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Published in: Acta Neurochirurgica 12/2010

01-12-2010 | Experimental research

Dose-dependent ultrastructural and morphometric alterations after erythropoietin treatment in rat femoral artery vasospasm model

Authors: Ismail Ulusal, Rabia Tari, Gulsah Ozturk, Ezgi Aycicek, Fadime Aktar, Kadir Kotil, Turgay Bilge, Talat Kırış

Published in: Acta Neurochirurgica | Issue 12/2010

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Abstract

Purpose

Cerebral vasospasm is the common cause of poor outcome after aneurysmal subarachnoid hemorrhage (aSAH). Although many agents are experimentally and clinicaly used to protect or recover from vasospasm, an effective neurotherapeutic drug is still missing. Erythropoietin (EPO) is recently a promising candidate. The aim of this study is to investigate the dose-dependent effects of recombinant human EPO (rhEPO) on arterial wall in a rat femoral artery vasospasm model.

Methods

Thirty two animals were divided into four groups: vasospasm without any treatment (group A), vasospasm +250 IU/kg rhEPO group (group B), vasospasm +500 IU/kg rhEPO group (group C), and control group (group D). Rat femoral artery vasospasm model was used. For groups B and C, 7 days of 250 IU/kg and 500 IU/kg intraperitoneal rhEPO in 0.3 ml saline were administered respectively; and for groups A and D, 0.3 ml saline were administered intraperitoneally without any treatment. After 7 days, histological and morphometric analyses were carried out.

Results

Vasospasm alone group demonstrated the highest vessel wall thicknesses, comparing to other groups (p < 0.001). While for groups B and C, vessel wall thickness values were significantly higher than the control group (p < 0.001), between these two groups, there was no significant difference achieved (p > 0.05).

