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ISSN: 1734-1922
Archives of Medical Science
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vol. 14
Experimental research

Comparative effects of methylprednisolone and tetracosactide (ACTH1–24) on ischemia/reperfusion injury of the rabbit spinal cord

Hayri Kertmen, Erhan Celikoglu, Ozden Caglar Ozturk, Bora Gürer, Huseyin Bozkurt, Mehmet Ali Kanat, Ata Turker Arikok, Berrin Imge Erguder, Mustafa Fevzi Sargon, Zeki Sekerci

Arch Med Sci 2018; 14, 6: 1459–1470
Online publish date: 2017/01/31
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Tetracosactide is an engineered peptide that applies the same biological impacts as the endogenous adrenocorticotropic hormone. Previous studies indicated that tetracosactide has anti-inflammatory, antioxidant and neurotrophic activity. In this study, we hypothesized that tetracosactide may have protective effects in spinal cord ischemia-reperfusion injury.

Material and methods
Rabbits were randomized into the accompanying four groups of eight animals each: group 1 (control), group 2 (ischemia), group 3 (methylprednisolone) and group 4 (tetracosactide). In the control group, just a laparotomy was performed. In the various groups, the spinal cord ischemia model was made by the impediment of the aorta only caudal to the renal vein. Neurological assessment was conducted with the Tarlov scoring system. Levels of myeloperoxidase, malondialdehyde and catalase were analyzed, similar to the activities of xanthine oxidase and caspase-3. Histopathological and ultrastructural assessments were additionally performed.

After ischemia-reperfusion injury, increments were found in the tissue myeloperoxidase levels (p < 0.001), malondialdehyde levels (p < 0.001), xanthine oxidase action (p < 0.001) and caspase-3 movement (p < 0.001). Conversely, both serum and tissue catalase levels were diminished (p < 0.001 for both). After the administration of tetracosactide, declines were seen in the tissue myeloperoxidase levels (p < 0.001), malondialdehyde levels (p = 0.003), xanthine oxidase action (p < 0.001) and caspase-3 movement (p < 0.001). Conversely, both the serum and tissue catalase levels were expanded (p < 0.001). Besides, tetracosactide treatment indicated enhanced results related to the histopathological scores (p < 0.001), the ultra-structural score (p = 0.008) and the Tarlov scores (p < 0.001).

The findings showed for the first time that tetracosactide shows significant neuroprotective activity against ischemia-reperfusion injury of the spinal cord.


adrenocorticotropic hormone, ischemia-reperfusion, methylprednisolone, neuroprotection, spinal cord, tetracosactide

