Letter to the Editor Stroke welcomes Letters to the Editor and will publish them, if suitable, as space permits. Letters must reference a Stroke published-ahead-of-print article or an article printed within the past 3 weeks. The maximum length is 750 words including no more than 5 references and 3 authors. Please submit letters typed double-spaced. Letters may be shortened or edited.
Response to Letter Regarding Article, “Preexisting Serum Autoantibodies Against the NMDAR Subunit NR1 Modulate Evolution of Lesion Size in Acute Ischemic Stroke” We thank Richard Macrez and colleagues for writing this complementary letter regarding our recent article.1 The letter nicely extends the discussion on possible mechanisms of action that might contribute to the consequences of preexisting N-methyl-d-aspartate-receptor subunit NR1 (NMDAR1) autoantibodies (AB) on brain functions. We agree that the role of endothelial NMDAR1 in blood–brain barrier (BBB) permeability and monocyte transmigration is intriguing. Also, the fact that in our study the modulating effects of NMDAR1-AB were less prominent in r-tPA (recombinant tissue-type plasminogen activator) as compared with non–r-tPA treated patients, despite their higher N number (see Figure IV),1 may support an additional modifier influence of (exogenous) r-tPA on outcome that is probably independent of its thrombolytic activity. BBB integrity before stroke, however, at least tended to have the same influence regardless of r-tPA treatment: Beneficial NMDAR1-AB effects in individuals with previously intact BBB but harmful effects in APOE4 carriers with leaky BBB before the ischemic insult. Nevertheless, beyond a potentially important role of the cerebrovascular endothelium, we have to consider that other cell types in the brain likely contribute to short-term and longterm outcome after stroke. Also cells of the oligodendrocyte lineage and astrocytes are known to express NMDAR1, which may influence their neuron/axon supporting, detoxifying, metabolic, protection, or defense properties.2–4 Blocking these NMDAR1 functions by AB may ultimately codetermine stroke outcome. In fact, antagonizing NMDAR1 not only on neurons and endothelial cells but also on glia by NMDAR1-AB in the event of a sudden BBB breakdown versus a subtle-permanent BBB leakage might variably contribute to the modulation of brain functions. Importantly, in conditions of hypoxia/ischemia, inflammation or demyelination but also during normal development and perhaps even intensive learning processes,
NMDAR1 expression may be significantly increased and thus effects of AB binding be more prominent.2–4 In conclusion, much more work will have to go into understanding consequences of circulating NMDAR1-AB in disease states with accompanying BBB breakdown, where these AB may possibly play the role of a double-edged sword. Reduction of lesion size during acute ischemia may be followed by an increased risk of cognitive decline, epilepsy, or psychosis on extended AB exposure of the brain because of a lastingly compromised BBB after stroke.1 Further studies will be necessary to evaluate potential benefits of passive (rather than active) immunization under carefully controlled conditions.
Disclosures None.
Esther Castillo-Gomez, PhD Hannelore Ehrenreich, MD, DVM Clinical Neuroscience Max Planck Institute of Experimental Medicine Göttingen, Germany DFG Center for Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB) Göttingen, Germany 1. Zerche M, Weissenborn K, Ott C, Dere E, Asif AR, Worthmann H, et al. Preexisting serum autoantibodies against the NMDAR subunit NR1 modulate evolution of lesion size in acute ischemic stroke. Stroke. 2015;46:1180–1186. doi: 10.1161/STROKEAHA.114.008323. 2. Stys PK, Lipton SA. White matter NMDA receptors: an unexpected new therapeutic target? Trends Pharmacol Sci. 2007;28:561–566. doi: 10.1016/j.tips.2007.10.003. 3. Kolodziejczyk K, Saab AS, Nave KA, Attwell D. Why do oligodendrocyte lineage cells express glutamate receptors? F1000 Biol Rep. 2010;2:57. doi: 10.3410/B2-57. 4. Dzamba D, Honsa P, Anderova M. NMDA receptors in glial cells: pending questions. Curr Neuropharmacol. 2013;11:250–262. doi: 10.2174/ 1570159X11311030002.