Conclusion

In our study, there was no significant difference between the two rhEPO treatment groups, but rhEPO treatment was shown to be histologically and morphometrically effective in vasospasm. However, if dosage of EPO treatment is augmented, successful results may be achieved.
Literature
1.
go back to reference 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 55:357–362PubMed 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 55:357–362PubMed
2.
go back to reference Ayer RE, Zhang JH (2008) Oxidative stress in subarachnoid haemorrhage: significance in acute brain injury and vasospasm. Acta Neurochir Suppl 104:33–41CrossRefPubMed Ayer RE, Zhang JH (2008) Oxidative stress in subarachnoid haemorrhage: significance in acute brain injury and vasospasm. Acta Neurochir Suppl 104:33–41CrossRefPubMed
3.
go back to reference Banerjee D, Rodriguez M, Nag M, Adamson JW (2000) Exposure of endothelial cells to recombinant human erythropoietin induces nitric oxide synthase activity. Kidney Int 57:1895–1904CrossRefPubMed Banerjee D, Rodriguez M, Nag M, Adamson JW (2000) Exposure of endothelial cells to recombinant human erythropoietin induces nitric oxide synthase activity. Kidney Int 57:1895–1904CrossRefPubMed
4.
go back to reference Beleslin-Cokic BB, Cokic VP, Yu X, Weksler BB, Schechter AN, Noguchi CT (2004) Erythropoietin and hypoxia stimulate erythropoietin receptor and nitric oxide production by endothelial cells. Blood 104:2073–2080CrossRefPubMed Beleslin-Cokic BB, Cokic VP, Yu X, Weksler BB, Schechter AN, Noguchi CT (2004) Erythropoietin and hypoxia stimulate erythropoietin receptor and nitric oxide production by endothelial cells. Blood 104:2073–2080CrossRefPubMed
5.
go back to reference 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 19:643–651CrossRefPubMed 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 19:643–651CrossRefPubMed
6.
go back to reference Brines ML, Ghezzi P, Kenan S, Agnello D, de Laner Olle NC, Cerami C et al (2000) Erytropoetin crosses the blood brain barrier to protect against experimental brain injury. Proc Natl Acad Sci USA 97(10):526–531 Brines ML, Ghezzi P, Kenan S, Agnello D, de Laner Olle NC, Cerami C et al (2000) Erytropoetin crosses the blood brain barrier to protect against experimental brain injury. Proc Natl Acad Sci USA 97(10):526–531
7.
go back to reference Cheng G, Wei L, Zhi-Dan S, Shi-Guang Z, Xiang-Zhen L (2009) Atorvastatin ameliorates cerebral vasospasm and early brain injury after subarachnoid hemorrhage and inhibits caspase-dependent apoptosis pathway. BMC Neurosci 21(10):7CrossRef Cheng G, Wei L, Zhi-Dan S, Shi-Guang Z, Xiang-Zhen L (2009) Atorvastatin ameliorates cerebral vasospasm and early brain injury after subarachnoid hemorrhage and inhibits caspase-dependent apoptosis pathway. BMC Neurosci 21(10):7CrossRef
8.
go back to reference Coleman TR, Westenfelder C, Togel FE, Yang Y, Hu Z, Swenson L et al (2006) Cytoprotective doses of erythropoietin or carbamylated erythropoietin have markedly different procoagulant and vasoactive activities. Proc Natl Acad Sci USA 103:5965–5970CrossRefPubMed Coleman TR, Westenfelder C, Togel FE, Yang Y, Hu Z, Swenson L et al (2006) Cytoprotective doses of erythropoietin or carbamylated erythropoietin have markedly different procoagulant and vasoactive activities. Proc Natl Acad Sci USA 103:5965–5970CrossRefPubMed
9.
go back to reference Dorhout Mees SM, Rinkel GJ, Feigin VL, Algra A, van den Bergh WM, Vermeulen M, van Gijn J (2007) Calcium antagonists for aneurysmal subarachnoid haemorrhage. Cochrane Database Syst Rev Jul 18(3):CD000277. Review Dorhout Mees SM, Rinkel GJ, Feigin VL, Algra A, van den Bergh WM, Vermeulen M, van Gijn J (2007) Calcium antagonists for aneurysmal subarachnoid haemorrhage. Cochrane Database Syst Rev Jul 18(3):CD000277. Review
10.
go back to reference d’Uscio LV, Smith LA, Santhanam AV, Richardson D, Nath KA, Katusic ZS (2007) Essential role of endothelial nitric oxide synthase in vascular effects of erythropoietin. Hypertension 49:1142–1148CrossRefPubMed d’Uscio LV, Smith LA, Santhanam AV, Richardson D, Nath KA, Katusic ZS (2007) Essential role of endothelial nitric oxide synthase in vascular effects of erythropoietin. Hypertension 49:1142–1148CrossRefPubMed
11.
