Animal Models of Global Ischemia

While global ischemia in humans typically results from cardiac arrest, investigators infrequently use cardiac arrest to produce brain ischemia in animal models. Instead, investigators commonly induce transient forebrain ischemia by interrupting the blood flow to the brain through the carotid and vertebral arteries. For instance, in rats this is achieved by either 2 or 4 vessel occlusion (2-VO, 4-VO) methods. In the 4-VO model, the two vertebral arteries are cauterized and this is followed a day later by brief bilateral common carotid artery occlusion (Pulsinelli and Brierley 1979). The 2-VO model similarly produces severe ischemia by combining systemic hypotension with common carotid artery occlusion (Smith et al. 1984). In contrast, gerbils usually experience severe forebrain ischemia with common carotid artery occlusion alone (Kirino 1982; Laidley et al. 2005). Global ischemia models exist in other higher species as well (e.g., cats, dogs, primates).

Rodent studies, using the aforementioned models, indicate that the CA1 zone is exquisitely sensitive to brief ischemia, with cell death typically occurring from 2 to 4 days post-ischemia (Kirino 1982; Pulsinelli et al. 1982). Other brain regions are additionally affected after more prolonged ischemia, including other cells within the hippocampal formation (e.g., the dentate hilus or CA4, CA2, CA3), striatum, cortex, and thalamus (Hossmann et al. 2001; Petito and Pulsinelli 1984b). Cell death in these areas occurs more rapidly than in CA1. Despite the importance of extra-hip-pocampal cell death to the clinical prognosis of cardiac arrest, most animal studies, whether mechanistic or neuroprotective, continue to focus on CA1 zone injury.

The duration of ischemia needed to produce consistent brain injury in any given structure, such as the CA1 zone, varies considerably among studies (range: 3-30 min) in part due to species differences, but also due to differences in intra-ischemic residual blood flow as well as post-ischemic hemodynamic differences (e.g., arterial occlusion models vs. cardiac arrest). Further complicating comparisons among studies are differences in the control of physiological variables (e.g., temperature, blood oxygenation, and glucose), animal age, etc. There is a trend for recent studies to use briefer insults than those used in the early studies. While this has probably resulted in part from improved technique (e.g., better temperature control) giving more consistent results, it may be that investigators are also now deliberately studying milder insults in an effort to maximize the likelihood of finding neuroprotective effects on a particular mode of cell death. The problem with this approach is that findings may be less likely to translate to cardiac arrest-induced injury in humans where injury is often considerably greater than that produced in the mild ischemia models in animals.

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