Fc. Barone et al., SE 201823-A ANTAGONIZES CALCIUM CURRENTS IN CENTRAL NEURONS AND REDUCES THE EFFECTS OF FOCAL ISCHEMIA IN RATS AND MICE, Stroke, 26(9), 1995, pp. 1683-1689
Background and Purpose Excessive calcium entry into depolarized neuron
s 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 P
atch-clamp electrophysiology and intracellular Ca2+ imaging in rat hip
pocampal and cerebellar neurons were used to determine effects on neur
onal calcium channel activity. Middle cerebral artery occlusion was pe
rformed in Fisher 344 rats and CD-1 mice to determine the effects on r
odent 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 cell
s, calcium current measured at plateau was reduced by 36+/-8% and 89+/
-4% after 5 and 20 mu mol/L SE 201823-A, respectively. In cerebellar g
ranule cells in culture, pretreatment with 2.5 mu mol/L SE 201823-A to
tally prevented initial calcium influx and reduced later calcium influ
x by 50+/-2.5% after N-methyl-D-aspartate/glycine stimulation (P<.01).
KCl depolarization-induced calcium influx also was reduced by more th
an 95%. In rats, a single treatment with 10 mg/kg IV SB 201823-A begin
ning 30 minutes after focal ischemia decreased (P<.05) hemispheric inf
arct 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 SE 201823-A beginning 30 minutes after focal ischemi
a significantly reduced infarct volume by 41.5% (P<.01). No blood pres
sure effects were observed with the therapeutic dose of the compound.
Conclusions These results indicate that the new neuronal calcium chann
el blocker SB 201823-A can block stimulated calcium influx into centra
l neurons and can provide neuroprotection in two models of focal cereb
ral ischemia without affecting blood pressure. Data from several diffe
rent studies now indicate that the neuronal calcium channel antagonist
s are a promising therapy for the postischemic treatment of stroke.