(Stroke. 2015;46:e178. DOI: 10.1161/STROKEAHA.115.009725.) © 2015 American Heart Association, Inc. Stroke is available at http://stroke.ahajournals.org
DOI: 10.1161/STROKEAHA.115.009725
Downloaded from http://stroke.ahajournals.org/ at e178 University of Pittsburgh--HSLS on November 20, 2015
Response to Letter Regarding Article, ''Preexisting Serum Autoantibodies Against the NMDAR Subunit NR1 Modulate Evolution of Lesion Size in Acute Ischemic Stroke'' Esther Castillo-Gomez and Hannelore Ehrenreich Stroke. 2015;46:e178; originally published online May 28, 2015; doi: 10.1161/STROKEAHA.115.009725 Stroke is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231 Copyright © 2015 American Heart Association, Inc. All rights reserved. Print ISSN: 0039-2499. Online ISSN: 1524-4628
The online version of this article, along with updated information and services, is located on the World Wide Web at: http://stroke.ahajournals.org/content/46/7/e178
Permissions: Requests for permissions to reproduce figures, tables, or portions of articles originally published in Stroke can be obtained via RightsLink, a service of the Copyright Clearance Center, not the Editorial Office. Once the online version of the published article for which permission is being requested is located, click Request Permissions in the middle column of the Web page under Services. Further information about this process is available in the Permissions and Rights Question and Answer document. Reprints: Information about reprints can be found online at: http://www.lww.com/reprints Subscriptions: Information about subscribing to Stroke is online at: http://stroke.ahajournals.org//subscriptions/
Downloaded from http://stroke.ahajournals.org/ at University of Pittsburgh--HSLS on November 20, 2015
Response to Letter Regarding Article, “Preexisting Serum Autoantibodies Against the NMDAR Subunit NR1 Modulate Evolution of Lesion Size in Acute Ischemic Stroke” We thank Richard Macrez and colleagues for writing this complementary letter regarding our recent article.1 The letter nicely extends the discussion on possible mechanisms of action that might contribute to the consequences of preexisting N-methyl-d-aspartate-receptor subunit NR1 (NMDAR1) autoantibodies (AB) on brain functions. We agree that the role of endothelial NMDAR1 in blood–brain barrier (BBB) permeability and monocyte transmigration is intriguing. Also, the fact that in our study the modulating effects of NMDAR1-AB were less prominent in r-tPA (recombinant tissue-type plasminogen activator) as compared with non–r-tPA treated patients, despite their higher N number (see Figure IV),1 may support an additional modifier influence of (exogenous) r-tPA on outcome that is probably independent of its thrombolytic activity. BBB integrity before stroke, however, at least tended to have the same influence regardless of r-tPA treatment: Beneficial NMDAR1-AB effects in individuals with previously intact BBB but harmful effects in APOE4 carriers with leaky BBB before the ischemic insult. Nevertheless, beyond a potentially important role of the cerebrovascular endothelium, we have to consider that other cell types in the brain likely contribute to short-term and longterm outcome after stroke. Also cells of the oligodendrocyte lineage and astrocytes are known to express NMDAR1, which may influence their neuron/axon supporting, detoxifying, metabolic, protection, or defense properties.2–4 Blocking these NMDAR1 functions by AB may ultimately codetermine stroke outcome. In fact, antagonizing NMDAR1 not only on neurons and endothelial cells but also on glia by NMDAR1-AB in the event of a sudden BBB breakdown versus a subtle-permanent BBB leakage might variably contribute to the modulation of brain functions. Importantly, in conditions of hypoxia/ischemia, inflammation or demyelination but also during normal development and perhaps even intensive learning processes,
NMDAR1 expression may be significantly increased and thus effects of AB binding be more prominent.2–4 In conclusion, much more work will have to go into understanding consequences of circulating NMDAR1-AB in disease states with accompanying BBB breakdown, where these AB may possibly play the role of a double-edged sword. Reduction of lesion size during acute ischemia may be followed by an increased risk of cognitive decline, epilepsy, or psychosis on extended AB exposure of the brain because of a lastingly compromised BBB after stroke.1 Further studies will be necessary to evaluate potential benefits of passive (rather than active) immunization under carefully controlled conditions.
Disclosures None.
Esther Castillo-Gomez, PhD Hannelore Ehrenreich, MD, DVM Clinical Neuroscience Max Planck Institute of Experimental Medicine Göttingen, Germany DFG Center for Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB) Göttingen, Germany 1. Zerche M, Weissenborn K, Ott C, Dere E, Asif AR, Worthmann H, et al. Preexisting serum autoantibodies against the NMDAR subunit NR1 modulate evolution of lesion size in acute ischemic stroke. Stroke. 2015;46:1180–1186. doi: 10.1161/STROKEAHA.114.008323. 2. Stys PK, Lipton SA. White matter NMDA receptors: an unexpected new therapeutic target? Trends Pharmacol Sci. 2007;28:561–566. doi: 10.1016/j.tips.2007.10.003. 3. Kolodziejczyk K, Saab AS, Nave KA, Attwell D. Why do oligodendrocyte lineage cells express glutamate receptors? F1000 Biol Rep. 2010;2:57. doi: 10.3410/B2-57. 4. Dzamba D, Honsa P, Anderova M. NMDA receptors in glial cells: pending questions. Curr Neuropharmacol. 2013;11:250–262. doi: 10.2174/ 1570159X11311030002.
(Stroke. 2015;46:e178. DOI: 10.1161/STROKEAHA.115.009725.) © 2015 American Heart Association, Inc. Stroke is available at http://stroke.ahajournals.org
DOI: 10.1161/STROKEAHA.115.009725
Downloaded from http://stroke.ahajournals.org/ at e178 University of Pittsburgh--HSLS on November 20, 2015
Response to Letter Regarding Article, ''Preexisting Serum Autoantibodies Against the NMDAR Subunit NR1 Modulate Evolution of Lesion Size in Acute Ischemic Stroke'' Esther Castillo-Gomez and Hannelore Ehrenreich Stroke. 2015;46:e178; originally published online May 28, 2015; doi: 10.1161/STROKEAHA.115.009725 Stroke is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231 Copyright © 2015 American Heart Association, Inc. All rights reserved. Print ISSN: 0039-2499. Online ISSN: 1524-4628
The online version of this article, along with updated information and services, is located on the World Wide Web at: http://stroke.ahajournals.org/content/46/7/e178
Permissions: Requests for permissions to reproduce figures, tables, or portions of articles originally published in Stroke can be obtained via RightsLink, a service of the Copyright Clearance Center, not the Editorial Office. Once the online version of the published article for which permission is being requested is located, click Request Permissions in the middle column of the Web page under Services. Further information about this process is available in the Permissions and Rights Question and Answer document. Reprints: Information about reprints can be found online at: http://www.lww.com/reprints Subscriptions: Information about subscribing to Stroke is online at: http://stroke.ahajournals.org//subscriptions/
Downloaded from http://stroke.ahajournals.org/ at University of Pittsburgh--HSLS on November 20, 2015
