Abstract
Lipid peroxidation has been reported to play an important role in spinal cord injury (SCI). Erythropoietin (EPO) is a hematopoietic growth factor that stimulates proliferation and differentiation of erythroid precursor cells and is also known to exert neurotrophic activity in the central nervous system. The purpose of this study was to investigate the effectiveness of recombinant human EPO in attenuating the severity of experimental SCI. Rats were divided into seven groups. Controls (1) received only laminectomy. The trauma-only group (2) underwent 50-g/cm contusion injury and had no medication. In group 3, 30 mg/kg of methylprednisolone was introduced. The vehicle group (4) received vehicle solution containing human serum albumin, which is a solvent of EPO. Groups 5, 6, and 7 received 100 IU/kg, 1,000 IU/kg, and 5,000 IU/kg of EPO, respectively. All treatments were given as single doses, intraperitoneally, immediately after injury. Thiobarbituric acid-reactive substances were estimated to demonstrate lipid peroxidation, and ultrastructure was evaluated by electron microscopy. The results showed that lipid peroxidation by-products increased after injury. Administration of EPO and methylprednisolone sodium succinate (MPSS) reduced thiobarbituric acid-reactive substances after trauma. The best biochemical results were obtained with 5,000 IU/kg of EPO. Electron microscopic findings showed that EPO protected the spinal cord from injury. Although 1,000 IU/kg and 5,000 IU/kg of EPO inhibited lipid peroxidation better than MPSS, ultrastructural neuroprotection was similar.
Similar content being viewed by others
References
Tator CH (1995) Update on the pathophysiology and pathology of acute spinal cord injury. Brain Pathol 5:407–413
Tator CH, Fehlings MG (1991) Review of the secondary injury theory of acute spinal cord trauma with emphasis on vascular mechanisms. J Neurosurg 75:15–26
Amar AP, Levy ML (1999) Pathogenesis and pharmacological strategies for mitigating secondary damage in acute spinal cord injury. Neurosurgery 44:1027–1040
Anderson DK, Hall ED (1993) Pathophysiology of spinal cord trauma. Ann Emerg Med 22:987–992
Dumont RJ, Okonkwo DO, Verma S, Hurlbert RJ, Boulos PT, Ellegala DB, Dumont AS (2001) Acute spinal cord injury, part I: Pathophysiologic mechanisms. Clin Neuropharmacol 24:254–264
Dumont RJ, Verma S, Okonkwo DO, Hurlbert RJ, Boulos PT, Ellegala DB, Dumont AS (2001) Acute spinal cord injury, part II: Contemporary pharmacotherapy. Clin Neuropharmacol 24:265–279
Bracken MB, Holford TR (1993) Effects of timing of methylprednisolone or naloxone administration on recovery of segmental and long-tract neurological function in NASCIS 2. J Neurosurg 79:500–507
Bracken MB, Shepard MJ, Holford TR, Leo-Summers L, Aldrich EF, Fazl M, Fehlings MG, Herr DL, Hitchon PW, Marshall LF, Nockels RP, Pascale V, Perot PL Jr, Piepmeier J, Sonntag VK, Wagner F, Wilberger JE, Winn HR, Young W (1998) Methylprednisolone or tirilazad mesylate administration after acute spinal cord injury: 1-year follow up. Results of the third National Acute Spinal Cord Injury Randomized Controlled Trial. J Neurosurg 89:699–706
Anderson DK, Demediuk P (1985) Spinal cord injury and protection. Ann Emerg Med 14:816–821
Hall ED (1992) The neuroprotective pharmacology of methylprednisolone. J Neurosurg 76:13–22
Hall ED, Braughler M (1982) Effects of intravenous methylprednisolone on spinal cord lipid peroxidation and (Na++K+)-ATPase activity. J Neurosurg 57:247–253
Hall ED (1993) Lipid antioxidants in acute central nervous system injury. Ann Emerg Med 22:1022–1027
Saunders RD, Dugan LL, Demediuk P, Means ED, Horrocks LA, Anderson DK (1987) Effects of methylprednisolone and the combination of alpha tocopherol and selenium on arachidonic acid metabolism and lipid peroxidation in traumatized spinal cord tissue. J Neurochem 49:24–31
