Use of PET Imaging to Assess the Efficacy of Thiethylperazine to Stimulate Cerebral MRP1 Transport Activity in Wild-Type and APP/PS1-21 Mice.

Abstract

Multidrug resistance-associated protein 1 (MRP1, encoded by the ABCC1 gene) may contribute to the clearance of amyloid-beta (Aβ) peptides from the brain into the blood and stimulation of MRP1 transport activity may be a therapeutic approach to enhance brain Aβ clearance. In this study, we assessed the effect of thiethylperazine, an antiemetic drug which was shown to stimulate MRP1 activity in vitro and to decrease Aβ load in a rapid β-amyloidosis mouse model (APP/PS1-21), on MRP1 transport activity by means of positron emission tomography (PET) imaging with the MRP1 tracer 6-bromo-7-[11C]methylpurine. Groups of wild-type, APP/PS1-21 and Abcc1(-/-) mice underwent PET scans before and after a 5-day oral treatment period with thiethylperazine (15 mg/kg, once daily). The elimination rate constant of radioactivity (kelim) was calculated from time-activity curves in the brain and the lungs as a measure of tissue MRP1 activity. Treatment with thiethylperazine had no significant effect on MRP1 activity in the brain and the lungs of wild-type and APP/PS1-21 mice. This may either be related to a lack of an MRP1-stimulating effect of thiethylperazine in vivo or to other factors, such as substrate-dependent MRP1 stimulation, insufficient target tissue exposure to thiethylperazine or limited sensitivity of the PET tracer to measure MRP1 stimulation.

• Authors: Michael Wölfl-Duchek, Severin Mairinger, Irene Hernández-Lozano, Thomas Filip, Viktoria Zoufal, Mathilde Löbsch, Johann Stanek, Claudia Kuntner, Thomas Wanek, Martin Bauer, Jens Pahnke, Oliver Langer
• Journal: International journal of molecular sciences (Int J Mol Sci) Vol. 23 Issue 12 (Jun 10 2022) ISSN: 1422-0067 [Electronic] Switzerland
• PMID: 35742960 (Publication Type: Journal Article)

Chemical References

• Amyloid beta-Peptides
• Amyloid beta-Protein Precursor
• Multidrug Resistance-Associated Proteins
• Presenilin-1
• Thiethylperazine
• multidrug resistance-associated protein 1

Topics

• Alzheimer Disease (diagnostic imaging, drug therapy, genetics)
• Amyloid beta-Peptides (metabolism)
• Amyloid beta-Protein Precursor (genetics, metabolism)
• Animals
• Brain (diagnostic imaging, metabolism)
• Disease Models, Animal
• Mice
• Mice, Transgenic
• Multidrug Resistance-Associated Proteins (genetics, metabolism)
• Positron-Emission Tomography (methods)
• Presenilin-1 (genetics)
• Thiethylperazine (metabolism)