Experimental ischemic stroke was induced by an occlusion of middle cerebral artery and common carotid artery of rats for 60 min. The occlusion was then released and the extent of neural damage was measured by the estimation of necrosis areas where the dead neurons lost their ability to take up triphenyl tetrazolium chloride. w-(N,N'-Diethylamino)-n-alkyl-3,4,5-trimethoxybenzoate (TMB) compounds are calcium antagonists capable of reducing intracellular free calcium through inhibition of calcium release from the sarcoplasmic reticulum. These compounds were found to prevent and/or reduce neural damage effectively. When the animals were pretreated with TMB-2, TMB-5 and TMB-8, 1 hr before ischemia, the areas of neural necrosis were reduced almost completely by 95%, 99% and 92%, respectively. When these TMB compounds were given at 0 time and 1 hr after ischemia, the prevention of necrosis was almost complete also. However, when TMB-2, TMB-5 and TMB-8 were administered 6 hr after ischemia, the necrosis areas were reduced less effectively by 83%, 78% and 91%, respectively. TMB compounds were also found to increase cAMP and to reduce intracellular free calcium concentration. These results indicate that TMB compounds are effective calcium antagonists to prevent/treat ischemic stroke by reducing the intracellular free calcium through reduction of calcium release from sarcoplasmic reticulum.