Histopathology Of Global Ischemia

The spectrum of brain pathology observed following global ischemic insults has been extensively studied in a range of clinical and experimental conditions (1). Neuron populations throughout the brain represent the major cell type at risk, illustrated in Figure 1 by the distribution of stress response gene induction in a rat model of cardiac arrest (2). A comparatively small subset of these neurons exhibits histopathologic evidence of vulnerability under the experimental conditions of commonly used experimental models.

Loss of hippocampal CA1 neurons is evident in patients who are resuscitated following cardiac arrest (3), and this has long been the most common endpoint examined in rodent studies of transient global ischemia (4-8). The experimental methods have largely evolved to meet the requirements for reproducible study of injury to this cell population. The well-defined and densely packed cell layers in the hippocampus permit straightforward anatomic identification, and the short temporal threshold for CA1 neuronal injury (typically 5-10 min) permits the use of brief experimental insults with low mortality. The most notable feature of this loss is its substantial delay, with the lesion evolving over an interval of several days (5,6). CA1 neuron vulnerability is largely restricted to the dorsal hippocampus, with greater sensitivity of medial CA1/subiculum and decreasing vulnerability more lateral to these structures. (7,9,10). However, the small CA2 region at the CA1/CA3 transition appears to be anatomically contiguous with subiculum (11) and can exhibit comparable vulnerability (9,11,12). A subset of neurons in the dentate hilus is recognized to be impacted earlier (8,13) and at a still lower threshold (7,14,15 ), sometimes showing loss after even the short 2- to 3-min ischemic insults used to induce CA1 neuronal protection in studies of ischemic preconditioning (14,16). Septal neurons with anatomic connections to CA1 are also vulnerable (8,17), whereas dentate granule (DG) cells and CA3 neurons typically become involved only under severe insult conditions (7 ).

The thalamic reticular nucleus is another region of recognized pathology in human brain following brief intervals of cardiac arrest (18 ), with parallels in many animal models (7,17,19-21). Lesions can occur after brief insults and progress surprisingly quickly, showing evidence of irreversible damage within minutes of recirculation (20,22). However, factors that determine the marked variability of reticular nucleus involvement in either clinical or experimental ischemia remain undefined ( 18 ).

Cortical neurons become progressively involved with increasing insult duration in animal models (5,7) , although the observed injury threshold can vary markedly with experimental conditions (8,23). Injury occurs with a laminar distribution in layers 3, 5, and 6 of the somatosensory

Figure 1 Potential neuron vulnerability identified by a persistent stress response after transient global ischemia. Induction of mRNA encoding the stress protein, hsp72, was detected by in situ hybridization in rat brain following 10-min cardiac arrest and 6-hr survival. Sustained expression of hsp72 mRNA is evident in hippocampal CA1 neurons that will undergo subsequent degeneration, as well as in more resistant CA3 neurons (middle panel). The mRNA was only transiently expressed in still less vulnerable dentate granule cells, which no longer display robust expression at this time point. Strong expression remains evident in outer layers of the cortical mantle, in which scattered neuronal loss is expected, particularly evident in frontal sections (upper pane). Signal is particularly evident in the densely packed cells of prepiriform cortex (PCx) and induseum griseum (ig), the frontal extension of CA3. Insults of this duration remain below the threshold for injury to striatum (St), which shows only weak expression. The Purkinje cell layer (P) exhibits foci of intense signal, consistent with the recognized vulnerability of this neuron population (lowerpane) (Th, thalamus). Source: Adapted from Ref. 2.

cortex (5,8), suggested to be in anatomic relationship with vulnerable regions of striatum (8). Injury to striatum typically occurs after still longer insults (7) but progresses rapidly with a time course of only a few hours (5,8). The vulnerable cells in the striatum include the "medium spiny" projection neurons that comprise as much as 90% of the population in this region (24,25). This component of global ischemic injury is particularly relevant to studies of experimental stroke, as focal ischemia produced by intraluminal filaments often involves comparatively short occlusion times to reduce mortality. Resulting striatal lesions in such cases can reflect the selective loss of these abundant neurons rather than tissue infarction (26,27) and clearly arise via distinct pathophysiologic mechanisms. Delayed damage in the substantia nigra can occur in the weeks following striatal injury (28).

Although not widely evaluated experimentally, postischemic injury to cerebellar Purkinje cells is recognized clinically (1) and was identified in early experimental studies (29). A hindbrain ischemia model specifically targeting cerebellum and brainstem structures identified acute vulnerability of additional cerebellar nuclei prior to any identifiable impact on Purkinje cells (30,31).

Apart from reactive glial responses in regions of neuronal injury, involvement of non-neuron cell types is rarely considered after global ischemia. However, oligodendrocyte injury has been quite extensively studied in developing brain (32,33). Evidence now suggests that oligodendrocytes may constitute the majority of cells that undergo histologically identifiable apoptosis after moderate durations of global ischemia in the adult rat (34,35), accounting for a wave of apoptotic cell death that peaks at 18 to 24 hr that was originally interpreted as neuronal in origin (36). This pathology should receive increasing attention in future studies.

Regions of infarction sometimes appeared in early experimental studies after long durations of global ischemia (7), particularly under conditions of elevated blood glucose (37). Partial ischemia has the potential to produce more severe pathology than a similar duration of complete ischemia, generally considered to reflect the consequences of sustained anaerobic metabolism supported by continued glucose delivery, ultimately resulting in higher lactate production and lower tissue pH (38). Watershed areas can become involved under conditions of globally impaired perfusion during recovery from cardiac arrest (1). Prolonged ischemia was also found in some early studies to result in a "no reflow" phenomenon (39,40), typically associated with more complete stasis during occlusion (41) or reduced blood pressure during early reperfusion (42,43). Even microinfarcts should not be detected after the short insults encountered in current models and, if they do appear, could be considered indicative of poor reperfusion.

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