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 (C...
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| Format: | Article |
| Language: | English |
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Wiley
2020-02-01
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| Series: | Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease |
| Subjects: | |
| Online Access: | https://www.ahajournals.org/doi/10.1161/JAHA.119.013368 |
| _version_ | 1797884392474935296 |
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| author | Sean X. Gu Vijay K. Sonkar Parmeshwar B. Katare Rahul Kumar Warren D. Kruger Erland Arning Teodoro Bottiglieri Steven R. Lentz Sanjana Dayal |
| author_facet | Sean X. Gu Vijay K. Sonkar Parmeshwar B. Katare Rahul Kumar Warren D. Kruger Erland Arning Teodoro Bottiglieri Steven R. Lentz Sanjana Dayal |
| author_sort | Sean X. Gu |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-10T04:06:30Z |
| format | Article |
| id | doaj.art-26ddcb95391e44e090c9768cbcf5a432 |
| institution | Directory Open Access Journal |
| issn | 2047-9980 |
| language | English |
| last_indexed | 2024-04-10T04:06:30Z |
| publishDate | 2020-02-01 |
| publisher | Wiley |
| record_format | Article |
| series | Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease |
| spelling | doaj.art-26ddcb95391e44e090c9768cbcf5a4322023-03-13T05:25:33ZengWileyJournal of the American Heart Association: Cardiovascular and Cerebrovascular Disease2047-99802020-02-019410.1161/JAHA.119.013368Memantine Protects From Exacerbation of Ischemic Stroke and Blood Brain Barrier Disruption in Mild But Not Severe HyperhomocysteinemiaSean X. Gu0Vijay K. Sonkar1Parmeshwar B. Katare2Rahul Kumar3Warren D. Kruger4Erland Arning5Teodoro Bottiglieri6Steven R. Lentz7Sanjana Dayal8Department of Internal Medicine University of Iowa Carver College of Medicine Iowa City IADepartment of Internal Medicine University of Iowa Carver College of Medicine Iowa City IADepartment of Internal Medicine University of Iowa Carver College of Medicine Iowa City IADepartment of Internal Medicine University of Iowa Carver College of Medicine Iowa City IAFox Chase Cancer Center Philadelphia PABaylor Institute of Metabolic Disease Dallas TXBaylor Institute of Metabolic Disease Dallas TXDepartment of Internal Medicine University of Iowa Carver College of Medicine Iowa City IADepartment of Internal Medicine University of Iowa Carver College of Medicine Iowa City IABackground 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.https://www.ahajournals.org/doi/10.1161/JAHA.119.013368blood brain barriercystathionine beta synthasehomocysteinestroke |
| spellingShingle | Sean X. Gu Vijay K. Sonkar Parmeshwar B. Katare Rahul Kumar Warren D. Kruger Erland Arning Teodoro Bottiglieri Steven R. Lentz Sanjana Dayal Memantine Protects From Exacerbation of Ischemic Stroke and Blood Brain Barrier Disruption in Mild But Not Severe Hyperhomocysteinemia Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease blood brain barrier cystathionine beta synthase homocysteine stroke |
| title | Memantine Protects From Exacerbation of Ischemic Stroke and Blood Brain Barrier Disruption in Mild But Not Severe Hyperhomocysteinemia |
| title_full | Memantine Protects From Exacerbation of Ischemic Stroke and Blood Brain Barrier Disruption in Mild But Not Severe Hyperhomocysteinemia |
| title_fullStr | Memantine Protects From Exacerbation of Ischemic Stroke and Blood Brain Barrier Disruption in Mild But Not Severe Hyperhomocysteinemia |
| title_full_unstemmed | Memantine Protects From Exacerbation of Ischemic Stroke and Blood Brain Barrier Disruption in Mild But Not Severe Hyperhomocysteinemia |
| title_short | Memantine Protects From Exacerbation of Ischemic Stroke and Blood Brain Barrier Disruption in Mild But Not Severe Hyperhomocysteinemia |
| title_sort | memantine protects from exacerbation of ischemic stroke and blood brain barrier disruption in mild but not severe hyperhomocysteinemia |
| topic | blood brain barrier cystathionine beta synthase homocysteine stroke |
| url | https://www.ahajournals.org/doi/10.1161/JAHA.119.013368 |
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