Mechanism of action of TSC

Previous studies have shown that using trans sodium crocetinate (TSC) as a treatment for hemorrhagic shock leads to increased survival, increased oxygen consumption, immediate increases in arterial blood pressure, and decreased tissue damage. These effects are all suggested to result from increased oxygen diffusion; however, this is a novel mechanism of action and is still not fully understood. The goal of this work is to better clarify the mechanism of action of TSC, using a variety of experiments to investigate the diffusion mechanism as well as other possible mechanisms.; For example, alteration of cytokine production is a commonly considered mechanism of action in hypoxic states, such as hemorrhagic shock. In the current study, results suggest that treatment of hemorrhagic shock with TSC results in lower concentrations of the cytokine TNF-alpha in the liver and spleen, and IL-10 in the spleen; however, no changes were seen in the plasma concentrations of these cytokines. A similar decrease in cytokine content has been seen with oxygen therapy as a treatment for hemorrhagic shock.; Another possible mechanism of action, the free radical scavenging ability of TSC, was also investigated. In vitro studies suggest that TSC scavenges hydroxyl radicals and nitric oxide; however, TSC did not scavenge free radicals in vivo.; Through further investigation of the diffusion mechanism, it has been demonstrated that TSC can result in an approximate 30% increase of the diffusion coefficient of glucose through water, which is similar to the effect seen previously for oxygen diffusion. This confirms results of previous computer simulation studies that suggested that the effect of TSC on diffusion due to solvent, not solute, changes.; It was also found that adding TSC to water results in a somewhat increased viscosity, and this increase is temperature dependent. Additionally, near infrared spectroscopy suggests that TSC acts to create more order and more hydrogen bonding in the surrounding water molecules. This influence on surrounding water molecules is apparently the source of TSC's effect on diffusion.; The use of TSC treatment for another condition where oxygen transport is limited was also studied. A rat model of acute lung injury (ALI) was used and treatment with TSC improved blood oxygenation, suggesting that it improves the transport of oxygen from the lungs to the red blood cells, as well as from the red cells to the mitochondria.; From these studies, it appears that the beneficial effects seen with TSC administration are consistent with the novel proposed mechanism of action of increased oxygen delivery via increased oxygen diffusion. While TSC was seen to act as a free radical scavenger in vitro, in vivo studies did not result in appreciable scavenging. The initial plasma concentration of TSC used during in vivo studies, both previously and currently, was within the range where increased diffusion coefficients were measured; however, this concentration is too dilute to observe free radical scavenging effects.