A genetic deficiency in folic acid metabolism impairs recovery after ischemic stroke
Stroke is a leading cause of disability and death world-wide and nutrition is a modifiable risk factor for stroke. Metheylenetetrahydrofolate reductase (MTHFR) is an enzyme involved in the metabolism of folic acid, a B-vitamin. In humans, a polymorphism in MTHFR (677C→T) is linked to increased risk...
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| Veröffentlicht in: | Experimental neurology 2018-11, Vol.309, p.14-22 |
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| creator | Jadavji, Nafisa M. Emmerson, Joshua T. Shanmugalingam, Ushananthini MacFarlane, Amanda J. Willmore, William G. Smith, Patrice D. |
| description | Stroke is a leading cause of disability and death world-wide and nutrition is a modifiable risk factor for stroke. Metheylenetetrahydrofolate reductase (MTHFR) is an enzyme involved in the metabolism of folic acid, a B-vitamin. In humans, a polymorphism in MTHFR (677C→T) is linked to increased risk of stroke, but the mechanisms remain unknown. The Mthfr+/− mice mimic a phenotype described in humans at bp677. Using this mouse model, the aim of this study was to investigate the impact of MTHFR deficiency on stroke outcome. Male Mthfr+/− and wildtype littermate control mice were aged (~1.5-year-old) and trained on the single pellet reaching task. After which the sensorimotor cortex was then damaged using photothrombosis (PT), a model for ischemic stroke. Post-operatively, animals were tested for skilled motor function, and brain tissue was processed to assess cell death. Mthfr+/− mice were impaired in skilled reaching 2-weeks after stroke but showed some recovery at 5-weeks compared to wild types after PT damage. Within the ischemic brain, there was increased expression of active caspase-3 and reduced levels of phospho-AKT in neurons of Mthfr+/− mice. Recent data suggests that astrocytes may play a significant role after damage, the impact of MTHFR and ischemic investigated the impact of MTHFR-deficiency on astrocyte function. MTHFR-deficient primary astrocytes showed reduced cell viability after exposure to hypoxia compared to controls. Increased immunofluorescence staining of active caspase-3 and hypoxia-inducible factor 1-alpha were also observed. The data suggest that MTHFR deficiency decreases recovery after stroke by reducing neuronal and astrocyte viability.
•Aged Mthfr+/− mice have impaired skilled reaching after stroke compared to Mthfr+/+.•Daily testing on skilled reaching task improved recovery in Mthfr+/− mice.•Mthfr+/− mice have mildly higher homocysteine, but lesion size does not differ.•There is lower neuronal survival within damage site of Mthfr+/− mice.•MTHFR deficiency results in reduced viability of primary astrocytes after hypoxia. |
| doi_str_mv | 10.1016/j.expneurol.2018.07.014 |
| format | Article |
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•Aged Mthfr+/− mice have impaired skilled reaching after stroke compared to Mthfr+/+.•Daily testing on skilled reaching task improved recovery in Mthfr+/− mice.•Mthfr+/− mice have mildly higher homocysteine, but lesion size does not differ.•There is lower neuronal survival within damage site of Mthfr+/− mice.•MTHFR deficiency results in reduced viability of primary astrocytes after hypoxia.