Determinants of drug brain uptake in a rat model of seizure-associated malformations of cortical development.
Neurobiol Dis
; 24(3): 429-42, 2006 Dec.
Article
em En
| MEDLINE
| ID: mdl-17027274
ABSTRACT
We examined the blood-brain barrier (BBB) function in methylazoxymethanol acetate (MAM)-treated rats, a model of human developmental brain malformations. We found aberrant vessels morphology and serum albumin leakage in the heterotopic (malformed) hippocampus; these changes were associated with a significant increase in endothelial P-glycoprotein (P-gp) expression. Seizures exacerbated BBB leakage and greatly augmented P-gp expression in vessels and additionally in perivascular/parenchymal astrocytes. The effects of seizures were observed to a much larger extent in malformed than in normal brain tissue. The intrinsic changes in BBB function in MAM-exposed rats were associated with increased blood-to-brain penetration of ondansetron, a P-gp substrate. However, a marked reduction in drug brain levels was provoked by seizures, and this effect was reversed by selective blockade of P-gp activity with tariquidar. Changes in BBB function may critically contribute to determine the brain uptake and distribution of P-gp substrates in epileptic tissue associated with developmental malformations.
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Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Convulsões
/
Barreira Hematoencefálica
/
Membro 1 da Subfamília B de Cassetes de Ligação de ATP
/
Células Endoteliais
/
Epilepsia
/
Hipocampo
Tipo de estudo:
Risk_factors_studies
Limite:
Animals
/
Pregnancy
Idioma:
En
Revista:
Neurobiol Dis
Assunto da revista:
NEUROLOGIA
Ano de publicação:
2006
Tipo de documento:
Article
País de afiliação:
Itália