Cuprizone-induced Demyelination in Mouse Brain is not due to Depletion of Copper
Bibliographic record
Abstract
The cuprizone (CPZ) model allows the study of the biochemical processes underlying nonautoimmune-mediated demyelination, remyelination, and chronic white matter disease progression. CPZ is a copper (Cu) chelator that chiefly causes oligodendrocyte apoptosis in the corpus callosum and cerebellum when administered in the mouse diet. While disruption of Cu homeostasis is known to cause neurodegeneration (as is observed in Wilson’s and Menkes disease), no consensus exists to date as to CPZ’s mechanism of action. We sought to determine whether CPZ-induced pathology is due to Cu depletion as is generally believed. Cu supplementation in chow, in stoichiometric excess to the added CPZ, did not reduce CPZ-induced demyelination in C57Bl/6 mice. Moreover, equivalent doses of other known Cu chelators neocuproine and D-penicillamine (D-Pen) failed to induce central nervous system (CNS) demyelination. Since administration of D-Pen in the treatment of Wilson’s disease can induce hypocupremia, we next sought to recreate penicillamine-induced Cu deficiency to compare with purported CPZ-induced Cu deficiency. The resulting clinical phenotype and histopathology were unlike that of CPZ. D-Pen-treated mice exhibited digit paralysis, tail flaccidity, subcutaneous hemorrhaging, and optic and sciatic neuropathy, all of which were prevented with Cu supplementation. No demyelination of the corpus callosum or cerebellum was observed, even with D-Pen doses tenfold higher than CPZ. Intriguingly, addition of D-Pen to the CPZ diet paradoxically prevented demyelination in a dose-dependent manner. Summary StatementThe demyelinating effects of CPZ are not due to Cu deficiency but are instead consistent with acute toxicity of a CPZ + Cu complex.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
How this classification was reachedexpand
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 | 0.001 |
| 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 itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, 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".