</description><identifier>ISSN: 0014-4886</identifier><identifier>EISSN: 1090-2430</identifier><identifier>DOI: 10.1016/j.expneurol.2018.07.014</identifier><identifier>PMID: 30055159</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Animals ; Apoptosis - genetics ; Astrocytes ; Astrocytes - metabolism ; Brain Ischemia - complications ; Cells, Cultured ; Cerebral Cortex - cytology ; Disease Models, Animal ; Embryo, Mammalian ; Female ; Folic Acid - metabolism ; Gene Expression Regulation - genetics ; Glial Fibrillary Acidic Protein - metabolism ; Homocysteine - blood ; Ischemia ; Male ; Metabolic Diseases - etiology ; Metabolic Diseases - genetics ; Metabolic Diseases - physiopathology ; Methylenetetrahydrofolate reductase ; Methylenetetrahydrofolate Reductase (NADPH2) - deficiency ; Methylenetetrahydrofolate Reductase (NADPH2) - genetics ; Mice ; Mice, Inbred C57BL ; Neurons - metabolism ; Neurons - pathology ; Photothrombosis ; Psychomotor Performance - physiology ; Recovery ; Recovery of Function - genetics ; Stroke - complications ; Stroke - etiology ; Stroke - genetics ; Stroke - physiopathology</subject><ispartof>Experimental neurology, 2018-11, Vol.309, p.14-22</ispartof><rights>2018 Elsevier Inc.</rights><rights>Copyright © 2018 Elsevier Inc. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c371t-dd114f8a93d3ba605ae48f54a4070508dd4437b1e746a8f46b637b0051b3ff0d3</citedby><cites>FETCH-LOGICAL-c371t-dd114f8a93d3ba605ae48f54a4070508dd4437b1e746a8f46b637b0051b3ff0d3</cites><orcidid>0000-0002-3557-7307 ; 0000-0002-1252-8043</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0014488618302644$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,776,780,3536,27903,27904,65309</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/30055159$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Jadavji, Nafisa M.</creatorcontrib><creatorcontrib>Emmerson, Joshua T.</creatorcontrib><creatorcontrib>Shanmugalingam, Ushananthini</creatorcontrib><creatorcontrib>MacFarlane, Amanda J.</creatorcontrib><creatorcontrib>Willmore, William G.</creatorcontrib><creatorcontrib>Smith, Patrice D.</creatorcontrib><title>A genetic deficiency in folic acid metabolism impairs recovery after ischemic stroke</title><title>Experimental neurology</title><addtitle>Exp Neurol</addtitle><description>Stroke is a leading cause of disability and death world-wide and nutrition is a modifiable risk factor for stroke. Metheylenetetrahydrofolate reductase (MTHFR) is an enzyme involved in the metabolism of folic acid, a B-vitamin. In humans, a polymorphism in MTHFR (677C→T) is linked to increased risk of stroke, but the mechanisms remain unknown. The Mthfr+/− mice mimic a phenotype described in humans at bp677. Using this mouse model, the aim of this study was to investigate the impact of MTHFR deficiency on stroke outcome. Male Mthfr+/− and wildtype littermate control mice were aged (~1.5-year-old) and trained on the single pellet reaching task. After which the sensorimotor cortex was then damaged using photothrombosis (PT), a model for ischemic stroke. Post-operatively, animals were tested for skilled motor function, and brain tissue was processed to assess cell death. Mthfr+/− mice were impaired in skilled reaching 2-weeks after stroke but showed some recovery at 5-weeks compared to wild types after PT damage. Within the ischemic brain, there was increased expression of active caspase-3 and reduced levels of phospho-AKT in neurons of Mthfr+/− mice. Recent data suggests that astrocytes may play a significant role after damage, the impact of MTHFR and ischemic investigated the impact of MTHFR-deficiency on astrocyte function. MTHFR-deficient primary astrocytes showed reduced cell viability after exposure to hypoxia compared to controls. Increased immunofluorescence staining of active caspase-3 and hypoxia-inducible factor 1-alpha were also observed. The data suggest that MTHFR deficiency decreases recovery after stroke by reducing neuronal and astrocyte viability.
