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

Sean X Gu; Vijay K Sonkar; Parmeshwar B Katare; Rahul Kumar; Warren D Kruger; Erland Arning; Teodoro Bottiglieri; Steven R Lentz; Sanjana Dayal

doi:10.1161/JAHA.119.013368

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

Journal article

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

Sean X Gu, Vijay K Sonkar, Parmeshwar B Katare, Rahul Kumar, Warren D Kruger, Erland Arning, Teodoro Bottiglieri, Steven R Lentz and Sanjana Dayal

Journal of the American Heart Association, Vol.9(4), pp.e013368-e013368

02/18/2020

DOI: 10.1161/JAHA.119.013368

PMCID: PMC7070222

PMID: 32067580

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Abstract

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 (6.1±0.3 μmol/L) or (309±18 μmol/L) mice versus (3.1±0.6 μmol/L) mice. Surprisingly, and mice exhibited similar increases in cerebral infarct size following middle cerebral artery ischemia/reperfusion injury, despite the much higher total homocysteine levels in mice. Likewise, disruption of the blood brain barrier was observed in both and mice. Administration of the N-methyl-D-aspartate receptor antagonist memantine protected but not mice from cerebral infarction and blood brain barrier disruption. Our data suggest that the differential effect of memantine in versus mice may be related to changes in expression of N-methyl-D-aspartate receptor subunits. , but not 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.

Infarction, Middle Cerebral Artery - prevention & control

Neurons - pathology

Receptors, N-Methyl-D-Aspartate - antagonists & inhibitors

Receptors, N-Methyl-D-Aspartate - metabolism

Infarction, Middle Cerebral Artery - metabolism

Homocystinuria - enzymology

Cystathionine beta-Synthase - deficiency

Neuroprotective Agents - pharmacology

Neurons - metabolism

Cell Death - drug effects

Cystathionine beta-Synthase - genetics

Neurons - drug effects

Disease Models, Animal

Hyperhomocysteinemia - enzymology

Severity of Illness Index

Hyperhomocysteinemia - blood

Memantine - pharmacology

Cells, Cultured

Homocysteine - blood

Excitatory Amino Acid Antagonists - pharmacology

Infarction, Middle Cerebral Artery - pathology

Blood-Brain Barrier - drug effects

Disease Progression

Hyperhomocysteinemia - drug therapy

Blood-Brain Barrier - metabolism

Mice, Knockout

Blood-Brain Barrier - pathology

Animals

Hyperhomocysteinemia - genetics

Homocystinuria - genetics

Details

Title: Subtitle: Memantine Protects From Exacerbation of Ischemic Stroke and Blood Brain Barrier Disruption in Mild But Not Severe Hyperhomocysteinemia
Creators: Sean X Gu - Department of Internal Medicine University of Iowa Carver College of Medicine Iowa City IA
Vijay K Sonkar - Department of Internal Medicine University of Iowa Carver College of Medicine Iowa City IA
Parmeshwar B Katare - Department of Internal Medicine University of Iowa Carver College of Medicine Iowa City IA
Rahul Kumar - Department of Internal Medicine University of Iowa Carver College of Medicine Iowa City IA
Warren D Kruger - Fox Chase Cancer Center Philadelphia PA
Erland Arning - Baylor Institute of Metabolic Disease Dallas TX
Teodoro Bottiglieri - Baylor Institute of Metabolic Disease Dallas TX
Steven R Lentz - Department of Internal Medicine University of Iowa Carver College of Medicine Iowa City IA
Sanjana Dayal - Department of Internal Medicine University of Iowa Carver College of Medicine Iowa City IA
Resource Type: Journal article
Publication Details: Journal of the American Heart Association, Vol.9(4), pp.e013368-e013368
DOI: 10.1161/JAHA.119.013368
PMID: 32067580
PMCID: PMC7070222
NLM abbreviation: J Am Heart Assoc
ISSN: 2047-9980
eISSN: 2047-9980
Publisher: England
Grant note: R01 DK101404 / NIDDK NIH HHS T32 HL007344 / NHLBI NIH HHS R01 AG049784 / NIA NIH HHS
Language: English
Date published: 02/18/2020
Academic Unit: Hematology, Oncology, and Blood & Marrow Transplantation; Iowa Neuroscience Institute; Fraternal Order of Eagles Diabetes Research Center; Internal Medicine
Record Identifier: 9984070564902771

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