Statins reduce human blood–brain barrier permeability and restrict leukocyte migration: Relevance to multiple sclerosis
Why this work is in the frame
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Bibliographic record
Abstract
OBJECTIVE: Dysregulation of the blood-brain barrier (BBB) and transendothelial migration of immune cells are among the earliest central nervous system changes partaking in lesion formation in both multiple sclerosis (MS) and its early clinical form, the clinically isolated syndrome. Evidence for the anti-inflammatory effects of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors within the central nervous system arose from studies demonstrating that statins improve clinical signs in the animal model of MS and reduce the number of gadolinium-enhancing lesions in MS. METHODS: We sought to describe the impact of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor treatment on the physiology and immunology of human BBB-derived endothelial cells (ECs). RESULTS: We demonstrate that lovastatin and simvastatin induce a 50 to 60% reduction in the diffusion rates of bovine serum albumin and [(14)C]-sucrose across human BBB-ECs in vitro through abrogation of isoprenylation processes, but independent of the expression of the tight junction molecules occludin, VE-cadherin, JAM-1, zonula occluden-1, and zonula occluden-2. Simvastatin and lovastatin were equipotent in reducing BBB permeability in vitro, with median effective concentration (EC(50)) of 9.5 x 10(-8) and 1.0 x 10(-7)M, respectively. We further demonstrate that lovastatin and simvastatin treatment of BBB-ECs significantly restricts the migration of clinically isolated syndrome-derived and MS-derived monocytes and lymphocytes across the human BBB in vitro, through a specific reduction in the secretion of the chemokines monocyte chemotactic protein-1/CCL2 and interferon-gamma-inducible protein-10/CXCL10 by BBB-ECs. INTERPRETATION: Our data parallel the previously reported magnetic resonance imaging-based radiological findings and suggest an effect of statins that could be beneficial in early MS, restricting the diffusion of molecular tracers and the migration of immune cells across the human BBB.
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Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.002 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 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 it