Assessment of a Fluorinated Analog of N-acetylglucosamine to Promote Myelin Regeneration (P1.174)
Bibliographic record
Abstract
OBJECTIVE: To assess the preclinical efficacy of a fluorinated analog of acetylated N-acetylglucosamine as a therapy to promote myelin repair in multiple sclerosis by normalizing the expression of inhibitory chondroitin sulfate proteoglycan barrier molecules. BACKGROUND: Remyelination, the generation of new myelin after CNS insult, is impeded largely by the inhibitory nature of the extracellular lesion microenvironment. Our group recently established that the chondroitin sulfate proteoglycans (CSPGs), which are upregulated in CNS conditions such as multiple sclerosis, are potent inhibitors of myelin repair by oligodendrocyte precursor cells (OPCs) (Lau et al., Ann Neurol 72:419-432, 2012). We aimed to reduce this aberrant CSPG with a fluorinated analog of acetylated N-acetylglucosamine (Ac-4-F-GlcNAc), a synthesis inhibitor. DESIGN/METHODS: Murine astrocytes, which produce CSPGs when stimulated, were cultured in the presence of Ac-4-F-GlcNAc. Treated media was analyzed for CSPG content as well as functional effects on OPCs in culture. Ac-4-F-GlcNAc was administered following dorsal column microinjections of the demyelinating detergent lysolecithin in mice, and the content of spinal cord CSPGs was later assessed. Ac-4-F-GlcNAc was also administered to mice afflicted with experimental autoimmune encephalomyelitis (EAE) to assess the effects on an inflammatory model of MS. RESULTS: Murine OPCs are potently inhibited in terms of cell adhesion and process outgrowth in the presence of CSPGs. Ac-4-F-GlcNAc dramatically reduces the CSPG content of astrocytes in culture without evidence of toxicity, and OPCs appear less inhibited in the presence of this media. In vivo, Ac-4-F-GlcNAc reduces the CSPG content of mouse spinal cords following lysolecithin, and reduces the severity of EAE. CONCLUSIONS: Ac-4-F-GlcNAc appears to be a safe, systemic approach to reduce CSPGs following demyelination as well as mitigate the inflammatory component of EAE. We are currently addressing whether Ac-4-F-GlcNAc results in improved OPC recruitment and maturation in the lesion environment, and ultimately the impact on remyelination. Study Supported by: Multiple Sclerosis Society of Canada
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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) | 0.001 | 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 | 0.001 | 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".