NPS 1506 Attenuates Cognitive Dysfunction and Hippocampal Neuron Death Following Brain Trauma in the Rat

• Published in: Experimental neurology Vol. 166; no. 2; pp. 442 - 449
• Main Authors: Leoni, Matthew J., Chen, Xiao-Han, Mueller, Alan L., Cheney, Jessica, McIntosh, Tracy K., Smith, Douglas H.
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Inc 01-12-2000; Elsevier
• Subjects: Animals; Biological and medical sciences; Brain Injuries - drug therapy; Brain Injuries - pathology; brain trauma; Cell Death - drug effects; Cognition - drug effects; fluid percussion; Fluorobenzenes - pharmacology; hippocampus; Hippocampus - pathology; Male; Maze Learning - drug effects; Medical sciences; memory; Memory Disorders - drug therapy; Memory Disorders - pathology; Neuropharmacology; Neuroprotective agent; Neuroprotective Agents - pharmacology; NMDA; NPS 1506; Pharmacology. Drug treatments; Pyramidal Cells - pathology; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate - antagonists & inhibitors; NMDA; fluid percussion; memory; NPS 1506; hippocampus; brain trauma; Nervous system diseases; Rat; Rodentia; Brain death; Neuroprotective agent; Trauma; Cerebral disorder; Vertebrata; Chemotherapy; Mammalia; Treatment; Dysfunction; Animal; Central nervous system disease; Antagonist; NMDA receptor; Hippocampus; Brain (vertebrata)
• ISSN: 0014-4886; 1090-2430
• DOI: 10.1006/exnr.2000.7513

Although several noncompetitive N-methyl-d-aspartate (NMDA) receptor antagonists have been shown to be substantially efficacious in experimental models of brain trauma, side effects associated with this class of compounds have impeded clinical application. Therefore, new noncompetitive NMDA receptor antagonists have been developed, including NPS 1506, that appear to be nontoxic but retain efficacy. In the present study, we evaluated the efficacy of NPS 1506 in a model of parasagittal fluid percussion brain trauma in the anesthetized rat. Administration of 1 mg/kg NPS 1506 at both 10 min and 4 h posttrauma induced no changes in brain temperature, mean arterial pressure, pulse, or arterial blood gasses. At 1 week postinjury, animals treated with the same dosing regimen of NPS 1506 demonstrated a dramatic attenuation of memory dysfunction evaluated by a water maze task (P < 0.02) and had greatly reduced neuron death in the CA3 subfield of the hippocampus (P < 0.01). However, NPS 1506 treatment did not significantly affect the extent of cortical tissue loss following injury. Since memory dysfunction and hippocampal damage are common and potentially related consequences of brain trauma in humans, our results suggest that NPS 1506 treatment may have clinical utility.