Metformin Activates Resident Neural Stem and Progenitor Cells, Reduces Inflammation and Improves Functional Recovery Following Spinal Cord Injury
Bibliographic record
Abstract
The mammalian spinal cord contains a population of neural stem and progenitor cells (NSPCs) located within the periventricular region lining the central canal. These cells are primarily quiescent under homeostatic conditions and are activated following injury, however, this response is not sufficient to support functional recovery in mammals. We propose that enhancing resident NSPC activation is a promising approach to promote neurorepair and improve functional outcomes following spinal cord injury (SCI). The FDA‐approved drug metformin has demonstrated efficacy in promoting functional recovery following brain injury through pleiotropic effects including NSPC activation, increased neurogenesis and oligodendrogenesis and modulation of the injury microenvironment including the inflammatory response. We hypothesize that metformin administration will promote functional recovery following SCI concomitant with activation of NSPCs and reduced inflammation. In a first series of in vitro experiments, we found that metformin significantly increases the size of the NSPC pool in females, but not males; increases neurogenesis in males and enhances oligodendrogenesis in both sexes. We next examined the effect of metformin treatment following SCI. Metformin was delivered to mice for 14 days starting immediately following SCI or starting at 7 days after SCI. Mice were tested on a skilled walking test and using gait analysis at 1 and 2 weeks following the start of metformin treatment. Mice that received metformin starting at the time of injury recovered motor function by 2 weeks post‐treatment however, delayed administration was not effective at improving functional outcomes. Interestingly, the functional outcomes observed in both treatment paradigms were correlated with metformin's effect on inflammation, as measured by the numbers of Iba1+ microglia/macrophages. In mice that received metformin immediately post‐SCI, Iba1+ cells were significantly reduced compared to vehicle‐treated SCI mice. Delayed metformin treatment did not lead to reduced inflammation relative to vehicle‐treated SCI mice. Together, these results support metformin as a viable therapeutic strategy to expand and enhance NSPCs, decrease inflammation and enhance functional outcomes when administered in the acute phase following SCI.
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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) | 0.001 | 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) | 0.001 | 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".