title: pH-sensitive NMDA inhibitors improve outcome in a murine model of SAH.
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.
authors.affiliation: Multidisciplinary Neuroprotection Laboratories, Durham, NC, USA.
authors.forename: Haichen
authors.initials: H
authors.lastname: Wang
authors.forename: Michael L
authors.initials: ML
authors.lastname: James
authors.forename: Talaignair N
authors.initials: TN
authors.lastname: Venkatraman
authors.forename: Lawrence J
authors.initials: LJ
authors.lastname: Wilson
authors.forename: Polina
authors.initials: P
authors.lastname: Lyuboslavsky
authors.forename: Scott J
authors.initials: SJ
authors.lastname: Myers
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Lascola
authors.forename: Daniel T
authors.initials: DT
authors.lastname: Laskowitz
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000502:physiology; D002121:Calcium Channel Blockers / Q000494:pharmacology; D004195:Disease Models, Animal; D006863:Hydrogen-Ion Concentration; D006943:Hyperglycemia / Q000139:chemically induced; D008279:Magnetic Resonance Imaging; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009553:Nimodipine / Q000494:pharmacology; D011897:Random Allocation; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D013345:Subarachnoid Hemorrhage / Q000150:complications / Q000188:drug therapy*
chemical_list: D002121:Calcium Channel Blockers; C121001:NR2B NMDA receptor; D018696:Neuroprotective Agents; D016194:Receptors, N-Methyl-D-Aspartate; D009553:Nimodipine