Effects of the novel NMDA antagonists CP-98,113, CP-101,581 and CP-101,606 on cognitive function and regional cerebral edema following experimental brain injury in the rat.

Abstract

The present study evaluated the effects of two novel N-methyl-D-aspartate (NMDA) receptor blockers and ifenprodil derivatives, CP-101,606 and CP-101,581, and their racemic mixture CP-98,113, on spatial memory and regional cerebral edema following experimental fluid-percussion (FP) brain injury in the rat (n = 66). Fifteen minutes after brain injury (2.5 atm), animals received either (1) CP-98,113 (5 mg/kg, i.p., n = 11), (2) CP-101,581 (5 mg/kg, i.p., n = 13), (3) CP-101,606 (6.5 mg/kg, i.p., n = 12), or (4) DMSO vehicle (equal volume, n = 12); followed by a continuous 24-h subcutaneous infusion of drug at a rate of 1.5 mg/kg/h by means of miniature osmotic (Alzet) pumps implanted subcutaneously. Control (uninjured) animals were subjected to identical anesthesia and surgery without injury and received DMSO vehicle (n = 8); CP-98,113 (5 mg/kg, i.p., n = 3); CP-101,581 (5 mg/kg, i.p., n = 3); or CP-101,606 (6.5 mg/kg, i.p., n = 3). FP brain injury produced a significant cognitive impairment assessed at 2 days postinjury using a well-characterized testing paradigm of visuospatial memory in the Morris Water Maze (MWM) (p < 0.001). Administration of either CP-98,113, CP-101,581, or CP-101,606 had no effect on sham (uninjured) animals, but significant attenuated spatial memory impairment assessed at 2 days postinjury (p = 0.004, p = 0.02, or p = 0.02, respectively). Administration of CP-89,113 but not CP-101,581 or CP-101,606 significantly reduced the extent of regional cerebral edema in the cortex adjacent to the site of injury (p < 0.05) and in the ipsilateral hippocampus (p < 0.05) and thalamus (p < 0.05). These results suggest that excitatory neurotransmission may play a pivotal role in the pathogenesis of memory dysfunction following traumatic brain injury (TBI) and that blockade of the NMDA receptor may significantly attenuate cognitive deficits associated with TBI.

• Authors: K Okiyama, D H Smith, W F White, K Richter, T K McIntosh
• Journal: Journal of neurotrauma (J Neurotrauma) Vol. 14 Issue 4 Pg. 211-22 (Apr 1997) ISSN: 0897-7151 [Print] United States
• PMID: 9151770 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• CP 101581
• CP 98113
• Excitatory Amino Acid Antagonists
• Piperidines
• Receptors, N-Methyl-D-Aspartate
• traxoprodil mesylate

Topics

• Animals
• Brain Edema (etiology, physiopathology)
• Brain Injuries (physiopathology, psychology)
• Cognition (drug effects, physiology)
• Excitatory Amino Acid Antagonists (administration & dosage, pharmacology)
• Infusions, Parenteral
• Male
• Maze Learning (drug effects, physiology)
• Memory (drug effects, physiology)
• Piperidines (administration & dosage, pharmacology)
• Rats
• Rats, Sprague-Dawley
• Reaction Time (drug effects)
• Receptors, N-Methyl-D-Aspartate (antagonists & inhibitors)