Excessive
calcium entry into depolarized neurons contributes significantly to cerebral tissue damage following
ischemia. Therefore, blocking voltage-operated
calcium channels on nerve cells should provide significant neuroprotection in
ischemia. We now report on a novel neuronal
calcium channel blocker,
NNC 09-0026, in terms of its selective effects on neuronal
calcium current and its efficacy in reducing
infarct size and neurological deficits in a rat model of focal
stroke. In the present studies, the effects of
NNC 09-0026 on neuronal
calcium influx,
calcium channel binding, and cardiovascular parameters were determined. Also,
phencyclidine,
NNC 09-0026, or vehicle were administered i.v. to rats subjected to permanent middle cerebral and common carotid artery occlusions.
Infarct volumes and contralateral forepaw and hindlimb neurological deficits were assessed at 24 and 48 h after onset of
stroke.
NNC 09-0026 exhibited a pharmacological profile suggesting selectivity at neuronal
calcium channels. It inhibited
potassium-stimulated
calcium uptake into rat synaptosomes with an IC50 of 13 microM. Voltage-operated
calcium currents measured from cultured rat dorsal root ganglion cells using the patch clamp technique were blocked by 43%
at 10 microM (p < 0.05). The compound showed only weak effects on smooth muscle from the guinea pig taenia coli and was relatively inactive at displacing
nitrendipine and
omega-conotoxin in receptor-binding studies. Single, bolus
injections of
NNC 09-0026 as high as 10 mg/kg i.v. produced only 12% reduction in heart rate and a 28% decrease in blood pressure.(ABSTRACT TRUNCATED AT 250 WORDS)