title: Regulation of P-glycoprotein expression in brain capillaries in Huntington's disease and its impact on brain availability of antipsychotic agents risperidone and paliperidone.
abstract: Huntington's disease (HD) is a neurodegenerative disease marked by an expanded polyglutamine (polyQ) tract on the huntingtin (HTT) protein that may cause transcriptional dysfunction. This study aimed to investigate the regulation and function of P-glycoprotein, an important efflux transporter, in brain capillaries in HD. The results showed that, compared with the littermate controls, R6/2 HD transgenic mice with the human mutant HTT gene had higher levels of P-glycoprotein mRNA and protein and enhanced NF-κB activity in their brain capillaries. Higher P-glycoprotein expression was also observed in the brain capillaries of human HD patients. Consistent with this enhanced P-glycoprotein expression, brain extracellular levels and brain-to-plasma ratios of the antipsychotic agents risperidone and paliperidone were significantly lower in R6/2 mice than in their littermate controls. Exogenous expression of human mutant HTT protein with expanded polyQ (mHTT-109Q) in HEK293T cells enhanced the levels of P-glycoprotein transcripts and NF-κB activity compared with cells expressing normal HTT-25Q. Treatment with the IKK inhibitor, BMS-345541, decreased P-glycoprotein mRNA level in cells transfected with mHTT-109Q or normal HTT-25Q In conclusion, mutant HTT altered the expression of P-glycoprotein through the NF-κB pathway in brain capillaries in HD and markedly affected the availability of P-glycoprotein substrates in the brain.
authors.affiliation: School of Pharmacy, National Taiwan University, Taipei, Taiwan.
authors.forename: Yu-Han
authors.initials: YH
authors.lastname: Kao
authors.affiliation: Department of Life Sciences and Institute of Genome Sciences, National Yang-Ming University, Taipei, Taiwan Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
authors.forename: Yijuang
authors.initials: Y
authors.lastname: Chern
authors.affiliation: School of Pharmacy, National Taiwan University, Taipei, Taiwan.
authors.forename: Hui-Ting
authors.initials: HT
authors.lastname: Yang
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
authors.forename: Hui-Mei
authors.initials: HM
authors.lastname: Chen
authors.affiliation: School of Pharmacy, National Taiwan University, Taipei, Taiwan clementumich@ntu.edu.tw.
authors.forename: Chun-Jung
authors.initials: CJ
authors.lastname: Lin
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics*; D000818:Animals; D014150:Antipsychotic Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D001682:Biological Availability; D001812:Blood-Brain Barrier / Q000378:metabolism*; D002196:Capillaries / Q000378:metabolism*; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006801:Humans; D000071058:Huntingtin Protein / Q000235:genetics; D006816:Huntington Disease / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000378:metabolism; D000068882:Paliperidone Palmitate / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018967:Risperidone / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D014150:Antipsychotic Agents; C086055:HTT protein, human; D000071058:Huntingtin Protein; D016328:NF-kappa B; D018967:Risperidone; D000068882:Paliperidone Palmitate
keywords: Blood–brain barrier; Huntington’s disease; P-glycoprotein; paliperidone; risperidone