go back to reference Grasso G, Buemi M, Corica F, Calapani G, Salpietro FM, Casuscelli T et al (2000) In vivo evidence that erythtropoetin has a neuro-protective effect during subarachnoid hemorrhage. Eur J Pharmacol 392:31–34CrossRefPubMed Grasso G, Buemi M, Corica F, Calapani G, Salpietro FM, Casuscelli T et al (2000) In vivo evidence that erythtropoetin has a neuro-protective effect during subarachnoid hemorrhage. Eur J Pharmacol 392:31–34CrossRefPubMed
12.
go back to reference Ito H, Fukunaga M, Suzuki H, Miyakoda G, Ishikawa M, Yabuuchi Y, Taki W (2008) Effect of cilostazol on delayed cerebral vasospasm after subarachnoid hemorrhage in rats: evaluation using black blood magnetic resonance imaging. Neurobiol Dis 32:157–161CrossRefPubMed Ito H, Fukunaga M, Suzuki H, Miyakoda G, Ishikawa M, Yabuuchi Y, Taki W (2008) Effect of cilostazol on delayed cerebral vasospasm after subarachnoid hemorrhage in rats: evaluation using black blood magnetic resonance imaging. Neurobiol Dis 32:157–161CrossRefPubMed
13.
go back to reference Kern M, Lam MM, Knuckey NW, Lind CR (2009) Statins may not protect against vasospasm in subarachnoid haemorrhage. J Clin Neurosci 16:527–530, Epub 2009CrossRefPubMed Kern M, Lam MM, Knuckey NW, Lind CR (2009) Statins may not protect against vasospasm in subarachnoid haemorrhage. J Clin Neurosci 16:527–530, Epub 2009CrossRefPubMed
14.
go back to reference Kiriş T, Karasu A, Yavuz C, Erdem T, Unal F, Hepgül K, Baloğlu H (1999) Reversal of cerebral vasospasm by the nitric oxide donor SNAP in an experimental model of subarachnoid haemorrhage. Acta Neurochir (Wien) 141:1323–1328, discussion 1328–1329CrossRef Kiriş T, Karasu A, Yavuz C, Erdem T, Unal F, Hepgül K, Baloğlu H (1999) Reversal of cerebral vasospasm by the nitric oxide donor SNAP in an experimental model of subarachnoid haemorrhage. Acta Neurochir (Wien) 141:1323–1328, discussion 1328–1329CrossRef
15.
go back to reference Kramer AH, Zygun DA, Bleck TP, Dumont AS, Kassell NF, Nathan B (2009) Relationship between hemoglobin concentrations and outcomes across subgroups of patients with aneurysmal subarachnoid hemorrhage. Neurocrit Care 10:157–165CrossRefPubMed Kramer AH, Zygun DA, Bleck TP, Dumont AS, Kassell NF, Nathan B (2009) Relationship between hemoglobin concentrations and outcomes across subgroups of patients with aneurysmal subarachnoid hemorrhage. Neurocrit Care 10:157–165CrossRefPubMed
16.
go back to reference Leist M, Ghezzi P, Grasso G, Bianchi R, Villa P, Fratelli M et al (2005) Derivatives of erythropoietin that are tissue protective but not erythropoietic. Science 305:239–242CrossRef Leist M, Ghezzi P, Grasso G, Bianchi R, Villa P, Fratelli M et al (2005) Derivatives of erythropoietin that are tissue protective but not erythropoietic. Science 305:239–242CrossRef
17.
go back to reference Mayberg MR, Okada T, Bark DH (1990) Morphologic changes in cerebral arteries after subarachnoid hemorrhage. Neurosurg Clin N Am 1:417–432PubMed Mayberg MR, Okada T, Bark DH (1990) Morphologic changes in cerebral arteries after subarachnoid hemorrhage. Neurosurg Clin N Am 1:417–432PubMed
18.
go back to reference Mayberg MR, Okada T, Bark DH (1990) The significance of morphological changes in cerebral arteries after subarachnoid hemorrhage. J Neurosurg 72:626–633CrossRefPubMed Mayberg MR, Okada T, Bark DH (1990) The significance of morphological changes in cerebral arteries after subarachnoid hemorrhage. J Neurosurg 72:626–633CrossRefPubMed
19.
go back to reference Mori K, Miyazaki M, Hara Y, Aiko Y, Yamamoto T, Nakao Y (2009) Novel vasodilatory effect of intracisternal injection of magnesium sulfate solution on spastic cerebral arteries in the canine two-hemorrhage model of subarachnoid hemorrhage. J Neurosurg 110:73–78CrossRefPubMed Mori K, Miyazaki M, Hara Y, Aiko Y, Yamamoto T, Nakao Y (2009) Novel vasodilatory effect of intracisternal injection of magnesium sulfate solution on spastic cerebral arteries in the canine two-hemorrhage model of subarachnoid hemorrhage. J Neurosurg 110:73–78CrossRefPubMed
20.
go back to reference Mori K, Miyazaki M, Iwata J, Yamamoto T, Nakao Y (2008) Intracisternal infusion of magnesium sulfate solution improved reduced cerebral blood flow induced by experimental subarachnoid hemorrhage in the rat. Neurosurg Rev 31:197–203, discussion 203CrossRefPubMed Mori K, Miyazaki M, Iwata J, Yamamoto T, Nakao Y (2008) Intracisternal infusion of magnesium sulfate solution improved reduced cerebral blood flow induced by experimental subarachnoid hemorrhage in the rat. Neurosurg Rev 31:197–203, discussion 203CrossRefPubMed
