SB-201823A

Background and Purpose 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. Methods In the gerbil BCAO model, isradipine was administered at 2.5 mg/kg IP 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 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=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 IP before occlusion, 1.25 mg/kg IP 1 hour after occlusion, 1.25 mg/kg IP 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. Results 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. Conclusions 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.

Background and Purpose Excessive calcium entry into depolarized neurons contributes significantly to cerebral tissue damage after ischemia. We evaluated the ability of a novel neuronal calcium channel blocker, SB 201823-A, to block central neuronal calcium influx in vitro and to reduce ischemic injury in two rodent models of focal stroke. Methods Patch-clamp electrophysiology and intracellular Ca 2+ imaging in rat hippocampal and cerebellar neurons were used to determine effects on neuronal calcium channel activity. Middle cerebral artery occlusion was performed in Fisher 344 rats and CD-1 mice to determine the effects on rodent focal ischemic injury and neurological deficits. Cardiovascular monitoring in conscious rats was conducted to determine cardiovascular liabilities of the compound. Results In cultured rat hippocampal cells, calcium current measured at plateau was reduced by 36±8% and 89±4% after 5 and 20 μmol/L SB 201823-A, respectively. In cerebellar granule cells in culture, pretreatment with 2.5 μmol/L SB 201823-A totally prevented initial calcium influx and reduced later calcium influx by 50±2.5% after N -methyl- d -aspartate/glycine stimulation ( P <.01). KCl depolarization–induced calcium influx also was reduced by more than 95%. In rats, a single treatment with 10 mg/kg IV SB 201823-A beginning 30 minutes after focal ischemia decreased ( P <.05) hemispheric infarct by 30.4% and infarct volume by 29.3% and reduced ( P <.05) forelimb deficits by 47.8% and hindlimb deficits by 36.3%. In mice, treatments with 10 mg/kg IP SB 201823-A beginning 30 minutes after focal ischemia significantly reduced infarct volume by 41.5% ( P <.01). No blood pressure effects were observed with the therapeutic dose of the compound. Conclusions These results indicate that the new neuronal calcium channel blocker SB 201823-A can block stimulated calcium influx into central neurons and can provide neuroprotection in two models of focal cerebral ischemia without affecting blood pressure. Data from several different studies now indicate that the neuronal calcium channel antagonists are a promising therapy for the postischemic treatment of stroke.