Animal Selection

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Although higher species, such as cats, rabbits, dogs, pigs, and nonhuman primates, can be used in focal ischemia models, small animals, such as rats, mice, and gerbils, are more commonly used. The rat is the most commonly used animal in stroke studies owing to numerous reasons, including (i ) their resemblance to humans in cerebrovascular anatomy and physiology, (i i) their moderate size, which allows researchers to easily monitor the physiologic parameters and collect the brain specimens, (iii) the low cost of animals, in terms of transportation, storage, and feeding, (iv) the relative homogeneity within strains from inbreeding, (v) their small brain size, which is well suited to fixation procedures and microscopic and macroscopic examination, (vi) the ease of conducting reproducible studies, and (vii) the greater acceptability of their use (compared to subhuman primates and pet animals) from ecologic and ethical perspectives (4-6). Mice have been of increasing interest because of the availability of transgenic technology, which offers new insights into the molecular mechanisms involved in ischemic stroke. The gerbil might not be a good candidate for testing potential neuroprotective agents, as many neuroprotective agents effective in the gerbil failed to protect against ischemic damage in other species (7). Brain infarcts are more uniform in lower animal species, and reproducibility is significantly better when the MCA is occluded proximally, preferably at or near its orifice. Models of MCA occlusion (MCAO) in primates were developed in the 1930s (8). However, because of the relatively higher cost, difficulty in experimental procedures, and ethical concerns, higher species of animals are used more limitedly. Nevertheless, it might be reasonable and necessary to consider testing neuroprotective agents in larger animal stroke models to determine if the compound is broadly effective before beginning clinical trials (7).

The spontaneously hypertensive rat (SHR) and its variant stroke-prone SHR develop larger infarcts with lesser variability following MCAO (9,10). Many SHRs develop large infarcts upon occlusion of the common carotid arteries bilaterally, whereas other rats do not develop macroscopic infarctions (11). The susceptibility of SHRs to developing larger infarcts probably stems from a lack of collateral blood flow. Reduction of infarct volume by experimental agents in SHRs is regarded as a more stringent test than in other rat strains but is more difficult to achieve. Stroke-prone SHRs frequently develop spontaneous infarcts and might be of use in chronic primary prevention studies.

Most researchers use solely male animals for brain ischemia studies, a practice well justified, as this approach avoids experimental variability caused by female hormones. The relationship between biologic sex and ischemic stroke outcome has been greatly explored mainly in rodents. The overwhelming majority of published studies reported that female rodents sustain smaller infarctions than males following focal brain ischemia (12-14), although one study showed no difference between genders (15). The menstrual cycle might be critical, as female rats in proestrus (high endogenous estradiol levels) developed significantly smaller infarcts than those in the metestrus phase (low endogenous estradiol levels), indicating that estrogen itself might have neuroprotec-tive properties (16). Furthermore, gender differences could be abolished following ovariectomy (12) or after menopause (17). Estrogen administration to female, intact male, and castrated male rats reduced infarct sizes in almost all studies (12,14,18). All of this evidence suggests that replicating studies in both sexes might add to our knowledge, but it is not yet known at what stage of the menstrual cycle female animals should undergo ischemia procedures.

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