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|Title:||THE RELATIONSHIP BETWEEN INFLAMMATION AND SECONDARY INJURY AFTER INTRACEREBRAL HEMORRHAGE|
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|Authors/Affiliations:||1 Jason Wasserman*; 1 Lyanne Schlichter; |
1 Toronto Western Hospital, ON, Canada
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|Content:||Intracerebral hemorrhage (ICH) is a catastrophic form of stroke caused by rupture of a blood vessel and subsequent accumulation of blood in the brain. ICH accounts for 10–30% of hospital admissions for stroke; there is ~50% mortality by 6 months, and only ~20% of survivors regain functional independence. No drugs exist to reduce ICH damage but there is evidence that an important target is the secondary injury in the parenchyma surrounding the hematoma. |
Objective: To study the spatial and temporal relationship between inflammation and secondary injury after ICH.
Materials and Methods: Collagenase was injected into the striatum of young (~3 months) or aged (~22 months) rats to induce an ICH. Animals were sacrificed at 6 hours or 1, 3, 7 or 28 days after ICH onset. Immunohistochemistry and real-time RT-PCR were performed to identify inflammatory cells and proteins and to assess changes in inflammatory gene expression. Staining for collagen type IV and IgG were used to identify areas of blood-brain barrier (BBB) disruption. Staining for amyloid precursor protein (APP) and damaged myelin identified injured and demyelinated axons. Dead or dying neurons were identified with Fluorojade-B or TUNEL. Edema was assessed by measuring brain water content 3 days after ICH onset.
Results: (i) In both young and aged animals, neuron death occurred from 6 hours to 3 days after ICH onset, but was limited to the core and a very thin band of tissue at the edge of the hematoma. (ii) Activated microglia (but not neutrophils) were associated with neuron death at the edge of the hematoma. There was less neuron death in aged animals at early time points, and this was associated with reduced numbers of activated microglia migrating to the lesion. (iii) In the surrounding parenchyma, no neuron death occurred, despite the presence of many activated microglia for at least 7 days after ICH onset. (iv) Axons that had accumulated amyloid precursor protein (APP) were present at the edge of the hematoma by 6 hours and in the surrounding parenchyma by 1 and 3 days. At 3 days, more were present in the aged animals. Interestingly, this APP accumulation was not associated with damaged myelin in the surrounding parenchyma, and activated microglia/macrophages infiltrated the white matter bundles only after the damage had occurred. (v) In young animals, edema was associated with damaged microvessels and a loss of collagen type IV at the edge of the hematoma and in the adjacent parenchyma. In these areas, damaged vessels were associated with neutrophils and matrix metalloprotease-12.
Conclusions: These results show that, in this model of ICH, there is a prominent and prolonged inflammatory response, which probably does not cause secondary neuron death and white matter injury. Instead, inflammation apparently contributes to BBB damage and edema, which may be amenable to treatment. Importantly, increased white matter injury in aged animals might contribute to the worse outcome observed after ICH, and thus, future studies should focus on identifying the causes of delayed white matter injury.
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