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. [³H]PGE₂ injected into the cerebral cortex was eliminated from the brain in rats, and the apparent brain-to-blood [³H]PGE₂ efflux clearance was found to be 60.1 µL/(min·g brain). Intracerebral pre-administration of 50 mM L-Glu significantly inhibited [³H]PGE₂ elimination across the BBB and this L-Glu-induced inhibition was abolished by co-administration of an intracellular Ca²⁺ chelator. The intracellular Ca²⁺ concentration is reported to be increased via N-methyl-d-aspartate (NMDA)-type L-Glu receptors (NMDAR) and [³H]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.