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The Journal of Neuroscience, November 26, 2003, 23(34):10913-10922

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Behavioral/Systems/Cognitive
Long-Lasting Functional Disabilities in Middle-Aged Rats with Small Cerebral Infarcts

Mark D. Lindner,¹ Valentin K. Gribkoff,¹ Nicole A. Donlan,² and Theresa A. Jones²

¹Neuroscience Drug Discovery, Bristol-Myers Squibb Pharmaceutical Research Institute, Wallingford, Connecticut 06492, and ²Department of Psychology and Neuroscience Institute, University of Texas at Austin, Austin, Texas 78712

Recommendations from experts and recently established guidelines on how to improve the face and predictive validity of animal models of stroke have stressed the importance of using older animals and long-term behavioral-functional endpoints rather than relying almost exclusively on acute measures of infarct volume in young animals. The objective of the present study was to determine whether we could produce occlusions in older rats with an acceptable mortality rate and then detect reliable, long-lasting functional deficits. A reversible intraluminar suture middle cerebral artery occlusion (MCAO) procedure was used to produce small infarcts in middle-aged rats. This resulted in an acceptable mortality rate, and robust disabilities were detected in functional assays, although the degree of total tissue loss measured 90 d after MCAO was quite modest. Infarcted animals were functionally impaired relative to sham control animals even 90 d after the occlusions, and when animals were subgrouped based on amount of tissue loss, MCAO animals with only 4% tissue loss exhibited enduring neurological-behavioral impairments relative to sham-operated controls, and the functional impairments in the group with the largest infarcts (20% tissue loss) were more severe than the functional impairments in the rats with 4% tissue loss. These results suggest that this model, using reversible MCAO to produce small infarcts and long-lasting functional-behavioral deficits in older rats, may represent an advance in the relatively higher-throughput modeling of stroke and its recovery in rodents and may be useful in the development and characterization of future stroke therapies.

Key words: MCAO; stroke; functional disabilities; behavioral deficits; age; preclinical models

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Received Aug 6, 2003; revised September 25, 2003; accepted September 29, 2003.

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