21.
go back to reference Murphy AM, Xenocostas A, Pakkiri P, Lee TY (2008) Hemodynamic effects of recombinanthuman erythropoietin on the central nervous system after subarachnoid hemorrhage: reduction of microcirculatory impairment and functional deficits in a rabbit model. J Neurosurg 109:1155–1164CrossRefPubMed Murphy AM, Xenocostas A, Pakkiri P, Lee TY (2008) Hemodynamic effects of recombinanthuman erythropoietin on the central nervous system after subarachnoid hemorrhage: reduction of microcirculatory impairment and functional deficits in a rabbit model. J Neurosurg 109:1155–1164CrossRefPubMed
22.
go back to reference Okada T, Harada T, Bark DH, Mayberg MR (1990) A rat femoral artery model for vasospasm. Neurosurgery 27:349–356CrossRefPubMed Okada T, Harada T, Bark DH, Mayberg MR (1990) A rat femoral artery model for vasospasm. Neurosurgery 27:349–356CrossRefPubMed
23.
go back to reference Pluta RM (2008) Dysfunction of nitric oxide synthases as a cause and therapeutic target in delayed cerebral vasospasm after SAH. Acta Neurochir Suppl 104:139–147, ReviewCrossRefPubMed Pluta RM (2008) Dysfunction of nitric oxide synthases as a cause and therapeutic target in delayed cerebral vasospasm after SAH. Acta Neurochir Suppl 104:139–147, ReviewCrossRefPubMed
24.
go back to reference Rinkel GJ, Feigin VL, Algra A, Vermeulen M, van Gijn J (2002) Calcium antagonists for aneurysmal subarachnoid haemorrhage. Cochrane Database Syst Rev 4:CD000277 Rinkel GJ, Feigin VL, Algra A, Vermeulen M, van Gijn J (2002) Calcium antagonists for aneurysmal subarachnoid haemorrhage. Cochrane Database Syst Rev 4:CD000277
25.
go back to reference Ruschitzka FT, Wenger RH, Stallmach T, Quaschning T, de Wit C et al (2000) Nitric oxide prevents cardiovascular disease and determines survival in polyglobulic mice overexpressing erythropoietin. Proc Natl Acad Sci USA 97:609–613CrossRef Ruschitzka FT, Wenger RH, Stallmach T, Quaschning T, de Wit C et al (2000) Nitric oxide prevents cardiovascular disease and determines survival in polyglobulic mice overexpressing erythropoietin. Proc Natl Acad Sci USA 97:609–613CrossRef
26.
go back to reference 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 USA 95:4635–4640CrossRefPubMed 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 USA 95:4635–4640CrossRefPubMed
27.
go back to reference Santhanam AV, Katusic ZS (2006) Erythropoietin and cerebral vascular protection:role of nitric oxide. Acta Pharmacol Sin 27:1389–1394, ReviewCrossRefPubMed Santhanam AV, Katusic ZS (2006) Erythropoietin and cerebral vascular protection:role of nitric oxide. Acta Pharmacol Sin 27:1389–1394, ReviewCrossRefPubMed
28.
go back to reference Santhanam AV, Smith LA, Akiyama M, Rosales AG, Bailey KR, Katusic ZS (2005) Role of endothelial NO synthase phosphorylation in cerebrovascular protective effect of recombinant erythropoietin during subarachnoid hemorrhage-induced cerebral vasospasm. Stroke 36:2731–2737CrossRefPubMed Santhanam AV, Smith LA, Akiyama M, Rosales AG, Bailey KR, Katusic ZS (2005) Role of endothelial NO synthase phosphorylation in cerebrovascular protective effect of recombinant erythropoietin during subarachnoid hemorrhage-induced cerebral vasospasm. Stroke 36:2731–2737CrossRefPubMed
29.
go back to reference Schubert GA, Schilling L, Thomè C (2008) Clazosentan, an endothelin receptor antagonist, prevents early hypoperfusion during the acute phase of massive experimental subarachnoid hemorrhage: a laser Doppler flowmetry study in rats. J Neurosurg 109:1134–1140CrossRefPubMed Schubert GA, Schilling L, Thomè C (2008) Clazosentan, an endothelin receptor antagonist, prevents early hypoperfusion during the acute phase of massive experimental subarachnoid hemorrhage: a laser Doppler flowmetry study in rats. J Neurosurg 109:1134–1140CrossRefPubMed
30.
go back to reference Springborg JB, Møller C, Gideon P, Jørgensen OS, Juhler M, Olsen NV (2007) Erythropoietin in patients with aneurysmal subarachnoid haemorrhage: a double blind randomised clinical trial. Acta Neurochir (Wien) 149:1089–1101, discussion 1101CrossRef Springborg JB, Møller C, Gideon P, Jørgensen OS, Juhler M, Olsen NV (2007) Erythropoietin in patients with aneurysmal subarachnoid haemorrhage: a double blind randomised clinical trial. Acta Neurochir (Wien) 149:1089–1101, discussion 1101CrossRef
