Drug Transporters on Arachnoid Barrier Cells Contribute to the Blood–Cerebrospinal Fluid Barrier

Yasuda, Kazuto; Cline, Cynthia; Vogel, Peter; Onciu, Mihaela; Fatima, Soghra; Sorrentino, Brian P.; Thirumaran, Ranjit K.; Ekins, Sean; Urade, Yoshihiro; Fujimori, Ko; Schuetz, Erin G.

doi:10.1124/dmd.112.050344

Cited by 115 publications

(124 citation statements)

References 32 publications

Supporting

Mentioning

119

Contrasting

Unclassified

Order By: Relevance

“…It is well recognized that P-gp may protect the brain from noxious substances [22]. Within the CNS, this transporter is located at the apical membranes of the blood-CNS barriers, adluminal to the blood at the (BBB, brain endothelial cells) [17] and the arachnoid barrier cells at the arachnoidea mater [23] as well as adluminal to the CSF at the blood CSF barrier (BCSFB, epithelial cells of the choroid plexus) [17]. The relative distribution and functionality of P-gp at the 3 barriers is unclear in humans.…”

Section: Resultsmentioning

confidence: 99%

Quantification of Bisoprolol and Metoprolol in Simultaneous Human Serum and Cerebrospinal Fluid Samples

et al. 2017

View full text Add to dashboard Cite

Background: Bisoprolol and metoprolol are moderately lipophilic, beta(1)-selective betablockers reported to cause adverse effects in the central nervous system (CNS), such as sleep disturbance, suggesting that both drugs may reach relevant concentrations in the brain. CNS beta(2)-receptor blockade has been suspected to be related to such effects. The higher molecular size of bisoprolol (325 Dalton) and the higher beta(1)-selectivity compared to metoprolol (267 Dalton) would suggest a lower rate of CNS effects. Methods: To address the pharmacokinetic background of this assumption, we quantified to which extent these beta(1)-blockers are able to enter the cerebrospinal fluid (CSF) in 9 (bisoprolol group) and 10 (metoprolol group) neurological patients who had received one of the drugs orally for therapeutic purposes prior to lumbar puncture. We quantified their total concentrations by liquid chromatography/tandem mass spectrometry in paired serum and CSF samples. Results: Median (interquartile range) in CSF reached 55% (47-64%) of total serum concentrations for bisoprolol and 43% (27-81%) for metoprolol, corresponding to 78% (67-92%) and 48% (30-91%) of respective unbound serum concentrations. Conclusion: The extent of penetration of bisoprolol and metoprolol into the CSF is similar and compatible with the assumption that both drugs may exert direct effects in the CNS.

show abstract

Section: Resultsmentioning

confidence: 99%

Quantification of Bisoprolol and Metoprolol in Simultaneous Human Serum and Cerebrospinal Fluid Samples

et al. 2017

View full text Add to dashboard Cite

show abstract

“…34) In addition to these reports, Yasuda et al have found that arachnoid barrier epithelial cells, which are present in meninges, express several kinds of transporters, such as P-glycoprotein and ATPbinding cassette transporter G2. 35) Thus, there is a possibility that these epithelial cells also involves in vivo spermine elimination from the CSF. Further studies involving identification of spermine-recognizing transporters which are distinct from well-known transporters and the expression of these molecules on choroid plexus epithelial cells, ependymal cells, and arachnoid barrier epithelial cells, may help us to better understand the details of this spermine elimination from the CSF.…”

Section: Resultsmentioning

confidence: 99%

Involvement of Carrier-Mediated Transport at the Blood–Cerebrospinal Fluid Barrier in Spermine Clearance from Rat Brain

