Vectorial Ligand Transport Through Mammalian Choroid Plexus

Spector, Reynold; Johanson, Conrad E.

doi:10.1007/s11095-010-0162-2

Cited by 35 publications

(48 citation statements)

References 37 publications

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“…It is not feasible to predict exactly the untoward responses by CP to potent noxious materials. A particular toxicant can interfere with tight junctions or with the nutritional/ trophic transporters at the BCSFB (Spector and Johanson 2010b) that vectorially direct solutes to neuronal targets via CSF. Extreme interference with CP function causes CSF dyshomeostasis that harms brain.…”

Section: Choroid Plexus-ependyma Disruption: Implications For Brainmentioning

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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Section: Choroid Plexus-ependyma Disruption: Implications For Brainmentioning

confidence: 99%

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

et al. 2010

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“…The influx carriers Rfc1 and Oat3 as well as efflux transporters Mrp1 and Mrp4 have been suggested to be involved in MTX transport across the blood-CSF barrier in human and rodent (Nies, 2007;Spector and Johanson, 2010). Because MTX has been also identified as a substrate for Oat1 and Bcrp, we investigated protein expression of Oat1, Oat3, Rfc1, Mrp1, and Bcrp in Z310 cells.…”

Section: Expression Of Organic Anion Transporters In Z310mentioning

confidence: 99%

“…It has been shown previously that uptake of MTX in CP epithelial cells is concentrative and sodium-dependent (Breen et al, 2004). However, the involvement of particular influx or efflux carrier proteins in MTX transport across the blood-CSF barrier remains unclear (Spector and Johanson, 2010).…”

Section: Introductionmentioning

confidence: 97%

“…The blood-cerebrospinal fluid barrier is composed of tight-junctioned choroid plexus (CP) epithelial cells with an apical side facing the cerebrospinal fluid (CSF) and a basolateral side facing the CP fenestrated capillaries (Spector and Johanson, 2010). The choroid plexus generally limits drug disposition of the brain parenchyma through the prevention of entry of systemically administered compounds into the CSF or excretion of intrathecally applied drugs from the CSF into blood.…”

Section: Introductionmentioning

confidence: 99%

“…The choroid plexus generally limits drug disposition of the brain parenchyma through the prevention of entry of systemically administered compounds into the CSF or excretion of intrathecally applied drugs from the CSF into blood. The latter is achieved by several plasma membrane proteins expressed at the luminal side of the CP that mediate uptake of drugs from the CSF into CP cells and carrier proteins located at the basolateral membrane mediating drug efflux from the CP into blood (Spector and Johanson, 2010).…”

Section: Introductionmentioning

confidence: 99%

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The Antiepileptic Drugs Phenobarbital and Carbamazepine Reduce Transport of Methotrexate in Rat Choroid Plexus by Down-Regulation of the Reduced Folate Carrier

Halwachs

Lakoma²,

Schäfer³

et al. 2011

Molecular Pharmacology

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Intrathecal methotrexate (MTX) has been associated with severe neurotoxicity. Because carrier-associated removal of MTX from the cerebrospinal fluid (CSF) into blood remains undefined, we determined the expression and function of MTX transporters in rat choroid plexus (CP). MTX neurotoxicity usually manifests as seizures requiring therapy with antiepileptic drugs (AEDs) such as phenobarbital (PB). Because we have demonstrated that PB reduces activity of MTX influx carrier reduced folate carrier (Rfc1) in liver, we investigated the influence of the AEDs PB, carbamazepine (CBZ), or gabapentin on Rfc1-mediated MTX transport in CP. Reverse transcriptase-polymerase chain reaction and Western blot analysis showed similar expression of the MTX influx carrier Rfc1 and organic anion transporter 3 or efflux transporter multidrug resistance-associated protein 1 (Mrp1) and breast cancer resistance protein (Bcrp) in rat CP tissue and choroidal epithelial Z310 cells. Confocal microscopy revealed subcellular localization of Rfc1 and Bcrp at the apical and of Mrp1 at the basolateral CP membrane. Uptake, efflux, and inhibition studies indicated MTX transport activity of Rfc1, Mrp1, and Bcrp. PB and CBZ but not gabapentin significantly inhibited Rfc1-mediated uptake of MTX in CP cells. Studies on the regulatory mechanism showed that PB significantly inhibited Rfc1 translation but did not alter carrier gene expression. Altogether, removal of intrathecal MTX across the blood-CSF barrier may be achieved through Rfc1-mediated uptake from the CSF followed by MTX extrusion into blood, particularly via Mrp1. Antiepileptic treatment with PB or CBZ causes post-transcriptional down-regulation of Rfc1 activity in CP. This mechanism may result in enhanced MTX toxicity in patients with cancer who are receiving intrathecal MTX chemotherapy by reduced CSF clearance of the drug.

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Blood–Brain Barrier Transporters and Central Nervous System Drug Response and Toxicity

Miller

Line

Safa

et al. 2021

Transporters and Drug‐Metabolizing Enzymes in Drug Toxicity

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Vectorial Ligand Transport Through Mammalian Choroid Plexus

Cited by 35 publications

References 37 publications

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

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

The Antiepileptic Drugs Phenobarbital and Carbamazepine Reduce Transport of Methotrexate in Rat Choroid Plexus by Down-Regulation of the Reduced Folate Carrier

Blood–Brain Barrier Transporters and Central Nervous System Drug Response and Toxicity

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