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

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.

• Authors: Nicola Marchi, Giovanna Guiso, Silvio Caccia, Massimo Rizzi, Barbara Gagliardi, Francesco Noé, Teresa Ravizza, Stefania Bassanini, Stefano Chimenti, Giorgio Battaglia, Annamaria Vezzani
• Journal: Neurobiology of disease (Neurobiol Dis) Vol. 24 Issue 3 Pg. 429-42 (Dec 2006) ISSN: 0969-9961 [Print] United States
• PMID: 17027274 (Publication Type: Comparative Study, Journal Article)

Chemical References

• ATP Binding Cassette Transporter, Subfamily B, Member 1
• Anticonvulsants
• RNA, Messenger
• Serum Albumin
• Ondansetron
• Methylazoxymethanol Acetate

Topics

• ATP Binding Cassette Transporter, Subfamily B, Member 1 (genetics, metabolism)
• Animals
• Anticonvulsants (pharmacokinetics)
• Astrocytes (metabolism)
• Blood-Brain Barrier (drug effects, metabolism)
• Brain (abnormalities, blood supply)
• Capillary Permeability (drug effects, physiology)
• Choristoma (chemically induced)
• Disease Models, Animal
• Drug Resistance (physiology)
• Endothelial Cells (drug effects, metabolism)
• Epilepsy (metabolism, pathology)
• Female
• Hippocampus
• Male
• Matched-Pair Analysis
• Methylazoxymethanol Acetate
• Ondansetron (pharmacokinetics)
• Pregnancy
• RNA, Messenger (analysis)
• Rats
• Seizures (metabolism, pathology)
• Serum Albumin (metabolism)