Neuroprotective role of pyrroloquinoline quinone in folate deficiency-induced blood-brain barrier disruption
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Bibliographic record
Abstract
Abstract Healthy neurodevelopment requires adequate folates (vitamin B9), which are critical for key biosynthetic and homeostatic processes in the central nervous system (CNS). In the brain, folate transport is mediated by three major pathways: folate receptor alpha (FRα), proton-coupled folate transporter (PCFT), and reduced folate carrier (RFC). Folate uptake primarily occurs at the blood-cerebrospinal fluid barrier (BCSFB) by concerted actions of FRα and PCFT. Alterations in this transport pathway can result in cerebral folate deficiency (CFD), a rare but devastating pediatric condition associated with neuroinflammation and oxidative stress. Recent findings highlight the blood-brain barrier (BBB) as an alternative route for folate delivery, particularly through RFC upregulation. We hypothesized that pyrroloquinoline quinone (PQQ), an activator of nuclear respiratory factor 1 (NRF-1) and PGC-1α, key regulators of mitochondrial biogenesis, could enhance RFC expression at the BBB and mitigate CFD-induced damage. Using in vitro and in vivo models of folate deficiency, we investigated its impact on BBB integrity, inflammation, oxidative stress, mitochondrial dysfunction, and assessed PQQ’s ability to reverse these effects. Human brain microvessel endothelial cells (hCMEC/D3) cultured in control folate-sufficient (FS) or folate-deficient (FD) medium were treated with PQQ (1 or 5 µM) or vehicle control for 24 h. Wildtype (C57BL6/N) mice received FD (0 mg/kg folate), or FS (2 mg/kg folate) diet and underwent a 10-day (20 mg/kg/day, i.p) PQQ treatment. Following treatment, hCMEC/D3 cells and isolated mouse brain capillaries were analyzed using qPCR, ELISA, and immunoblotting to assess gene and protein expression of tight junction proteins, inflammatory and oxidative stress markers, mitochondrial transcription factors, and folate transporters. BBB permeability was evaluated in vivo using the sodium fluorescein (NaFl) assay. FD significantly increased the gene and/or protein expression of inflammatory cytokines/chemokines, endothelial adhesion molecules and oxidative stress markers, while tight junction proteins were significantly downregulated both in vitro and in vivo. The NaFl assay confirmed increased BBB permeability in FD mice. PQQ treatment effectively reversed these changes by upregulating RFC and PCFT expression, restoring BBB permeability, mitigating inflammatory and oxidative stress responses and improving mitochondrial biogenesis via PGC-1α/NRF-1 signaling. These results highlight the impact of brain FD on BBB integrity, potentially contributing to neurological deficits seen in CFD disorders with PQQ providing a promising therapeutic strategy.
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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 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 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 | 0.001 |
| Insufficient payload (model declined to judge) | 0.150 | 0.001 |
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