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  2. Regulation of P-glycoprotein expression in brain capillaries in Huntington's disease and its impact on brain availability of antipsychotic agents risperidone and paliperidone

Regulation of P-glycoprotein expression in brain capillaries in Huntington's disease and its impact on brain availability of antipsychotic agents risperidone and paliperidone

  • J Cereb Blood Flow Metab. 2016 Aug;36(8):1412-23. doi: 10.1177/0271678X15606459.
Yu-Han Kao 1 Yijuang Chern 2 Hui-Ting Yang 1 Hui-Mei Chen 3 Chun-Jung Lin 4
Affiliations

Affiliations

  • 1 School of Pharmacy, National Taiwan University, Taipei, Taiwan.
  • 2 Department of Life Sciences and Institute of Genome Sciences, National Yang-Ming University, Taipei, Taiwan Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
  • 3 Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
  • 4 School of Pharmacy, National Taiwan University, Taipei, Taiwan clementumich@ntu.edu.tw.
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.

Keywords

Blood–brain barrier; Huntington’s disease; P-glycoprotein; paliperidone; risperidone.

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