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

Abstract

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.

Membrane Transporters Contributing to PGE₂ Distribution in Central Nervous System

“…The uptake was inhibited by various organic anions, especially bromocresol green (an inhibitor for OATP2A1), and to a lesser extent benzylpenicillin and p-aminohippuric acid, whereas digoxin did not affect it. This observation agrees with the facts that PGD 2 was actively uptaken by rat CP, 59) implying a role of organic anion carriers in PGE 2 clearance from CSF at the CP.…”

“…[53][54][55][56] K m values of PGE 2 to OAT3 range from 345 to 4240 nM, whereas those to OATP2A1 are approximately 100 to 300 nM [53][54][55][56] (Table 1); therefore, OAT3 is regarded as a low-affinity/high-capacity transporter for PGs. [57][58][59] Indeed, efflux rate of externally pre-injected PGE 2 into the rat brain was significantly reduced in the presence of an OAT3 substrate benzylpenicillin. 60) This suggests that OAT3 is likely a candidate carrier for PGE 2 efflux at the BBB.…”

“…Oatp2a1 is expressed at the CP in rats, 29,75) and more recently its immunoreactivity was confirmed at the apical membranes of epithelial cells at the CP in mice and rats. 59,76) Currently, there is no information on OATP2A1 expression in the CP in humans. Moreover, sophisticated in situ hybridization with immunohistochemical approach revealed Oatp2a1 expression at the apical side (facing the subarachnoidal space) of arachnoid membranes in rats.…”

“…28) Elimination clearance of radiolabeled PGD 2 , which is another substrate of OATP2A1 with similar affinity to PGE 2 , [53][54][55] was approximately 15 times greater than inulin, a reference compound for CSF turnover and diffusion into the brain interstitial space, and significantly inhibited by co-injection of unlabeled PGD 2 . 59) In addition, Hosotani et al 76) suggested that elevated expression of Oatp2a1 in blood vessels of subarachnoid space facilitates elimination of PGE 2 from CSF. Thus OATP2A1 expressed at the CP is considered one of the molecular determinants of PGE 2 in CSF.…”

Inhibition of human microsomal PGE2 synthase‐1 reduces seizure‐induced increases of P‐glycoprotein expression and activity at the blood‐brain barrier

“…hmPGES-1 (Clo-ne6C6) antibody for Western blotting and immunostaining was from Cayman Chemical (Ann Arbor, MI, USA; 10004350, RRID: AB_10079051). Guinea pig-derived anti-mPGES-1 pAb was kindly provided by Ken-Ichi Hosoya (Toyama University, Toyama, Japan) (28)(29)(30). Kainic acid and b-actin antibody (ab8226) were obtained from Abcam (Cambridge, MA, USA).…”