Altered GABAA receptor density and unaltered blood-brain barrier transport in a kainate model of epilepsy: an in vivo study using 11C-flumazenil and PET.

Abstract

UNLABELLED:

The aim of the present study was to investigate if flumazenil blood-brain barrier transport and binding to the benzodiazepine site on the γ-aminobutyric acid A (GABA(A)) receptor complex is altered in an experimental model of epilepsy and subsequently to study if changes in P-glycoprotein (P-gp)-mediated efflux of flumazenil at the blood-brain barrier may confound interpretation of (11)C-flumazenil PET in epilepsy.

METHODS:

The transport of flumazenil across the blood-brain barrier and the binding to the benzodiazepine site on the GABA(A) receptors in 5 different brain regions was studied and compared between controls and kainate-treated rats, a model of temporal lobe epilepsy, with and without tariquidar pretreatment. In total, 29 rats underwent 2 consecutive (11)C-flumazenil PET scans, each one lasting 30 min. The tracer was mixed with different amounts of isotopically unmodified flumazenil (4, 20, 100, or 400 μg) to cover a wide range of receptor occupancies during the scan. Before the second scan, the rats were pretreated with a 3 or 15 mg/kg dose of the P-gp inhibitor tariquidar. The second scan was then obtained according to the same protocol as the first scan.

RESULTS:

GABA(A) receptor density, B(max), was estimated as 44 ± 2 ng x mL(-1) in the hippocampus and as 33 ± 2 ng x mL(-1) in the cerebellum, with intermediate values in the occipital cortex, parietal cortex, and caudate putamen. B(max) was decreased by 12% in kainate-treated rats, compared with controls. The radiotracer equilibrium dissociation constant, K(D), was similar in both rat groups and all brain regions and was estimated as 5.9 ± 0.9 ng x mL(-1). There was no difference in flumazenil transport across the blood-brain barrier between control and kainate-treated rats, and the effect of tariquidar treatment was similar in both rat groups. Tariquidar treatment also decreased flumazenil transport out of the brain by 73%, increased the volume of distribution in the brain by 24%, and did not influence B(max) or K(D), compared with baseline.

CONCLUSION:

B(max) was decreased in kainate-treated rats, compared with controls, but no alteration in the blood-brain barrier transport of flumazenil was observed. P-gp inhibition by tariquidar treatment increased brain concentrations of flumazenil in both groups, but B(max) estimates were not influenced, suggesting that (11)C-flumazenil scanning is not confounded by alterations in P-gp function.

• Authors: Stina Syvänen, Maaike Labots, Yoshihiko Tagawa, Jonas Eriksson, Albert D Windhorst, Adriaan A Lammertsma, Elizabeth C de Lange, Rob A Voskuyl
• Journal: Journal of nuclear medicine : official publication, Society of Nuclear Medicine (J Nucl Med) Vol. 53 Issue 12 Pg. 1974-83 (Dec 2012) ISSN: 1535-5667 [Electronic] United States
• PMID: 23143088 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• ATP Binding Cassette Transporter, Subfamily B, Member 1
• Carbon Radioisotopes
• Quinolines
• Receptors, GABA-A
• Flumazenil
• tariquidar
• Kainic Acid

Topics

• ATP Binding Cassette Transporter, Subfamily B, Member 1 (antagonists & inhibitors)
• Animals
• Biological Transport (drug effects)
• Blood-Brain Barrier (drug effects, metabolism)
• Carbon Radioisotopes
• Epilepsy (diagnostic imaging, metabolism)
• Flumazenil (metabolism)
• Kainic Acid (pharmacology)
• Male
• Positron-Emission Tomography
• Quinolines (pharmacology)
• Rats
• Rats, Sprague-Dawley
• Receptors, GABA-A (metabolism)