Involvement of Multidrug Resistance-Associated Protein 4 in Efflux Transport of Prostaglandin E<sub>2</sub> across Mouse Blood-Brain Barrier and Its Inhibition by Intravenous Administration of Cephalosporins

Akanuma, Shin Ichi; Hosoya, Ken; Ito, Shingo; Tachikawa, Masanori; Ohtsuki, Sumio

doi:10.1124/jpet.109.165332

Cited by 32 publications

(46 citation statements)

References 35 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Efflux systems at the BBB have been characterized for compounds whose accumulation in the CNS would lead to neuronal damage such as amyloid b (Shibata et al, 2000), prostaglandin E 2 (Akanuma et al, 2010), and interleukin-2 (Banks et al, 2004). We observed that an efflux system also exists for CCL11.…”

Section: Discussionmentioning

confidence: 69%

Rapid Transport of CCL11 across the Blood-Brain Barrier: Regional Variation and Importance of Blood Cells

Erickson

Morofuji

Owen

et al. 2014

J Pharmacol Exp Ther

View full text Add to dashboard Cite

Increased blood levels of the eotaxin chemokine C-C motif ligand 11 (CCL11) in aging were recently shown to negatively regulate adult hippocampal neurogenesis. How circulating CCL11 could affect the central nervous system (CNS) is not clear, but one possibility is that it can cross the blood-brain barrier (BBB). Here, we show that CCL11 undergoes bidirectional transport across the BBB. Transport of CCL11 from blood into whole brain (influx) showed biphasic kinetics, with a slow phase preceding a rapid phase of uptake. We found that the slow phase was explained by binding of CCL11 to cellular components in blood, whereas the rapid uptake phase was mediated by direct interactions with the BBB. CCL11, even at high doses, did not cause BBB disruption. All brain regions except striatum showed a delayed rapid-uptake phase. Striatum had only an early rapid-uptake phase, which was the fastest of any brain region. We also observed a slow but saturable transport system for CCL11 from brain to blood. C-C motif ligand 3 (CCR3), an important receptor for CCL11, did not facilitate CCL11 transport across the BBB, although high concentrations of a CCR3 inhibitor increased brain uptake without causing BBB disruption. Our results indicate that CCL11 in the circulation can access many regions of the brain outside of the neurogenic niche via transport across the BBB. This suggests that blood-borne CCL11 may have important physiologic functions in the CNS and implicates the BBB as an important regulator of physiologic versus pathologic effects of this chemokine.

show abstract

Section: Discussionmentioning

confidence: 69%

Rapid Transport of CCL11 across the Blood-Brain Barrier: Regional Variation and Importance of Blood Cells

Erickson

Morofuji

Owen

et al. 2014

J Pharmacol Exp Ther

View full text Add to dashboard Cite

show abstract

“…The present study indicates that indomethacin and diclofenac inhibit OAT3-mediated PGD 2 transport (Table 2). Furthermore, we have found that cefmetazole, cefazolin, ceftriaxone, and cefotaxime, administered intravenously to mice, inhibit [ 3 H]PGE 2 efflux transport from the brain across the blood-brain barrier most likely because of the inhibition of MRP4 (Akanuma et al, 2010). Thus, the inhibitory effect on the PGT-and OAT3-mediated PGD 2 transport should be taken into consideration in the development of new drugs.…”

Section: Discussionmentioning

confidence: 99%

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

Tachikawa

Tsuji

Yokoyama

et al. 2012

J Pharmacol Exp Ther

Self Cite

View full text Add to dashboard Cite

Although the level of prostaglandin (PG) D 2 in cerebrospinal fluid (CSF) affects the action of D-type prostanoid receptors that promote physiological sleep, the regulatory system of PGD 2 clearance from the CSF is not fully understood. The purpose of this study was to investigate PGD 2 elimination from the CSF via the blood-CSF barrier (BCSFB). The in vivo PGD 2 elimination clearance from the CSF was 16-fold greater than that of inulin, which is considered to reflect CSF bulk flow. This process was inhibited by the simultaneous injection of unlabeled PGD 2 . The characteristics of PGD 2 uptake by isolated choroid plexus were, at least partially, consistent with those of PG transporter (PGT) and organic anion transporter 3 (OAT3). Studies using an oocyte expression system showed that PGT and OAT3 were able to mediate PGD 2 transport with a Michaelis-Menten constant of 1.07 and 7.32 M, respectively. Reverse transcription-polymerase chain reaction and immunohistochemical analyses revealed that PGT was localized on the brush-border membrane of the choroid plexus epithelial cells. These findings indicate that the system regulating the PGD 2 level in the CSF involves PGT-and OAT3-mediated PGD 2 uptake by the choroid plexus epithelial cells, acting as a pathway for PGD 2 clearance from the CSF via the BCSFB.

show abstract

“…The transporters were shown to allow prostaglandin outflow from the brain tissue by exerting their actions at the polarized CNS-blood barrier. It was also demonstrated that this process is slowed at the transporter level by β-lactam antibiotics like cefmetazole and cefazolin or during inflammation (Akanuma et al, 2010;Akanuma et al, 2011;Tachikawa et al, 2012). Prostaglandin influx transporters are found in both the solute carrier organic anion (Slco) transporter family and the cation (Slc) transporter family.…”

