Abstract WMP80: Cystathionine β Synthase Deficiency Exacerbates Cerebral Ischemia Reperfusion Injury Through Activation of the NMDA Receptor and Loss of Blood Brain Barrier Integrity in Mice
Bibliographic record
Abstract
Hyperhomocysteinemia is a risk factor for stroke; however the mechanisms by which elevated homocysteine leads to stroke are poorly defined. In a murine model of cystathionine β synthase (CBS) deficiency, we tested the hypothesis that mild to severe elevation in plasma total homocysteine (tHcy) increases susceptibility to cerebral infarction through N-methyl-D-aspartate (NMDA) receptor activation and is associated with altered permeability of the blood brain barrier. We studied male Cbs -/- mice conditionally expressing a zinc-inducible mutated human CBS (I278T) transgene along with Cbs+/- and Cbs+/+ littermates at 10-14 weeks of age. The human transgene was allowed to express only until weaning to overcome the early mortality of Cbs-/- mice. A mild to severe increase in plasma total homocysteine levels (tHcy) were observed in Cbs +/- and Cbs -/- mice (6.1±0.3 and 309±18 μM respectively) compared with Cbs+/+ littermates (3.1±0.6 μM, P<0.01). Experimental stroke was induced with middle cerebral artery occlusion for one hour followed by 24 hours of reperfusion. Both Cbs +/- and Cbs -/- mice exhibited significant increase in cerebral infarct size following ischemia-reperfusion (12.2±3% in Cbs+/+ mice, vs 35.1±7.7% in Cbs+/- and 27.7±7.8% in Cbs-/- mice, P<0.05). BBB integrity was tested with Evan’s blue (EB) permeation, and a significant increase in EB extravasation was observed in Cbs+/- and Cbs -/- mice (3.8±0.8 and 4.8±0.2 EB/g respectively) compared to Cbs+/+ mice (1.7±0.4 EB/g, P<0.05). Treatment for 2 weeks with a NMDA receptor antagonist (memantine) rescued Cbs+/- mice from cerebral ischemia reperfusion injury and reduced blood brain barrier permeability in Cbs+/- mice. These data provide evidence that both NMDA receptor activation and blood brain barrier disruption contribute to the mechanism of stroke in hyperhomocysteinemia and that modulation of the NMDA pathway may represent a novel therapeutic target.
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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 | 0.001 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.002 |
| Insufficient payload (model declined to judge) | 0.005 | 0.002 |
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".