Crawford ES, Crawford JL, Safi HJ, et al. Thoracoabdominal aortic aneurysms: preoperative and intraoperative factors determining immediate and long-term results of operations in 605 patients. J Vasc Surg 1986; 3: 389-404.
Gürer B, Kertmen H, Kasim E, et al. Neuroprotective effects of testosterone on ischemia/reperfusion injury of the rabbit spinal cord. Injury 2015; 46: 240-8.
Kertmen H, Gürer B, Yılmaz ER, et al. The protective effect of low-dose methotrexate on ischemia-reperfusion injury of the rabbit spinal cord. Eur J Pharmacol 2013; 714: 148-56.
Lu K, Cho CL, Liang CL, et al. Inhibition of the MEK/ERK pathway reduces microglial activation and interleukin-1-beta expression in spinal cord ischemia/reperfusion injury in rats. J Thorac Cardiovasc Surg 2007; 133: 934-41.
Matsumoto S, Matsumoto M, Yamashita A, et al. The temporal profile of the reaction of microglia, astrocytes, and macrophages in the delayed onset paraplegia after transient spinal cord ischemia in rabbits. Anesth Analg 2003; 96: 1777-84.
Agee JM, Flanagan T, Blackbourne LH, Kron IL, Tribble CG. Reducing postischemic paraplegia using conjugated superoxide dismutase. Ann Thorac Surg 1991; 51: 911-4.
Ueno T, Furukawa K, Katayama Y, Suda H, Itoh T. Spinal cord protection: development of a paraplegia-preventive solution. Ann Thorac Surg 1994; 58: 116-20.
Cassada DC, Gangemi JJ, Rieger JM, et al. Systemic adenosine A2A agonist ameliorates ischemic reperfusion injury in the rabbit spinal cord. Ann Thorac Surg 2001; 72: 1245-50.
Kanellopoulos GK, Kato H, Wu Y, et al. Neuronal cell death in the ischemic spinal cord: the effect of methylprednisolone. Ann Thorac Surg 1997; 64: 1279-85.
Cassada DC, Tribble CG, Laubach VE, et al. An adenosine A2A agonist, ATL-146e, reduces paralysis and apoptosis during rabbit spinal cord reperfusion. J Vasc Surg 2001; 34: 482-8.
Yilmaz ER, Kertmen H, Dolgun H, et al. Effects of darbepoetin-alpha in spinal cord ischemia-reperfusion injury in the rabbit. Acta Neurochir 2012; 154: 1037-43.
Martin L, Chaabo A, Lasne F. Detection of tetracosactide in plasma by enzyme-linked immunosorbent assay (ELISA). Drug Test Anal 2015; 7: 531-4.
Bazzani C, Guarini S, Botticelli AR, et al. Protective effect of melanocortin peptides in rat myocardial ischemia. J Pharmacol Exp Ther 2001; 297: 1082-7.
Lipton JM, Catania A, Delgado R. Peptide modulation of inflammatory processes within the brain. Neuroimmunomodulation 1998; 5: 178-83.
Lipton JM, Catania A. Anti-inflammatory actions of the neuroimmunomodulator alpha-MSH. Immunol Today 1997; 18: 140-5.
Wikberg JES. Melanocortin receptors: perspectives for novel drugs. Eur J Pharmacol 1999; 375: 295-310.
Guarini S, Bazzani C, Bini A, Cainazzo MM, Tomasi A, Bertolini A. Adrenocorticotropin counteracts the increase in free radical blood levels, detected by electron spin resonance spectrometry, in rats subjected to prolonged asphyxia. Life Sci 1998; 63: 97-104.
Mioni C, Giuliani D, Cainazzo MM, et al. Further evidence that melanocortins prevent myocardial reperfusion injury by activating melanocortin MC3 receptors. Eur J Pharmacol 2003; 477: 227-34.
Muller CA, McArthur N, Belyaev O, et al. The effect of synacthen on acute necrotizing pancreatitis in rats. Pancreas 2008; 37: 316-20.
Lukácová N, Halát G, Chavko M, Marsala J. Ischemia-reperfusion injury in the spinal cord of rabbits strongly enhances lipid peroxidation and modifies phospholipid profiles. Neurochem Res 1996; 21: 869-73.
Ilhan A, Yilmaz HR, Armutcu F, Gurel A, Akyol O. The protective effect of nebivolol on ischemia/reperfusion injury in rabbit spinal cord. Prog Neuropsychopharmacol Biol Psychiatry 2004; 28: 1153-60.
Zivin JA, DeGirolami U. Spinal cord infarction: a highly reproducible stroke model. Stroke 1980; 11: 200-2.
Prajda N, Weber G. Malignant transformation-linked imbalance: decreased xanthine oxidase activity in hepatomas. FEBS Lett 1975; 59: 245-9.
Umehara S, Goyagi T, Nishikawa T, Tobe Y, Masaki Y. Esmolol and landiolol, selective beta1-adrenoreceptor antagonists, provide neuroprotection against spinal cord ischemia and reperfusion in rats. Anesth Analg 2010; 110: 1133-7.
Kaptanoğlu E, Palaoglu S, Surucu HS, Hayran M, Beskonakli E. Ultrastructural scoring of graded acute spinal cord injury in the rat. J Neurosurg 2002; 97: 49-56.
Lee BY, Al-Waili N, Butler G. The effect of adrenergic beta(2) receptor agonist on paraplegia following clamping of abdominal aorta. Arch Med Sci 2011; 7: 597-603.
Dumont RJ, Okonkwo DO, Verma S, et al. Acute spinal cord injury, part I: pathophysiologic mechanisms. Clin Neuropharmacol 2001; 24: 254-64.
