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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References
Linn FH, Rinkel GJ, Algra A, van Gijn J. Incidence of subarachnoid hemorrhage: role of region, year, and rate of computed tomography: a meta-analysis. Stroke. 1996;27(4):625–9.
van Gijn J, Kerr RS, Rinkel GJ. Subarachnoid haemorrhage. Lancet. 2007;369(9558):306–18.
Locksley HB. Natural history of subarachnoid hemorrhage, intracranial aneurysms and arteriovenous malformations. Based on 6,368 cases in the cooperative study. J Neurosurg. 1966;25(2):219–39.
Longstreth WT Jr, Nelson LM, Koepsell TD, van Belle G. Clinical course of spontaneous subarachnoid hemorrhage: a population-based study in King County, Washington. Neurology. 1993;43(4):712–8.
Treggiari MM, Walder B, Suter PM, Romand JA. Systematic review of the prevention of delayed ischemic neurological deficits with hypertension, hypervolemia, and hemodilution therapy following subarachnoid hemorrhage. J Neurosurg. 2003;98(5):978–84.
Gump W, Laskowitz DT. Management of post-subarachnoid hemorrhage vasospasm. Curr Atheroscler Rep. 2008;10(4):354–60.
Dearden NM. Mechanisms and prevention of secondary brain damage during intensive care. Clin Neuropathol. 1998;17(4):221–8.
Kemp JA, McKernan RM. NMDA receptor pathways as drug targets. Nat Neurosci. 2002;5(Suppl):1039–42.
Choi D. Antagonizing excitotoxicity: a therapeutic strategy for stroke? Mt Sinai J Med. 1998;65(2):133–8.
Palmer GC. Neuroprotection by NMDA receptor antagonists in a variety of neuropathologies. Curr Drug Targets. 2001;2(3):241–71.
Low SJ, Roland CL. Review of NMDA antagonist-induced neurotoxicity and implications for clinical development. Int J Clin Pharmacol Ther. 2004;42(1):1–14.
Kornhuber J, Weller M. Psychotogenicity and N-methyl-d-aspartate receptor antagonism: implications for neuroprotective pharmacotherapy. Biol Psychiatry. 1997;41(2):135–44.
Lutsep HL, Clark WM. Neuroprotection in acute ischaemic stroke. Current status and future potential. Drugs R D. 1999;1(1):3–8.
Giffard RG, Monyer H, Christine CW, Choi DW. Acidosis reduces NMDA receptor activation, glutamate neurotoxicity, and oxygen-glucose deprivation neuronal injury in cortical cultures. Brain Res. 1990;506(2):339–42.
Tang CM, Dichter M, Morad M. Modulation of the N-methyl-d-aspartate channel by extracellular H+. Proc Natl Acad Sci USA. 1990;87(16):6445–9.
Traynelis SF, Cull-Candy SG. Proton inhibition of N-methyl-d-aspartate receptors in cerebellar neurons. Nature. 1990;345(6273):347–50.
Traynelis SF, Cull-Candy SG. Pharmacological properties and H+ sensitivity of excitatory amino acid receptor channels in rat cerebellar granule neurones. J Physiol. 1991;433:727–63.
Vyklicky L Jr, Vlachova V, Krusek J. The effect of external pH changes on responses to excitatory amino acids in mouse hippocampal neurones. J Physiol. 1990;430:497–517.
Mott DD, Doherty JJ, Zhang S, Washburn MS, Fendley MJ, Lyuboslavsky P, et al. Phenylethanolamines inhibit NMDA receptors by enhancing proton inhibition. Nat Neurosci. 1998;1(8):659–67.
Silver IA, Erecinska M. Ion homeostasis in rat brain in vivo: intra- and extracellular [Ca2+] and [H+] in the hippocampus during recovery from short-term, transient ischemia. J Cereb Blood Flow Metab. 1992;12(5):759–72.
Katsura K, Asplund B, Ekholm A, Siesjo BK. Extra- and intra-cellular pH in the brain during ischaemia, related to tissue lactate content in normo- and hyper-capnic rats. Eur J Neurosci. 1992;4(2):166–76.
McEvoy RC, Andersson J, Sandler S, Hellerstrom C. Multiple low-dose streptozotocin-induced diabetes in the mouse. Evidence for stimulation of a cytotoxic cellular immune response against an insulin-producing beta cell line. J Clin Invest. 1984;74(3):715–22.
Parra A, McGirt MJ, Sheng H, Laskowitz DT, Pearlstein RD, Warner DS. Mouse model of subarachnoid hemorrhage associated cerebral vasospasm: methodological analysis. Neurol Res. 2002;24(5):510–6.
Zhou J, Payen JF, Wilson DA, Traystman RJ, van Zijl PC. Using the amide proton signals of intracellular proteins and peptides to detect pH effects in MRI. Nat Med. 2003;9(8):1085–90.
