Transporter-mediated prostaglandin E₂ elimination across the rat blood-brain barrier and its attenuation by the activation of N-methyl-D-aspartate receptors.
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.
Department of Pharmaceutics, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama.
Shin-ichi
S
Akanuma
Takanori
T
Higuchi
Hideyuki
H
Higashi
Go
G
Ozeki
Masanori
M
Tachikawa
Yoshiyuki
Y
Kubo
Ken-ichi
K
Hosoya
D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects* / Q000378:metabolism*; D015232:Dinoprostone / Q000008:administration & dosage / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D018698:Glutamic Acid / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D007276:Injections, Intraventricular; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D013329:Structure-Activity Relationship
D016194:Receptors, N-Methyl-D-Aspartate; D018698:Glutamic Acid; D015232:Dinoprostone