Loading...
Please wait, while we are loading the content...
Similar Documents
In Vivo Induction of P-Glycoprotein Function can be Measured with [18F]MC225 and PET.
| Content Provider | Europe PMC |
|---|---|
| Author | García-Varela, Lara Rodríguez-Pérez, Manuel Custodia, Antía Moraga-Amaro, Rodrigo Colabufo, Nicola A. Aguiar, Pablo Sobrino, Tomás Dierckx, Rudi A.J.O. van Waarde, Aren Elsinga, Philip H. Luurtsema, Gert |
| Copyright Year | 2021 |
| Abstract | P-Glycoprotein (P-gp)is an efflux pump located at the blood–brainbarrier (BBB) that contributes to the protection of the central nervoussystem by transporting neurotoxic compounds out of the brain. A declinein P-gp function has been related to the pathogenesis of neurodegenerativediseases. P-gp inducers can increase the P-gp function and are consideredas potential candidates for the treatment of such disorders. The P-gpinducer MC111 increased P-gp expression and function in SW480 humancolon adenocarcinoma and colo-320 cells, respectively. Our study aimsto evaluate the P-gp inducing effect of MC111 in the whole brain in vivo, using the P-gp tracer [18F]MC225 andpositron emission tomography (PET). Eighteen Wistar rats were treatedwith either vehicle solution, 4.5 mg/kg of MC111 (low-dose group),or 6 mg/kg of MC111 (high-dose group). Animals underwent a 60 mindynamic PET scan with arterial-blood sampling, 24 h after treatmentwith the inducer. Data were analyzed using the 1-tissue-compartmentmodel and metabolite-corrected plasma as the input function. Modelparameters such as the influx constant (K1) and volume of distribution (VT) werecalculated, which reflect the in vivo P-gp function.P-gp and pregnane xenobiotic receptor (PXR) expression levels of thewhole brain were assessed using western blot. The administration ofMC111 decreased K1 and VT of [18F]MC225 in the whole brain and allof the selected brain regions. In the high-dose group, whole-brain K1 was decreased by 34% (K1-high-dose = 0.20 ± 0.02 vs K1-control = 0.30 ± 0.02; p < 0.001) and inthe low-dose group by 7% (K1-low-dose= 0.28 ± 0.02 vs K1-control = 0.30± 0.02; p = 0.42) compared to controls. Whole-brain VT was decreased by 25% in the high-dose group(VT-high-dose = 5.92 ± 0.41 vs VT-control = 7.82 ± 0.38; p < 0.001) and by 6% in the low-dose group (VT-low-dose = 7.35 ± 0.38 vs VT-control = 7.82 ± 0.37; p = 0.38) comparedto controls. k2 values did not vary aftertreatment. The treatment did not affect the metabolism of [18F]MC225. Western blot studies using the whole-brain tissue did notdetect changes in the P-gp expression, however, preliminary resultsusing isolated brain capillaries found an increasing trend up to 37%in treated rats. The decrease in K1 and VT values after treatment with the inducer indicatesan increase in the P-gp functionality at the BBB of treated rats.Moreover, preliminary results using brain endothelial cells also sustainedthe increase in the P-gp expression. In conclusion, the results verifythat MC111 induces P-gp expression and function at the BBB in rats.An increasing trend regarding the P-gp expression levels is foundusing western blot and an increased P-gp function is confirmed with[18F]MC225 and PET. |
| Related Links | https://europepmc.org/backend/ptpmcrender.fcgi?accid=PMC8383301&blobtype=pdf |
| ISSN | 15438384 |
| Journal | Molecular Pharmaceutics [Mol Pharm] |
| Volume Number | 18 |
| DOI | 10.1021/acs.molpharmaceut.1c00302 |
| PubMed Central reference number | PMC8383301 |
| Issue Number | 8 |
| PubMed reference number | 34228458 |
| e-ISSN | 15438392 |
| Language | English |
| Publisher | American ChemicalSociety |
| Publisher Date | 2021-07-06 |
| Access Restriction | Open |
| Rights License | Permits non-commercial access and re-use, provided that author attribution and integrity are maintained; but does not permit creation of adaptations or other derivative works (https://creativecommons.org/licenses/by-nc-nd/4.0/). © 2021 The Authors. Publishedby AmericanChemical Society |
| Subject Keyword | ABC transporters brain Imaging efflux transporters P-glycoprotein P-gp inducers |
| Content Type | Text |
| Resource Type | Article |
| Subject | Drug Discovery Molecular Medicine Pharmaceutical Science |
