Role of P-glycoprotein in mediating rivastigmine effect on amyloid-β brain load and related pathology in Alzheimer's disease mouse model

Biochimica Et Biophysica Acta
Loqman A MohamedAmal Kaddoumi

Abstract

Recently, we showed that rivastigmine decreased amyloid-β (Aβ) brain load in aged rats by enhancing its clearance across the blood-brain barrier (BBB) via upregulation of P-glycoprotein (P-gp) and low-density lipoprotein receptor-related protein 1 (LRP1). Here, we extend our previous work to clarify P-gp role in mediating rivastigmine effect on Aβ brain levels and neuroprotection in a mouse model of Alzheimer's disease (AD) that expresses different levels of P-gp. APPSWE mice were bred with mdr1a/b knockout mice to produce littermates that were divided into three groups; APP(+)/mdr1(+/+), APP(+)/mdr1(+/-) and APP(+)/mdr1(-/-). Animals received rivastigmine treatment (0.3mg/kg/day) or vehicle for 8weeks using Alzet osmotic mini-pumps. ELISA analysis of brain homogenates for Aβ showed rivastigmine treatment to significantly decrease Aβ brain load in APP(+)/mdr1(+/+) by 25% and in APP(+)/mdr1(+/-) mice by 21% compared to their vehicle treated littermates, but not in APP(+)/mdr1(-/-) mice. In addition, rivastigmine reduced GFAP immunostaining of astrocytes by 50% and IL-1β brain level by 43% in APP(+)/mdr1(+/+) mice, however its effect was less pronounced in P-gp knockout mice. Moreover, rivastigmine demonstrated a P-gp expression ...Continue Reading

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Citations

Mar 10, 2016·International Journal of Molecular Sciences·Yazan S BatarsehAmal Kaddoumi
Jan 11, 2018·Oxidative Medicine and Cellular Longevity·Giulia SitaFabiana Morroni
Aug 31, 2017·PloS One·Jose A Muñoz-MorenoUNKNOWN TRIANT-TE Study Group
Apr 13, 2019·Current Topics in Medicinal Chemistry·Niraj Kumar JhaRituraj Niranjan
Oct 26, 2018·Journal of Cerebral Blood Flow and Metabolism : Official Journal of the International Society of Cerebral Blood Flow and Metabolism·Viktoria ZoufalOliver Langer
Jan 13, 2019·British Journal of Pharmacology·Jessica S Sadick, Shane A Liddelow
Jul 23, 2016·Clinical Pharmacology and Therapeutics·H QosaA Kaddoumi
Sep 16, 2016·Journal of Neuroendocrinology·A C DuarteC R A Santos
Feb 19, 2020·Translational Psychiatry·Balmiki RayDebomoy K Lahiri
Jan 31, 2021·International Journal of Molecular Sciences·Ihab M AbdallahAmal Kaddoumi
May 1, 2021·International Journal of Molecular Sciences·Sweilem B Al RihaniVeronique Michaud
Jun 5, 2021·Journal of Controlled Release : Official Journal of the Controlled Release Society·Nazneen Pathan, Pravin Shende

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