Haptoglobin Attenuates Cerebrospinal Fluid Hemoglobin-Induced Neurological Deterioration in Sheep.

Autor: Thomson BR; Department of Neurosurgery, Clinical Neuroscience Center, Universitätsspital and University of Zurich, Zurich, Switzerland.; Division of Internal Medicine, Universitätsspital and University of Zurich, Zurich, Switzerland., Schwendinger N; Department of Neurosurgery, Clinical Neuroscience Center, Universitätsspital and University of Zurich, Zurich, Switzerland., Beckmann K; Neurology Service, Department of Small Animals, Vetsuisse Faculty, University of Zurich, Zurich, Switzerland., Gentinetta T; CSL Biologics Research Centre, Swiss Institute for Translational and Entrepreneurial Medicine, CSL, sitem-insel, Bern, Switzerland., Couto D; CSL Biologics Research Centre, Swiss Institute for Translational and Entrepreneurial Medicine, CSL, sitem-insel, Bern, Switzerland., Wymann S; CSL Biologics Research Centre, Swiss Institute for Translational and Entrepreneurial Medicine, CSL, sitem-insel, Bern, Switzerland., Verdon V; CSL Biologics Research Centre, Swiss Institute for Translational and Entrepreneurial Medicine, CSL, sitem-insel, Bern, Switzerland., Buzzi RM; Division of Internal Medicine, Universitätsspital and University of Zurich, Zurich, Switzerland., Akeret K; Department of Neurosurgery, Clinical Neuroscience Center, Universitätsspital and University of Zurich, Zurich, Switzerland., Kronen PW; Veterinary Anaesthesia Services - International, Winterthur, Switzerland.; Center for Applied Biotechnology and Molecular Medicine (CABMM), University of Zurich, Zurich, Switzerland., Weinberger EM; Department of Neurosurgery, Clinical Neuroscience Center, Universitätsspital and University of Zurich, Zurich, Switzerland., Held U; Department of Biostatistics and Epidemiology, Biostatistics and Prevention Institute, University of Zurich, Zurich, Switzerland., Seehusen F; Laboratory of Animal Model Pathology, Institute of Veterinary Pathology, Vetsuisse Faculty, University of Zurich, Zurich, Switzerland., Richter H; Center for Applied Biotechnology and Molecular Medicine (CABMM), University of Zurich, Zurich, Switzerland.; Diagnostic Imaging Research Unit (DIRU), Clinic for Diagnostic Imaging, Vetsuisse Faculty, University of Zurich, Zurich, Switzerland., Schaer DJ; Division of Internal Medicine, Universitätsspital and University of Zurich, Zurich, Switzerland., Hugelshofer M; Department of Neurosurgery, Clinical Neuroscience Center, Universitätsspital and University of Zurich, Zurich, Switzerland. Michael.Hugelshofer@usz.ch.; Center for Applied Biotechnology and Molecular Medicine (CABMM), University of Zurich, Zurich, Switzerland. Michael.Hugelshofer@usz.ch.
Jazyk: angličtina
Zdroj: Translational stroke research [Transl Stroke Res] 2024 Apr 23. Date of Electronic Publication: 2024 Apr 23.
DOI: 10.1007/s12975-024-01254-9
Abstrakt: 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. We modeled the CSF-Hb exposure observed in aSAH patients in conscious sheep, which allowed us to assess neurological functions in a gyrencephalic species. Twelve animals were randomly assigned for 3-day bi-daily intracerebroventricular (ICV) injections of either Hb or Hb combined with the high-affinity Hb scavenger protein haptoglobin (Hb-Hp, CSL888). Repeated CSF sampling confirmed clinically relevant CSF-Hb concentrations. This prolonged CSF-Hb exposure over 3 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. 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.
(© 2024. The Author(s).)
Databáze: MEDLINE
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