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

Nicola Marchi, Giovanna Guiso, Silvio Caccia, Massimo Rizzi, Barbara Gagliardi, Francesco Noé, Teresa Ravizza, Stefania Bassanini, Stefano Chimenti, Giorgio Battaglia, Annamaria Vezzani

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)429-442
Number of pages14
JournalNeurobiology of Disease
Volume24
Issue number3
DOIs
Publication statusPublished - Dec 2006

Keywords

  • Blood-brain barrier
  • Epilepsy
  • Methylazoxymethanol acetate
  • Multidrug transport proteins
  • P-glycoprotein
  • Pharmacoresistance

ASJC Scopus subject areas

  • Neurology

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