ABSTRACT
Permanent or transient focal cerebral ischemia was induced in spontaneously hypertensive rats (SHR) using the intraluminal filament method. Successful occlusion of the middle cerebral artery (MCA) was achieved using 4/O filaments (terminal diameter 0.20-0.25 mm) coated with poly-L-lysine. The L-type calcium channel blocker isradipine (2.5 mg/kg) administered subcutaneously 30 min following permanent MCA occlusion significantly reduced the volume of ischemic brain damage in the cerebral hemisphere (25%; P = 0.0001), cerebral cortex (18%; P = 0.0034), and caudate nucleus (33%; P = 0.0002) when assessed at 24 h post-MCA occlusion. Isradipine did not affect the functional deficit (measured using a subjective neurological scoring system) induced by MCA occlusion. In SHR undergoing transient (2 h) MCA occlusion isradipine administered 30 min post-MCA occlusion produced a significant reduction (47%; P = 0.001) in hemispheric infarct volume, whereas isradipine administered at the onset of reperfusion did not confer any significant neuroprotection. No change in functional deficit was seen with isradipine with either dosing paradigm at 24 h post-MCA occlusion. These results demonstrate that the intraluminal filament method of MCA occlusion can be used in the SHR strain and also substantiates the neuroprotective efficacy of isradipine in SHR models of permanent and transient focal cerebral ischemia.
Subject(s)
Brain Ischemia/drug therapy , Calcium Channel Blockers/therapeutic use , Calcium Channels/drug effects , Ischemic Attack, Transient/drug therapy , Isradipine/therapeutic use , Nerve Tissue Proteins/drug effects , Neuroprotective Agents/therapeutic use , Animals , Behavior, Animal , Brain Damage, Chronic/etiology , Brain Damage, Chronic/prevention & control , Brain Edema/drug therapy , Brain Edema/etiology , Brain Edema/pathology , Brain Ischemia/complications , Brain Ischemia/metabolism , Brain Ischemia/pathology , Calcium Channel Blockers/administration & dosage , Calcium Channel Blockers/pharmacology , Calcium Channels, L-Type , Drug Administration Schedule , Drug Evaluation, Preclinical , Ischemic Attack, Transient/complications , Ischemic Attack, Transient/metabolism , Ischemic Attack, Transient/pathology , Isradipine/administration & dosage , Isradipine/pharmacology , Male , Neuroprotective Agents/administration & dosage , Neuroprotective Agents/pharmacology , Rats , Rats, Inbred SHRABSTRACT
BACKGROUND AND PURPOSE: There have been a number of recent reports describing the relationship between ischemic damage and various behavioral and functional measures, although there have been few studies that have demonstrated a direct correlation between functional impairment and lesion volume. The purpose of the present study was to assess functional outcome by measurement of motor impairment and to determine whether this correlated to a range of infarct volumes induced by varying the duration of focal ischemic insult in the rat. METHODS: Male Sprague Dawley rats were subjected to 0, 30, 60, of 120 minutes or permanent middle cerebral artery (MCA) occlusion by the intraluminal filament technique. Motor impairment was assessed by the accelerating rota-rod and grid-walking tests, and the brains were perfusion-fixed for histological determination of infarct volume and brain swelling 24 hours after MCA occlusion. RESULTS: Marked impairment in performance of both motor tests was recorded in the 60-minute, 120-minute, and the permanent MCA occlusion groups when compared with sham-operated rats. There were significant correlations between regional infarct volume, brain swelling, and all behavioral measurements (all r2 > .5, P < .001). CONCLUSIONS: The rota-rod and grid-walking tests of motor performance provide quantitative, objective, and reproducible measures of functional impairment of rats following an ischemic insult. These impairments correlate directly with infarct volume and provide information integral to future studies evaluating the effects of potential neuroprotective agents.