Jelkmann W (1992) Erythropoietin: structure, control of production, and function. Physiol Rev 72:449–489
Koury MJ, Bondurant MC (1992) The molecular mechanism of erythropoietin action. Eur J Biochem 210:649–663
Dame C, Juul SE, Christensen RD (2001) The biology of erythropoietin in the central nervous system and its neurotrophic and neuroprotective potential. Biol Neonate 79:228–235
Konishi Y, Chui DH, Hirose H, Kunishita T, Tabira T (1993) Tropic effect of erythropoietin and other hematopoietic factors central colinergic neurons in vitro and in vivo. Brain Res 609:29–35
Brines ML, Ghezzi P, Keenan S, de Lanerolle NC, Cerami C, Itri LM, Cerami A (2000) Erythropoietin crosses the blood-brain barrier to protect against experimental brain injury. PNAS 97:10526–10531
Bernaudin M, Marti HH, Roussel S, Divoux D, Nouvelot A, MacKenzie ET, Petit E (1999) A Potential role for erythropoietin in focal permanent cerebral ischemia in mice. J Cereb Blood Flow Metab 19:643–651
Kawakami M, Sekiguchi M, Sato K, Kozaki S, Takahashi M (2001) Erythropoietin receptor-mediated inhibition of excitotoxic glutamate release confers neuroprotection during chemical ischemia. J Biol Chem 276:39469–39475
Siren AL, Fratelli M, Brines M, Goemans C, Casagrande S, Lewczuk P, Keenan S, Gleiter C, Pasquali C, Capobianco A, Mennini T, Heumann R, Cerami A, Ehrenreich H, Ghezzi P (2001) Erythropoietin prevents neuronal apoptosis after cerebral ischemia and metabolic stress. Proc Natl Acad Sci U S A 98:4044–4049
Alafaci C, Salpietro F, Grasso G, Sfacteria A, Passalacqua M, Morabito A, Tripodo E, Calapai G, Buemi M, Tomasello F (2000) Effect of human erythropoietin on cerebral ischemia following experimental subarachnoid hemorrhage. Eur J Pharmacol 406:219–225
Buemi M, Grasso G, Corica F, Calapai G, Salpietro FM, Casuscelli T, Sfacteria A, Aloisi C, Concetta A, Sturiale A, Frisina N, Tomasello F (2000) In vivo evidence that erythropoietin has a neuroprotective effect during subarachnoid hemorrhage. Eur J Pharmacol 392:31–34
Grasso G (2001) Neuroprotective effect of recombinant human erythropoietin in experimental subarachnoid hemorrhage. J Neurosurg Sci 45:7–14
Bany-Mohammed FM, Slivka S, Hallman M (1996) Recombinant human erythropoietin: possible role as an antioxidant in premature rabbits. Pediatr Res 40:381–387
Sakanaka M, Wen TC, Matsuda S, Masuda S, Morishita E, Nagao M, Sasaki R (1998) In vivo evidence that erythropoietin protects neurons from ischemic damage. Proc Natl Acad Sci U S A 95:4635–4640
Allen AR (1911) Surgery of experimental lesion of spinal cord equivalent to crush injury of fracture dislocation of spinal column. A preliminary report. JAMA 57:878–880
Uchiyama M, Mihara S (1978) Determination of malonaldehyde precursors in tissues by thiobarbituric acid test. Annal Biochem 86:271–278
Kaptanoglu E, Palaoglu S, Surucu S, Hayran M, Beskonakli E (2002) Ultrastructural scoring of graded acute spinal cord injury in rats. J Neurosurg (Spine 1) 97:43–50
Kaptanoglu E, Caner HH, Surucu SH., Akbiyik F (1999) Effect of mexiletine on lipid peroxidation and early ultrastructural findings in experimental spinal cord injury. J Neurosurg (Spine 2) 91:200–204
Kaptanoglu E, Tuncel M, Palaoglu S, Konan A, Demirpence E, Kilinc K (2000) Comparison of the effects of melatonin and methylprednisolone in experimental spinal cord injury. J Neurosurg (Spine 1) 93:77–84
Kaptanoglu E, Sen S, Beskonakli E, Surucu HS, Tuncel M, Kilinc K, Taskin Y (2002) Antioxidant actions and early ultrastructural findings of thiopental and propofol in experimental spinal cord injury. J Neurosurg Anesthesiol 14:114–122
