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

Abstract

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...

A Critical Role for Astrocytes in Hypercapnic Vasodilation in Brain

“…Astrocytes are immunoreactive for both the enzyme proteins COX-1 (Takano et al, 2006; Gordon et al, 2008) and mPgES-1 (see Fig. 3 A and Tachikawa et al, 2012). mPgES-1, the form of prostaglandin E synthase expressed in astrocytes, requires the cofactor glutathione (GSH) (Jakobsson et al, 1999; Murakami et al, 2000) that is present in high levels in astrocytes (see Fig.…”

Molecular anatomy and functions of the choroidal blood-cerebrospinal fluid barrier in health and disease

“…The BCSFB is involved in the continuous removal of prostaglandin E2 from the CSF, keeping low the intracerebral levels of this proinflammatory mediator [156]. A downregulation of prostaglandin E2 efflux transporters occurs in the models of bacterial meningitis and viral infection, and may exacerbate the effects of neuroinflammation [57,67].…”

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

“…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.…”

“…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).…”

“…Nonetheless, the PGE2 elevation in CSF precedes the up-regulation of the mPGES-1 transcript. Several explanations for this apparent contradiction could be considered, such as the presence of a preexisting PGE2 pool in, for example, the cell components of the neuro-vascular unit (Tachikawa et al, 2012), or an initial effect mediated by constitutively expressed enzymes coupled transiently to rapidly produce and release PGE2 (Turrin and Rivest, 2004). The latter hypothesis is supported by studies identifying a COX-1 dependency of the early behavior changes (Swiergiel and Dunn, 2002), the initiation of fever (Zhang et al, 2003), the hypothermic response after the first phase of fever (Steiner et al, 2009), and the HPA-activation (Elander et al, 2009;Elander et al, 2010).…”