Cortical focal stroke model to evaluate neuroprotective action of drugs

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Abstract

The experimental central nervous system (CNS) stroke model of cerebral cortical focal isch‐ emia in the rat is detailed to produce consistent and reproducible ischemic injuries, and is discussed for its adequacy to investigate the molecular mechanisms of ischemic injuries and to evaluate the neuroprotective efficacy of drugs. The model involves the permanent occlusion of ipsilateral (left) common carotid artery (CCAo) and middle cerebral artery (MCAod), and 1 hr occlusion of contralateral (right) CCAo. It is relatively easy to perform, highly reproducible, and does not result in mortality, and therefore is most suitable to delineate the time‐dependent changes in biochemical processes associated with various CNS injuries to anatomically distinct regions of the brain initiated after ischemia. These injuries include primary and peri‐ischemic injuries due to direct interruption of blood supply, and secondary non‐ischemic injuries in brain areas with intact blood circulation. The consistency, reproducibility, and reliability are based on the analyses of several physiological (tissue levels of edema, Na+, K+, and Ca++) and biochemical (membrane levels of fatty acids, [Na+ + K+]‐ATPases, Ca++‐ATPase, and levels of enzymes of oxy‐radical metabolism) indices of plasma membrane dysfunction which paralleled the functional deficits. These characteristics of the model make it possible for us to investigate the temporal relationship of a cascade of these acute physiological and biochemical processes in addition to loss of energy and nutrition, alterations in membrane lipid metabolism, increased lipid peroxidation, and alterations in receptor‐mediated transfer of information. These processes, if not attenuated in time, can lead to cellular death. Since the ischemic injury affects several neurotransmitter systems simultaneously in anatomically distinct areas of the brain, probably through generalized alterations of cellular plasma membrane physicochemical properties, the MCAo model is also well suited to compare efficacy of drugs with a wide range of physiological actions using a large number of the same biochemical and behavioral param‐ eters. In summary, a highly reproducible and consistent MCAo model of ischemia is adequate, if not identical to human ischemic stroke, to study several relevant variables of human stroke which include transient ischemia, reperfusion, different degree of ischemia due to varying lengths of occlusion or site of occlusion, hemorrhage, hypoglycemia, and hypothermia, and to evaluate the efficacy of a drug to stop the most acute injury process(es) before injury reaches the “point of no return.” © 1992 Wiley‐Liss, Inc.

Keywords

  • cortical focal ischemia
  • middle cerebral artery occlusion
  • neuroprotection
  • rat

ASJC Scopus subject areas

  • Drug Discovery

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