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Inadequate preclinical testing (e.g., rodent studies) has been partly blamed for the failure of many cytoprotectants to effectively treat stroke in humans. For example, some drugs went to clinical trial without rigorous functional and histological assessment over long survival times. In this study, we characterized recent experimental practices in rodent cytoprotection experiments to determine whether the limitations of early studies have been rectified.
We identified 138 rodent cytoprotection studies published in several leading journals (Journal of Neuroscience, Stroke, Journal of Cerebral Blood Flow and Metabolism and Experimental Neurology) for 2000 - 2002 and compared these to those published in 1990. From each study we determined the ischemia model, age and sex of the animal, the histological and functional endpoints used, and the methodology used to assess intra- and postischemic temperature.
Ninety-eight percent of recent studies used young adult rodents and most used males. Most studies (60%) did not assess functional outcome and survival times were often ≤ 48 hr (66%) for focal ischemia and ≤ 7 days (80%) for global ischemia. Over 60% of the experiments relied solely upon rectal temperature during ischemia and only 32.6% of ischemia studies measured temperature after surgery. The 1990 data were similar.
Many investigators ignore the need to assess long-term functional and histological outcome and do not accurately represent clinical conditions of ischemia (e.g., use of aged animals). In addition, intra- and postischemic temperature measurement and control is frequently neglected or inadequately performed. Further clinical failures are likely.
Background: Brain injury after intracerebral hemorrhage (ICH) arises from numerous contributors, of which some also play essential roles. Notably, thrombin production, needed to stop bleeding, also causes acute cell death and edema. In some rodent models of ICH, peri-hematoma neurons die over weeks. Hence we evaluated whether thrombin is responsible for this chronic degeneration. Functional impairments after ICH also result from sub-lethal damage to neurons, especially the loss of dendrites. Thus, we evaluated whether thrombin infusion alone, a reductionist model of ICH, causes similar injury. Methods: Adult rats had a modest intra-striatal infusion of thrombin (1 U) or saline followed by a behavioral test, to verify impairment, 7 days later. After this they were euthanized and tissue stained with Golgi-Cox solution to allow the assessment of dendritic morphology in striatal neurons. In a second experiment, rats survived 7 or 60 days after thrombin infusion in order to histologically determine lesion volume. Results: Thrombin caused early cell death and considerable atrophy in surviving peri-lesion neurons, which had less than half of their usual numbers of branches. However, total tissue loss was comparable at 7 (24.1 mm3) and 60 days (25.6 mm3). Conclusion: Thrombin infusion causes early cell death and neuronal atrophy in nearby surviving striatal neurons but thrombin does not cause chronic tissue loss. Thus, the chronic degeneration found after ICH in rats is not simply and solely due to acute thrombin production. Nonetheless, thrombin is an important contributor to behavioral dysfunction because it causes cell death and substantial dendritic injury.
Computerized tomography scans are rapid, readily available, and relatively inexpensive. Volume of hemorrhage on computerized tomography (CT) is an important predictor of mortality and functional ability after intracerebral hemorrhage (ICH). Computerized tomography angiography (CTA) offers many clinical advantages over cerebral digital subtraction angiography (DSA) for the evaluation of intracranial vascular abnormalities in cases of ICH. CTA must be shown to have similar sensitivity and specificity as DSA in the detection of secondary causes of ICH. The use of non-contrast CT in the initial evaluation of patients presenting with suspected ICH is well established and universally accepted. Recently, advances in CTA have enabled this modality to gain wide acceptance in evaluating possible secondary causes of ICH, such as aneurysm or vascular malformation. As scanner technology and software rendering capabilities continue to improve, CTA appears poised to replace DSA and become the new gold standard for such evaluations.