Akanuma

Shimada

Kubo

et al. 2017

Biological & Pharmaceutical Bulletin

View full text Add to dashboard Cite

Spermine is the end-product in the polyamine biosynthetic pathway, and its excess accumulation induces neuroexcitatory responses and neurotoxicity. The purpose of this study was to elucidate the involvement of transport systems at the brain barriers in the clearance of spermine. In vivo rat spermine elimination from brain parenchyma across the blood-brain barrier (BBB) and blood-cerebrospinal fluid (CSF) barrier (BCSFB) was assessed by intracerebral and intracerebroventricular administration techniques, respectively. To characterize spermine transport at the BCSFB, a transport study using rat choroid plexus was performed. After the intracerebral microinjection of [ Spermine is a natural polyamine, and the end-product in the polyamine biosynthetic pathway.1) In the brain, spermine binds to N-methyl-D-aspartate receptors, and is involved in the modulation of learning and memory.2,3) In addition, excess accumulation of spermine induces neuroexcitatory responses and, thus, neurotoxicity. 4) Therefore, it is considered that some mechanisms for control of the cerebral spermine concentration are present in the brain to maintain homeostasis of cerebral function via spermine-related neuro-responses. The precursor of spermine is spermidine, 5) which is synthesized from putrescine and it has been reported that the biosynthesis of spermine from spermidine is superior to that of spermidine from spermine.6-8) Hence, neural spermine transport system(s) could be important for the removal of spermine from the brain, and the modulation of cerebral spermine concentration.Brain parenchyma and cerebrospinal fluid (CSF) are separated from the circulating blood by the blood-brain barrier (BBB) and blood-CSF barrier (BCSFB), respectively. The BBB and BCSFB are formed by brain capillary endothelial and choroid plexus epithelial cells, respectively, and express some transporting molecules which are involved in active elimination of compound from the brain or CSF.9) Regarding the cationic compound elimination system(s) at these barriers, mRNAs of plasma membrane monoamine transporter (PMAT/ solute carrier (SLC)29A4), organic cation/carnitine transporter 1-2 (OCTN1-2/SLC22A4-5), organic cation transporter 1-3 (OCT1-3/SLC22A1-3), and multidrug and toxin extrusion 1-2 (MATE1-2/SLC47A1-2) are expressed in rat BBB and BCSFB cell lines. 10) Among these transporters, PMAT is, at least in part, involved in brain/CSF-to-blood transport of 1-methyl-4-phenylpyridinium (MPP + ) 10) and CSF-to-blood transport of histamine.11) In addition, OCT3 takes part in the efflux transport of creatinine, a cationic guanidino compound.12) Therefore, it is possible that cerebral spermine is eliminated across these brain barriers.Some previous studies have reported that polyamines including spermine are transported in a carrier-mediated manner in some organs and it has been reported that carrier-mediated transport of polyamines is present in mammalian intestine, liver, and kidney. [13][14][15] In addition, we have demonstrated that the rat inner blood-retinal barr...

show abstract

“…There are many differences between the transporters and enzymes expressed in the different barrier layers, suggesting that they play different but complementary roles in regulation of molecular fl ux (Strazielle and Ghersi-Egea 2013 ;Saunders et al 2013 ;Yasuda et al 2013 ). The transporters present include considerable overlap in function/apparent redundancy at each site, refl ecting their evolutionary history (Dean and Annilo 2005 ) and ensuring maintained function in case of loss or defect of a single transporter.…”

Section: Small Solute Transport At the Barrier Layersmentioning

confidence: 99%

Anatomy and Physiology of the Blood–Brain Barriers

Abbott

2013

AAPS Advances in the Pharmaceutical Sciences Series

View full text Add to dashboard Cite

This chapter covers the three main barrier layers separating blood and the central nervous system (CNS): the endothelium of the brain vasculature, the epithelium of the choroid plexus secreting cerebrospinal fl uid (CSF) into the ventricles and the arachnoid epithelium forming the middle layer of the meninges on the brain surface. There are three key barrier features at each site that control the composition of brain fl uids and regulate CNS drug permeation: (1) physical barriers result from features of the cell membranes and of the tight junctions restricting the paracellular pathway through intercellular clefts; (2) transport barriers result from membrane transporters mediating solute uptake and effl ux, together with vesicular mechanisms mediating transcytosis of larger molecules such as peptides and proteins and (3) enzymatic barriers result from cell surface and intracellular enzymes that can modify molecules in transit. Brain fl uids (CSF and brain interstitial fl uid) are secreted, fl ow through particular routes and then drain back into the venous system; this fl uid turnover aids central homeostasis and also affects CNS drug concentration. Several CNS pathologies involve changes in the barrier layers and the fl uid systems. Many of these aspects of physiology and pathology have implications for drug delivery.

show abstract

Drug Transporters on Arachnoid Barrier Cells Contribute to the Blood–Cerebrospinal Fluid Barrier

Cited by 115 publications

References 32 publications

Quantification of Bisoprolol and Metoprolol in Simultaneous Human Serum and Cerebrospinal Fluid Samples

Quantification of Bisoprolol and Metoprolol in Simultaneous Human Serum and Cerebrospinal Fluid Samples

Involvement of Carrier-Mediated Transport at the Blood–Cerebrospinal Fluid Barrier in Spermine Clearance from Rat Brain

Anatomy and Physiology of the Blood–Brain Barriers

Contact Info

Product

Resources

About