Peptide and peptide analog transport systems at the blood?CSF barrier

Smith, David Eugene; Johanson, Conrad E.; Keep, Richard F.

doi:10.1016/j.addr.2004.07.008

Cited by 145 publications

(165 citation statements)

References 176 publications

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“…In addition, the activity of PMAT is known to be stimulated by an acidic extracellular pH. Although the pH of the bulk CSF is similar to that of plasma, a proton-rich microenvironment near the CP apical domain has been proposed to provide a driving force of protoncoupled transporters such as PEPT2 (38,39). If such a microenvironment indeed exists, it could serve as an additional driving force to energize PMAT-mediated OC uptake into CP epithelial cells.…”

Section: Discussionmentioning

confidence: 99%

Impaired Monoamine and Organic Cation Uptake in Choroid Plexus in Mice with Targeted Disruption of the Plasma Membrane Monoamine Transporter (Slc29a4) Gene

Duan

Wang

2013

Journal of Biological Chemistry

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Background: Some CNS active compounds are transported into or out of the brain by transporters in the choroid plexus (CP). Results: PMAT is a major CP transporter for bioactive amines and xenobiotic cations. Conclusion: PMAT transports organic cations from the cerebrospinal fluid into the CP. Significance: PMAT may be an important determinant of brain exposure to cationic neurotoxins and bioactive amines.

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Section: Discussionmentioning

confidence: 99%

Impaired Monoamine and Organic Cation Uptake in Choroid Plexus in Mice with Targeted Disruption of the Plasma Membrane Monoamine Transporter (Slc29a4) Gene

Duan

Wang

2013

Journal of Biological Chemistry

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“…Basically two types of epithelial cells form the border that encompasses the CSF: choroidal and ependymal. Thus the internal (ventricular) surface of the brain is comprised mainly of a single layer of choroid plexus epithelium or ependyma (D. E. Smith, Johanson, and Keep 2004). CP epithelial cells do not generally contact the brain; rather, they extend into the ventricular CSF.…”

Section: Toxicology and Pathology Models Of Damage To Csfbordering Cellsmentioning

confidence: 99%

“…LRP-2 (or megalin) has also been implicated in removing amyloid from CSF (Alvira-Botero and Carro Forthcoming). Other apically located organic solute transporters, including PEPT2 (proton-coupled oligopeptide transporter 2), prevent CSF accumulation of compounds (e.g., 5-aminolevulinic acid [ALA], a heme precursor) to toxic levels (Hu et al 2007;D. E. Smith, Johanson, and Keep 2004).…”

Section: Choroid Plexus Epithelial Cellsmentioning

confidence: 99%

The Distributional Nexus of Choroid Plexus to Cerebrospinal Fluid, Ependyma and Brain

et al. 2010

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Bordering the ventricular cerebrospinal fluid (CSF) are epithelial cells of choroid plexus (CP), ependyma and circumventricular organs (CVOs) that contain homeostatic transporters for mediating secretion/reabsorption. The distributional pathway (''nexus'') of CP-CSF-ependyma-brain furnishes peptides, hormones, and micronutrients to periventricular regions. In disease/toxicity, this nexus becomes a conduit for infectious and xenobiotic agents. The sleeping sickness trypanosome (a protozoan) disrupts CP and downstream CSF-brain. Piperamide is anti-trypanosomic but distorts CP epithelial ultrastructure by engendering hydropic vacuoles; this reflects phospholipidosis and altered lysosomal metabolism. CP swelling by vacuolation may occlude CSF flow. Toxic drug tools delineate injuries to choroidal compartments: cyclophosphamide (vasculature), methylcellulose (interstitium), and piperazine (epithelium). Structurally perturbed CP allows solutes to penetrate the ventricles. There, CSF-borne pathogens and xenobiotics may permeate the ependyma to harm neurogenic stem cell niches. Amoscanate, an anti-helmintic, potently injures rodent ependyma. Ependymal/brain regions near CP are vulnerable to CSF-borne toxicants; this proximity factor links regional barrier breakdown to nearby periventricular pathology. Diverse diseases (e.g., African sleeping sickness, multiple sclerosis) take early root in choroidal, circumventricular, or perivascular loci. Toxicokinetics informs on pathogen, anti-parasitic agent, and auto-antibody distribution along the CSF nexus. CVOs are susceptible to plasma-borne toxicants/pathogens. Countering the physico-chemical and pathogenic insults to the homeostasis-mediating ventricle-bordering cells sustains brain health and fluid balance.

