It has been stated that the focal stroke models are of greater relevance to the human condition of stroke. However, global ischemia is of clear relevance to cardiac arrest and asphyxia in humans. In addition, it should be noted that the physiological, biochemical, and functional measurements made during recovery from a global model of reversible ischemia may be important in identifying the molecular and cellular mechanism and action of potential neuroprotective agents. Global models of cerebral ischemia may thus be as useful as focal models, provided that care is taken in the interpretation of the data. The three most widely used animal models of global ischemia are: (1) four-vessel occlusion (4-VO) and two-vessel occlusion (2-VO) combined with hypotension in the rat, (2) 2-VO occlusion in the gerbil, and (3) 2-VO in the mouse. A 2-VO mouse model was developed recently to study transgenic mice and is now being systematically studied (Kitagawa et al., 1998).
4-VO. This model has several advantages, including ease of preparation, a high incidence of predictable ischemic neuronal damage, a low incidence of seizures, and the absence of anesthesia (i.e., at the time of carotid occlusion). This particular model has been, and still is, widely used to investigate the effectiveness of potential therapeutic agents. The rat 4-VO model involves permanent coagulation of the vertebral arteries, which alone has no deleterious effects, and temporary ligation of the two common carotid arteries. Experimental results show loss of righting reflex within 15 s, and a blood flow decrease to 3% of control values in hippocampus, striatum, and neocortex (McBean and Kelly, 1998).
2-VO. This model is carried out under a general anesthetic and requires the administration of a muscle relaxant. It has been well documented that a bilateral occlusion of the common carotid arteries alone is not sufficient either to bring the cerebral blood flow down below the ischemic threshold or to upset the energy state of the brain tissue to an extent sufficient to produce detectable cell death. To produce a damaging ischemic insult, the brain blood flow has to be reduced at the same time as the carotid arteries are occluded. The hypotension normally is produced in one of three ways: (1) controlled exsanguinations, (2) adjunctive administration of peripheral vasodilators, or (3) a combination of both approaches. The ligation of both common carotid arteries along with a BP reduction to 50 mm Hg causes as much or more damage than 4-VO. Blood flows fall to 3 to 5% in hippocampus, neocortex, and striatum. However, in some cases blood flow is reduced to 15% of control levels (McBean and Kelly, 1998; Swan et al., 1988).
Gerbil model of global stroke This is induced by temporarily ligating the carotid arteries, with no reduction in BP. Because there are no posterior communicating arteries in gerbils, this produces profound forebrain ischemia. Changes are similar to those in the rat models: blood flow in cortex is 1% and in hippocampus is 4% of control values (Herrmann et al., 2004).
Mouse model of global stroke Mouse models of global stroke are similar to rat 2-VO models using bilateral occlusion of the common carotid arteries. Several studies showed mouse global ischemia models with quantitatively uniform injury to CA1 neurons, using techniques including two-vessel occlusion and two-vessel occlusion with hypotension (Yonekura et al., 2004). However, because of the variability of collateral flow via the posterior communicating artery, it has been difficult to obtain uniform injury in CA1 while retaining high survival and success rates. One model combines basilar artery occlusion with bilateral common carotid artery occlusion (three-vessel occlusion; Panahian et al., 1996). However, in this model the animal survival rate was low and CA1 neuronal injury was inconsistent. Because the basilar artery of mice runs through a narrow groove in the brain stem and is attached to the pia mater and arachnoid membrane with arachnoid trabeculae, it is difficult to isolate and occlude.
Complete global ischemia Finally, there is complete global ischemia, generally achieved by neck-cuff, cardiac arrest, or by ligating or compressing all arteries from the heart (Bottiger et al., 1999). Blood flow to the whole brain is zero or <1% in these models. Due to high mortality associated with this model, it is not widely used.
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