P-gp Transporter and its Role in Neurodegenerative Diseases

Rapposelli, Simona; Digiacomo, Maria; Balsamo, Aldo

doi:10.2174/156802609787521544

Cited by 31 publications

(26 citation statements)

References 77 publications

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“…Conversely, inhibition of p-gp on the BBB has been shown to increase substrate concentrations in the brain (60-64). Several studies point to the possible role of p-gp in diseases of the central nervous system including Alzheimer disease (65,66), Parkinson disease (65,66), Huntington’s disease (66), Creutzfeldt-Jakob’s disease (66), amyotrophic lateral sclerosis (66), and epilepsy (66). The role that p-gp plays in numerous neurodegenerative diseases is believed to be in part due to the protection that it provides at the BBB to maintain homeostasis in the brain and protect it against toxic compounds.…”

Section: P-glycoprotein and Its Role In The Pathophysiology Of Hydrocmentioning

confidence: 99%

A proposed role for efflux transporters in the pathogenesis of hydrocephalus

et al. 2014

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Hydrocephalus is a common brain disorder that is treated only with surgery. The basis for surgical treatment rests on the circulation theory. However, clinical and experimental data to substantiate circulation theory have remained inconclusive. In brain tissue and in the ventricles, we see that osmotic gradients drive water diffusion in water-permeable tissue. As the osmolarity of ventricular CSF increases within the cerebral ventricles, water movement into the ventricles increases and causes hydrocephalus. Macromolecular clearance from the ventricles is a mechanism to establish the normal CSF osmolarity, and therefore ventricular volume. Efflux transporters, (p-glycoprotein), are located along the blood brain barrier and play an important role in the clearance of macromolecules (endobiotics and xenobiotics) from the brain to the blood. There is clinical and experimental data to show that macromolecules are cleared out of the brain in normal and hydrocephalic brains. This article summarizes the existing evidence to support the role of efflux transporters in the pathogenesis of hydrocephalus. The location of p-gp along the pathways of macromolecular clearance and the broad substrate specificity of this abundant transporter to a variety of different macromolecules are reviewed. Involvement of p-gp in the transport of amyloid beta in Alzheimer disease and its relation to normal pressure hydrocephalus is reviewed. Finally, individual variability of p-gp expression might explain the variability in the development of hydrocephalus following intraventricular hemorrhage.

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Section: P-glycoprotein and Its Role In The Pathophysiology Of Hydrocmentioning

confidence: 99%

A proposed role for efflux transporters in the pathogenesis of hydrocephalus

et al. 2014

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“…Increasing number of studies suggested alteration of expression and functional activity of LRP1 and P-gp contribute to the accumulation of Aβ in the brain, and lead to increased risk for developing AD [17–19]. Moreover, recent evidence indicated a progressive decline in the levels of LRP1 and P-gp at the BBB during normal aging, and this decline was positively correlated with accumulation of Aβ in AD [20].…”

Section: Introductionmentioning

confidence: 99%

Enhanced Brain Amyloid-β Clearance by Rifampicin and Caffeine as a Possible Protective Mechanism Against Alzheimer's Disease

Qosa

Abuznait

Hill

et al. 2012

JAD

137

144

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Rifampicin and caffeine are widely used drugs with reported protective effect against Alzheimer’s disease (AD). However, the mechanism underlying this effect is incompletely understood. In this study, we have hypothesized that enhanced amyloid-β (Aβ) clearance from the brain across the blood-brain barrier (BBB) of wild-type mice treated with rifampicin or caffeine is caused by both drugs potential to upregulate low-density lipoprotein receptor related protein-1 (LRP1) and/or P-glycoprotein (P-gp) at the BBB. Expression studies of LRP1 and P-gp in brain endothelial cells and isolated mice brain microvessels following treatment with rifampicin or caffeine demonstrated both drugs as P-gp inducers, and only rifampicin as an LRP1 inducer. Also, brain efflux index (BEI%) studies conducted on C57BL/6 mice treated with either drug to study alterations in Aβ clearance demonstrated the BEI% of Aβ in rifampicin (82.4 ± 4.3%) and caffeine (80.4 ± 4.8%) treated mice were significantly higher than those of control mice (62.4 ±6.1%, p <0.01). LRP1 and P-gp inhibition studies confirmed the importance of both proteins to the clearance of Aβ, and that enhanced clearance following drugs treatment was caused by LRP1 and/or P-gp upregulation at the mouse BBB. Furthermore, our results provided evidence for the presence of a yet to be identified transporter/receptor that plays significant role in Aβ clearance and is upregulated by caffeine and rifampicin. In conclusion, our results demonstrated the upregulation of LRP1 and P-gp at the BBB by rifampicin and caffeine enhanced brain Aβ clearance, and this effect could explain, at least in part, the protective effect of rifampicin and caffeine against AD.

