title: The immunophilin ligand FK506 protects against methamphetamine-induced dopaminergic neurotoxicity in mouse striatum.
abstract: Repeated use of methamphetamine (MAP) is known to cause neurotoxicity in the dopaminergic neurons of the striatum. Recently, we reported that FK506, a calcineurin inhibitor and immunosuppressive agent, could attenuate acute behavioral changes and the development of sensitization after administration of MAP. In this study, we investigated the effects of FK506 on the neurotoxicity in the dopaminergic neurons induced by repeated administration of MAP. BALB/c mice were injected subcutaneously (s.c.) with vehicle (10 ml/kg) or MAP (4 mg/kg) four times every 2h. Vehicle (10 ml/kg) or FK506 (0.1, 0.3, 1 or 3 mg/kg i.p.) was administered 15 min before the first MAP administration. Three days later, we assessed the contents of dopamine (DA) and its major metabolite, 3,4-dihydroxyphenylacetic acid (DOPAC), in the mouse striatum using high-performance liquid chromatography (HPLC). We also examined the immunohistochemistry of dopamine transporter (DAT) and tyrosine hydroxylase (TH) in the mouse brain. Repeated administration of MAP decreased significantly the contents of DA and DOPAC in the mouse striatum, and pretreatment with FK506 inhibited significantly the reduction of DA and DOPAC in the mouse brain by repeated administration of MAP. Furthermore, repeated administration of MAP decreased significantly the immunoreactivity of DAT and TH in the striatum as compared to controls. Pretreatment with FK506 (3 mg/kg) attenuated significantly the reduction of DAT and TH immunoreactivity after repeated administration of MAP. These results suggest that FK506 shows protective effects on the MAP-induced neurotoxicity in the dopaminergic neurons of the mouse striatum.
authors.affiliation: Department of Psychiatry, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chiba 260-8670, Japan.
authors.forename: Kaori
authors.initials: K
authors.lastname: Koike
authors.forename: Kenji
authors.initials: K
authors.lastname: Hashimoto
authors.forename: Goro
authors.initials: G
authors.lastname: Fukami
authors.forename: Naoe
authors.initials: N
authors.lastname: Okamura
authors.forename: Lin
authors.initials: L
authors.lastname: Zhang
authors.forename: Shintaro
authors.initials: S
authors.lastname: Ohgake
authors.forename: Hiroki
authors.initials: H
authors.lastname: Koizumi
authors.forename: Daisuke
authors.initials: D
authors.lastname: Matsuzawa
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Kawamura
authors.forename: Eiji
authors.initials: E
authors.lastname: Shimizu
authors.forename: Masaomi
authors.initials: M
authors.lastname: Iyo
mesh_terms: D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D020104:Immunophilins / Q000494:pharmacology; D008297:Male; D008694:Methamphetamine / Q000633:toxicity*; D051379:Mice; D008807:Mice, Inbred BALB C; D018696:Neuroprotective Agents / Q000494:pharmacology*; D016559:Tacrolimus / Q000494:pharmacology*
chemical_list: D018696:Neuroprotective Agents; D008694:Methamphetamine; D020104:Immunophilins; D004298:Dopamine; D016559:Tacrolimus