31.
go back to reference Springborg JB, Sonne B, Frederiksen HJ, Foldager N, Poulsgaard L, Klausen T, Jorgensen OS, Olsen NV (2003) Erythropoietin in the cerebrospinal fluid of patients with aneurysmal subarachnoid haemorrhage originates from the brain. Brain Res 984:143–148CrossRefPubMed Springborg JB, Sonne B, Frederiksen HJ, Foldager N, Poulsgaard L, Klausen T, Jorgensen OS, Olsen NV (2003) Erythropoietin in the cerebrospinal fluid of patients with aneurysmal subarachnoid haemorrhage originates from the brain. Brain Res 984:143–148CrossRefPubMed
32.
go back to reference Squadrito F, Altavilla D, Squadrito G, Campo GM, Arlotta M, Quartarone C, Saitta A, Caputi AP (1999) Recombinant human erythropoietin inhibits iNOS activity and reverts vascular dysfunction in splanchnic artery occlusion shock. Br J Pharmacol 127:482–488CrossRefPubMed Squadrito F, Altavilla D, Squadrito G, Campo GM, Arlotta M, Quartarone C, Saitta A, Caputi AP (1999) Recombinant human erythropoietin inhibits iNOS activity and reverts vascular dysfunction in splanchnic artery occlusion shock. Br J Pharmacol 127:482–488CrossRefPubMed
33.
go back to reference Sugawara T, Ayer R, Zhang JH (2008) Role of statins in cerebral vasospasm. Acta Neurochir Suppl 104:287–290CrossRefPubMed Sugawara T, Ayer R, Zhang JH (2008) Role of statins in cerebral vasospasm. Acta Neurochir Suppl 104:287–290CrossRefPubMed
34.
go back to reference Suzuki Y, Shibuya M, Satoh S, Sugiyama H, Seto M, Takakura K (2008) Safety and efficacy of fasudil monotherapy and fasudil-ozagrel combination therapy in patients with subarachnoid hemorrhage: sub-analysis of the post-marketing surveillance study. Neurol Med Chir (Tokyo) 48:241–247, discussion 247–248CrossRef Suzuki Y, Shibuya M, Satoh S, Sugiyama H, Seto M, Takakura K (2008) Safety and efficacy of fasudil monotherapy and fasudil-ozagrel combination therapy in patients with subarachnoid hemorrhage: sub-analysis of the post-marketing surveillance study. Neurol Med Chir (Tokyo) 48:241–247, discussion 247–248CrossRef
35.
go back to reference Tseng MY, Hutchinson PJ, Richards HK, Czosnyka M, Pickard JD, Erber WN, Brown S, Kirkpatrick PJ (2009) Acute systemic erythropoietin therapy to reduce delayed ischemic deficits following aneurysmal subarachnoid hemorrhage: a Phase II randomized, double-blind, placebo-controlled trial. J Neurosurg 111:171–180CrossRefPubMed Tseng MY, Hutchinson PJ, Richards HK, Czosnyka M, Pickard JD, Erber WN, Brown S, Kirkpatrick PJ (2009) Acute systemic erythropoietin therapy to reduce delayed ischemic deficits following aneurysmal subarachnoid hemorrhage: a Phase II randomized, double-blind, placebo-controlled trial. J Neurosurg 111:171–180CrossRefPubMed
36.
go back to reference Villa P, van Beek J, Larsen AK, Gerwien J, Christensen S, Cerami A, Brines M, Leist M, Ghezzi P, Torup L (2007) Reduced functional deficits, neuroinflammation, and secondary tissue damage after treatment of stroke by nonerythropoietic erythropoietin derivatives. J Cereb Blood Flow Metab 27:552–563CrossRefPubMed Villa P, van Beek J, Larsen AK, Gerwien J, Christensen S, Cerami A, Brines M, Leist M, Ghezzi P, Torup L (2007) Reduced functional deficits, neuroinflammation, and secondary tissue damage after treatment of stroke by nonerythropoietic erythropoietin derivatives. J Cereb Blood Flow Metab 27:552–563CrossRefPubMed
37.
go back to reference Wang H, Gao J, Lassiter TF, McDonagh DL, Sheng H, Warner DS, Lynch JR, Laskowitz DT (2006) Levetiracetam is neuroprotective in murine models of closed head injury and subarachnoid hemorrhage. Neurocrit Care 5:71–78CrossRefPubMed Wang H, Gao J, Lassiter TF, McDonagh DL, Sheng H, Warner DS, Lynch JR, Laskowitz DT (2006) Levetiracetam is neuroprotective in murine models of closed head injury and subarachnoid hemorrhage. Neurocrit Care 5:71–78CrossRefPubMed
Metadata
Title
Dose-dependent ultrastructural and morphometric alterations after erythropoietin treatment in rat femoral artery vasospasm model
Authors
Ismail Ulusal
Rabia Tari
Gulsah Ozturk
Ezgi Aycicek
Fadime Aktar
Kadir Kotil
Turgay Bilge
Talat Kırış
Publication date
01-12-2010
Publisher
Springer Vienna
Published in
Acta Neurochirurgica / Issue 12/2010
Print ISSN: 0001-6268
Electronic ISSN: 0942-0940
DOI
https://doi.org/10.1007/s00701-010-0775-6

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