Therapeutic effects of serotonin antagonists on the development of systemic edema in the early phase of burn disease and overall survival in rats

Status:

completed 10/2013

Aims:

Burns represent a common cause of traumatic injury that is still associated with significant morbidity and high mortality rates. The systemic response to burns is characterized not only by local destruction of tissue but also by systemic capillary leakage and immunologic activation, which occurs as early as two to four h post trauma. The purpose of this study is to determine the influence of specific and nonspecific serotonin antagonists (methysergide, cetanserin and ceinanserin) on microvascular permeability changes in postcapillary venules after burns in vivo and to evaluate if systemic application of these antagonists leads to reduced plasma extravasation. Differences in edema formation (shown by extravasation of linked proteins) will be measured early after burn plasma transfer in male wistar rats. In addition, serum levels of important mediators, such as IL-6 and TNF alpha, will be evaluated. Initially, non-specific antagonists will be assessed followed by studies on specific serotonin antagonism. Preliminary results will be available by the end of 2010. Efficacy studies and the therapeutic benefit will hopefully be finally assessable by July 2011.

Activities/Methods:

By using of a high-resolution digital camera, digitization of intravital microscopic studies with improved picture resolution and evaluation quality is enabled. Data analysis is obtained with a new and individualized analysis software. During the upcoming weeks, medical students will be educated in the experimental methodology (animal preparation/ intravital-microscopy/ data processing / ELISA technique). The first experimental series will start in August 2010 with optimization of negative control results to exclude systemic bias followed by evaluation of serotonin antagonism as mentioned above.

Results:

Using intravital microscopy evaluation of systemic burn shock and potential therapeutic agents can easily be analyzed. Highly specific (Ketanserin) as well as unspecific (Methysergide and Cinanserin) serotonin antagonism reduce macromolecular efflux after burn plasma transfer to baseline levels. The 5-HT2a receptor seems to play a crucial role in the development of early burn edema. These effects may partially result from leukocyte dependent as well as independent mechanisms. Bradycardia was observed as a major side effect after serotonin antagonist administration. Further investigations are strongly required to detect side effects and to focus on clinical applicability. The presented data identify a new promising approach to burntrauma treatment. Further investigations are required to reveal unwanted effects after treatment with serotonin antagonists.

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