Abstract | 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 Ca2+ 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 mumol/L SB 201823-A, respectively. In cerebellar granule cells in culture, pretreatment with 2.5 mumol/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:
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Authors | F C Barone, P G Lysko, W J Price, G Feuerstein, K A al-Baracanji, C D Benham, D C Harrison, M H Harries, S J Bailey, A J Hunter |
Journal | Stroke
(Stroke)
Vol. 26
Issue 9
Pg. 1683-9; discussion 1689-90
(Sep 1995)
ISSN: 0039-2499 [Print] United States |
PMID | 7660415
(Publication Type: Journal Article)
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Chemical References |
- Calcium Channel Blockers
- Calcium Channels
- Neuroprotective Agents
- Piperidines
- SB 201823-A
- N-Methylaspartate
- Potassium Chloride
- Calcium
- Glycine
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Topics |
- Animals
- Blood Pressure
(drug effects)
- Calcium
(antagonists & inhibitors)
- Calcium Channel Blockers
(pharmacology, therapeutic use)
- Calcium Channels
(drug effects)
- Cells, Cultured
- Cerebellum
(drug effects, metabolism)
- Cerebral Infarction
(prevention & control)
- Disease Models, Animal
- Glycine
(pharmacology)
- Hippocampus
(drug effects, metabolism)
- Ischemic Attack, Transient
(drug therapy, metabolism)
- Male
- Mice
- Mice, Inbred Strains
- N-Methylaspartate
(pharmacology)
- Neurons
(drug effects)
- Neuroprotective Agents
(pharmacology)
- Patch-Clamp Techniques
- Piperidines
(pharmacology, therapeutic use)
- Potassium Chloride
(pharmacology)
- Rats
- Rats, Inbred F344
- Rats, Inbred Strains
- Rats, Sprague-Dawley
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