Anesthesia affects P-glycoprotein function at the Blood-Brain Barrier: A PET study with [18F] MC225 in rats

Lara Garcia Varela, David Vállez García, Aren van Waarde, Jurgen Sijbesma, Rudi Dierckx, Anna Schildt, Chantal Kwizera, Philip H. Elsinga, Geert Luurtsema



Introduction: P-glycoprotein transporters (P-gp) at the Blood-Brain barrier (BBB) are efflux pumps that play an important role in protecting the brain against harmful substances. The expression and function of these proteins is of great interest in neurodegenerative diseases and drug resistance. Its function can be measured in vivo with positron emission tomography (PET) using the novel tracer 5-(1-(2-[18F]fluoroethoxy))-[3-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-propyl]-5,6,7,8-tetrahydronaphthalen, [18F]MC225. Preclinical PET scans are performed under anesthesia, and in most longitudinal studies the animals are repeatedly anesthetized. However, the potential effect of anesthesia on P-gp function has not been explored yet using this tracer. Therefore, the aim of this study is to assess the effect of a pre-exposure to anesthesia on P-gp function in rats with [18F]MC225. Material and Methods: Six rats were anesthetized with isoflurane for 90 minutes. Five other rats were not subjected to anesthesia. One week later, all rats underwent a dynamic PET scan (60 min) with arterial blood sampling. [18F]MC225 with a dose of 32±6 MBq and a molar activity higher than 29000 GBq/mmol was injected into a tail vein as a bolus of 1ml/min. After tracer injection, blood samples (0.15 ml) were collected to measure radioactivity in whole blood and plasma, besides the parent fraction of the tracer and its radioactive metabolites. The images were processed with PMOD software, and registered to a tracer-specific brain template. A total of 16 regions inside the brain were selected from a Wistar brain rat atlas. The volume of distribution (VT) which reflects P-gp function was calculated by Logan analysis using plasma activity corrected for metabolites as input function. Results: Significant differences in VT of the whole brain were observed (p=0.002) between the 2 groups. In control animals, VT of the whole brain was 11.04±1.25, whereas in animals pretreated with anesthesia it was 7.89±1.25, a decrease of 29%. Moreover, significant decreases in VT were found between groups in all the brain regions analyzed such as amygdala, hippocampus, hypothalamus, midbrain. Tracer concentration in whole-blood and plasma, and the rate of metabolism were not significantly different between the groups. Discussion/Conclusion: Our results suggest that anesthesia has a prolonged effect on P-gp function at the BBB, lasting at least one week. The group with additional anesthesia displayed a significant decrease of tracer uptake in brain indicating an up-regulation of P-gp. The results indicate that [18F]MC225 is suitable for the detection of increases of P-gp function after drug treatment.
Originele taal-2English
TijdschriftEJNMMI Radiopharmacy and Chemistry
StatusPublished - 7-apr.-2018
Evenement19th European Symposium
on Radiopharmacy and Radiopharmaceuticals
- Groningen, Netherlands
Duur: 5-apr.-20188-apr.-2018

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