title: Evaluation of neurotoxicity of TIQ and MPTP and of parkinsonism-preventing effect of 1-MeTIQ by in vivo measurement of pre-synaptic dopamine transporters and post-synaptic dopamine D(2) receptors in the mouse striatum.
abstract: Parkinsonism-inducing neurotoxicity of 1,2,3,4-tetrahydroisoquinoline (TIQ), as contrasted to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), and parkinsonism-preventing effect of 1-methyl-1,2,3,4-tetrahydroisoquinoline (1-MeTIQ) have been investigated in mice by measuring their effects on the in vivo binding of radioligand to pre-synaptic dopamine transporters (DATs) or to dopamine D(2) receptors (D2R) in the striatum. A significant reduction of the ligand-DATs binding was found in the mice treated with MPTP, but not with TIQ, under the dosage inducing behavioral abnormality and loss of tyrosine hydroxylase-positive cells in the substantia nigra. A slight decrease in the ligand-DATs binding was observed in the mice given a larger dose of TIQ. Compensatory up-regulation in the post-synaptic D2Rs was found in the MPTP-treated mice. Pre-treatment with (S)-enantiomer, but not (R)-enantiomer, of 1-MeTIQ prevented the degeneration of DATs to some extent. We concluded that the TIQ-induced parkinsonism model is different from the MPTP-induced model as evaluated by the radioligand-DATs binding and that (S)-1-MeTIQ has a preventing effect for the degeneration of the DATs to a certain extent.
authors.affiliation: Positron Medical Center, Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan. ishiwata@pet.tmig.or.jp
authors.forename: K
authors.initials: K
authors.lastname: Ishiwata
authors.forename: Y
authors.initials: Y
authors.lastname: Koyanagi
authors.forename: K
authors.initials: K
authors.lastname: Abe
authors.forename: K
authors.initials: K
authors.lastname: Kawamura
authors.forename: K
authors.initials: K
authors.lastname: Taguchi
authors.forename: T
authors.initials: T
authors.lastname: Saitoh
authors.forename: J
authors.initials: J
authors.lastname: Toda
authors.forename: M
authors.initials: M
authors.lastname: Senda
authors.forename: T
authors.initials: T
authors.lastname: Sano
mesh_terms: D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D050483:Dopamine Plasma Membrane Transport Proteins; D004305:Dose-Response Relationship, Drug; D018476:Hypokinesia / Q000139:chemically induced / Q000517:prevention & control; D007546:Isoquinolines / Q000494:pharmacology* / Q000633:toxicity*; D008024:Ligands; D008297:Male; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009419:Nerve Tissue Proteins; D020734:Parkinsonian Disorders / Q000139:chemically induced / Q000503:physiopathology / Q000517:prevention & control*; D011869:Radioligand Assay; D017448:Receptors, Dopamine D2 / Q000378:metabolism*; D013237:Stereoisomerism; D013378:Substantia Nigra / Q000187:drug effects / Q000378:metabolism; D013569:Synapses / Q000378:metabolism; D044005:Tetrahydroisoquinolines; D014446:Tyrosine 3-Monooxygenase / Q000096:biosynthesis; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D050483:Dopamine Plasma Membrane Transport Proteins; D007546:Isoquinolines; D008024:Ligands; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D017448:Receptors, Dopamine D2; D044005:Tetrahydroisoquinolines; C050386:1-methyl-1,2,3,4-tetrahydroisoquinoline; C014843:1,2,3,4-tetrahydroisoquinoline; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D014446:Tyrosine 3-Monooxygenase