Failure of isradipine to reduce infarct size in mouse, gerbil, and rat models of cerebral ischemia.

Abstract

The dihydropyridine L-type calcium channel blocker isradipine has been reported to exhibit neuroprotective properties in some, but not all, studies performed in the rat middle cerebral artery occlusion (MCAO) model. In the present study, we examined isradipine in several other models of focal and global ischemia: rat rose bengal, mouse MCAO, and gerbil bilateral carotid artery occlusion (BCAO). For comparison, a novel calcium channel blocker, SB201823A, that we have previously shown to be neuroprotective in rat and gerbil models was also examined in the mouse. In the gerbil BCAO model, isradipine was administered at 2.5 mg/kg i.p. as a single dose 60 minutes after ischemia (n = 10). Corresponding controls received vehicle (n = 10), and sham-operated animals received no treatment (n = 6). Locomotor activity and histological assessments were made at 4 days after ischemia. In the rat photothrombotic occlusion model, isradipine was administered at 2.5 mg/kg i.p. as a single dose 60 minutes after ischemia (n = 10), and corresponding controls (n = 10) received vehicle. Histological assessment was made at 7 days after ischemia. In the mouse MCAO model, isradipine was also administered at 2.5 mg/kg i.p. as a single dose 60 minutes after ischemia. Histological assessments were made at 1 (n = 13), 2 (n = 9), and 4 (n = 9) days after ischemia. Vehicle numbers were n = 10, n = 6, and n = 8, respectively. Isradipine and SB201823A were also examined using a combined preischemia and postischemia regimen. Isradipine was administered at 2.5 mg/kg i.p. before occlusion, 1.25 mg/kg i.p. 1 hour after occlusion, 1.25 mg/kg i.p. 2 hours after occlusion, and 2.5 mg/kg twice a day for 3 days after occlusion (n = 16). Corresponding controls received vehicle at the same time points (n = 14). SB201823A was administered 30 minutes before occlusion, 30 minutes after occlusion, and twice daily for 3 days (n = 12). Corresponding controls received vehicle (n = 9). Histological assessment was performed at 4 days after ischemia. When given after ischemia, isradipine failed to affect lesion volume in both the rat and mouse models. In the gerbil, locomotor hyperactivity and hippocampal cell loss were unaffected. Given before and after ischemia in the mouse, isradipine was also ineffective, whereas SB201823A produced a significant reduction in lesion volume. The L-type calcium channel blocker isradipine was devoid of neuroprotective activity in focal and global models of cerebral ischemia in three species of normotensive animals. These results were compared with data for the novel calcium channel blocker SB201823A, which exhibited a significant effect after pre- and postocclusion administration in the mouse model of permanent focal ischemia.