GABAergic drugs, such as benzodiazepines, are widely used in clinical practice yet their immune side effects are poorly understood. Preliminary studies have suggested that immune cells express GABAA receptors indicating that they may be controlled by GABA signaling. Herein parallel preclinical, translational and epidemiological approaches are described to help understand the importance of GABAA immunomodulation. The hypothesis is that GABA signaling acts to reduce responsiveness to a pathogen and thus that GABAergic drugs will increase susceptibility to infection. To inform on the clinical importance of this work, data from a subgroup analysis of the Maximizing Efficacy of Targeted Sedation and Reducing Neurological Dysfunction (MENDS) trial (where the relative effects of lorazepam, and dexmedetomidine were compared) are described in septic and non‐septic patients. Consistent with the hypothesis, avoidance of lorazepam sedation decreased mortality by 70% in septic patients but did not affect outcome in non‐septic patients. As preclinical data suggests that benzodiazepines increase mortality at subsedative doses we next conducted a population‐based cohort and nested case‐control design analysis of The Health Improvement Network (THIN), a comprehensive UK general practice database. Benzodiazepines exposure increased the incidence of community acquired pneumonia (CAP) and both 30‐day and long‐term mortality from CAP. Based on these significant accumulating data of the harm of exposure to benzodiazepines during an infection, animal studies were conducted to understand (i) the biological plausibility of our findings and (ii) the mechanism of the effect. In a series of mouse studies the prototypical benzodiazepine, diazepam, increased mortality from Streptococcus pneumoniae through potentiation of GABAA signaling. The increased mortality was associated with increased pathogen load and a delayed cytokine response to the infection. However cellular recruitment was not affected, indicating that local mechanisms were perturbed. Immune cell profiling revealed that alveolar macrophage and monocytes abundantly expressed subunits of the GABAA receptor, compatible with benzodiazepine sensitivity. Ex vivo studies showed that GABAA receptor activation decreased cytokine responses, phagocytosis and bacterial killing by alveolar macrophage likely via inducing an intracellular acidosis. Finally based on the immune cell profile of GABAA receptors we predicted that benzodiazepines that do not target the α1 GABAA subunit would lack the immune suppression observed by nonselective drugs. In accordance with this hypothesis we show that these selective benzodiazepines do not provoke intracellular acidosis, affect cytokine release or bacterial killing of macrophage ex vivo. In vivo the selective benzodiazepine did not increase mortality from infection or increase pathogen load.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:560673 |
| Date | January 2012 |
| Creators | Sanders, Robert A. |
| Contributors | Hussell, Tracy ; Maze, Mervyn |
| Publisher | Imperial College London |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://hdl.handle.net/10044/1/9981 |
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