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“…Erre mutatunk be néhány példát az 1. táblázatban [12][13][14][15][16][17][18][19][20][21][22][23][24][25][26].…”

Section: öSszefoglaló Közleményunclassified

A vér–agy gát működése, öregedése és diszfunkciója. Átjutás a barrieren

Hutka

Dénès

2016

Orvosi Hetilap

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Az agy és a keringés kapcsolatát biztosító, mikroerek szintjén megjelenő védelmi vonal a vér-agy gát, amely az idegrendszer homeosztázisának fenntartásában, az agy védelmében, táplálásában és finoman regulált működésének biztosításában játszik jelentős szerepet. Funkcióját számos sejttípus összehangolt működése és molekuláris rendszerek szabályozott kifejeződése teszi lehetővé. Azonban ez a komplex rendszer bizonyos behatásokra károsodik, szerkezete megbomlik, s akkor a védelmi struktúra permeabilitása megnő. Ez nemkívánatos exogén és endogén anyagok idegrendszeri megjelenését vagy szintjének emelkedését eredményezi, amely számos akut és krónikus központi idegrendszeri betegség patomechanizmusában játszik szerepet. A vér-agy gát károsodásának legfőbb rizikófaktora maga az öregedés, amely DNS-mutáción, oxidatív károsodáson és gyulladásos mediátorok megjelenésén keresztül destrukturálja a védelmi rendszert. Ez bizonyos fokig a természetes öregedés velejárója, de a membrántranszporterek műkö-désének diszfunkciója patológiás állapotok kialakulásához is vezethet, amely a krónikus neurodegeneratív betegségek oki tényezői között szerepel. Ebben a közleményben a vér-agy gát felépítését, működését, károsodását és az agyi gyógyszerbeviteli lehetőségeket foglaljuk össze. Orv. Hetil., 2016, 157(51), 2019-2027. Kulcsszavak: vér-agy gát, membrántranszporterek, öregedés, gyógyszerátvitel a vér-agy gáton Function, aging and dysfunction of blood-brain barrier. Crossing the barrierThe blood-brain barrier is an interface between the circulation and brain. It is responsible for the homeostasis of central nervous system, protection and feeding of the brain and for providing the conditions for fine regulation of neurons. The coordinated function of different cell types and the regulated expression of molecular systems make possible the functionality of blood-brain barrier. However, this complex system can be broken due to different insults with a consequence of appearance of elevated levels of unwanted exogenous and endogenous molecules in the brain involved in the pathomechanisms of several disorders. The most important risk factor for the damage of blood-brain barrier is the aging itself, which causes disruption of the barrier through DNA mutation, oxidative stress and release of inflammatory mediators. Although the physiological aging is accompanied by morphological changes, the dysfunction of membrane transporters could also lead to neurodegenerative disorders. Structure, function and breakdown of the blood-brain barrier and the possibilities to cross it, are presented.Keywords: blood-brain barrier, membrane transporter proteins, aging, drug delivery , F., Hutka, B., Dénes, L. [Function, aging and dysfunction of blood-brain barrier. Crossing the barrier]. Orv. Hetil., 2016, 157(51), 2019-2027. (Beérkezett: 2016 elfogadva: 2016. Rövidítések Ang-1 = angiopoetin-1, a vascularis növekedési faktorok egyik típusa, az embrionális fejlődésben van szerepe; AQP-4 = aquaporin-4, membránprotein, amely a vízmolekulákat átvezeti a membrá...

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P-gp Transporter and its Role in Neurodegenerative Diseases

Cited by 31 publications

References 77 publications

A proposed role for efflux transporters in the pathogenesis of hydrocephalus

A proposed role for efflux transporters in the pathogenesis of hydrocephalus

Enhanced Brain Amyloid-β Clearance by Rifampicin and Caffeine as a Possible Protective Mechanism Against Alzheimer's Disease

A vér–agy gát működése, öregedése és diszfunkciója. Átjutás a barrieren

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