Multidrug resistance proteins in tuberous sclerosis and refractory epilepsy

Lazarowski, Alberto; Lubieniecki, Fabiana; Camarero, Sandra; Pomata, H.; Bartuluchi, Marcelo; Sevlever, Gustavo; Taratuto, Ana Lía

doi:10.1016/s0887-8994(03)00407-7

Cited by 82 publications

(50 citation statements)

References 36 publications

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“…MRP1 is an important multidrug transporter in the brain [11,12] , despite the fact that it is mainly distributed in the choroid plexus and ependymal epithelial cells and is found in lower levels in neurons and glial cells in the normal brain [13,14] . This trend is consistent with our observation that MRP1 mRNA and protein levels were low in the cortex and hippocampus of normal rats.…”

Section: Discussionmentioning

confidence: 99%

“…MRP1 is not only located in the cell membrane but also present in the endoplasmic reticulum and Golgi apparatus, suggesting that in addition to its function as an efflux pump, MRP1 can also isolate drugs in cells and inhibit their ability to directly bind to their target, resulting in drug resistance. MRP1 is able to pump AEDs out of the brain tissue or cells, leading to a decrease in the concentrations of AEDs in the brain extracellular fluid, cytoplasm, and even organelles [13] , which may account for multidrug resistance in refractory epilepsy. Our studies confirmed that the decrease of PHT and CBZ concentrations in the cortical extracellular fluid was associated with the upregulation of MRP1 in the epileptic brain in vivo.…”

Section: Discussionmentioning

confidence: 99%

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Multidrug resistance-associated protein 1 decreases the concentrations of antiepileptic drugs in cortical extracellular fluid in amygdale kindling rats

et al. 2013

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Aim: To investigate whether multidrug resistance-associated protein 1 (MRP1) was responsible for drug resistence in refractory epilepsy in amygdale kindling rats. Methods: Rat amygdale kindling was used as a model of refractory epilepsy. The expression of MRP1 mRNA and protein in the brains was examined using RT-PCR and Western blot. MRP1-positive cells in the cortex and hippocampus were studied with immunohistochemical staining. The rats were intraperitoneally injected with phenytoin (50 mg/kg) or carbamazepine (20 mg/kg), and their concentrations in the cortical extracellular fluid were measured using microdialysis and HPLC. Probenecid, a MRP1 inhibitor (40 mmol/L, 50 μL) was administered through an inflow tube into the cortex 30 min before injection of the antiepileptic drugs. Results: The expression of MRP1 mRNA and protein was significantly up-regulated in the cortex and hippocampus in amygdale kindling rats compared with the control group. Furthermore, the number of MRP1-positive cells in the cortex and hippocampus was also significantly increased in amygdale kindling rats. Microdialysis studies showed that the concentrations of phenytoin and carbamazepine in the cortical extracellular fluid were significantly decreased in amygdale kindling rats. Pre-administration of probenecid could restore the concentrations back to their control levels. Conclusion: Up-regulation of MRP1 is responsible for the resistance of brain cells to antiepileptic drugs in the amygdale kindling rats.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Multidrug resistance-associated protein 1 decreases the concentrations of antiepileptic drugs in cortical extracellular fluid in amygdale kindling rats

et al. 2013

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“…However, how pharmacoresistant seizures would relate to the presence of subependymal giant cell astrocytomas is not clear [9] . In previous study, we reported the abnormal overexpression of ATP-Binding cassette proteins (ABC-transporters: MDR1, MRP1 and BCRP) in cortical tubers from patients with TSC and RE [10,11] and more recently, the relationship between MDR-1 overexpression in hippocampus and epileptogenesis have been described [12] .…”

Section: Brief Report Highlightmentioning

confidence: 94%

CD34 stem-cell marker and multidrug resistance proteins P-gp and BCRP in SEGA

Lazarowski

Fabiana²,

Sandra³

et al. 2014

Receptor Clin Invest

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The resistance of human malignancy to multiple chemotherapeutic agents remains a major obstacle in cancer therapy due to in part to increased expression of ATP-binding cassette (ABC) transporters gene family, including "multidrug resistance 1", and "breast cancer resistant protein". These proteins are differentially expressed during normal hematopoiesis with the highest levels in primitive bone marrow CD34 stem cell population, and similarly, it was also suggested to occur transiently during neurulation. Subependymal Giant Cell Astrocytoma (SEGA) is a periventricular-low-grade tumor usually associated with tuberous sclerosis complex. We previously described that several multidrug-resistance proteins are overexpressed in brain cortical tubers associated with refractory epilepsy; however, they have not been investigated in SEGA. From a previous reported study of 15 brain specimens of SEGA, 6 randomized cases were selected for the immunostaining with specific monoclonal antibodies to multidrug resistance 1, breast cancer resistant protein and CD34 stem-cell marker. Heterogeneous distributions for these markers were detected with differential immunostaining pattern, showing high immunoreactivity in SEGA cells far of vessels, and low or negative expression in SEGA cells near the vessels. This particular expression pattern of both ABCtransporters, and CD34 antigen could identify different stem-cell subset in SEGA.Keywords: CD34; P-gp; BCRP; SEGA; Hypoxia; Tuberous Sclerosis; Stem-Cell To cite this article: Alberto L, et al. Stem-cell marker CD34, multidrug resistance proteins P-gp and BCRP in SEGA.

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“…Expression in normal epithelial cells of the canine duodenum is minimal, and only slightly greater in colonic epithelial cells (Conrad et al, 2001). High expression of p-gp in T cells of human patients suffering from rheumatoid arthritis, systemic lupus erythematosus, drug-resistant epilepsy and renal graft rejection is associated with poor response to treatment (Zanker et al, 1995;Maillefert et al, 1996;Montano et al, 1996;Diaz-Borjon et al, 2000;Lazarowski et al, 2004). Farrell et al (2000) showed that human IBD patients who responded to steroid therapy differed from those who did not in expressing less p-gp in their peripheral T lymphocytes and intra-epithelial lymphatic cells.…”

Section: Introductionmentioning

confidence: 99%