Cell death in experimental intracerebral hemorrhage: The “black hole” model of hemorrhagic damage

Abstract

Intracerebral hemorrhage (ICH) has a poor prognosis that may be the consequence of the hematoma's effect on adjacent and remote brain regions. Little is known about the mechanism, location, and severity of such effects. In this study, rats subjected to intracerebral blood injection were examined at 100 days. Stereology (neuronal count and density) and volume measures in the perihematoma rim, the adjacent and overlying brain, and the substantia nigra pars reticulata (SNr) were compared with contralateral brain regions at 100 days and the perihemorrhage region at 24 hours and 7 days. In addition, cytochrome c release was investigated at 24 hours, 3 days, and 7 days. At 100 days, post-ICH rats showed no difference in neuronal density in the perihemorrhagic scar region or regions of the striatum immediately surrounding and distal to the perihemorrhage scar. The cell density index in the ipsilateral field was 16.2 +/- 3.8 versus the contralateral control field of 15.6 +/- 3.2 (not significant). Volume measurements of the ipsilateral striatum revealed a 20% decrease that was compensated by an increase in ipsilateral ventricular size. The area of the initial ICH as measured by magnetic resonance imaging correlated with the degree of atrophy. In the region immediately surrounding the hematoma, cytochrome c immunoreactivity increased at 24 hours and 3 days, and returned toward baseline by day 7. At 24 hours, stereology in the peri-ICH region showed decreased density in the region where cytochrome c immunoreactivity was the highest. Neuronal density of the ipsilateral SNr was significantly less than the contralateral side (9.6 +/- 1.9 vs 11.6 +/- 2.3). Histologic damage from ICH occurred mainly in the immediate perihemorrhage region. Except for SNr, we found no evidence of neuronal loss in distal regions. We have termed this continued destruction of neurons, which occurs over at least 3 days as the neurons come into proximity to the hematoma, the "black hole" model of hemorrhagic damage.

Progressive Brain Damage and Alterations in Dendritic Arborization after Collagenase-Induced Intracerebral Hemorrhage in Rats

“…Thus, while it is possible that atrophied neurons did recover, they may also have died off thereby giving the impression of recovery. Arguing against this are collagenase studies that show only a few neurons dying beyond 7 days post-ICH (Felberg et al, 2002;Xue and Del Bigio, 2003). This finding, however, may depend upon initial insult severity, which appears in those studies to be less than that presently used.…”

Mouse Intracerebral Hemorrhage Models Produce Different Degrees of Initial and Delayed Damage, Axonal Sprouting, and Recovery

“…Collagenase intracerebral hemorrhage causes significantly greater loss of cortical projections, particularly in the projections from the somatosensory and motor cortical areas contralateral to the striatum, which are nearly completely lost after cICH. In rat cICH, there is loss of connections to the striatum with a modest reduction in neurons that project from the substantia nigra to the striatum, 31 a decrease in cortical projections from the ipsilateral motor cortex 32 and thinning of ipsilateral cortex. 26 There are no reports of axonal loss in the rat in bICH.…”

A Critical Appraisal of Experimental Intracerebral Hemorrhage Research

“…This is followed by delayed neuronal injury in the peri-hematoma region (Del Bigio et al, 1996;Felberg et al, 2002), which is sometimes quite limited. Several studies have shown cell loss in distal, interconnected regions such as the substantia nigra (Felberg et al, 2002;MacLellan et al, 2008). It is clear that progressive atrophy occurs after ICH (Nguyen et al, 2008b).…”