Does ticagrelor have a protective effect on intestinal injury induced by ischemia reperfusion


YARDIMOĞLU YILMAZ M. , YAZIR Y. , KAVRAM K., FURAT RENÇBER S. H. , ŞİRİN G. , FINDIK O.

The 16th European Microscopy Congress, Lyon, Fransa, 28 August - 02 September 2016

Özet

Does ticagrelor have a protective effect on small intestine injury induced by
ischemia/reperfusion?

Authors: Melda YARDIMOGLU (1), Yusufhan YAZIR (2), Kübra KAVRAM (3), Selenay FURAT RENÇBER (1), Göktuğ Şirin (4), Orhan Fındık (5)
1. Department of Histology and Embryology, Faculty of Medicine, Kocaeli University, Kocaeli, TURKEY
2. Department of Histology and Embryology; Center of Stem Cell and Gene Therapies Research and Practice,
Faculty of Medicine, Kocaeli University, Kocaeli, TURKEY
3. Department of Histology and Embryology, The Institute of Health Sciences, Kocaeli University , Kocaeli,
TURKEY
4. Department of Gastroenterology, Faculty of Medicine, Kocaeli University, Kocaeli, TURKEY
5. Department of Cardiovascular Surgery, Derince Training and Research Hospital, Kocaeli, TURKEY
DOI: 10.1002/EMC2016.0006
Corresponding email: melda.yardimoglu@gmail.com

Keywords: Ticagrelor, ischemia-reperfuison, small intestine, apoptosis
Ischemia-reperfusion injury (IRI) occurs after different surgical treatments and may have an effect in remote organs, causing multiple organ dysfunction syndrome and death (1, 2). Several studies consistently showed that ticagrelor inhibits the cellular uptake of adenosine, in addition to antagonizing the P2Y12 receptor (3, 4). The platelet inhibitor ticagrelor is strongly recommended during 12 months post-acute coronary syndrome in
European guidelines (5). The aim of this study is to evaluate the protective effect of ticagrelor on small intestine in ischemia-reperfusion model. 35 Spraque-Dawley rats were divided into 5 groups: In group 1, only laparotomy was performed. In all groups
except for the sham (group 1) group, IRI was induced by clamping the aorta with atraumatic vascular clamp infrarenally for 2 hours, followed by 4 hours of reperfusion. In groups 2 to 5, animals were treated with 0.1 ml saline, doses of 7.5 mg/kg, 15 mg/kg and 25 mg/kg ticagrelor, respectively. At the end of the experiment, for histological examination, small intestine were taken 60 min after reperfusion. The tissue were fixed in 10% formaldehyde for 48 h at room temperature, dehydrated by graded ethanol, and embedded in Paraffin. 4-5 μm thick sections were obtained, then stained with H&E and TdTmediated dUTP nick end labeling (TUNEL) assay (ApopTag Plus Peroxidase In Situ Apoptosis Detection Kit, S7101; EMD Millipore Corp., Temeculla, CA) was treated, and then studied using light microscopy. Apoptotic index was assessed. The histological structure of intestinal mucosae was intact and clearly visible in group 1; histological changes were observed in groups 2-3 with inflammatory cells compared with the group 1. In groups 4-5, histological damage decreased, mucosal epithelium exhibited approximately normal instestine architecture compared with the groups 2-3. In the present study, we conclude that ticagrelor has a prophylactic effect against intestinal damage induced by IRI for local mucosal protection, and increase in mucosal blood flow, mucus secretion. Our results suggest that ticagrelor plays a protective role against IR induced pathology and apoptosis. Although future clinical trials are required, the effective dose of ticagrelor may be used in IR- induced intestine damage.
REFERENCES
1. Stringa P. et al. Pretreatment combination reduces remote organ damage secondary to intestinal reperfusion injury in mice:follow-up study. Taranslantation Proceedings 48, 210e216, 2016.
2. 2. Kalogeris T. et al. Cell biology of ischemia/reperfusion injury. Int Rev Cell Mol Biol, 298:229-317, 2012.
3. 3. Catteneo M, Schulz R, Nylander S. Adenosine-mediated effects of Ticagrelor. J Am Coll Cardiol 2014;63:2503-2509.
4. Cattaneo M. The platelet P2Y12 receptor for adenosine diphosphate: congenital and drug-induced defects. Blood 2011;117:2102–12. Wallentin L, Becker RC, Budaj A, et al., for the PLATO Investigators. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2009;361:1045–57.
5. 5.Sahlén A,Varenhorst C, Lagerqvist B, Renlund H, Wallentin L, James SK, Jernberg T. Contemporary use of ticagrelor in patients with acute coronary syndrome: insights from Swedish Web System for Enhancement and Development of Evidence-Based Care in Heart Disease Evaluated According to Recommended Therapies (SWEDEHEART). European Heart Journal - Cardiovascular Pharmacotherapy Advance Access published
September 18, 2015.

