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pH-sensitive NMDA inhibitors improve outcome in a murine model of SAH.

Publication ,  Journal Article
Wang, H; James, ML; Venkatraman, TN; Wilson, LJ; Lyuboslavsky, P; Myers, SJ; Lascola, CD; Laskowitz, DT
Published in: Neurocrit Care
February 2014

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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Published In

Neurocrit Care

DOI

EISSN

1556-0961

Publication Date

February 2014

Volume

20

Issue

1

Start / End Page

119 / 131

Location

United States

Related Subject Headings

  • Subarachnoid Hemorrhage
  • Receptors, N-Methyl-D-Aspartate
  • Random Allocation
  • Nimodipine
  • Neuroprotective Agents
  • Neurology & Neurosurgery
  • Mice, Inbred C57BL
  • Mice
  • Male
  • Magnetic Resonance Imaging
 

Citation

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Wang, H., James, M. L., Venkatraman, T. N., Wilson, L. J., Lyuboslavsky, P., Myers, S. J., … Laskowitz, D. T. (2014). pH-sensitive NMDA inhibitors improve outcome in a murine model of SAH. Neurocrit Care, 20(1), 119–131. https://doi.org/10.1007/s12028-013-9944-9
Wang, Haichen, Michael L. James, Talaignair N. Venkatraman, Lawrence J. Wilson, Polina Lyuboslavsky, Scott J. Myers, Christopher D. Lascola, and Daniel T. Laskowitz. “pH-sensitive NMDA inhibitors improve outcome in a murine model of SAH.Neurocrit Care 20, no. 1 (February 2014): 119–31. https://doi.org/10.1007/s12028-013-9944-9.
Wang H, James ML, Venkatraman TN, Wilson LJ, Lyuboslavsky P, Myers SJ, et al. pH-sensitive NMDA inhibitors improve outcome in a murine model of SAH. Neurocrit Care. 2014 Feb;20(1):119–31.
Wang, Haichen, et al. “pH-sensitive NMDA inhibitors improve outcome in a murine model of SAH.Neurocrit Care, vol. 20, no. 1, Feb. 2014, pp. 119–31. Pubmed, doi:10.1007/s12028-013-9944-9.
Wang H, James ML, Venkatraman TN, Wilson LJ, Lyuboslavsky P, Myers SJ, Lascola CD, Laskowitz DT. pH-sensitive NMDA inhibitors improve outcome in a murine model of SAH. Neurocrit Care. 2014 Feb;20(1):119–131.
Journal cover image

Published In

Neurocrit Care

DOI

EISSN

1556-0961

Publication Date

February 2014

Volume

20

Issue

1

Start / End Page

119 / 131

Location

United States

Related Subject Headings

  • Subarachnoid Hemorrhage
  • Receptors, N-Methyl-D-Aspartate
  • Random Allocation
  • Nimodipine
  • Neuroprotective Agents
  • Neurology & Neurosurgery
  • Mice, Inbred C57BL
  • Mice
  • Male
  • Magnetic Resonance Imaging