Warfarin Treatment Alters Gas6 and Protein S Activity and Their Downstream Signaling Pathways in Brain, and Stimulates Microglial Activity (P24-002-19)
Bibliographic record
Abstract
There is now convincing evidence that vitamin K (VK) has important actions in the nervous system and cognition. Two VK-dependent proteins are closely linked to the brain namely Gas6 and protein S (PS). Functionally, both proteins are ligands for receptors of tyrosine kinases Tyro3, Axl, and Mer. In vitro, Gas6 and PS have been shown to possess pro-survival activity towards neurons and glia through stimulation of the extracellular signal-regulated (ERK) and serine-threonine (Akt) kinases pathways. In a previous study, targeted depletion of VK in brain induced by warfarin (W) treatment, a VK antagonist, resulted in cognitive and behavioral impairment. In the present study, we aimed to characterize the role of Gas6 and PS and their signaling pathways in W-treated rats fed or not with supplemental menaquinone-4 (MK-4), the principal K vitamer in brain. Male Wistar rats (n = 5–7/gp) were randomly allocated to a AIN-93 based diet containing 750 mcg phylloquinone (K1)/kg/d supplemented with 100 mg MK-4/kg/d (MK-4) or not (N). After one week, rats were administered 14 mg W/kg/d (in drinking water) and subcutaneous K1 (94 mg/kg), 3X/wk, for 9 wks. [Subcutaneous K1 treatment is required to maintain the coagulation function]. A control gp (C) treated with normal water and injected with saline was also included. Gas6, PS, pAkt, pERK as well as brain-derived neurotrophic factor (BDNF) and microglial CD11b/c protein, were assessed in hippocampus (HPP), frontal cortex (FC) and striatum (STR), three regions involved in cognition, by immunoblotting. Group difference were tested by one-way ANOVA. Impact of W treatment was particularly marked in HPP, rats from N group showing decreased Gas6, PS and ERK activity as well as decreased BDNF expression, compared to C gp. Further, rats from N group presented increased expression of CD11bc, a marker of inflammation (all P < 0.05). Supplementing the diet with MK-4 normalized PS activity and BDNF and CD11bc expression in HPP, Gas6 and pERK in CF, and pAkt in STR (all P < 0.05). Results indicate that W treatment as used in the present study alters Gas6 and PS activity and their downstream signaling pathways, and stimulates microglial activity. Supplementing the diet with large amounts of MK-4 normalized much of the phenotype. Study funded by CIHR.
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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 | 0.000 |
| 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 | 0.000 |
| 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".