Haptoglobin attenuates cerebrospinal fluid hemoglobin-induced neurological deterioration in sheep

Author:

R. Thomson Bart1ORCID,Nina Schwendinger 2,Katrin Beckmann 3ORCID,Thomas Gentinetta 4,Daniel Couto 4,Sandra Wymann 4,Valérie Verdon 4,M. Buzzi Raphael5ORCID,Kevin Akeret 2ORCID,W. Kronen Peter6,Eva Weinberger 2,Ulrike Held 7ORCID,Frauke Seehusen 8ORCID,Henning Richter 9ORCID,J. Schaer Dominik5ORCID,Michael Hugelshofer 10ORCID

Affiliation:

1. Department of Neurosurgery, Clinical Neuroscience Center, Universitätsspital and University of Zurich, Zurich, Switzerland; Division of Internal Medicine, Universitätsspital and University of Zurich, Zurich, Switzerland

2. Department of Neurosurgery, Clinical Neuroscience Center, Universitätsspital and University of Zurich, Zurich, Switzerland

3. Neurology Service, Department of Small Animals, Vetsuisse Faculty, University of Zurich, Zurich, Switzerland

4. CSL, CSL Biologics Research Centre, Bern, Switzerland; Swiss Institute for Translational and Entrepreneurial Medicine, sitem-insel, Bern, Switzerland

5. Division of Internal Medicine, Universitätsspital and University of Zurich, Zurich, Switzerland

6. Veterinary Anaesthesia Services – International, Winterthur

7. Department of Biostatistics and Epidemiology, Biostatistics and Prevention Institute, University of Zurich

8. Laboratory of Animal Model Pathology, Institute of Veterinary Pathology, Vetsuisse Faculty, University of Zurich, Zurich, Switzerland

9. Diagnostic Imaging Research Unit (DIRU), Clinic for Diagnostic Imaging, Vetsuisse Faculty, University of Zurich, Zurich, Switzerland

10. Department of Neurosurgery, Clinical Neuroscience Center, Universitätsspital und University of Zurich; Zurich, Switzerland

Abstract

Abstract Background Secondary brain injury (SBI) occurs with a lag of several days post-bleeding in patients with aneurysmal subarachnoid hemorrhage (aSAH) and is a strong contributor to mortality and long-term morbidity. aSAH-SBI coincides with cell-free hemoglobin (Hb) release into the cerebrospinal fluid. This temporal association and convincing pathophysiological concepts suggest that CSF-Hb could be a targetable trigger of SBI. However, sparse experimental evidence for Hb’s neurotoxicity in vivo defines a significant research gap for clinical translation. Methods We modeled the CSF-Hb exposure observed in aSAH patients in conscious sheep, which allowed us to assess neurological functions. Twelve animals were randomly assigned for three-day bi-daily intracerebroventricular (ICV) injections of either Hb or Hb combined with the high-affinity Hb scavenger protein haptoglobin (Hb-Hp, CSL888). Results Repeated CSF sampling confirmed clinically relevant CSF-Hb concentrations. This prolonged CSF-Hb exposure over three days resulted in disturbed movement activity, reduced food intake, and impaired observational neuroscores. The Hb-induced neurotoxic effects were significantly attenuated when Hb was administered with equimolar haptoglobin. Preterminal magnetic resonance imaging (MRI) showed no CSF-Hb-specific structural brain alterations. In both groups, histology demonstrated an inflammatory response and revealed enhanced perivascular histiocytic infiltrates in the Hb-Hp group, indicative of adaptive mechanisms. Heme exposure in CSF and iron deposition in the brain were comparable, suggesting comparable clearance efficiency of Hb and Hb-haptoglobin complexes from the intracranial compartment. Conclusion We identified a neurological phenotype of CSF-Hb toxicity in conscious sheep, which is rather due to neurovascular dysfunction than structural brain injury. Haptoglobin was effective at attenuating CSF-Hb-induced neurological deterioration, supporting its therapeutic potential.

Funder

Innosuisse - Schweizerische Agentur für Innovationsförderung

Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung

Uniscientia Foundation

Publisher

Research Square Platform LLC

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