FAILURE OF ISRADIPINE TO REDUCE INFARCT SIZE IN MOUSE, GERBIL, AND RAT MODELS OF CEREBRAL-ISCHEMIA

Background and Purpose The dihydropyridine L-type calcium channel bloc ker isradipine has been reported to exhibit neuroprotective properties in some, but not all, studies performed in the rat middle cerebral ar tery occlusion (MCAO) model. In the present study, we examined isradip ine in several other models of focal and global ischemia: rat rose ben gal, mouse MCAO, and gerbil bilateral carotid artery occlusion (BCAO). For comparison, a novel calcium channel blocker, SB201823A, that we h ave previously shown to be neuroprotective in rat and gerbil models wa s also examined in the mouse. Methods In the gerbil BCAO model, isradi pine was administered at 2.5 mg/kg IP as a single dose 60 minutes afte r ischemia (n = 10). Corresponding controls received vehicle (n = 10), and sham-operated animals received no treatment (n = 6). Locomotor ac tivity and histological assessments were made at 4 days after ischemia . In the rat photothrombotic occlusion model, isradipine was administe red at 2.5 mg/kg IP 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 IP as a single dose 60 minutes after ischemia. Histological assessments were made at 1 (n = 1 3), 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 IP before occlusion, 1.25 mg/ kg IP 1 hour after occlusion, 1.25 mg/kg IP 2 hours after occlusion, a nd 2.5 mg/kg twice a day for 3 days after occlusion (n = 16). Correspo nding controls received vehicle at the same time points (n = 14). SB20 1823A was administered 30 minutes before occlusion, 30 minutes after o cclusion, and twice daily for 3 days (n = 12). Corresponding controls received vehicle (n = 9). Histological assessment was performed at 4 d ays after ischemia. Results When given after ischemia, isradipine fail ed to affect lesion volume in both the rat and mouse models. In the ge rbil, locomotor hyperactivity and hippocampal cell loss were unaffecte d. Given before and after ischemia in the mouse, isradipine was also i neffective, whereas SB201823A produced a significant reduction in lesi on volume. Conclusions The L-type calcium channel blocker isradipine w as devoid of neuroprotective activity in focal and global models of ce rebral ischemia in three species of normotensive animals. These result s were compared with data for the novel calcium channel blocker SB2018 23A, which exhibited a significant effect after pre- and postocclusion administration in the mouse model of permanent focal ischemia.