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01-02-2014 | Translational Research

pH-Sensitive NMDA Inhibitors Improve Outcome in a Murine Model of SAH

Authors: Haichen Wang, Michael L. James, Talaignair N. Venkatraman, Lawrence J. Wilson, Polina Lyuboslavsky, Scott J. Myers, Christopher D. Lascola, Daniel T. Laskowitz

Published in: Neurocritical Care | Issue 1/2014

Abstract

Background

Despite intensive research, neurological morbidity from delayed cerebral ischemia remains common after aneurysmal subarachnoid hemorrhage (SAH). In the current study, we evaluate the neuroprotective effects of a pH-dependent GluN2B subunit-selective NMDA receptor antagonist in a murine model of SAH.

Methods

Following induction of SAH, 12 ± 2 week old male C57-BL/6 mice received NP10075, a pH-dependent NMDA receptor antagonist, or vehicle. In a separate series of experiments, NP10075 and the non-pH sensitive NMDA antagonist, NP10191, were administered to normoglycemic and hyperglycemic mice. Both histological (right middle cerebral artery diameter, NeuN, and Fluoro-Jade B staining) and functional endpoints (rotarod latency and neuroseverity score) were evaluated to assess the therapeutic benefit of NP10075.

Results

Administration of NP10075 was well tolerated and had minimal hemodynamic effects following SAH. Administration of the pH-sensitive NMDA antagonist NP10075, but not NP10191, was associated with a durable improvement in the functional performance of both normoglycemic and hyperglycemic animals. NP10075 was also associated with a reduction in vasospasm in the middle cerebral artery associated with hemorrhage. There was no significant difference between treatment with nimodipine + NP10075, as compared to NP10075 alone.

Conclusions

These data demonstrate that use of a pH-dependent NMDA antagonist has the potential to work selectively in areas of ischemia known to undergo acidic pH shifts, and thus may be associated with selective regional efficacy and fewer behavioral side effects than non-selective NMDA antagonists.

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Title: pH-Sensitive NMDA Inhibitors Improve Outcome in a Murine Model of SAH
Authors: Haichen Wang
Michael L. James
Talaignair N. Venkatraman
Lawrence J. Wilson
Polina Lyuboslavsky
Scott J. Myers
Christopher D. Lascola
Daniel T. Laskowitz
Publication date: 01-02-2014
Publisher: Springer US
Published in: Neurocritical Care / Issue 1/2014
Print ISSN: 1541-6933
Electronic ISSN: 1556-0961
DOI: https://doi.org/10.1007/s12028-013-9944-9

Keynote webinar | Spotlight on medication adherence

Springer Medicine

pH-Sensitive NMDA Inhibitors Improve Outcome in a Murine Model of SAH

Abstract

Background

Methods

Results

Conclusions

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

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