•Aged Mthfr+/− mice have impaired skilled reaching after stroke compared to Mthfr+/+.•Daily testing on skilled reaching task improved recovery in Mthfr+/− mice.•Mthfr+/− mice have mildly higher homocysteine, but lesion size does not differ.•There is lower neuronal survival within damage site of Mthfr+/− mice.•MTHFR deficiency results in reduced viability of primary astrocytes after hypoxia.</description><subject>Animals</subject><subject>Apoptosis - genetics</subject><subject>Astrocytes</subject><subject>Astrocytes - metabolism</subject><subject>Brain Ischemia - complications</subject><subject>Cells, Cultured</subject><subject>Cerebral Cortex - cytology</subject><subject>Disease Models, Animal</subject><subject>Embryo, Mammalian</subject><subject>Female</subject><subject>Folic Acid - metabolism</subject><subject>Gene Expression Regulation - genetics</subject><subject>Glial Fibrillary Acidic Protein - metabolism</subject><subject>Homocysteine - blood</subject><subject>Ischemia</subject><subject>Male</subject><subject>Metabolic Diseases - etiology</subject><subject>Metabolic Diseases - genetics</subject><subject>Metabolic Diseases - physiopathology</subject><subject>Methylenetetrahydrofolate reductase</subject><subject>Methylenetetrahydrofolate Reductase (NADPH2) - deficiency</subject><subject>Methylenetetrahydrofolate Reductase (NADPH2) - genetics</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Neurons - metabolism</subject><subject>Neurons - pathology</subject><subject>Photothrombosis</subject><subject>Psychomotor Performance - physiology</subject><subject>Recovery</subject><subject>Recovery of Function - genetics</subject><subject>Stroke - complications</subject><subject>Stroke - etiology</subject><subject>Stroke - genetics</subject><subject>Stroke - physiopathology</subject><issn>0014-4886</issn><issn>1090-2430</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2018</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkMlOwzAQQC0EgrL8AvjIJWEcO7F7rCo2CYlLOVtOPAaXLMVOEf17XFq4chrN6M32CLlikDNg1c0yx69Vj-swtHkBTOUgc2DigEwYTCErBIdDMoFUyoRS1Qk5jXEJAFNRyGNywgHKkpXTCVnM6Cv2OPqGWnS-8dg3G-p76oY21UzjLe1wNHVKY0d9tzI-RBqwGT4xbKhxIwbqY_OGXeLjGIZ3PCdHzrQRL_bxjLzc3S7mD9nT8_3jfPaUNVyyMbOWMeGUmXLLa1NBaVAoVwojQEIJylohuKwZSlEZ5URVVylNp7OaOweWn5Hr3dxVGD7WGEfdpUuwbU2PwzrqAqQqFS-4TKjcoU0YYgzo9Cr4zoSNZqC3SvVS_ynVW6UapE7-Uuflfsm67tD-9f06TMBsB2B69dNj0PFHI1qfNI3aDv7fJd9x8oyr</recordid><startdate>201811</startdate><enddate>201811</enddate><creator>Jadavji, Nafisa M.</creator><creator>Emmerson, Joshua T.</creator><creator>Shanmugalingam, Ushananthini</creator><creator>MacFarlane, Amanda J.</creator><creator>Willmore, William G.</creator><creator>Smith, Patrice D.</creator><general>Elsevier Inc</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0002-3557-7307</orcidid><orcidid>https://orcid.org/0000-0002-1252-8043</orcidid></search><sort><creationdate>201811</creationdate><title>A genetic deficiency in folic acid metabolism impairs recovery after ischemic stroke</title><author>Jadavji, Nafisa M. ; Emmerson, Joshua T. ; Shanmugalingam, Ushananthini ; MacFarlane, Amanda J. ; Willmore, William G. ; Smith, Patrice D.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c371t-dd114f8a93d3ba605ae48f54a4070508dd4437b1e746a8f46b637b0051b3ff0d3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2018</creationdate><topic>Animals</topic><topic>Apoptosis - genetics</topic><topic>Astrocytes</topic><topic>Astrocytes - metabolism</topic><topic>Brain Ischemia - complications</topic><topic>Cells, Cultured</topic><topic>Cerebral Cortex - cytology</topic><topic>Disease Models, Animal</topic><topic>Embryo, Mammalian</topic><topic>Female</topic><topic>Folic Acid - metabolism</topic><topic>Gene Expression Regulation - genetics</topic><topic>Glial Fibrillary Acidic Protein - metabolism</topic><topic>Homocysteine - blood</topic><topic>Ischemia</topic><topic>Male</topic><topic>Metabolic Diseases - etiology</topic><topic>Metabolic Diseases - genetics</topic><topic>Metabolic Diseases - physiopathology</topic><topic>Methylenetetrahydrofolate reductase</topic><topic>Methylenetetrahydrofolate Reductase (NADPH2) - deficiency</topic><topic>Methylenetetrahydrofolate Reductase (NADPH2) - genetics</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Neurons - metabolism</topic><topic>Neurons - pathology</topic><topic>Photothrombosis</topic><topic>Psychomotor Performance - physiology</topic><topic>Recovery</topic><topic>Recovery of Function - genetics</topic><topic>Stroke - complications</topic><topic>Stroke - etiology</topic><topic>Stroke - genetics</topic><topic>Stroke - physiopathology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Jadavji, Nafisa M.