Functional expression and localization of P‐glycoprotein at the blood brain barrier
Bibliographic record
Abstract
Until recently, the blood-brain barrier was viewed as a static lipid membrane barrier. Physical attributes of the cerebral endothelial cells such as the presence of tight junctions, paucity of vesicles or caveolae, and high electrical resistance were believed to be the primary components that provide the membrane selectivity of the blood-brain barrier to a variety of circulating compounds from the periphery. However, results from molecular biology, immunocytochemistry, biochemistry, and transport studies show that the cerebral endothelial cells possess an asymmetrical array of metabolic enzymes (i.e., alkaline phosphatase, cytochrome P450 enzymes, glutathione transferases) and energy-dependent efflux transport proteins (i.e., P-glycoprotein and Multidrug-resistance proteins) that are instrumental to the barrier function. P-glycoprotein, a membrane-associated, energy-dependent, efflux transporter, is expressed in brain parenchyma (i.e., astrocytes and microglia) as well as in blood-brain and blood-cerebrospinal fluid barriers. Its function along the blood-brain barrier is believed to prevent the accumulation of potentially harmful compounds in the brain by actively removing them from the brain into the peripheral circulation. This is a brief review on the expression and activity of P-glycoprotein at the blood-brain barrier, which reports on the localization of the protein in rat brain capillaries in situ as well as in a well-characterized in vitro model of the blood-brain barrier, an immortalized rat brain endothelial cell line, the RBE4. Immunocytochemical analysis employing various P-glycoprotein monoclonal antibodies, demonstrated the presence of the protein along the plasma membrane, in plasmalemmal vesicles and nuclear envelope of rat cerebral endothelial cells, both in situ and in vitro. Western blot analysis revealed a single band with a molecular weight of 170-180 kDa, a size previously reported for P-glycoprotein, in RBE4 cells. In addition, results from functional studies show that the accumulation of the P-glycoprotein substrate digoxin by RBE4 monolayer cells is significantly enhanced in the presence of standard P-glycoprotein inhibitors (verapamil, cyclosporin A, PSC 833), protease inhibitors (saquinavir, ritonavir, indinavir), and the metabolic inhibitor, sodium azide. These results demonstrate the functional expression of P-glycoprotein in the immortalized rat brain endothelial cell line, RBE4. Novel in situ and in vitro intracellular locations of P-glycoprotein in cerebral endothelial cells have been identified suggesting that this transporter may play a significant role in the subcellular distribution of substrates in the brain.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".