tended to be higher in the cilostazol-treated group than in the nontreated ischemia group (mean ± SD, 3.66 ± 0.40 versus 2.32 ± 0.80; P = .08). Spinal cord tissue MDA levels (per gram protein) were lower in the cilostazol-treated group than in the nontreated ischemia group (0.27 ± 0.01 mmol/g versus 0.33 ± 0.04 mmol/g, P = .026), and the cilostazol-treated group had higher activities of tissue SOD (519.6 ± 56.3 U/g versus 438.9 ± 67.4 U/g, P = .016) and GSH-Px (4.07 ± 1.37 U/g versus 3.21 ± 1.02 U/g, P = .47) than the nontreated ischemia group. Histopathologic analyses demonstrated that cilostazol treatment attenuated I/R-induced cellular damage.

Conclusion: Administration of cilostazol before spinal cord ischemia reduced neurologic injury and produced clinical improvement by attenuating oxidative stress in this rat spinal cord I/R model.

References

Awad H, Ankeny DP, Guan Z, Wei P, McTigue DM, Popovich PG. 2010. A mouse model of ischemic spinal cord injury with delayed paralysis caused by aortic cross-clamping. Anesthesiology 113:880-91.nBisleri G, Tisi G, Negri A, et al. 2005. The bicircuit system: innovative perfusional options for surgical treatment of the thoracic aorta. Ann Thorac Surg 79:678-80.nBoyle EJ, Pohlman TH, Cornejo CJ, Verrier ED. 1996. Endothelial cell injury in cardiovascular surgery: ischemia-reperfusion. Ann Thorac Surg 62:1868-75.nChoi JM, Shin HK, Kim KY, Lee JH, Hong KW. 2002. Neuroprotective effect of cilostazol against focal cerebral ischemia via antiapoptotic action in rats. J Pharmacol Exp Ther 300:787-93.nCoselli JS, LeMaire SA, Koksoy C, Schmittling ZC, Curling PE. 2002. Cerebrospinal fluid drainage reduces paraplegia after thoracoabdominal aortic aneurysm repair: results of a randomized clinical trial. J Vasc Surg 35:631-9.nCoselli JS, LeMaire SA, Poli de Figueiredo L, Kirby RP. 1997. Paraplegia after thoracoabdominal aortic aneurysm repair: Is dissection a risk factor? Ann Thorac Surg 63:28-36.nDickens BF, Mak IT, Weglicki WB. 1988. Lysosomal lipolytic enzymes, lipid peroxidation, and injury. Mol Cell Biochem 82:119-23.nDobashi K, Ghosh B, Orak JK, Singh I, Singh AK. 2000. Kidney ischemia-reperfusion: modulation of antioxidant defenses. Mol Cell Biochem 205:1-11.nGüler A, Sahin MA, Ucak A, et al. 2010. Protective effects of angiotensin II type-1 receptor blockade with olmesartan on spinal cord ischemia-reperfusion injury: an experimental study on rats. Ann Vasc Surg 24:801-8.nHonda F, Imai H, Ishikawa M, et al. 2006. Cilostazol attenuates gray and white matter damage in a rodent model of focal cerebral ischemia. Stroke 37:223-8.nKimura Y, Tani T, Kanbe T, Watanabe K. 1985. Effect of cilostazol on platelet aggregation and experimental thrombosis. Arzneimmittelforschung 35:1144-9.nKirsch JR, Helfaer MA, Lange DG, Traystman RJ. 1992. Evidence for free radical mechanisms of brain injury resulting from ischemia/reperfusion-induced events. J Neurotrauma 9:157-63.nKohda N, Tani T, Nakayama S, et al. 1999. Effect of cilostazol, a phosphodiesterase III inhibitor, on experimental thrombosis in the porcine carotid artery. Thromb Res 96:261-8.nLee JH, Kim YH, Lee YK, et al. 2004. Cilostazol prevents focal cerebral ischemic injury by enhancing casein kinase 2 phosphorylation and suppression of phosphate and tension homolog deleted from chromosome 10 phosphorylation in rats. J Pharmacol Exp Ther 308:896-903.nLee JH, Lee YK, Ishikawa M, et al. 2003. Cilostazol reduces brain lesion induced by focal cerebral ischemia in rats—an MRI study. Brain Res 994:91-8.nLowry OH, Rosebrough NJ, Farr AL, Randall RJ. 1951. Protein measurement with the Folin phenol reagent. J Biol Chem 193:265-75.nManickavasagam S, Ye Y, Lin Y, et al. 2007. The cardioprotective effect of a statin and cilostazol combination: relationship to Akt and endothelial nitric oxide synthase activation. Cardiovasc Drugs Ther 21:321-30.nOhkawa H, Ohishi N, Yagi K. 1979. Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Anal Biochem 95:351-8.nOta H, Eto M, Kano MR, et al. 2008. Cilostazol inhibits oxidative stress-induced premature senescence via upregulation of Sirt1 in human endothelial cells. Arterioscler Thromb Vasc Biol 28:1634-9.nPaglia DE, Valentine WN. 1967. Studies on the quantitative and qualitative characterization of erythrocyte glutathione peroxidase. J Lab Clin Med 70:158-69.nSekiguchi M, Aoki Y, Konno S, Kikuchi S. 2008. The effects of cilostazol on nerve conduction velocity and blood flow: acute and chronic cauda equina compression in a canine model. Spine (Phila Pa 1976) 33:2605-11.nSun Y, Oberley LW, Li Y. 1988. A simple method for clinical assay of superoxide dismutase. Clin Chem 34:497-500.nTakei K, Tokuyama K, Kato M, Morikawa A. 1998. Role of cyclic adenosine monophosphate in reducing superoxide anion generation in guinea pig alveolar macrophages. Pharmacology 57:1-7.nTanaka K, Gotoh F, Fukuuchi Y, et al. 1989. Effects of a selective inhibitor of cyclic AMP phosphodiesterase on the pial microcirculation in feline cerebral ischemia. Stroke 20:668-73.nTarlov IM. 1972. Acute spinal cord compression in paralysis. J Neurosurg 36:10-20.nUeno T, Furukawa K, Katayama Y, Suda H, Itoh T. 1994. Spinal cord protection: development of a paraplegia-preventive solution. Ann Thorac Surg 58:116-20.nWada T, Yao H, Miyamoto T, Mukai S, Yamamura M. 2001. Prevention and detection of spinal cord injury during thoracic and thoracoabdominal aortic repairs. Ann Thorac Surg 72:80-5.nWatanabe T, Zhang N, Liu M, Tanaka R, Mizuno Y, Urabe T. 2006. Cilostazol protects against brain white matter damage and cognitive impairment in a rat model of chronic cerebral hypoperfusion. Stroke 37:1539-45.n

Published

2011-06-15

How to Cite

Sahin, M. A., Onan, B., Guler, A., Oztas, E., Uysal, B., Arslan, S., Demirkilic, U., & Tatar, H. (2011). Cilostazol, a Type III Phosphodiesterase Inhibitor, Reduces Ischemia/Reperfusion-Induced Spinal Cord Injury. The Heart Surgery Forum, 14(3), E171-E177. https://doi.org/10.1532/HSF98.20101126

Issue

Section

Article