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The selective poly(ADP)ribose-polymerase 1 inhibitor INO1001 reduces spinal cord injury during porcine aortic cross-clamping-induced ischemia/reperfusion injury

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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 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.

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Acknowledgements

This study was supported by the Deutsche Forschungsgemeinschaft (DFG Sche 899/2-1). B.H. was the recipient of a Roman Herzog research fellowship of the Alexander von Humboldt Stiftung and the Gemeinnützige Hertie Stiftung. INO1001 was kindly provided by Drs. Garry Southan and Andrew Salzman (Inotek Pharmaceuticals Corp., Beverly, Mass., USA). Special thanks are dedicated to Wolfgang Siegler, Tanja Schulz, and Ingrid Eble for their skillful technical assistance.

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Authors and Affiliations

  1. Sektion Anästhesiologische Pathophysiologie und Verfahrensentwicklung, Universitätsklinikum, 89073, Ulm, Germany

    Christian Maier, Balázs Hauser & Peter Radermacher

  2. Abteilung Thorax- und Gefäßchirurgie, Universitätsklinikum, 89070, Ulm, Germany

    Christian Maier, Hubert Schelzig & Jochen Kick

  3. Sektion Neuropathologie, Universitätsklinikum, 89081, Ulm, Germany

    Angelika Scheuerle

  4. Aneszteziológiai és Intenzív Terápiás Klinika, Semmelweis Egyetem, 1125, Budapest, Hungary

    Balázs Hauser

  5. Department of Surgery, University of Medicine and Dentistry, Newark, N.J., USA

    Csaba Szabó

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  1. Christian Maier
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  2. Angelika Scheuerle
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  3. Balázs Hauser
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  7. Jochen Kick
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Correspondence to Peter Radermacher.

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C. Maier and A. Scheuerle equally contributed to this manuscript.

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Maier, C., Scheuerle, A., Hauser, B. et al. The selective poly(ADP)ribose-polymerase 1 inhibitor INO1001 reduces spinal cord injury during porcine aortic cross-clamping-induced ischemia/reperfusion injury. Intensive Care Med 33, 845–850 (2007). https://doi.org/10.1007/s00134-007-0585-3

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