P3‐390: The synthetic retinoid, AHPN, attenuates lipopolysaccharide and β‐amyloid–induced microglial activation: A possible therapeutic agent for inflammatory‐mediated neurodegenerative diseases
Bibliographic record
Abstract
Chronic neuroinflammation, mediated by sustained microglial activation, is now recognised to play a vital role in the pathogenesis of various neurodegenerative diseases, particularly Alzheimer's disease (AD). Endogenous retinoid ligands, all-trans-retinoic acid (RA) and 9-cis-RA, have been previously shown to exhibit anti-inflammatory actions against β-amyloid (Aβ)/lipopolysaccharide (LPS) -mediated activation of microglia in vitro. Synthetic retinoids have received much attention as therapeutic agents for cancer, leukaemia and proliferative skin disorders but their effects in brain-mediated inflammation remain unknown. One such analog, 6-[3-adamantyl-4-hydroxyphenyl]-2-napthalene carboxylic acid (AHPN or CD437), is a highly potent apoptotic agent in cancer and leukemia cell lines. The current study aimed to determine the effects of AHPN on the activation profile of dissociated microglia in culture. Microglia cells were exposed to either 1 μg/ml LPS or 10 μM Aβ1-42 plus 10 ng/ml IFN-γ in the presence of AHPN (0.5-100 μM) for 24 h. Cell-free culture supernatant was investigated for the accumulation of nitrite (NO2), cytokines (via ELISA analysis), and lactate dehydrogenase (LDH) for cell death. Labelling the cells with anti-CD-11b (OX-42) enabled microglia morphology to be visualised under microscopy for qualitative assessment of activation. Findings from these experiments showed that AHPN (5-100 μM) decreased LPS-mediated production of NO2 but not cytokines. Western immunoblotting demonstrated a significant attenuation of phosphorylated nuclear factor kappa B (NF-κB) and iNOS by 5 μM AHPN. Microscopy analysis of CD-11b-positive cells indicated that 5 μM AHPN reverted LPS-induced activated morphologies whilst reducing cell number through Cyclin D1 inhibition. However, higher concentrations of AHPN (50-100 μM) induced cell death through increased LDH accumulation and condensation of nuclei (through Hoechst dye staining). Preliminary results also indicated that production of NO2 by Aβ1-42 (+ IFN-γ) was reduced by AHPN. Taken together, the results show that microglial activation can be attenuated by AHPN, as evidenced by the inhibition of both proliferation and NO2 production - through reduced NF-κB activation and iNOS production. In conclusion, these new findings provide a possible anti-inflammatory role for synthetic retinoids, which could be a useful therapeutic strategy for neurodegenerative diseases that involve an inflammatory component, such as AD.
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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 | 0.000 | 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 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 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".