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Setting-up an In Vitro Model of Rat Blood-brain Barrier (BBB): A Focus on BBB Impermeability and Receptor-mediated Transport
Published on: June 28, 2014
[¹¹C]befloxatone brain kinetics is not influenced by Bcrp function at the blood-brain barrier: a PET study using Bcrp
Benoit Hosten1, Raphaël Boisgard, Aude Jacob
1INSERM U705, CNRS UMR8206, Faculté de Pharmacie, Université Paris Descartes, Sorbonne Paris Cité, Université Paris Diderot, Paris F-75006, France.
Abstract:
Knockout (KO) animals are useful tools with which to assess the interplay between P-glycoprotein (P-gp; Abcb1) and the breast cancer resistance protein (Bcrp, Abcg2), two major ABC-transporters expressed at the blood-brain barrier (BBB). However, one major drawback of such deficient models is the possible involvement of compensation between transporters. In the present study, P-gp and Bcrp distribution in the brain as well as P-gp expression levels at the BBB were compared between the Bcrp TGEM KO rat model and the wild-type (WT) strain. Therefore, we used confocal microscopy of brain slices and western blot analysis of the isolated brain microvessels forming the BBB. This deficient rat model was used to assess the influence of Bcrp on the brain and peripheral kinetics of its substrate [(11)C]befloxatone using positron emission tomography (PET). The influence of additional P-gp inhibition was tested using elacridar (GF120918) 2 mg/kg in Bcrp KO rats. The distribution pattern of P-gp in the brain as well as P-gp expression levels at the BBB was similar in Bcrp-deficient and WT rats. Brain and peripheral kinetics of [(11)C]befloxatone were not influenced by the lack of Bcrp. Neither was the brain uptake of [(11)C]befloxatone in Bcrp-deficient rats influenced by the inhibition of P-gp. In conclusion, the Bcrp-deficient rat strain, in which we detected no compensatory mechanism or modification of P-gp expression as compared to WT rats, is a suitable model to study Bcrp function separately from that of P-gp at the BBB. However, although selectively transported by BCRP in vitro, our results suggest that [(11)C]befloxatone PET imaging might not be biased by impaired function of this transporter in vivo.
Insights
A new Bcrp knockout rat model shows no P-gp compensation, making it suitable for studying breast cancer resistance protein (Bcrp) function at the blood-brain barrier (BBB). This finding is crucial for understanding drug transport and brain barrier research.
Area of Science:
- Neuroscience and Pharmacology
- Blood-Brain Barrier (BBB) Transport Mechanisms
- Drug Discovery and Development
Background:
- P-glycoprotein (P-gp) and breast cancer resistance protein (Bcrp) are key ABC-transporters at the BBB, influencing drug distribution to the brain.
- Knockout (KO) models are valuable for studying transporter function, but compensatory upregulation of other transporters can be a confounding factor.
- Understanding the interplay between P-gp and Bcrp is essential for predicting drug efficacy and toxicity.
Purpose of the Study:
- To evaluate the Bcrp knockout (KO) rat model for potential compensatory changes in P-glycoprotein (P-gp) expression or distribution at the blood-brain barrier (BBB).
- To assess the influence of Bcrp deficiency on the brain and peripheral pharmacokinetics of its substrate, [(11)C]befloxatone, using positron emission tomography (PET).
- To investigate the combined effects of Bcrp deficiency and P-gp inhibition on [(11)C]befloxatone brain uptake.
Main Methods:
- Comparison of P-gp distribution and expression levels at the BBB in Bcrp KO rats versus wild-type (WT) rats using confocal microscopy and western blot.
- In vivo PET imaging to determine the brain and peripheral kinetics of [(11)C]befloxatone in Bcrp KO rats.
- Pharmacokinetic assessment of [(11)C]befloxatone in Bcrp KO rats following administration of the P-gp inhibitor elacridar.
Main Results:
- P-gp distribution and expression at the BBB were comparable between Bcrp KO and WT rats, indicating no compensatory upregulation of P-gp.
- The absence of Bcrp did not affect the brain or peripheral kinetics of [(11)C]befloxatone.
- Inhibition of P-gp did not alter [(11)C]befloxatone brain uptake in Bcrp-deficient rats.
Conclusions:
- The Bcrp KO rat model is a suitable tool for studying Bcrp function independently of P-gp at the BBB due to the absence of compensatory mechanisms.
- Despite in vitro substrate selectivity, [(11)C]befloxatone brain imaging may not be significantly confounded by Bcrp dysfunction in vivo.
- This study validates a novel model for investigating transporter roles in drug disposition at the blood-brain barrier.
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