Christian Maier1,2, Angelika Scheuerle3, Balázs Hauser1,4, Hubert Schelzig2, Csaba Szabó5, Peter Radermacher6, Jochen Kick2. 1. Sektion Anästhesiologische Pathophysiologie und Verfahrensentwicklung, Universitätsklinikum, 89073, Ulm, Germany. 2. Abteilung Thorax- und Gefäßchirurgie, Universitätsklinikum, 89070, Ulm, Germany. 3. Sektion Neuropathologie, Universitätsklinikum, 89081, Ulm, Germany. 4. Aneszteziológiai és Intenzív Terápiás Klinika, Semmelweis Egyetem, 1125, Budapest, Hungary. 5. Department of Surgery, University of Medicine and Dentistry, Newark, N.J., USA. 6. Sektion Anästhesiologische Pathophysiologie und Verfahrensentwicklung, Universitätsklinikum, 89073, Ulm, Germany. peter.radermacher@medizin.uni-ulm.de.
Abstract
OBJECTIVE: It is well-established that poly(ADP)ribose-polymerase (PARP) assumes major importance during ischemic brain damage, and the selective PARP-1 inhibitor PJ34 reduced spinal cord damage in murine aortic occlusion-induced ischemia/reperfusion injury. We investigated the effect of the PARP-1 inhibitor INO1001 on aortic-occlusion-related porcine spinal cord injury. DESIGN AND SETTING: Prospective, randomized, controlled experimental study in an animal laboratory. PATIENTS AND PARTICIPANTS: Ten anesthetized, mechanically ventilated, and instrumented pigs. INTERVENTIONS: Animals underwent 45 min of thoracic aortic cross-clamping after receiving vehicle (n=5) or intravenous INO1001 (n=5, total dose 4 mg/kg administered both before clamping and during reperfusion). During reperfusion continuous intravenous norepinephrine was incrementally adjusted to maintain blood pressure at or above 80% of the preclamping level. Plasma INO1001 levels were analyzed by HPLC. After 4[Symbol: see text]h of reperfusion spinal cord biopsy samples were analyzed for neuronal damage (hematoxyline-eosine and Nissl staining), expression of the cyclin-dependent kinase inhibitor genes p21 and p27 (immunohistochemistry), and apoptosis (terminal deoxynucleotidyl transferase mediated nick end labeling assay). MEASUREMENTS AND RESULTS: Plasma INO1001 levels were 0.8-2.3 and 0.30-0.76 mM before and after clamping, respectively. While 3-5% of the spinal cord neurons were irreversibly damaged in the INO1001 animals, the neuronal cell injury was three times higher in the control group. Neither p21 and p27 expression nor apoptosis showed any intergroup difference. CONCLUSIONS: The selective PARP-1 inhibitor INO1001 markedly reduced aortic occlusion-induced spinal cord injury. Given the close correlation reported in the literature between morphological damage and impaired spinal cord function, INO1001 may improve spinal cord recovery after thoracic aortic cross-clamping.
OBJECTIVE: It is well-established that poly(ADP)ribose-polymerase (PARP) assumes major importance during ischemic brain damage, and the selective PARP-1 inhibitor PJ34 reduced spinal cord damage in murine aortic occlusion-induced ischemia/reperfusion injury. We investigated the effect of the PARP-1 inhibitor INO1001 on aortic-occlusion-related porcine spinal cord injury. DESIGN AND SETTING: Prospective, randomized, controlled experimental study in an animal laboratory. PATIENTS AND PARTICIPANTS: Ten anesthetized, mechanically ventilated, and instrumented pigs. INTERVENTIONS: Animals underwent 45 min of thoracic aortic cross-clamping after receiving vehicle (n=5) or intravenous INO1001 (n=5, total dose 4 mg/kg administered both before clamping and during reperfusion). During reperfusion continuous intravenous norepinephrine was incrementally adjusted to maintain blood pressure at or above 80% of the preclamping level. Plasma INO1001 levels were analyzed by HPLC. After 4[Symbol: see text]h of reperfusion spinal cord biopsy samples were analyzed for neuronal damage (hematoxyline-eosine and Nissl staining), expression of the cyclin-dependent kinase inhibitor genes p21 and p27 (immunohistochemistry), and apoptosis (terminal deoxynucleotidyl transferase mediated nick end labeling assay). MEASUREMENTS AND RESULTS: Plasma INO1001 levels were 0.8-2.3 and 0.30-0.76 mM before and after clamping, respectively. While 3-5% of the spinal cord neurons were irreversibly damaged in the INO1001 animals, the neuronal cell injury was three times higher in the control group. Neither p21 and p27 expression nor apoptosis showed any intergroup difference. CONCLUSIONS: The selective PARP-1 inhibitor INO1001 markedly reduced aortic occlusion-induced spinal cord injury. Given the close correlation reported in the literature between morphological damage and impaired spinal cord function, INO1001 may improve spinal cord recovery after thoracic aortic cross-clamping.
