Brain Pathologic Response To Ich In Animal Models

Overall, the brain pathologic responses to an intracerebral hematoma in experimental animal models are comparable to those seen in human ICH (20,56,58,78,103-105). The three stages of perihematomal tissue injury defined by Spatz in 1939 (104)—initial deformation, edema and necrosis, and clot absorption and scar or cavity formation—have also been regularly described in animal models, albeit at a faster rate. An excellent description of these changes in rat was provided, in which regions of pallor and spongiform change due to edema formation developed adjacent to clots within 2 hr (105). By 6 to 15 hr, disrupted myelinated nerve fibers and degeneration bulbs were present, along with increasing swelling of the corona radiata as edema fluid continued to accumulate. At 24 hr, white-matter edema was more marked and extensive. By 48 hr, hematomas in rat and dog ICH models were surrounded by edema, vacuolation, and acellular plasma accumulations, with astrocytic swelling present adjacent to, and distant from, the hematoma.

In our porcine ICH model, marked, rapidly developing perihematomal edema with a high water content is already present in white matter by 1 hr after ICH (17). This edema produces perihematomal hyperintensity on T2-weighted MRI (20,38) similar to that in ICH patients (106). We observed increases in edema volumes by 50% over the first 24 hr in the porcine ICH model due to delayed BBB opening (17). In the collagenase ICH model, similar hyperintensi-ties on T2-weighted imaging surround hematomas and extend along posterior white-matter fiber tracts (85). Histologically, by 3 days, we observed decreased Luxol fast blue staining in edematous white matter, suggestive of myelin injury, and markedly increased glial fibrillary acidic protein immunoreactivity, indicative of reactive astrocytosis (20). In our porcine model, neovascularization is present at 7 days. By 2 weeks, continued hematoma resolution and glial scar and cyst formation are similar to both rodent and human ICH pathologies. A similar brain pathologic response occurs in porcine white matter, in which only plasma is infused, thereby demonstrating the significance of the blood's plasma protein component in ICH-induced brain injury (20,107).

The time course of inflammation and cell death following infusion of whole blood into the rat striatum has been carefully examined by several groups (44,108). They have also characterized the cellular perihematomal inflammatory response, including the infiltration of immune cells and activation of microglia. Several others have examined DNA fragmentation using terminal deoxynucleotidyl transferase dUTP nick-end labeling staining (107,109-111). In addition, molecular analyses of the proinflammatory transcription factor, nuclear factor-K B, and cytokine responses to ICH have been conducted (26,64,112-114).

An interesting concept of the mechanism of cell death after ICH has been proposed from studies of ICH in rat, i.e., the "black hole" model of hemorrhagic damage by Felberg and coworkers (115). These investigators showed that histologic damage from ICH is very prominent in the immediate perihematomal region. Except for substantia nigra pars reticulata, they found no evidence of neuronal loss in distal regions. The term "black hole" refers to this continued destruction of neurons, which occurs over at least 3 days, as the neurons come into proximity to the hematoma.

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