A Clearance System for Prostaglandin D<sub>2</sub>, a Sleep-Promoting Factor, in Cerebrospinal Fluid: Role of the Blood-Cerebrospinal Barrier Transporters

Tachikawa, Masanori; Tsuji, Kazuhiro; Yokoyama, Reiji; Higuchi, Takanori; Ozeki, Go; Yashiki, Ayane; Akanuma, Shin Ichi; Hayashi, Kazuyuki; Nishiura, Akio; Hosoya, Ken

doi:10.1124/jpet.112.197012

Cited by 30 publications

(26 citation statements)

References 35 publications

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“…For example, prostaglandins are thought to utilize plasma membrane-localized transporters to traverse biological membranes [21,22]. In contrast to such charged lipids, endocannabinoids are uncharged and more lipophilic and readily cross synthetic [23,24] and biological membranes [20,25,26], although the existence of an endocannabinoid transmembrane transporter has also been proposed [27].…”

Section: Discussionmentioning

confidence: 99%

Role of FAAH-Like Anandamide Transporter in Anandamide Inactivation

et al. 2013

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The endocannabinoid system modulates numerous physiological processes including nociception and reproduction. Anandamide (AEA) is an endocannabinoid that is inactivated by cellular uptake followed by intracellular hydrolysis by fatty acid amide hydrolase (FAAH). Recently, FAAH-like anandamide transporter (FLAT), a truncated and catalytically-inactive variant of FAAH, was proposed to function as an intracellular AEA carrier and mediate its delivery to FAAH for hydrolysis. Pharmacological inhibition of FLAT potentiated AEA signaling and produced antinociceptive effects. Given that endocannabinoids produce analgesia through central and peripheral mechanisms, the goal of the current work was to examine the expression of FLAT in the central and peripheral nervous systems. In contrast to the original report characterizing FLAT, expression of FLAT was not observed in any of the tissues examined. To investigate the role of FLAT as a putative AEA binding protein, FLAT was generated from FAAH using polymerase chain reaction and further analyzed. Despite its low cellular expression, FLAT displayed residual catalytic activity that was sensitive to FAAH inhibitors and abolished following mutation of its catalytic serine. Overexpression of FLAT potentiated AEA cellular uptake and this appeared to be dependent upon its catalytic activity. Immunofluorescence revealed that FLAT localizes primarily to intracellular membranes and does not contact the plasma membrane, suggesting that its capability to potentiate AEA uptake may stem from its enzymatic rather than transport activity. Collectively, our data demonstrate that FLAT does not serve as a global intracellular AEA carrier, although a role in mediating localized AEA inactivation in mammalian tissues cannot be ruled out.

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Section: Discussionmentioning

confidence: 99%

Role of FAAH-Like Anandamide Transporter in Anandamide Inactivation

et al. 2013

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“…9,[14][15][16][29][30][31][32][33] Brain efflux index study: In vivo rat BBB-mediated efflux transport was evaluated using an intracerebral microinjection technique: the BEI method. 34) The detailed procedure is described in the Supplemental materials.…”

Section: Methodsmentioning

confidence: 99%

Transporter-mediated Prostaglandin E2 Elimination across the Rat Blood-brain Barrier and Its Attenuation by the Activation of N-methyl-D-aspartate Receptors

Akanuma

Higuchi

Higashi

et al. 2014

Drug Metabolism and Pharmacokinetics

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Prostaglandin (PG) E2 is involved in neuroinflammation and neurotoxicity, and the cerebral PGE2 concentration is increased in neurodegenerative diseases. Because the intracerebral concentration of L-glutamate (L-Glu) is reported to be also elevated in neurodegenerative diseases, it has been proposed that L-Glu affects PGE2 dynamics in the brain, and thus exacerbates neural excitotoxicity. The purpose of this study was to investigate the effect of intracerebral L-Glu on PGE2 elimination across the blood-brain barrier (BBB) in rats by using the intracerebral microinjection technique. [(3)H]PGE2 injected into the cerebral cortex was eliminated from the brain in rats, and the apparent brain-to-blood [(3)H]PGE2 efflux clearance was found to be 60.1 µL/(min·g brain). Intracerebral pre-administration of 50 mM L-Glu significantly inhibited [(3)H]PGE2 elimination across the BBB and this L-Glu-induced inhibition was abolished by co-administration of an intracellular Ca(2+) chelator. The intracellular Ca(2+) concentration is reported to be increased via N-methyl-d-aspartate (NMDA)-type L-Glu receptors (NMDAR) and [(3)H]PGE2 elimination was attenuated by intracerebral pre-administration of a mixture of NMDA and D-serine. Moreover, the co-administration of antagonists of NMDAR with L-Glu abolished the attenuation of PGE2 elimination induced by intracerebral L-Glu administration. These results suggest that L-Glu attenuates BBB-mediated PGE2 elimination via NMDAR-mediated processes.

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“…) and PGT‐mediated [ 3 H]PGD 2 uptake (Tachikawa et al . ; in press). This raises one possibility that oatp1a5 and/or PGT would be responsible for the benzylpenicillin‐insensitive [ 3 H]PGE 2 uptake by the choroid plexus.…”

Section: Discussionmentioning

confidence: 98%

“…, ; Tachikawa et al . , in press). The elimination process via transporter(s) at the BCSFB should be responsible for the accumulation of PGE 2 in the CSF, being a therapeutic target for drugs which can prevent PGE 2 accumulation in the CSF.…”

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confidence: 99%

Role of the blood–cerebrospinal fluid barrier transporter as a cerebral clearance system for prostaglandin E₂ produced in the brain

Tachikawa

Ozeki

Higuchi

et al. 2012

Journal of Neurochemistry

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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...

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A Clearance System for Prostaglandin D₂, a Sleep-Promoting Factor, in Cerebrospinal Fluid: Role of the Blood-Cerebrospinal Barrier Transporters

Cited by 30 publications

References 35 publications

Role of FAAH-Like Anandamide Transporter in Anandamide Inactivation

Role of FAAH-Like Anandamide Transporter in Anandamide Inactivation

Transporter-mediated Prostaglandin E2 Elimination across the Rat Blood-brain Barrier and Its Attenuation by the Activation of N-methyl-D-aspartate Receptors

Role of the blood–cerebrospinal fluid barrier transporter as a cerebral clearance system for prostaglandin E₂ produced in the brain

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A Clearance System for Prostaglandin D2, a Sleep-Promoting Factor, in Cerebrospinal Fluid: Role of the Blood-Cerebrospinal Barrier Transporters

Cited by 30 publications

References 35 publications

Role of FAAH-Like Anandamide Transporter in Anandamide Inactivation

Role of FAAH-Like Anandamide Transporter in Anandamide Inactivation

Transporter-mediated Prostaglandin E2 Elimination across the Rat Blood-brain Barrier and Its Attenuation by the Activation of N-methyl-D-aspartate Receptors

Role of the blood–cerebrospinal fluid barrier transporter as a cerebral clearance system for prostaglandin E2 produced in the brain

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A Clearance System for Prostaglandin D₂, a Sleep-Promoting Factor, in Cerebrospinal Fluid: Role of the Blood-Cerebrospinal Barrier Transporters

Role of the blood–cerebrospinal fluid barrier transporter as a cerebral clearance system for prostaglandin E₂ produced in the brain