Akisu M, Kullahcioglu GF, Baka M, Husseyinov A, Kultursay N (2001) The role of recombinant human erythropoietin in lipid peroxidation and platelet-activating factor generation in a rat model of necrotizing enterocolitis. Eur J Pediatr Surg 11:167–172
Akisu M, Tuzun S, Arslanoglu S, Yalaz M, Kultursay N (2001) Effect of recombinant human erythropoietin administration on lipid peroxidation and antioxidant enzyme(s) activities in preterm infants. Acta Med Okayama 55:357–362
Celik M, Gokmen N, Erbayraktar S, Akhisaroglu M, Konakc S, Ulukus C, Genc S, Genc K, Sagiroglu E, Cerami A, Brines M (2002) Erythropoietin prevents motor neuron apoptosis and neurologic disability in experimental spinal cord ischemic injury. Proc Natl Acad Sci U S A 99:2258–2263
Gorio A, Gokmen N, Erbayraktar S, Yilmaz O, Madaschi L, Cichetti C, Di Giulio AM, Vardar E, Cerami A, Brines M (2002) Recombinant human erythropoietin counteracts secondary injury and markedly enhances neurological recovery from experimental spinal cord trauma. Proc Natl Acad Sci USA 99:9450–9455
Chattopadhyay A, Choudhury TD, Bandyopadhyay D, Datta AG (2000) Protective effect of erythropoietin on the oxidative damage of erythrocyte membrane by hydroxyl radical. Biochem Pharmacol 59:419–425
Solaroglu I, Solaroglu A, Kaptanoglu E, Dede S, Haberal A, Beskonakli E, Kilinc K (2003) Erythropoietin prevents ischemia-reperfusion from inducing oxidative damage in fetal rat brain. Childs Nerv Syst 19:19–22
Wrathall JR, Pettegrew RK, Harvey F (1985) Spinal cord contusion in the rat: production of graded, reproducible, injury groups. Exp Neurol 88:108–122
Anderson DK, Nicolosi GR, Means ED, Hartley LE (1978) Effects of laminectomy on spinal cord blood flow. J Neurosurg 48:232–238
Anderson DK, Means ED, Waters TR (1980) Spinal cord energy metabolism in normal and postlaminectomy cats. J Neurosurg 52:387–391
Belayev L, Saul I, Huh PW, Finotti N, Zhao W, Busto R, Ginsberg MD (1999) Neuroprotective effect of high-dose albumin therapy against global ischemic brain injury in rats. Brain Res 845:107–111
Belayev L, Liu Y, Zhao W, Busto R, Ginsberg MD (2001) Human albumin therapy of acute ischemic stroke: marked neuroprotective efficacy at moderate doses and with a broad therapeutic window. Stroke 32:553–560
Belayev L, Pinard E, Nallet H, Seylaz J, Liu Y, Riyamongkol P, Zhao W, Busto R, Ginsberg MD (2002) Albumin therapy of transient focal cerebral ischemia: in vivo analysis of dynamic microvascular responses. Stroke 33:1077–1084
Ginsberg MD, Zhao W, Belayev L, Alonso OF, Liu Y, Loor JY, Busto R (2001) Diminution of metabolism/blood flow uncoupling following traumatic brain injury in rats in response to high-dose human albumin treatment. J Neurosurg 94:499–509
Hurlbert RJ (2000) Methylprednisolone for acute spinal cord injury: an inappropriate standard of care. J Neurosurg (Spine 1) 93:1–7
Matsumoto T, Tamaki T, Kawakami M, Yoshida M, Ando M, Yamada H (2001) Early complications of high-dose methylprednisolone sodium succinate treatment in the follow-up of acute cervical spinal cord injury. Spine 26:426–430
Bracken MB, Holford TR (2002) Neurological and functional status 1 year after acute spinal cord injury: estimates of functional recovery from results modeled in National Acute Spinal Cord Injury Study II. J Neurosurg (Spine 3) 96:259–266
Young W (1992) Medical treatments of acute spinal cord injury. J Neurol Neurosurg Psychiatry 55:635–639
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Kaptanoglu, E., Solaroglu, I., Okutan, O. et al. Erythropoietin exerts neuroprotection after acute spinal cord injury in rats: effect on lipid peroxidation and early ultrastructural findings. Neurosurg Rev 27, 113–120 (2004). https://doi.org/10.1007/s10143-003-0300-y
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10143-003-0300-y