Neurocritical Care

, Volume 20, Issue 1, pp 119–131 | Cite as

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

  • Haichen Wang
  • Michael L. James
  • Talaignair N. Venkatraman
  • Lawrence J. Wilson
  • Polina Lyuboslavsky
  • Scott J. Myers
  • Christopher D. Lascola
  • Daniel T. Laskowitz
Translational Research

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.

Keywords

Subarachnoid hemorrhage Vasospasm Neuroprotection Excitotoxicity pH 

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Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Haichen Wang
    • 1
    • 2
  • Michael L. James
    • 1
    • 2
    • 3
  • Talaignair N. Venkatraman
    • 1
    • 4
  • Lawrence J. Wilson
    • 6
  • Polina Lyuboslavsky
    • 6
  • Scott J. Myers
    • 6
  • Christopher D. Lascola
    • 1
    • 4
    • 5
  • Daniel T. Laskowitz
    • 1
    • 2
    • 3
    • 5
  1. 1.Multidisciplinary Neuroprotection LaboratoriesDurhamUSA
  2. 2.Department of NeurologyDuke University School of MedicineDurhamUSA
  3. 3.Department of AnesthesiologyDuke University School of MedicineDurhamUSA
  4. 4.Department of RadiologyDuke University School of MedicineDurhamUSA
  5. 5.Department of NeurobiologyDuke University School of MedicineDurhamUSA
  6. 6.NeurOp Inc.AtlantaUSA

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