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Brain MRI and Neurological Deficit Measurements in Focal Stroke: Rapid Throughput Validated with Isradipine

Lenhard S.C.a · Strittmatter R.a · Price W.J.a · Chandra S.c · White R.F.b · Barone F.C.b
aCardiovascular and Urogenital Center of Excellence for Drug Discovery and bHigh Throughput, Discovery Research, GlaxoSmithKline, King of Prussia, Pa., and cPhilips Medical, Molecular Imaging, Corporate Technologies, Andover, Mass., USA Pharmacology 2008;81:1–10 (DOI:10.1159/000107661)

Abstract

Background/Aims: Isradipine, a calcium channel blocker, provides consistent protection of the brain from injury and reduces neurological deficits produced by ischemic stroke in hypertensive rats. In these experiments, isradipine was utilized to cross-validate both the serial MRI measurement of brain infarctions with histology measurements and to validate a series of simple neurological deficit tests in order to establish a more rapid, higher throughput approach to screening compounds for utility in stroke. Methods: Spontaneously hypertensive rats were treated with vehicle, or 2.5 or 5.0 mg/kg isradipine and middle cerebral artery occlusion. T2-weighted MRI image analysis was compared to standard triphenyltetrazolium chloride-stained histological image analysis of brain sections to quantify isradipine neuroprotection 1, 3, and 30 days after middle cerebral artery occlusion (MCAO; stroke). In addition, serial evaluation (i.e. 1, 2, 5, 12, 20 and 30 days after MCAO) of four simple neurobehavioral tests were completed for each animal. Tests included assessment of hindlimb and forelimb function, and balance beam and proprioception performance. Results: At 1, 3 and 30 days there was a significant positive correlation of the percent hemispheric infarct for T2-weighted MRI and histology (p < 0.05). Practically identical isradipine dose-response neuroprotection curves were observed for both measurement procedures. Isradipine produced a dose-related reduction in all neurological deficits scored by the four neurological deficit tests (p < 0.05). In addition, a significant time-related recovery from neurological deficits in vehicle-treated rats was observed (p < 0.05). The four different neurological deficit tests did provide unique time-related profiles of neurological recovery. Conclusions: The present study validates the use of serial MRI in experimental stroke and establishes several simple neurological tests that can be used to measure neurological/behavioral deficits associated with brain injury and brain recovery of function over time. Under these conditions, T2-weighted MRI and neurological testing required only about 10 min each per animal, thus providing rapid data collection and analysis and requiring reduced scientific personnel.

 

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