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- W2895880006 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." @default.
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- W2895880006 date "2018-01-22" @default.
- W2895880006 modified "2023-09-26" @default.
- W2895880006 title "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" @default.
- W2895880006 doi "https://doi.org/10.1161/str.49.suppl_1.wmp80" @default.
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