dextrorphan and Brain-Injuries

Effects of single-drug and combination drug treatments were examined in a model of lateral fluid percussion-induced traumatic brain injury (TBI) in rats. Treatments included the opioid receptor antagonist nalmefene, the thyrotropin releasing hormone (TRH) analog YM14673, the noncompetitive N-methyl-D-aspartate (NMDA) antagonist dextrorphan, nalmefene + dextrorphan, YM14673 + nalmefene, YM14673 + dextrorphan, and equal volume saline. Single-dose treatment with nalmefene, YM14673, or dextrorphan at 30 min after trauma each significantly improved behavioral recovery at two weeks as compared with vehicle-treated controls, confirming earlier studies with these agents. No combination treatment was superior to treatment with the most effective individual drug alone. Combination treatment with the TRH analog and the NMDA antagonist resulted in significantly less effectiveness than treatment with either drug alone. These findings indicate the need for preclinical studies to examine potential drug-drug interactions in the treatment of central nervous system (CNS) trauma.

Topics: Animals; Azetidines; Behavior, Animal; Brain Injuries; Dextrorphan; Dipeptides; Drug Therapy, Combination; Forelimb; Magnesium Sulfate; Male; Movement; Naltrexone; Narcotic Antagonists; Rats; Rats, Sprague-Dawley

After central nervous system (CNS) trauma, there are marked elevations in the extracellular levels of excitatory amino acids (EAA), which are believed to contribute to delayed tissue damage. Administration of N-methyl-D-aspartate (NMDA) receptor antagonists reduces injury severity after brain or spinal cord trauma, presumably by blocking the postsynaptic NMDA receptor. In the present studies, levels of extracellular amino acids were monitored by microdialysis during, and after, a moderately severe fluid-percussion brain injury to rats. Pretreatment (15 min prior to injury) with the non-competitive NMDA antagonist dextrorphan or the competitive NMDA antagonist CGS 19755 significantly attenuated the post-traumatic increase in extracellular glutamate. Pretreatment with dextrorphan attenuated the post-traumatic increase in extracellular levels of aspartate; although these differences did not reach significance when examined as absolute values, they were significant when analyzed as percent increase over pre-trauma baseline levels. These results are consistent with recent experiments and suggest that NMDA antagonists may limit the release of glutamate and aspartate after trauma through a presynaptic mechanism.

Topics: Amino Acids; Animals; Brain Injuries; Chromatography, High Pressure Liquid; Dextrorphan; Dialysis; Glutamates; Glutamic Acid; Male; N-Methylaspartate; Pipecolic Acids; Rats; Rats, Inbred Strains; Receptors, N-Methyl-D-Aspartate

Brain injury induced by fluid percussion in rats caused a marked elevation in extracellular glutamate and aspartate adjacent to the trauma site. This increase in excitatory amino acids was related to the severity of the injury and was associated with a reduction in cellular bioenergetic state and intracellular free magnesium. Treatment with the noncompetitive N-methyl-D-aspartate (NMDA) antagonist dextrophan or the competitive antagonist 3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid limited the resultant neurological dysfunction; dextrorphan treatment also improved the bioenergetic state after trauma and increased the intracellular free magnesium. Thus, excitatory amino acids contribute to delayed tissue damage after brain trauma; NMDA antagonists may be of benefit in treating acute head injury.

Topics: Animals; Aspartic Acid; Binding, Competitive; Brain; Brain Injuries; Dextrorphan; Glutamates; Glutamic Acid; Magnesium; Magnetic Resonance Spectroscopy; Male; N-Methylaspartate; Phosphates; Phosphocreatine; Piperazines; Rats; Rats, Inbred Strains; Receptors, N-Methyl-D-Aspartate; Receptors, Neurotransmitter