Novel hypoglycemic injury mechanism: N-methyl-D-aspartate receptor-mediated white matter damage
Objective: Hypoglycemia is a common adverse event and can injure central nervous system (CNS) white matter (WM). We determined if glutamate receptors were involved in hypoglycemic WM injury. Methods: Mouse optic nerves (MON), CNS WM tracts, were maintained at 37°C with oxygenated artificial cerebro...
| Main Authors: | , , , , , , |
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| Format: | Article |
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Wiley
2014
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| Online Access: | https://eprints.nottingham.ac.uk/35413/ |
| _version_ | 1848795071422398464 |
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| author | Yang, Xin Hamner, Margaret A. Brown, Angus M. Evans, Richard D. Ye, Zu-Cheng Chen, Shengdi Ransom, Bruce R. |
| author_facet | Yang, Xin Hamner, Margaret A. Brown, Angus M. Evans, Richard D. Ye, Zu-Cheng Chen, Shengdi Ransom, Bruce R. |
| author_sort | Yang, Xin |
| building | Nottingham Research Data Repository |
| collection | Online Access |
| description | Objective: Hypoglycemia is a common adverse event and can injure central nervous system (CNS) white matter (WM). We determined if glutamate receptors were involved in hypoglycemic WM injury.
Methods: Mouse optic nerves (MON), CNS WM tracts, were maintained at 37°C with oxygenated artificial cerebrospinal fluid (ACSF) containing 10 mM glucose. Aglycemia was produced by switching to 0 glucose ACSF. Supra-maximal compound action potentials (CAPs) were elicited using suction electrodes and axon function was quantified as the area under the CAP. Amino acid release was measured using HPLC. Extracellular [lactate] was measured using an enzyme electrode.
Results: About 50% of MON axons were injured after 60 min of aglycemia (90% after 90 min); injury was not affected by animal age. Blockade of NMDA-type glutamate receptors improved recovery after 90 min of aglycemia by 250%. Aglycemic injury was increased by reducing [Mg2+]o or increasing [glycine]o, and decreased by lowering pHo, expected results for NMDA receptor-mediated injury. Extracellular pH increased during aglycemia, due to a drop in [lactate-]o. Aglycemic injury was dramatically reduced in the absence of [Ca2+]o. Extracellular aspartate, a selective NMDA receptor agonist, increased during aglycemia.
Interpretation: Aglycemia injured WM by a unique excitotoxic mechanism involving NMDA receptors (located primarily on oligodendrocytes). During WM aglycemia, the selective NMDA agonist, aspartate, is released, probably from astrocytes. Injury is mediated by Ca2+ influx through aspartate-activated NMDA receptors made permeable by an accompanying alkaline shift in pHo caused by a fall in [lactate-]o. These insights have important clinical implications. |
| first_indexed | 2025-11-14T19:26:15Z |
| format | Article |
| id | nottingham-35413 |
| institution | University of Nottingham Malaysia Campus |
| institution_category | Local University |
| last_indexed | 2025-11-14T19:26:15Z |
| publishDate | 2014 |
| publisher | Wiley |
| recordtype | eprints |
| repository_type | Digital Repository |
| spelling | nottingham-354132020-05-04T16:46:51Z https://eprints.nottingham.ac.uk/35413/ Novel hypoglycemic injury mechanism: N-methyl-D-aspartate receptor-mediated white matter damage Yang, Xin Hamner, Margaret A. Brown, Angus M. Evans, Richard D. Ye, Zu-Cheng Chen, Shengdi Ransom, Bruce R. Objective: Hypoglycemia is a common adverse event and can injure central nervous system (CNS) white matter (WM). We determined if glutamate receptors were involved in hypoglycemic WM injury. Methods: Mouse optic nerves (MON), CNS WM tracts, were maintained at 37°C with oxygenated artificial cerebrospinal fluid (ACSF) containing 10 mM glucose. Aglycemia was produced by switching to 0 glucose ACSF. Supra-maximal compound action potentials (CAPs) were elicited using suction electrodes and axon function was quantified as the area under the CAP. Amino acid release was measured using HPLC. Extracellular [lactate] was measured using an enzyme electrode. Results: About 50% of MON axons were injured after 60 min of aglycemia (90% after 90 min); injury was not affected by animal age. Blockade of NMDA-type glutamate receptors improved recovery after 90 min of aglycemia by 250%. Aglycemic injury was increased by reducing [Mg2+]o or increasing [glycine]o, and decreased by lowering pHo, expected results for NMDA receptor-mediated injury. Extracellular pH increased during aglycemia, due to a drop in [lactate-]o. Aglycemic injury was dramatically reduced in the absence of [Ca2+]o. Extracellular aspartate, a selective NMDA receptor agonist, increased during aglycemia. Interpretation: Aglycemia injured WM by a unique excitotoxic mechanism involving NMDA receptors (located primarily on oligodendrocytes). During WM aglycemia, the selective NMDA agonist, aspartate, is released, probably from astrocytes. Injury is mediated by Ca2+ influx through aspartate-activated NMDA receptors made permeable by an accompanying alkaline shift in pHo caused by a fall in [lactate-]o. These insights have important clinical implications. Wiley 2014-04-10 Article PeerReviewed Yang, Xin, Hamner, Margaret A., Brown, Angus M., Evans, Richard D., Ye, Zu-Cheng, Chen, Shengdi and Ransom, Bruce R. (2014) Novel hypoglycemic injury mechanism: N-methyl-D-aspartate receptor-mediated white matter damage. Annals of Neurology, 75 (4). pp. 492-507. ISSN 0364-5134 http://onlinelibrary.wiley.com/doi/10.1002/ana.24050/abstract doi:10.1002/ana.24050 doi:10.1002/ana.24050 |
| spellingShingle | Yang, Xin Hamner, Margaret A. Brown, Angus M. Evans, Richard D. Ye, Zu-Cheng Chen, Shengdi Ransom, Bruce R. Novel hypoglycemic injury mechanism: N-methyl-D-aspartate receptor-mediated white matter damage |
| title | Novel hypoglycemic injury mechanism: N-methyl-D-aspartate receptor-mediated white matter damage |
| title_full | Novel hypoglycemic injury mechanism: N-methyl-D-aspartate receptor-mediated white matter damage |
| title_fullStr | Novel hypoglycemic injury mechanism: N-methyl-D-aspartate receptor-mediated white matter damage |
| title_full_unstemmed | Novel hypoglycemic injury mechanism: N-methyl-D-aspartate receptor-mediated white matter damage |
| title_short | Novel hypoglycemic injury mechanism: N-methyl-D-aspartate receptor-mediated white matter damage |
| title_sort | novel hypoglycemic injury mechanism: n-methyl-d-aspartate receptor-mediated white matter damage |
| url | https://eprints.nottingham.ac.uk/35413/ https://eprints.nottingham.ac.uk/35413/ https://eprints.nottingham.ac.uk/35413/ |