The lipophilicity trend line constructed from the RUI and DC values is considered to reflect the transport properties of drugs undergoing passive diffusion across the BRB.

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Prostaglandin E 2 (PGE 2 ) acts as a modulator of synaptic signaling and excitability in the brain. Because PGE 2 is barely inactivated enzymatically in adult brain, its brain level is considered to be controlled by efflux transport across the bloodbrain barrier (BBB). The purpose of the present study was to clarify the efflux transport of PGE 2 at the BBB and the interaction of various drugs with this process. [ 3 H]PGE 2 was eliminated from brain across the BBB with a half-life of 16.3 min, and the elimination was inhibited by 3 mM unlabeled PGE 2 . Multidrug resistance-associated protein 4 (MRP4/ABCC4) was reported to be localized at the luminal membrane of the BBB. MRP4-expressing membrane vesicles showed significant uptake of 3 H]PGE 2 elimination across the BBB (ID 50 ϭ 120 mg/kg). These results indicate that PGE 2 is eliminated from the brain by MRP4-mediated efflux transport at the BBB, and peripheral administration of cefmetazole decreases the efflux transport of PGE 2 at the BBB; this interaction may influence brain function.Prostaglandin E 2 (PGE 2 ) is a main product of the cyclooxygenase (COX)

An increasing level of prostaglandin (PG) E 2 is involved in the progression of neuroinflammation induced by ischemia and bacterial infection. Although an imbalance in the rates of production and clearance of PGE 2 under these pathological conditions appears to affect the concentration of PGE 2 in the cerebrospinal fluid (CSF), the regulatory system remains incompletely understood. The purpose of this study was to investigate the cellular system of PGE 2 production via microsomal PGE synthetase-1 (mPGES-1), the inducible PGE 2 -generating enzyme, and PGE 2 elimination from the CSF via the blood-CSF barrier (BCSFB). Immunohistochemical analysis revealed that mPGES-1 was expressed in the soma and perivascular sheets of astrocytes, pia mater, and brain blood vessel endothelial cells, suggesting that these cells are local production sites of PGE 2 in the CSF. The in vivo PGE 2 elimination clearance from the CSF was eightfold greater than that of D-mannitol, which is considered to reflect CSF bulk flow. This process was inhibited by the simultaneous injection of unlabeled PGE 2 and b-lactam antibiotics, such as benzylpenicillin, cefazolin, and ceftriaxone, which are substrates and/or inhibitors of organic anion transporter 3 (OAT3). The characteristics of PGE 2 uptake by the isolated choroid plexus were at least partially consistent with those of OAT3. OAT3 was able to mediate PGE 2 transport with a Michaelis-Menten constant of 4.24 lM. These findings indicate that a system regulating the PGE 2 level in the CSF involves OAT3-mediated PGE 2 uptake by choroid plexus epithelial cells, acting as a cerebral clearance pathway via the BCSFB of locally produced PGE 2 . Keywords: blood-cerebrospinal fluid barrier, clearance, inflammation, mPGES-1, prostaglandin E 2 , prostaglandin synthase. J. Neurochem. (2012) 123, 750-760. Prostaglandin (PG) E 2 is the crucial mediator, which propagates neuroinflammation induced by ischemia and bacterial infection. The PGE 2 level is significantly increased in the Cerebrospinal fluid (CSF) of the patients suffering from stroke (0.57-8.5 nM;Carasso et al. 1977) and lipopolysaccharide (LPS)-treated rats (~3.4 nM; Gao et al. 2009), although the PGE 2 concentration in normal CSF is below the detection limit in humans (Romero et al. 1984) and 0.15 nM in rats (Gao et al. 2009). As a positive correlation has been found between the PGE 2 level in the CSF and the severity and clinical outcome of the stroke (Carasso et al. 1977), the CSF concentration of PGE 2 appears to be a key determinant of the progression of neuroinflammation.Received June 12, 2012; revised manuscript received August 29, 2012; accepted September 08, 2012.Address correspondence and reprint requests to Ken-ichi Hosoya, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama 930-0194, Japan. E-mail: hosoyak@pha.u-toyama.ac.jp Abbreviations used: BBB, blood-brain barrier; BCSFB, bloodcerebrospinal fluid barrier; CHO, Chinese hamster ovary; cPGES, cytosolic prostaglandin E synthetase; CSF, cer...

Amyloid-b peptide (Ab) concentration in CSF is potentially a diagnostic and therapeutic target for Alzheimer's disease (AD). The purpose of this study was to clarify the elimination mechanism of human Ab(1-40) human receptor-associated protein (RAP) and the elimination was attenuated in either anti-low-density lipoprotein receptorrelated protein (LRP)1 antibody-treated or RAP-deficient mice, suggesting that a member(s) of the low-density lipoprotein receptor gene family is involved in the elimination of hAb(1-40) from CSF. The amounts of LRP1 and LRP2 proteins were determined by means of liquid chromatographytandem mass spectrometry, and the LRP1 content in rat choroid plexus was determined to be 3.7 fmol/lg protein, whereas the LRP2 content was below the detection limit (< 0.2 fmol/lg protein). Conditionally, immortalized rat choroid plexus epithelial cells exhibited predominant apical-to-basal and apical-to-cell transport of [ 125 I]hAb(1-40). These results indicated that hAb(1-40) is actively eliminated from CSF and this process is at least partly mediated by LRP1 expressed at choroid plexus epithelial cells, which therefore play a role in determining CSF concentrations of hAb(1-40). Keywords: Alzheimer's disease, amyloid-b peptide, bloodcerebrospinal fluid barrier, choroid plexus, conditionally immortalized rat choroid plexus epithelial cell line cells, lowdensity lipoprotein receptor-related protein-1.