Abstract

Intracerebral hemorrhage (ICH) is a devastating condition. Existing preclinical ICH models focus largely on striatum but neglect other brain areas such as ventricle, cortex, and hippocampus. Clinically, however, hemorrhagic strokes do occur in these other brain regions. In this study, we established mouse hemorrhagic models that utilize stereotactic injections of autologous whole blood or collagenase to produce ventricular, cortical, and hippocampal injury. We validated and characterized these models by histology, immunohistochemistry, and neurobehavioral tests. In the intraventricular hemorrhage (IVH) model, C57BL/6 mice that received unilateral ventricular injections of whole blood demonstrated bilateral ventricular hematomas, ventricular enlargement, and brain edema in the ipsilateral cortex and basal ganglia at 72 h. Unilateral injections of collagenase (150 U/ml) caused reproducible hematomas and brain edema in the frontal cortex in the cortical ICH (c-ICH) model and in the hippocampus in the hippocampal ICH (h-ICH) model. Immunostaining revealed cellular inflammation and neuronal death in the periventricular regions in the IVH brain and in the perihematomal regions in the c-ICH and h-ICH brains. Locomotor abnormalities measured with a 24-point scoring system were present in all three models, especially on days 1, 3, and 7 post-ICH. Locomotor deficits measured by the wire-hanging test were present in models of IVH and c-ICH, but not h-ICH. Interestingly, mice in the c-ICH model demonstrated emotional abnormality, as measured by the tail suspension test and forced swim test, whereas h-ICH mice exhibited memory abnormality, as measured by the novel object recognition test. All three ICH models generated reproducible brain damage, brain edema, inflammation, and consistent locomotor deficits. Additionally, the c-ICH model produced emotional deficits and the h-ICH model produced cognitive deficits. These three models closely mimic human ICH and should be useful for investigating the pathophysiology of ICH in ventricle, cortex, and hippocampus and for evaluating potential therapeutic strategies.

Highlights

  • Intracerebral hemorrhage (ICH), one of the most damaging types of stroke, is associated with high morbidity and mortality [1,2]

  • At 72 h after collagenase injection, hematoma was present in the cortex in the cortical ICH (c-ICH) group and in the hippocampus in the hICH group (Fig 1C and 1E)

  • A good animal model that can mimic the natural events of human ICH should have high standards, high reproducibility, and high clinical relevance

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Summary

Introduction

Intracerebral hemorrhage (ICH), one of the most damaging types of stroke, is associated with high morbidity and mortality [1,2]. Much progress has been made in our understanding of ICH-induced brain injury. The initial bleed and the physiologic response to hematoma cause the primary brain injury, and inflammation contributes to the progression of secondary brain injury [4,5,6,7]. One characteristic of brain inflammation is microglial activation [8], which occurs much earlier than neutrophil infiltration and acts as a major cellular mediator of secondary brain injury after ICH [4,7,9]. Astrocytes are activated after ICH [4,5]. Despite these recent findings, the exact mechanisms of ICH-induced brain injury are still not fully known

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