Memantine Protects From Exacerbation of Ischemic Stroke and Blood Brain Barrier Disruption in Mild But Not Severe Hyperhomocysteinemia

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 μmol/L) or Cbs−/− (309±18 μmol/L) mice versus Cbs+/+ (3.1±0.6 μmol/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.