Authors: M E Mackey; Y Wu; R Hu; J A DeMaro; M F Jacquin; G K Kanellopoulos; C Y Hsu; N T Kouchoukos Journal: Stroke Date: 1997-10 Impact factor: 7.914
Authors: H Kato; G K Kanellopoulos; S Matsuo; Y J Wu; M F Jacquin; C Y Hsu; N T Kouchoukos; D W Choi Journal: Exp Neurol Date: 1997-12 Impact factor: 5.330
Authors: Gábor Szabó; Pál Soós; Susanne Mandera; Ulrike Heger; Christa Flechtenmacher; Susanne Bährle; Leila Seres; Attila Cziráki; Andre Gries; Zsuszanna Zsengellér; Christian F Vahl; Siegfried Hagl; Csaba Szabó Journal: Shock Date: 2004-05 Impact factor: 3.454
Authors: Hubert Schelzig; Archil B Chkhotua; Peter Wiegand; Stephan Grosse; Simone Reis; Martina Art; Dietmar Abendroth Journal: Ann Transplant Date: 2003 Impact factor: 1.530
Authors: Tanveer A Khan; Marc Ruel; Cesario Bianchi; Pierre Voisine; Katalin Komjáti; Csaba Szabo; Frank W Sellke Journal: J Am Coll Surg Date: 2003-08 Impact factor: 6.113
Authors: Nathan A Berger; Valerie C Besson; A Hamid Boulares; Alexander Bürkle; Alberto Chiarugi; Robert S Clark; Nicola J Curtin; Salvatore Cuzzocrea; Ted M Dawson; Valina L Dawson; György Haskó; Lucas Liaudet; Flavio Moroni; Pál Pacher; Peter Radermacher; Andrew L Salzman; Solomon H Snyder; Francisco Garcia Soriano; Robert P Strosznajder; Balázs Sümegi; Raymond A Swanson; Csaba Szabo Journal: Br J Pharmacol Date: 2017-03-26 Impact factor: 8.739
Authors: Florian Simon; Angelika Scheuerle; Michael Gröger; Brigitta Vcelar; Oscar McCook; Peter Möller; Michael Georgieff; Enrico Calzia; Peter Radermacher; Hubert Schelzig Journal: Intensive Care Med Date: 2011-07-16 Impact factor: 17.440
Authors: Massimo Antonelli; Elie Azoulay; Marc Bonten; Jean Chastre; Giuseppe Citerio; Giorgio Conti; Daniel De Backer; François Lemaire; Herwig Gerlach; Johan Groeneveld; Goran Hedenstierna; Duncan Macrae; Jordi Mancebo; Salvatore M Maggiore; Alexandre Mebazaa; Philipp Metnitz; Jerôme Pugin; Jan Wernerman; Haibo Zhang Journal: Intensive Care Med Date: 2008-01-04 Impact factor: 17.440
Authors: Andre Bredthauer; Karla Lehle; Angelika Scheuerle; Hubert Schelzig; Oscar McCook; Peter Radermacher; Csaba Szabo; Martin Wepler; Florian Simon Journal: Intensive Care Med Exp Date: 2018-10-24