Checkpoints and pitfalls in the experimental neuropathology of circulatory disturbance

In neural tissue injury many pathological processes are common to different neurological disorders, including cerebral ischemia. Because ischemia has a fundamentally simple impact on neural tissue, good laboratory modeling can help improve the general understanding of the neuropathological processes involved. Summarized here are some basic principles that should be followed to ensure that cerebral ischemia studies are reproducible and informative: (i) selection of an appropriate model of cerebral ischemia in an appropriate species (although rodents are widely used for genomic studies, the use of larger animals, with brain structures macroscopically similar to those of humans, is appropriate for many studies, e.g. of white matter lesions or the pathophysiology of cerebral edema); (ii) correct maintenance of physiological parameters, including body temperature, systemic blood pressure, and blood gas tensions, under appropriate general anesthesia; (iii) selection of an appropriate method of cerebral blood flow (CBF) monitoring (decisions include whether or not the experiment requires real-time monitoring, in vivo measurement, and CBF mapping); (iv) appropriate timing of drug application in therapeutic studies (many drugs that are effective when given immediately after a short period of ischemia are ineffective in clinical trials, probably because of longer periods of ischemia and delayed drug delivery in clinical settings); and (v) multiparametric evaluation of therapeutic effect (with the recent increase in diagnosis of cases of mild stroke, measurement of mortality and infarct size have proven to be insufficient for the evaluation of therapeutic effect). Use of mild ischemia models and batteries of neurological tests for individual neurological functions, such as motor, somatosensory, and visual function, are becoming important in experimental ischemia research. In histological evaluation, assessment of the extent of both selective neuronal loss and the infarct will become mandatory. Regional analysis of each brain structure and coordination of the results with the apparent neurological dysfunction is a promising approach.