</creatorcontrib><creatorcontrib>Emmerson, Joshua T.</creatorcontrib><creatorcontrib>Shanmugalingam, Ushananthini</creatorcontrib><creatorcontrib>MacFarlane, Amanda J.</creatorcontrib><creatorcontrib>Willmore, William G.</creatorcontrib><creatorcontrib>Smith, Patrice D.</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Experimental neurology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Jadavji, Nafisa M.</au><au>Emmerson, Joshua T.</au><au>Shanmugalingam, Ushananthini</au><au>MacFarlane, Amanda J.</au><au>Willmore, William G.</au><au>Smith, Patrice D.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>A genetic deficiency in folic acid metabolism impairs recovery after ischemic stroke</atitle><jtitle>Experimental neurology</jtitle><addtitle>Exp Neurol</addtitle><date>2018-11</date><risdate>2018</risdate><volume>309</volume><spage>14</spage><epage>22</epage><pages>14-22</pages><issn>0014-4886</issn><eissn>1090-2430</eissn><abstract>Stroke is a leading cause of disability and death world-wide and nutrition is a modifiable risk factor for stroke. Metheylenetetrahydrofolate reductase (MTHFR) is an enzyme involved in the metabolism of folic acid, a B-vitamin. In humans, a polymorphism in MTHFR (677C→T) is linked to increased risk of stroke, but the mechanisms remain unknown. The Mthfr+/− mice mimic a phenotype described in humans at bp677. Using this mouse model, the aim of this study was to investigate the impact of MTHFR deficiency on stroke outcome. Male Mthfr+/− and wildtype littermate control mice were aged (~1.5-year-old) and trained on the single pellet reaching task. After which the sensorimotor cortex was then damaged using photothrombosis (PT), a model for ischemic stroke. Post-operatively, animals were tested for skilled motor function, and brain tissue was processed to assess cell death. Mthfr+/− mice were impaired in skilled reaching 2-weeks after stroke but showed some recovery at 5-weeks compared to wild types after PT damage. Within the ischemic brain, there was increased expression of active caspase-3 and reduced levels of phospho-AKT in neurons of Mthfr+/− mice. Recent data suggests that astrocytes may play a significant role after damage, the impact of MTHFR and ischemic investigated the impact of MTHFR-deficiency on astrocyte function. MTHFR-deficient primary astrocytes showed reduced cell viability after exposure to hypoxia compared to controls. Increased immunofluorescence staining of active caspase-3 and hypoxia-inducible factor 1-alpha were also observed. The data suggest that MTHFR deficiency decreases recovery after stroke by reducing neuronal and astrocyte viability.
•Aged Mthfr+/− mice have impaired skilled reaching after stroke compared to Mthfr+/+.•Daily testing on skilled reaching task improved recovery in Mthfr+/− mice.•Mthfr+/− mice have mildly higher homocysteine, but lesion size does not differ.•There is lower neuronal survival within damage site of Mthfr+/− mice.•MTHFR deficiency results in reduced viability of primary astrocytes after hypoxia.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>30055159</pmid><doi>10.1016/j.expneurol.2018.07.014</doi><tpages>9</tpages><orcidid>https://orcid.org/0000-0002-3557-7307</orcidid><orcidid>https://orcid.org/0000-0002-1252-8043</orcidid></addata></record> |
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| subjects | Animals Apoptosis - genetics Astrocytes Astrocytes - metabolism Brain Ischemia - complications Cells, Cultured Cerebral Cortex - cytology Disease Models, Animal Embryo, Mammalian Female Folic Acid - metabolism Gene Expression Regulation - genetics Glial Fibrillary Acidic Protein - metabolism Homocysteine - blood Ischemia Male Metabolic Diseases - etiology Metabolic Diseases - genetics Metabolic Diseases - physiopathology Methylenetetrahydrofolate reductase Methylenetetrahydrofolate Reductase (NADPH2) - deficiency Methylenetetrahydrofolate Reductase (NADPH2) - genetics Mice Mice, Inbred C57BL Neurons - metabolism Neurons - pathology Photothrombosis Psychomotor Performance - physiology Recovery Recovery of Function - genetics Stroke - complications Stroke - etiology Stroke - genetics Stroke - physiopathology |
| title | A genetic deficiency in folic acid metabolism impairs recovery after ischemic stroke |
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