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Determinants of drug brain uptake in a rat model of seizure-associated malformations of cortical development.

Marchi N, Guiso G, Caccia S, Rizzi M, Gagliardi B, Noé F, Ravizza T, Bassanini S, Chimenti S, Battaglia G, Vezzani A

Dept Neuroscience, Mario Negri Inst for Pharmacol Res, Via Eritrea 62, 20157 Milano, Italy.

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.

Published 19 November 2006 in Neurobiol Dis, 24(3): 429-42.
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