title: Decreased expression of organic cation transporters, Oct1 and Oct2, in brain microvessels and its implication to MPTP-induced dopaminergic toxicity in aged mice.
abstract: This study was to investigate the influence of age on the expression of organic cation transporters (OCTs) that belong to the SLC22 family in brain microvessels (BMVs) and its implications for 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced dopaminergic toxicity in mice. Here, we showed that Oct1 and Oct2, but not Oct3, mRNAs were detected and enriched (compared with cerebral cortex) in BMVs of C57BL/6 (B6) mice using reverse transcription-quantitative PCR (RT-qPCR), and immunofluorescence analysis further revealed that Oct1 and Oct2 proteins were colocalized with endothelial markers. Both the mRNA and protein levels of Oct1 and Oct2 were reduced in aged mice. After an intraperitoneal administration of MPTP, brain extracellular levels of MPTP and 1-methyl-4-phenyl-pyridinium (MPP(+)) were much lower in aged mice and in Oct1/2(-/-) mice compared with younger mice and wild-type control mice, respectively. Knockout of Oct1/Oct2 protected Oct1/2(-/-) mice from MPTP-induced neurotoxicity, whereas the loss of tyrosine hydroxylase (TH)-positive neurons was slightly greater in aged than in younger mice. However, intrastriatal infusion of low-dose MPTP caused more severe dopaminergic toxicity in the substantia nigra of both aged mice and Oct1/2(-/-) mice. These findings show that age-dependent downregulation or knockout of Oct1/Oct2 in BMVs may reduce the transport of MPTP, which, in part, affects its dopaminergic toxicity.
authors.affiliation: School of Pharmacy, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Kuo-Chen
authors.initials: KC
authors.lastname: Wu
authors.affiliation: School of Pharmacy, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Ya-Hsuan
authors.initials: YH
authors.lastname: Lu
authors.affiliation: School of Pharmacy, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Yi-Hsuan
authors.initials: YH
authors.lastname: Peng
authors.affiliation: Department of Life Sciences and Institute of Genome Sciences, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Ting-Fen
authors.initials: TF
authors.lastname: Tsai
authors.affiliation: School of Pharmacy, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Yu-Han
authors.initials: YH
authors.lastname: Kao
authors.affiliation: School of Pharmacy, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Hui-Ting
authors.initials: HT
authors.lastname: Yang
authors.affiliation: School of Pharmacy, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Chun-Jung
authors.initials: CJ
authors.lastname: Lin
mesh_terms: D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000493:pharmacokinetics; D015655:1-Methyl-4-phenylpyridinium / Q000378:metabolism; D000375:Aging / Q000378:metabolism*; D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism; D001921:Brain / Q000098:blood supply* / Q000378:metabolism; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D004285:Dogs; D004298:Dopamine / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D007274:Injections, Intraperitoneal; D020267:MPTP Poisoning / Q000378:metabolism*; D061985:Madin Darby Canine Kidney Cells; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017551:Microdialysis; D055806:Microvessels / Q000378:metabolism*; D050811:Octamer Transcription Factor-1 / Q000235:genetics*; D027701:Organic Cation Transport Proteins / Q000235:genetics*; D000075102:Organic Cation Transporter 2; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014162:Transfection
chemical_list: D050811:Octamer Transcription Factor-1; D027701:Organic Cation Transport Proteins; D000075102:Organic Cation Transporter 2; C494166:Pou2f1 protein, mouse; D012333:RNA, Messenger; C491012:Slc22a2 protein, mouse; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D015655:1-Methyl-4-phenylpyridinium; D004298:Dopamine