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“…In recent years the importance of the BCSFB as a site for drug metabolism and in governing the composition of cerebrospinal fluid (CSF) has gained more attention due to its significance in normal physiology and disease pathology (1). The BCSFB is formed from the epithelial cells of the choroid plexus (CP) facing the CSF, which are sealed by the tight junctions (2).…”

Section: Introductionmentioning

confidence: 99%

“…The CP epithelium is a dynamic tissue which has a greater perfusion rate compared to the cerebral blood flow and weighing only 2 g (3-6). It secretes CSF at a rate of 25 mL/hour in humans (7) which helps to maintain brain extracellular fluid (ECF) and CSF homeostasis (2,8) as well as providing mechanical support to the brain, removal of metabolic products (9) and as a route for the distribution of nutrients, neurotransmitters and hormones across the CNS (10,11) (12,13).…”

Section: Introductionmentioning

confidence: 99%

Phytoestrogens Modulate Breast Cancer Resistance Protein Expression and Function at the Blood-Cerebrospinal Fluid Barrier

Kaur

Badhan

2015

J Pharm Pharm Sci

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-PURPOSE: Breast cancer resistance protein (BCRP/ABCG2) is a drug efflux transporter expressed at the blood cerebrospinal fluid barrier (BCSFB), and influences distribution of drugs into the central nervous systems (CNS). Current inhibitors have failed clinically due to neurotoxicity. Novel approaches are needed to identify new modulators to enhance CNS delivery. This study examines 18 compounds (mainly phytoestrogens) as modulators of the expression/function of BCRP in an in vitro rat choroid plexus BCSFB model. METHODS: Modulators were initially subject to cytotoxicity (MTT) assessment to determine optimal non-toxic concentrations. Reverse-transcriptase PCR and confocal microscopy were used to identify the presence of BCRP in Z310 cells. Thereafter modulation of the intracellular accumulation of the fluorescent BCRP probe substrate Hoechst 33342 (H33342), changes in protein expression of BCRP (western blotting) and the functional activity of BCRP (membrane insert model) were assessed under modulator exposure. RESULTS: A 24 hour cytotoxicity assay (0.001 µM-1000 µM) demonstrated the majority of modulators possessed a cellular viability IC50 > 148 µM. Intracellular accumulation of H33342 was significantly increased in the presence of the known BCRP inhibitor Ko143 and, following a 24 hour pre-incubation, all modulators demonstrated statistically significant increases in H33342 accumulation (P < 0.001), when compared to control and Ko143. After a 24 hour pre-incubation with modulators alone, a 0.16-2.5 -fold change in BCRP expression was observed for test compounds. The functional consequences of this were confirmed in a permeable insert model of the BCSFB which demonstrated that 17-β-estradiol, naringin and silymarin (down-regulators) and baicalin (up-regulator) can modulate BCRP-mediated transport function at the BCSFB. CONCLUSION: We have successfully confirmed the gene and protein expression of BCRP in Z310 cells and demonstrated the potential for phytoestrogen modulators to influence the functionality of BCRP at the BCSFB and thereby potentially allowing manipulation of CNS drug disposition.

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Peptide and peptide analog transport systems at the blood?CSF barrier

Cited by 145 publications

References 176 publications

Impaired Monoamine and Organic Cation Uptake in Choroid Plexus in Mice with Targeted Disruption of the Plasma Membrane Monoamine Transporter (Slc29a4) Gene

Impaired Monoamine and Organic Cation Uptake in Choroid Plexus in Mice with Targeted Disruption of the Plasma Membrane Monoamine Transporter (Slc29a4) Gene

The Distributional Nexus of Choroid Plexus to Cerebrospinal Fluid, Ependyma and Brain

Phytoestrogens Modulate Breast Cancer Resistance Protein Expression and Function at the Blood-Cerebrospinal Fluid Barrier

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