This Article Full Text Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Di, X. Articles by Corwin, F. Search for Related Content PubMed PubMed Citation Articles by Di, X. Articles by Corwin, F.

(Stroke. 1997;28:2244-2251.)
© 1997 American Heart Association, Inc.

Articles

Effect of CP101,606, a Novel NR2B Subunit Antagonist of the N-Methyl-D-Aspartate Receptor, on the Volume of Ischemic Brain Damage and Cytotoxic Brain Edema After Middle Cerebral Artery Occlusion in the Feline Brain

Xiao Di, MD, PhD; Ross Bullock, MD, PhD; Joe Watson, MD; Panos Fatouros, PhD; Bertrand Chenard; Frost White; Frank Corwin, MS

From the Divisions of Neurosurgery (X.D., R.B., J.W.) and Radiation Biology (P.F., F.C.), Medical College of Virginia, Virginia Commonwealth University, Richmond, Va, and Pfizer Central Research, Groton, Ct (B.C., F.W.).

Correspondence to Ross Bullock, MD, PhD, Division of Neurosurgery, Medical College of Virginia, Virginia Commonwealth University, Box 980631, MCV Station, Richmond, VA 23298-0631.

Background and Purpose The purpose of this study was to test the hypothesis that the neuroprotective compound CP101,606 will ameliorate the increase in lactate, retard the development of cytotoxic edema, and decrease the infarct volume after ischemic stroke.

Methods Seventeen adult cats were allocated to control (n=7) and CP101,606-treated groups (n=10). Transorbital middle cerebral artery occlusion was performed under anesthesia. Extracellular fluid lactate by microdialysis as well as infarct volume measurement by triphenyltetrazolium chloride (TTC)–stained section, with and without neuroprotective agents, was used to determine the value of these potential "surrogate markers" of ischemic damage.

Results The control group showed an increased dialysate lactate (15.5% increase) at 30 minutes and a peak (332.0% increase) in dialysate lactate at 1 hour after middle cerebral artery occlusion compared with the drug-treated group. Significant differences between control and drug-treated groups were seen in the rate of fall of the apparent diffusion coefficient at both 1 and 5 hours. A close correlation was seen between the 1- and 5-hour apparent diffusion coefficient maps and the TTC-stained sections. There was a significantly smaller lesion in the CP101,606-treated group (62.9% reduction in infarct size compared with the control group; P<.001).

Conclusions CP101,606 ranks very highly among the current neuroprotection candidates for clinical trials, and its excellent safety record in both animals and phase II studies in conscious, moderate head injury patients suggests that it will be highly effective in human occlusive stroke.

Key Words: brain edema • glutamate antagonist • cats

This article has been cited by other articles:

				M. Philip, M. Benatar, M. Fisher, and S. I. Savitz Methodological Quality of Animal Studies of Neuroprotective Agents Currently in Phase II/III Acute Ischemic Stroke Trials Stroke, February 1, 2009; 40(2): 577 - 581. [Abstract] [Full Text] [PDF]

				G. H. Danton and W. D. Dietrich The Search for Neuroprotective Strategies in Stroke AJNR Am. J. Neuroradiol., February 1, 2004; 25(2): 181 - 194. [Full Text] [PDF]

				K. Johnson, A. Shah, S. Jaw-Tsai, J. Baxter, and C. Prakash Metabolism, Pharmacokinetics, and Excretion of a Highly Selective N-Methyl-D-aspartate Receptor Antagonist, Traxoprodil, in Human Cytochrome P450 2D6 Extensive and Poor Metabolizers Drug Metab. Dispos., January 1, 2003; 31(1): 76 - 87. [Abstract] [Full Text] [PDF]

				R. Gill, A. Alanine, A. Bourson, B. Buttelmann, G. Fischer, M.-P. Heitz, J. N. C. Kew, B. Levet-Trafit, H.-P. Lorez, P. Malherbe, et al. Pharmacological Characterization of Ro 63-1908 (1-[2-(4-Hydroxy-phenoxy)-ethyl]-4-(4-methyl-benzyl)-piperidin-4-ol), a Novel Subtype-Selective N-Methyl-D-Aspartate Antagonist J. Pharmacol. Exp. Ther., September 1, 2002; 302(3): 940 - 948. [Abstract] [Full Text] [PDF]

				J. Nabekura, T. Ueno, S. Katsurabayashi, A. Furuta, N. Akaike, and M. Okada Reduced NR2A expression and prolonged decay of NMDA receptor-mediated synaptic current in rat vagal motoneurons following axotomy J. Physiol., March 15, 2002; 539(3): 735 - 741. [Abstract] [Full Text] [PDF]

				E. Morikawa, H. Mori, Y. Kiyama, M. Mishina, T. Asano, and T. Kirino Attenuation of Focal Ischemic Brain Injury in Mice Deficient in the epsilon 1 (NR2A) Subunit of NMDA Receptor J. Neurosci., December 1, 1998; 18(23): 9727 - 9732. [Abstract] [Full Text] [PDF]

				J. N C Kew and J. A Kemp An allosteric interaction between the NMDA receptor polyamine and ifenprodil sites in rat cultured cortical neurones J. Physiol., October 1, 1998; 512(1): 17 - 28. [Abstract] [Full Text] [PDF]

				J. Nabekura, T. Ueno, S. Katsurabayashi, A. Furuta, N. Akaike, and M. Okada Reduced NR2A expression and prolonged decay of NMDA receptor-mediated synaptic current in rat vagal motoneurons following axotomy J. Physiol., March 15, 2002; 539(3): 735 - 741. [Abstract] [Full Text] [PDF]