Low (Therapeutic) Dose of Warfarin Is Not Associated with Cognitive and Exploratory Behavior Impairment in Rats: Mechanistic Studies (OR15-01-19)
Bibliographic record
Abstract
In addition to its role in hemostasis, vitamin K (VK) is involved in brain function through various proteins and sphingolipid metabolism. Warfarin (W), a widely prescribed anticoagulant drug, exerts its beneficial effect in coagulation by partially blocking the recycling of the vitamin. In previous studies, we provided evidence that, when administered in large doses, W leads to cognitive and exploratory behavior impairment, and alteration in the VK dependent proteins Gas6 and protein S (PS) and their downstream pro-survival extracellular signal-regulated (ERK) and serine-threonine (Akt) kinases pathways. In light of its widespread use as oral anticoagulant, the present study aimed to investigate the impact of W on cognition and behavior, Gas6 and PS and their signaling pathways when administered in doses comparable to those used in the clinical setting. Male Wistar rats (n = 14/gp) were fed an AIN-93 based diet containing 750 mcg phylloquinone/kg/d and were randomly allocated to treatment with 0,1 mg W/kg/d (in drinking water) (W group) or not (C group), for 9 wks. Spatial memory (Morris Water Maze) and exploratory behavior (Open Field) were assessed. Gas6, PS, pAkt, pERK, caspases −3 and −12 (apoptosis), brain-derived neurotrophic factor (BDNF), and microglial CD11b/c protein (a marker of inflammation), were assessed by immunoblotting in hippocampus (HPP), frontal cortex (FC), and striatum (STR), three regions involved in cognition. VK contents were determined in these 3 brain regions by HPLC. Group difference was tested by unpaired Student t-test. Low dose W had no impact on brain VK concentrations, spatial memory, and exploratory behavior (all P > 0.05). In contrast, W treatment was associated with numerous cell-signaling modulations, namely increased PS, ERK and Akt activity, and caspase −3 and −12 expression, in HPP; increased BDNF in FC and STR; increased expression of CD11bc in STR, (all P < 0.05). This study provides evidence that low dose W is not associated with cognitive and behavioral impairment despite numerous cell-signaling modulations that have the potential to be beneficial or detrimental to the brain. Whether these events represent compensatory mechanisms to maintain homeostasis deserves further investigation. Study funded by CIHR.
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 | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.001 |
| 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".