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Zinc inhibits NMDA receptor function through both voltage-dependent and voltage-independent mechanisms. In this report we have investigated the role that the NR1 subunit plays in voltage-independent Zn2+ inhibition. Our data show that inclusion of exon 5 into the NR1 subunit increases the IC50 for voltage-independent Zn2+ inhibition from 3-fold to 10-fold when full length exon 22 is also splice...
Recent studies propose that sigma site ligands antagonize N-methyl-D-aspartate (NMDA) receptors by either direct, or indirect mechanisms of inhibition. To investigate this question further we used electrical recordings to assay actions of seventeen structurally diverse sigma site ligands on three diheteromeric subunit combinations of cloned rat NMDA receptors expressed in Xenopus oocytes: NR1a ...
Stroke remains a significant problem despite decades of work on neuroprotective strategies. NMDA receptor (NMDAR) antagonists are neuroprotective in preclinical models, but have been clinically unsuccessful, in part due to side effects. Here we describe a prototypical GluN2B-selective antagonist with an IC50 value that is 10-fold more potent at acidic pH 6.9 associated with ischemic tissue comp...
Memantine is an uncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist which is registered in both Europe and the USA for the treatment of Alzheimer's disease (AD). Cultured rat hippocampal neurons were used to evaluate the potency and blocking kinetics of this therapeutically very well-tolerated agent in the presence of various concentrations of the synthetic agonist NMDA and a constant...
Zinc (Zn2+) inhibition of N-methyl-D-aspartate receptor (NMDAR) activity involves both voltage-independent and voltage-dependent components. Recombinant NR1/NR2A and NR1/NR2B receptors exhibit similar voltage-dependent block, but voltage-independent Zn2+ inhibition occurs with much higher affinity for NR1/NR2A than NR1/NR2B receptors (nanomolar versus micromolar IC50, respectively). Here, we sh...
Background: Acute lung injury (ALI) is a pulmonary pathology occuring in context of infection, trauma, burn, and sepsis. Tissue injury and release of chemical mediators result in tissue damage and organ failure especially respiratory failure. Many therapeutic modalities including vitamin E, allopurinol, and N-acetylcystein (NAC) have been used to decrease levels of inflammatory factors and to c...
49 HYDROCORTISONE IMPROVED HAEMODYNAMICS AND FLUID REQUIREMENT IN SURVIVING BUT NOT NONSURVIVING OF SEVERELY BURNED PATIENTS The administration of hydrocortisone can lead to a reduction of catecholamines and improved outcome in septic patients. However, no data exist regarding the use of hydrocortisone in burn patients although, in such patients, the reduction of vasopressors may be even more c...
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