Mesis RG, Wang H, Lombard FW, Yates R, Vitek MP, Borel CO, et al. Dissociation between vasospasm and functional improvement in a murine model of subarachnoid hemorrhage. Neurosurg Focus. 2006;21(3):E4.
Schmued LC, Hopkins KJ. Fluoro-Jade B: a high affinity fluorescent marker for the localization of neuronal degeneration. Brain Res. 2000;874(2):123–30.
Wang H, Durham L, Dawson H, Song P, Warner DS, Sullivan PM, et al. An apolipoprotein E-based therapeutic improves outcome and reduces Alzheimer’s disease pathology following closed head injury: evidence of pharmacogenomic interaction. Neuroscience. 2007;144(4):1324–33.
Traynelis SF, Burgess MF, Zheng F, Lyuboslavsky P, Powers JL. Control of voltage-independent zinc inhibition of NMDA receptors by the NR1 subunit. J Neurosci. 1998;18(16):6163–75.
Takata K, Sheng H, Borel CO, Laskowitz DT, Warner DS, Lombard FW. Simvastatin treatment duration and cognitive preservation in experimental subarachnoid hemorrhage. J Neurosurg Anesthesiol. 2009;21(4):326–33.
Sun PZ, Zhou J, Sun W, Huang J, van Zijl PC. Detection of the ischemic penumbra using pH-weighted MRI. J Cereb Blood Flow Metab. 2007;27(6):1129–36.
Petruk KC, West M, Mohr G, Weir BK, Benoit BG, Gentili F, et al. Nimodipine treatment in poor-grade aneurysm patients. Results of a multicenter double-blind placebo-controlled trial. J Neurosurg. 1988;68(4):505–17.
Pickard JD, Murray GD, Illingworth R, Shaw MD, Teasdale GM, Foy PM, et al. Effect of oral nimodipine on cerebral infarction and outcome after subarachnoid haemorrhage: British aneurysm nimodipine trial. BMJ. 1989;298(6674):636–42.
Boyce S, Wyatt A, Webb JK, O’Donnell R, Mason G, Rigby M, et al. Selective NMDA NR2B antagonists induce antinociception without motor dysfunction: correlation with restricted localisation of NR2B subunit in dorsal horn. Neuropharmacology. 1999;38(5):611–23.
Koroshetz WJ, Moskowitz MA. Emerging treatments for stroke in humans. Trends Pharmacol Sci. 1996;17(6):227–33.
Hickenbottom SL, Grotta J. Neuroprotective therapy. Semin Neurol. 1998;18(4):485–92.
Rogawski MA. Low affinity channel blocking (uncompetitive) NMDA receptor antagonists as therapeutic agents toward an understanding of their favorable tolerability. Amino Acids. 2000;19(1):133–49.
Bian L, Liu L, Wang C, Hussain M, Yuan Y, Liu G, Wang W, Zhao X. Hyperglycemia within day 14 of aneurysmal subarachnoid hemorrhage predicts 1-year mortality. Clin Neurol Neurosurg. 2013;115(7):959–64.
Parsons MW, Barber PA, Desmond PM, Baird TA, Darby DG, Byrnes G, Tress BM, Davis SM. Acute hyperglycemia adversely affects stroke outcome: a magnetic resonance imaging and spectroscopy study. Ann Neurol. 2002;52(1):20–8.
Schlenk F, Vajkoczy P, Sarrafzadeh A. Inpatient hyperglycemia following aneurysmal subarachnoid hemorrhage: relation to cerebral metabolism and outcome. Neurocrit Care. 2009;11(1):56–63.
Holmgaard K, Aalkjaer C, Lambert JD, Bek T. N-Methyl-d-aspartic acid causes relaxation of porcine retinal arterioles through an adenosine receptor-dependent mechanism. Invest Ophthalmol Vis Sci. 2008;49(10):4590–4.
Busija DW, Bari F, Domoki F, Louis T. Mechanisms involved in the cerebrovascular dilator effects of N-methyl-d-aspartate in cerebral cortex. Brain Res Rev. 2007;56(1):89–100.
Stroke Therapy Academic Industry Roundtable (STAIR). Recommendations for standards regarding preclinical neuroprotective and restorative drug development. Stroke. 1999;30(12):2752–8.
Acknowledgments
This work was supported by NIH Grant 1R41NS056858-01A2 (DTL), 2R44NS049666-02A1(SJM), and AHA-SDG (MLJ). Lawrence J. Wilson is now in the Department of Chemistry at Emory University, Atlanta GA.
Conflict of interest
Dr. Laskowitz has served as a consultant for NeurOp Inc.
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Wang, H., James, M.L., Venkatraman, T.N. et al. pH-Sensitive NMDA Inhibitors Improve Outcome in a Murine Model of SAH. Neurocrit Care 20, 119–131 (2014). https://doi.org/10.1007/s12028-013-9944-9
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DOI: https://doi.org/10.1007/s12028-013-9944-9