Purpose: Overexpression of multidrug transporters may play a role in the development of pharmacoresistance by decreasing extracellular drug levels in the brain. However, it is not known whether overexpression is due to an initial insult or evolves more gradually because of recurrent spontaneous seizures. In the present study, we investigated the expression of different multidrug transporters during epileptogenesis in the rat. In addition, we determined whether these transporters affected phenytoin (PHT) distribution in the brain.
Methods: Expression of multidrug resistance-associated proteins MRP1 and MRP2 and breast cancer-resistance protein (BCRP) was examined after electrically induced status epilepticus (SE) by immunocytochemistry and Western blot analysis. Brain/blood PHT levels were determined by high-performance liquid chromatography (HPLC) analysis in the presence and absence of the MRP inhibitor probenecid.
Results: Shortly after SE, MRP1, MRP2, and BCRP were upregulated in astrocytes within several limbic structures, including hippocampus. In chronic epileptic rats, these proteins were overexpressed in the parahippocampal cortex, specifically in blood vessels and astrocytes surrounding these vessels. Overexpression was related to the occurrence of SE and was present mainly in rats with a high seizure frequency. Brain PHT levels were significantly lower in epileptic rats compared with control rats, but pharmacologic inhibition of MRPs increased the PHT levels.
Conclusions: Overexpression of MRP and BCRP was induced by SE as well as recurrent seizures. Moreover, overexpression was associated with lower PHT levels in the brain, which was reversed through inhibition of MRPs. These data suggest that administration of antiepileptic drugs in combination with specific inhibitors for multidrug transporters may be a promising therapeutic strategy in pharmacoresistant patients.
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http://dx.doi.org/10.1111/j.1528-1167.2005.00250.x | DOI Listing |
Alzheimers Dement
December 2024
University of Toronto, Toronto, ON, Canada.
Background: Drug discovery efforts in neurological diseases, such as Alzheimer's disease (AD), have had particularly poor outcomes due to the lack of models that capture the cerebral vasculature. There is an unmet need to develop models that capture the physiological challenge of overcoming the blood-brain barrier (BBB) and impacts of blood flow-induced shear stress. In this work, we use a microfluidic platform to model the cerebral vasculature in familial AD (fAD) using patient-derived brain endothelial-like cells (BECs) and neurons.
View Article and Find Full Text PDFMicrobiol Spectr
December 2024
Institute of Antibiotics, Huashan Hospital, Fudan University, Shanghai, China.
Unlabelled: RamA is an intrinsic regulator in , belonging to the AraC family of transcription factors and conferring a multidrug resistance phenotype, especially for tetracycline-class antibiotics. The ATP-binding cassette transporters MlaFEDCB in bacteria play essential roles in functions essential for cell survival and intrinsic resistance to many antibiotics. We found deletion of resulted in a fivefold decrease in the transcriptional levels of the operon.
View Article and Find Full Text PDFMikrobiyol Bul
October 2024
İnönü University Faculty of Medicine, Deparment of Medical Microbiology, Malatya, Türkiye.
The increasing antibiotic resistance in Pseudomonas aeruginosa, responsible for both community-acquired and hospital-acquired infections, is of global significance. The primary mechanisms contributing to resistance development in P.aeruginosa include the increased activity of efflux pumps, decreased permeability of outer membrane porins and the production of carbapenemases.
View Article and Find Full Text PDFZhongguo Shi Yan Xue Ye Xue Za Zhi
December 2024
Department of Pediatrics, Binzhou Medical University Hospital, Binzhou 256603, Shandong Province, China.
Objective: To investigate the reversal effect and mechanism of asiatic acid (AA) on multidrug resistance in human adriamycin (ADR) chronic myeloid leukemia K562/ADR cells.
Methods: CCK-8 assay was used to detect the resistance of K562 cells and K562/ADR cells to ADR. CCK-8 assay was used to detect the effect of AA on K562/ADR cell viability and adriamycin sensitization.
Biomed Pharmacother
December 2024
Department of Biophysics and Cell Biology, Faculty of Medicine, University of Debrecen, Debrecen 4032, Hungary; Doctoral School of Molecular Cell and Immune Biology, University of Debrecen, Debrecen 4032, Hungary; Dean's office, Faculty of Pharmacy, University of Debrecen, Debrecen 4032, Hungary. Electronic address:
ABCB1/MDR-1/P-glycoprotein (Pgp) is an ABC transporter responsible for cancer cell multi-drug resistance. It is expressed in cytotoxic T lymphocytes (CTL). Eliminating sensitive cancer cells during high-dose chemotherapy can also damage immune cells.
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