Selective induction of P-glycoprotein at the CNS barriers during symptomatic stage of an ALS animal model
| Autor: | David B. Banks, Gary N.Y. Chan, David S. Miller, Emily V. Mesev, Ronald E. Cannon, Rebecca A Evans |
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| Rok vydání: | 2017 |
| Předmět: |
Central Nervous System
0301 basic medicine Abcg2 Central nervous system SOD1 Pharmacology Blood–brain barrier Article 03 medical and health sciences 0302 clinical medicine medicine Animals ATP Binding Cassette Transporter Subfamily B Member 1 Amyotrophic lateral sclerosis P-glycoprotein biology General Neuroscience Multidrug resistance-associated protein 2 Amyotrophic Lateral Sclerosis Membrane Transport Proteins Biological Transport medicine.disease Rats Up-Regulation Disease Models Animal 030104 developmental biology medicine.anatomical_structure Blood-Brain Barrier biology.protein Signal transduction 030217 neurology & neurosurgery |
| Zdroj: | Neuroscience Letters. 639:103-113 |
| ISSN: | 0304-3940 |
| Popis: | P-glycoprotein (P-gp), Breast cancer resistance protein (BCRP) and Multidrug resistance-associated protein 2 (MRP2) residing at the blood-brain barrier (BBB) and the blood-spinal cord barrier (BSCB) are major obstacles for drug delivery to the Central Nervous System (CNS). Disease-induced changes of these xenobiotic transporters at the CNS barriers have been previously documented. Changes in the functional expression of these transporters at the CNS barriers would limit the clinical efficacy of therapeutic agents targeting the CNS. In this study, we characterized the changes in expression and efflux activity of P-gp, BCRP and MRP2 at the BBB and BSCB of an amyotrophic lateral sclerosis (ALS) SOD1-G93A transgenic rat model across the three stages of disease progression: pre-onset, onset and symptomatic. Up-regulation of P-gp and BCRP at the BBB and BSCB during disease progression of ALS would reduce drug entry to the CNS, while any decreases in transport activity would increase drug entry. In SOD rats at the ALS symptomatic stage, we observed increases in both P-gp transport activity and expression compared to age-matched wildtypes. BCRP and MRP2 levels were unchanged in these animals. Immunohistochemical analysis in brain and spinal cord capillaries of SOD rats from all three ALS stages and age-matched wildtypes showed no differences in nuclear localization of a known P-gp regulator, nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB). It suggests that NFκB may have a limited role during P-gp induction observed in our study and additional signaling pathways could be responsible for this response. Our observations imply that novel pharmacological approaches for treating ALS require selecting drugs that are not P-gp substrates in order to improve therapeutic efficacy in the CNS during ALS progression. |
| Databáze: | OpenAIRE |
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