Does ticagrelor have a protective effect on small intestine injury induced by
ischemia/reperfusion?

Authors: Melda YARDIMOGLU (1), Yusufhan YAZIR (2), Kübra KAVRAM (3), Selenay FURAT RENÇBER (1), Göktuğ Şirin (4), Orhan Fındık (5)
1. Department of Histology and Embryology, Faculty of Medicine, Kocaeli University, Kocaeli, TURKEY
2. Department of Histology and Embryology; Center of Stem Cell and Gene Therapies Research and Practice,
Faculty of Medicine, Kocaeli University, Kocaeli, TURKEY
3. Department of Histology and Embryology, The Institute of Health Sciences, Kocaeli University , Kocaeli,
TURKEY
4. Department of Gastroenterology, Faculty of Medicine, Kocaeli University, Kocaeli, TURKEY
5. Department of Cardiovascular Surgery, Derince Training and Research Hospital, Kocaeli, TURKEY
DOI: 10.1002/EMC2016.0006
Corresponding email: melda.yardimoglu@gmail.com

Keywords: Ticagrelor, ischemia-reperfuison, small intestine, apoptosis
Ischemia-reperfusion injury (IRI) occurs after different surgical treatments and may have an effect in remote organs, causing multiple organ dysfunction syndrome and death (1, 2). Several studies consistently showed that ticagrelor inhibits the cellular uptake of adenosine, in addition to antagonizing the P2Y12 receptor (3, 4). The platelet inhibitor ticagrelor is strongly recommended during 12 months post-acute coronary syndrome in
European guidelines (5). The aim of this study is to evaluate the protective effect of ticagrelor on small intestine in ischemia-reperfusion model. 35 Spraque-Dawley rats were divided into 5 groups: In group 1, only laparotomy was performed. In all groups
except for the sham (group 1) group, IRI was induced by clamping the aorta with atraumatic vascular clamp infrarenally for 2 hours, followed by 4 hours of reperfusion. In groups 2 to 5, animals were treated with 0.1 ml saline, doses of 7.5 mg/kg, 15 mg/kg and 25 mg/kg ticagrelor, respectively. At the end of the experiment, for histological examination, small intestine were taken 60 min after reperfusion. The tissue were fixed in 10% formaldehyde for 48 h at room temperature, dehydrated by graded ethanol, and embedded in Paraffin. 4-5 μm thick sections were obtained, then stained with H&E and TdTmediated dUTP nick end labeling (TUNEL) assay (ApopTag Plus Peroxidase In Situ Apoptosis Detection Kit, S7101; EMD Millipore Corp., Temeculla, CA) was treated, and then studied using light microscopy. Apoptotic index was assessed. The histological structure of intestinal mucosae was intact and clearly visible in group 1; histological changes were observed in groups 2-3 with inflammatory cells compared with the group 1. In groups 4-5, histological damage decreased, mucosal epithelium exhibited approximately normal instestine architecture compared with the groups 2-3. In the present study, we conclude that ticagrelor has a prophylactic effect against intestinal damage induced by IRI for local mucosal protection, and increase in mucosal blood flow, mucus secretion. Our results suggest that ticagrelor plays a protective role against IR induced pathology and apoptosis. Although future clinical trials are required, the effective dose of ticagrelor may be used in IR- induced intestine damage.
REFERENCES
1. Stringa P. et al. Pretreatment combination reduces remote organ damage secondary to intestinal reperfusion injury in mice:follow-up study. Taranslantation Proceedings 48, 210e216, 2016.
2. 2. Kalogeris T. et al. Cell biology of ischemia/reperfusion injury. Int Rev Cell Mol Biol, 298:229-317, 2012.
3. 3. Catteneo M, Schulz R, Nylander S. Adenosine-mediated effects of Ticagrelor. J Am Coll Cardiol 2014;63:2503-2509.
4. Cattaneo M. The platelet P2Y12 receptor for adenosine diphosphate: congenital and drug-induced defects. Blood 2011;117:2102–12. Wallentin L, Becker RC, Budaj A, et al., for the PLATO Investigators. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2009;361:1045–57.
5. 5.Sahlén A,Varenhorst C, Lagerqvist B, Renlund H, Wallentin L, James SK, Jernberg T. Contemporary use of ticagrelor in patients with acute coronary syndrome: insights from Swedish Web System for Enhancement and Development of Evidence-Based Care in Heart Disease Evaluated According to Recommended Therapies (SWEDEHEART). European Heart Journal - Cardiovascular Pharmacotherapy Advance Access published
September 18, 2015.