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1.
Drug Metab Pharmacokinet ; 29(5): 387-93, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24717839

RESUMO

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.


Assuntos
Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/metabolismo , Dinoprostona/metabolismo , Ácido Glutâmico/farmacologia , Receptores de N-Metil-D-Aspartato/metabolismo , Animais , Dinoprostona/administração & dosagem , Relação Dose-Resposta a Droga , Ácido Glutâmico/administração & dosagem , Ácido Glutâmico/metabolismo , Injeções Intraventriculares , Masculino , Ratos , Ratos Wistar , Relação Estrutura-Atividade
2.
J Neurochem ; 123(5): 750-60, 2012 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-22978524

RESUMO

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 ß-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 µM. 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) .


Assuntos
Barreira Hematoencefálica/metabolismo , Plexo Corióideo/metabolismo , Dinoprostona/metabolismo , Animais , Encéfalo/metabolismo , Immunoblotting , Imuno-Histoquímica , Oxirredutases Intramoleculares/biossíntese , Masculino , Camundongos , Transportadores de Ânions Orgânicos Sódio-Independentes/metabolismo , Prostaglandina-E Sintases , Ratos , Xenopus laevis
3.
J Pharmacol Exp Ther ; 343(3): 608-16, 2012 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-22931759

RESUMO

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 µM, 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.


Assuntos
Barreira Hematoencefálica/metabolismo , Transportadores de Ânions Orgânicos Sódio-Independentes/líquido cefalorraquidiano , Transportadores de Ânions Orgânicos/líquido cefalorraquidiano , Prostaglandina D2/líquido cefalorraquidiano , Sono/fisiologia , Animais , Transporte Biológico , Plexo Corióideo/metabolismo , Cromatografia Líquida de Alta Pressão , Células Epiteliais/metabolismo , Feminino , Imuno-Histoquímica , Injeções Intraventriculares , Masculino , Taxa de Depuração Metabólica , Camundongos , Camundongos Endogâmicos , Oócitos/metabolismo , Transportadores de Ânions Orgânicos/sangue , Transportadores de Ânions Orgânicos/genética , Transportadores de Ânions Orgânicos Sódio-Independentes/sangue , Transportadores de Ânions Orgânicos Sódio-Independentes/genética , Prostaglandina D2/administração & dosagem , Prostaglandina D2/genética , Prostaglandina D2/farmacocinética , Ratos , Ratos Wistar , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Distribuição Tecidual , Xenopus laevis
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