U-92032, A T-TYPE CA2+ CHANNEL BLOCKER AND ANTIOXIDANT, REDUCES NEURONAL ISCHEMIC INJURIES

Several diphenylmethylpiperazine derivatives are potential therapeutic agents for prevention of ischemic injuries in the heart and brain, because of their ability to block Ca2+ currents and their antioxidant activity. In this study, the current lead compound, U-92032 ((7-((bis-4-fluorophenyl)methyl)-1-piperazinyl)-2-(2-hydroxyethylamino)-4-(1-methylethyl)-2,4,6-cycloheptatrien-1-one), has been compared with flunarizine and nifedipine (well-known T- and L-type Ca2+ channel antagonists, respectively) for their effects on Ca2+ channels in a mouse neuronal cell line, N1E-115 cells, and their ability to preserve the phenomenon of long-term potentiation and to improve neurological symptoms in gerbil ischemic models. U-92032, like flunarizine, blocked transient Ba2+ currents (I-Ba) through T-type Ca2+ channels with no effect on nifedipine-sensitive non-inactivating currents. Transient I-Ba was reduced by U-92032 at a constant rate, the magnitude of which depended on the drug concentration, probably because of a time-dependent accumulation of the lipophilic drug in the membrane phase. For instance, the drug at 6 mu M reduced I-Ba by 21% per min and abolished it in less than 5 min, about 3 times faster than flunarizine at the same concentration. Otherwise, U-92032 behaved like flunarizine, showing a use-dependent block without noticeable effects on the current-voltage relationship for transient I-Ba. Oral administration of U-92032 (1 and 25 mg/kg) or flunarizine (25 mg/kg), but not nifedipine (50 mg/kg), to gerbils 1 h prior to bilateral carotid artery occlusion, preserved long-term potentiation in hippocampal CA1 neurons, which were largely abolished by ischemia without the drug treatment. Also, U-92032 and flunarizine (10 mg/kg) improved neurological symptoms in gerbils with unilateral carotid artery occlusion. Similar improvements by nifedipine were observed at a higher dose (30 mg/kg). It appears that U-92032 is a potent, selective T-type Ca2+ channel antagonist, and possesses the ability to protect neurons from ischemic injuries at least as effectively as flunarizine. At present, we do not know the extent of contribution by the antioxidant activity of U-92032 to its neuroprotective actions, but are certain of its beneficial effects because of the involvement of the oxygen-induced toxicity in the cascade of neuronal ischemic injuries.