Section: Pge2 Transportersmentioning

confidence: 99%

“…In the same study, another contradiction discussed by the authors was the early drop of PGE2 in CSF despite remaining high levels of COX-2 and mPGES-1. This as yet unsolved problem might have been answered in paper II by the up-regulation of the prostaglandin transporters in the barrier that by their suggested functions and cellular membrane localizations would contribute to the brain PGE2 clearance (Akanuma et al, 2010;Tachikawa et al, 2012).…”

Section: Brain Pge2 As a Mediator Of Fever At The Preoptic Regionmentioning

confidence: 99%

“…Cation influx transporters shown so far to have prostaglandin affinity are Slc22a8 (Oat3) (Kobayashi et al, 2004) and Slc22a22, (Shiraya et al, 2010), with Slc22a22 mostly expressed in the kidneys. The best characterized efflux transporter is a membrane transport pump, Multi drug resistance-associated protein 4 or ATP-binding cassette transporter 4 (Mrp4/Abcc4) (Akanuma et al, 2010;Reid et al, 2003), but still more transporters might be expected to exist.…”

Section: Pge2 Transportersmentioning

confidence: 99%

See 1 more Smart Citation

Talking to the Brain at the Blood-Brain Barrier through Inflammation-Induced Prostaglandin E2

Vasilache¹

2015

View full text Add to dashboard Cite

The immune-to-brain signaling is a critical survival factor when the body is confronted by pathogens, and in particular by microorganisms. During infections, the ability of the immune system to engage the central nervous system (CNS) in the management of the inflammatory response is just as important as its ability to mount a specific immune response against the pathogen, since the CNS can provide a systemic negative feed-back to the immune activation by release of stress hormones and also can prioritize the usage of the energy resources by the vital organs. Prostaglandin E2 (PGE2) and pro-inflammatory cytokines were among the first mediators to be identified to participate in the immune-to-brain signaling, a process that is clinically recognized by the development of manifestations of common illness such as fever, anorexia, decreased social interactions, lethargy, sleepiness, and hyperalgesia.In this thesis the contribution of PGE2 to the immune-to-brain signaling was further characterized at the blood-brain-barrier (BBB) and in the anterior preoptic area (POA) of the hypothalamus (i.e. the thermoregulatory region or, in sickness, the fever generating region).BBB is the major interface region between peripheral circulating cytokines and the neuronal parenchyma and a critical source of PGE2. Using chimeric mice lacking the inducible enzyme for PGE2 synthesis, microsomal PGE synthase-1 (mPGES-1), in either hematopoietic or nonhematopoietic cells, we demonstrate in paper I that brain endothelial cells are the critical source of PGE2 in BBB during peripheral inflammation. For the demonstration of the mPGES-1 expression in the BBB cells we developed in paper I a method for enzymatic dissociation of these cells, followed by fluorescence activated cell sorting (FACS). Using the same method, we show in paper II that the BBB response to immune stimuli is towards an increased production of PGE2 in endothelial cells and an increased sensitivity of these cells for proinflammatory cytokines. These changes are supported by decreased PGE2 degradation and decreased synthesis of other prostanoids in perivascular macrophages, which hence respond in concordance with the endothelial cells in enhancing PGE2 signaling.Once released in the neuronal tissue, PGE2 has been shown to be critical for the fever response by acting on the type 3 PGE2 receptors (EP3) within POA. By laser capture microdissection (LCM) we extracted the EP3 receptor expressing region in POA, defined by in situ hybridization histochemistry, from mouse brain sections. We demonstrate in paper III that the predominant subtypes of the EP3 receptor in POA are EP3α and EP3γ. In paper IV we further analyze the effect of PGE2 on the LCM dissected EP-rich POA using gene expression microarrays. We demonstrate that PGE2 has a limited effect on the gene expression changes within POA, suggesting that the neuronal activity is modulated by PGE2 in a transcriptionindependent manner and that the profound gene expression changes that are seen in the CNS during inflammation ...

show abstract

Involvement of Multidrug Resistance-Associated Protein 4 in Efflux Transport of Prostaglandin E₂ across Mouse Blood-Brain Barrier and Its Inhibition by Intravenous Administration of Cephalosporins

Cited by 32 publications

References 35 publications

Rapid Transport of CCL11 across the Blood-Brain Barrier: Regional Variation and Importance of Blood Cells

Rapid Transport of CCL11 across the Blood-Brain Barrier: Regional Variation and Importance of Blood Cells

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

Talking to the Brain at the Blood-Brain Barrier through Inflammation-Induced Prostaglandin E2

Contact Info

Product

Resources

About

Involvement of Multidrug Resistance-Associated Protein 4 in Efflux Transport of Prostaglandin E2 across Mouse Blood-Brain Barrier and Its Inhibition by Intravenous Administration of Cephalosporins

Cited by 32 publications

References 35 publications

Rapid Transport of CCL11 across the Blood-Brain Barrier: Regional Variation and Importance of Blood Cells

Rapid Transport of CCL11 across the Blood-Brain Barrier: Regional Variation and Importance of Blood Cells

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

Talking to the Brain at the Blood-Brain Barrier through Inflammation-Induced Prostaglandin E2

Contact Info

Product

Resources

About

Involvement of Multidrug Resistance-Associated Protein 4 in Efflux Transport of Prostaglandin E₂ across Mouse Blood-Brain Barrier and Its Inhibition by Intravenous Administration of Cephalosporins

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