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Gu SX , Sonkar VK , Katare PB , Kumar R , Kruger WD , Arning E , Bottiglieri T , Lentz SR , Dayal S
Memantine Protects From Exacerbation of Ischemic Stroke and Blood Brain Barrier Disruption in Mild But Not Severe Hyperhomocysteinemia
J Am Heart Assoc. 2020 Feb 18;9(4) :e013368
PMID: 32067580    PMCID: PMC7070222    URL: https://www.ncbi.nlm.nih.gov/pubmed/32067580
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Background Hyperhomocysteinemia is a risk factor for ischemic stroke; however, a targeted treatment strategy is lacking partly because of limited understanding of the causal role of homocysteine in cerebrovascular pathogenesis. Methods and Results In a genetic model of cystathionine beta synthase (CBS) deficiency, we tested the hypothesis that elevation in plasma total homocysteine exacerbates cerebrovascular injury and that memantine, a N-methyl-D-aspartate receptor antagonist, is protective. Mild or severe elevation in plasma total homocysteine was observed in Cbs+/- (6.1+/-0.3 mumol/L) or Cbs-/- (309+/-18 mumol/L) mice versus Cbs+/+ (3.1+/-0.6 mumol/L) mice. Surprisingly, Cbs-/- and Cbs+/- mice exhibited similar increases in cerebral infarct size following middle cerebral artery ischemia/reperfusion injury, despite the much higher total homocysteine levels in Cbs-/- mice. Likewise, disruption of the blood brain barrier was observed in both Cbs+/- and Cbs-/- mice. Administration of the N-methyl-D-aspartate receptor antagonist memantine protected Cbs+/- but not Cbs-/- mice from cerebral infarction and blood brain barrier disruption. Our data suggest that the differential effect of memantine in Cbs+/- versus Cbs-/- mice may be related to changes in expression of N-methyl-D-aspartate receptor subunits. Cbs-/-, but not Cbs+/- mice had increased expression of NR2B subunit, which is known to be relatively insensitive to homocysteine. Conclusions These data provide experimental evidence that even a mild increase in plasma total homocysteine can exacerbate cerebrovascular injury and suggest that N-methyl-D-aspartate receptor antagonism may represent a strategy to prevent reperfusion injury after acute ischemic stroke in patients with mild hyperhomocysteinemia.
2047-9980 Gu, Sean X Sonkar, Vijay K Katare, Parmeshwar B Kumar, Rahul Kruger, Warren D Arning, Erland Bottiglieri, Teodoro Lentz, Steven R Dayal, Sanjana T32 GM007337/GM/NIGMS NIH HHS/United States Journal Article England J Am Heart Assoc. 2020 Feb 18;9(4):e013368. doi: 10.1161/JAHA.119.013368. Epub 2020 Feb 13.