Hasturk A, Atalay B, Calisaneller T, Ozdemir O, Oruckaptan H, Altinors N. Analysis of serum pro-inflammatory cytokine levels after rat spinal cord ischemia/reperfusion injury and correlation with tissue damage. Turk Neurosurg 2009; 19: 353-9.
Fan L, Wang K, Shi Z, Die J, Wang C, Dang X. Tetramethylpyrazine protects spinal cord and reduces inflammation in a rat model of spinal cord ischemia-reperfusion injury. J Vasc Surg 2011; 54: 192-200.
Reece TB, Okonkwo DO, Ellman PI, et al. The evolution of ischemic spinal cord injury in function, cytoarchitecture, and inflammation and the effects of adenosine A2A receptor activation. J Thorac Cardiovasc Surg 2004; 128: 925-32.
Li C, Zhao R, Gao K, et al. Astrocytes: implications for neuroinflammatory pathogenesis of Alzheimer’s disease. Curr Alzheimer Res 2011; 8: 67-80.
Brossaud J, Gatta B, Tabarin A, Corcuff JB. Different methods to estimate serum free cortisol: a comparison during cortisol tetracosactide testing. Clin Chem Lab Med 2015; 53: 1367-73.
Lux AL, Edwards SW, Hancock E, et al. The United Kingdom Infantile Spasms Study comparing vigabatrin with prednisolone or tetracosactide at 14 days: a multicentre, randomised controlled trial. Lancet 2004; 364: 1773-8.
Getting SJ. Melanocortin peptides and their receptors: new targets for anti-inflammatory therapy. Trends Pharmacol Sci 2002; 23: 447-9.
Luger TA, Scholzen T, Grabbe S. The role of alpha-melanocyte-stimulating hormone in cutaneous biology. J Investig Dermatol Symp Proc 1997; 2: 87-93.
Guarini S, Bazzani C, Mattera Ricigliano G, Bini A, Tomasi A, Bertolini A. Influence of ACTH-(1–24) on free radical levels in the blood of haemorrhage-shocked rats: direct ex vivo detection by electron spin resonance spectrometry. Br J Pharmacol 1996; 119: 29-34.
Darlington CL, Gilchrist DP, Smith PF. Melanocortins and lesion-induced plasticity in the CNS: a review. Brain Res Brain Res Rev 1996; 22: 245-57.
Kokubo M, Asai K, Yamamoto N, et al. ACTH(1-24) down-regulates expression of ciliary neurotrophic factor mRNA in cultured rat astrocyte. Pediatr Res 2002; 52: 950-7.
Mocchetti I, Spiga G, Hayes VY, Isackson PJ, Colangelo A. Glucocorticoids differentially increase nerve growth factor and basic fibroblast growth factor expression in the rat brain. J Neurosci 1996; 16: 2141-8.
Chen HC, Fong TH, Lee AW, Chiu WT. Autophagy is activated in injured neurons and inhibited by methylprednisolone after experimental spinal cord injury. Spine 2012; 37: 470-5.
Kwon BK, Tetzlaff W, Grauer JN, Beiner J, Vaccaro AR. Pathophysiology and pharmacologic treatment of acute spinal cord injury. Spine J 2004; 4: 451-64.
Bracken MB. Steroids for acute spinal cord injury. Cochrane Database Syst Rev 2012; 1: CD001046.
Bracken MB, Shepard MJ, Holford TR, et al. Administration of methylprednisolone for 24 or 48 hours or tirilazad mesylate for 48 hours in the treatment of acute spinal cord injury. Results of the Third National Acute Spinal Cord Injury Randomized Controlled Trial. National Acute Spinal Cord Injury Study. JAMA 1997; 277: 1597-604.
Ahuja CS, Martin AR, Fehlings M. Recent advances in managing a spinal cord injury secondary to trauma. F1000Res. 2016; 5: pii: F1000 Faculty Rev-1017.
Taoka Y, Okajima K, Uchiba M, et al. Role of neutrophils in spinal cord injury in the rat. Neuroscience 1997; 79: 1177-82.
Sanli AM, Serbes G, Sargon MF, et al. Methothrexate attenuates early neutrophil infiltration and the associated lipid peroxidation in the injured spinal cord but does not induce neurotoxicity in the uninjured spinal cord in rats. Acta Neurochir 2012; 154: 1045-54.
Diaz-Ruiz A, Rios C, Duarte I, et al. Lipid peroxidation inhibition in spinal cord injury: cyclosporin-A vs methylprednisolone. Neuroreport 2000; 11: 1765-67.
Qian H, Liu D. The time course of malondialdehyde production following impact injury to rat spinal cord as measured by microdialysis and high pressure liquid chromatography. Neurochem Res 1997; 22: 1231-6.
Chan PH. Role of oxidants in ischemic brain damage. Stroke 1996; 27: 1124-29.
Krieglstein CF, Granger DN. Adhesion molecules and their role in vascular disease. Am J Hypertens 2001; 14: 44S-54S.
Ustün ME, Duman A, Oğun CO, Vatansev H, Ak A. Effects of nimodipine and magnesium sulfate on endogenous antioxidant levels in brain tissue after experimental head trauma. J Neurosurg Anesthesiol 2001; 13: 227-32.
Hille R, Nishino T. Flavoprotein structure and mechanism. 4. Xanthine oxidase and xanthine dehydrogenase. FASEB J 1995; 9: 995-1003.
Schwab ME, Bartholdi D. Degeneration and regeneration of axons in the lesioned spinal cord. Physiol Rev 1996; 76: 319-70.
Keane RW, Kraydieh S, Lotocki G, et al. Apoptotic and anti-apoptotic mechanisms following spinal cord injury. J Neuropathol Exp Neurol 2001; 60: 422-9.
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