Article
Parenchymal damage and neurological outcome after intracerebral haemorrhage depends on the activation of the local cerebral thrombin system
Die Aktivierung des zerebralen Thrombinsystems durch intrazerebrale Blutungen beeinflusst die Entstehung des Sekundärschadens und neurologischer Defizit
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Authors
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Harald Krenzlin
- Universitätsmedizin Mainz, Neurochirurgische Klinik und Poliklinik, Mainz, Deutschland; Universitätsmedizin Mainz, Institut für Neurochirurgische Pathophysiologie, Mainz, Deutschland
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Beat Alessandri
- Institut für Neurochirurgische Pathophysiologie, Universitätsmedizin Mainz, Mainz, Deutschland
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Eva Gresser
- Institut für Neurochirurgische Pathophysiologie, Universitätsmedizin Mainz, Mainz, Deutschland
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Florian Ringel
- Neurochirurgische Klinik und Poliklinik, Universitätsmedizin Mainz, Mainz, Deutschland
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Oliver Kempski
- Neurochirurgische Klinik und Poliklinik, Universitätsmedizin Mainz, Mainz, Deutschland
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Naureen Keric
- Neurochirurgische Klinik und Poliklinik, Universitätsmedizin Mainz, Mainz, Deutschland
| Published: | May 8, 2019 |
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Outline
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Objective: Spontaneous intracerebral hemorrhage (ICH) is a devastating disease and a substantial burden for our public health system. Despite raising numbers of ICH admissions, effective treatment methods are missing due to a still poorly understood patho-mechanism. Increasing evidence of a cerebral thrombin system constitutes a potential new target for pharmacotherapy. The aim of this study is to elucidate the activation of the cerebral thrombin system and to analyze the influence of thrombin on the pathogenesis of ICH.
Methods: We established a novel ICH model in mice were silicon oil is injected into the right basal ganglia to distinctively study ICH lesions in the absence of whole blood constituents. Intra-operative monitoring comprised intracranial pressure (ICP), cerebral blood flow (CBF) and blood pressure (BP). Neuroscore and Rotarod testing was used to objectify neurological outcome. The mice were euthanized 24 hours after ICH. Frozen sections were stained with hematoxylin and eosin to evaluate clot size and cellular damage. Immunohistochemistry was used to detect thrombin and its precursor prothrombin. Slices were additionally stained for NeuN, GFAP and IBA-1 to evaluate parenchymal damage and inflammatory reactions.
Results: The course of ICP, CBF and BP are similar after blood- or silicone oil injection (n=5/group). Likewise, lesion size after blood or silicone oil (n=10/group) injection did not differ between both groups. NeuN immunoreactivity is decreased in the perihematomal zone compared to the contralateral side (blood: 53.96+-4.40% (p=<0.05), silicone: 61.82+-7.39 (P=0.02)), while peri-lesional thrombin concentration were increased (blood: 4.24+-0.5 (P=<0.05), silicone: 3.10+-0.54 (P=<0.05)). Thrombin expression co-localized with NeuN reactivity in IF imaging and in vivo tagging analysis (flag-tag). No changes in GFAP or IBA-1 expression were detected after 24h. Animals injected with blood or silicone oil performed significantly worse on the rotarod performance test (blood: 3.25 sec; silicone: 1.75 sec; sham: 71.5 sec; p<0.0001) No statistically significant disparities were detected between blood or silicone oil injected animals.
Conclusion: For the first time, we demonstrate the activation of the cerebral thrombin system after ICH. Neuronal damage and neurological deficit are determined by local thrombin expression, rather than its systemic influx. These findings highlight the importance of thrombin as target of novel treatment strategies.
