title: U-92032, a T-type Ca2+ channel blocker and antioxidant, reduces neuronal ischemic injuries.
abstract: 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-hydroxyethylamin o)- 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 (IBa) through T-type Ca2+ channels with no effect on nifedipine-sensitive non-inactivating currents. Transient IBa 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 microM reduced IBa 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 IBa. 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.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: Upjohn Tsukuba Laboratory, Japan.
authors.forename: C
authors.initials: C
authors.lastname: Ito
authors.forename: W B
authors.initials: WB
authors.lastname: Im
authors.forename: H
authors.initials: H
authors.lastname: Takagi
authors.forename: M
authors.initials: M
authors.lastname: Takahashi
authors.forename: K
authors.initials: K
authors.lastname: Tsuzuki
authors.forename: S Y
authors.initials: SY
authors.lastname: Liou
authors.forename: M
authors.initials: M
authors.lastname: Kunihara
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology / Q000627:therapeutic use*; D002545:Brain Ischemia / Q000188:drug therapy* / Q000503:physiopathology; D002121:Calcium Channel Blockers / Q000494:pharmacology / Q000627:therapeutic use*; D005444:Flunarizine / Q000494:pharmacology; D005849:Gerbillinae; D006624:Hippocampus / Q000187:drug effects / Q000502:physiology; D015227:Lipid Peroxidation / Q000187:drug effects; D017774:Long-Term Potentiation / Q000187:drug effects; D008315:Malondialdehyde / Q000378:metabolism; D051379:Mice; D009447:Neuroblastoma; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D010879:Piperazines / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D014334:Tropolone / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D014407:Tumor Cells, Cultured
chemical_list: D000975:Antioxidants; D002121:Calcium Channel Blockers; D010879:Piperazines; C086422:U 92032; D008315:Malondialdehyde; D014334:Tropolone; D005444:Flunarizine