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Published on: November 20, 2015
Increased Hypothalamic Levels of Endozepines, Endogenous Ligands of Benzodiazepine Receptors, in a Rat Model of
Thomas Clavier1, Emmanuel Besnier, Antoine Lefevre-Scelles
1*National Institute for Medical Research (INSERM), U982 †Institute for Research and Innovation in Biomedicine (IRIB), Normandy University ‡Laboratory of Neuronal and Neuroendocrine Differentiation and Communication, Rouen University, Mont-Saint-Aignan §Department of Anesthesiology and Critical Care, Rouen University Hospital, Rouen, France ||Institute of Cardiology and Pneumology, Quebec City, Canada ¶Laboratory of Functional Neurophysiology and Pathology, Research Unit UR/11ES09, Tunis, Tunisia #Oncology, Molecular Endocrinology, and Human Genomics Research Center, Quebec, Canada.
Background:
The mechanisms involved in septic anorexia are mainly related to the secretion of inflammatory cytokines. The term endozepines designates a family of neuropeptides, including the octadecaneuropeptide (ODN), originally isolated as endogenous ligands of benzodiazepine receptors. Previous data showed that ODN, produced and released by astrocytes, is a potent anorexigenic peptide. We have studied the effect of sepsis by means of a model of cecal ligation and puncture (CLP) on the hypothalamic expression of endozepines (DBI mRNA and protein levels), as well as on the level of neuropeptides controlling energy homeostasis mRNAs: pro-opiomelanocortin, neuropeptide Y, and corticotropin-releasing hormone. In addition, we have investigated the effects of two inflammatory cytokines, TNF-α and IL-1β, on DBI mRNA levels in cultured rat astrocytes.
Methods:
Studies were performed on Sprague-Dawley male rats and on cultures of rat cortical astrocytes. Sepsis was induced using the CLP method. Sham-operated control animals underwent the same procedure, but the cecum was neither ligated nor incised.
Results:
Sepsis caused by CLP evoked an increase of DBI mRNA levels in ependymal cells bordering the third ventricle and in tanycytes of the median eminence. CLP-induced sepsis was also associated with stimulated ODN-like immunoreactivity (ODN-LI) in the hypothalamus. In addition, TNF-α, but not IL-1β, induced a dose-dependent increase in DBI mRNA in cultured rat astrocytes. An increase in the mRNA encoding the precursor of the anorexigenic peptide α-melanocyte stimulating hormone, the pro-opiomelanocortin, and the corticotropin-releasing hormone was observed in the hypothalamus.
Conclusion:
These results suggest that during sepsis, hypothalamic mRNA encoding endozepines, anorexigenic peptide as well as stress hormone could play a role in the anorexia/cachexia associated with inflammation due to sepsis and we suggest that this hypothalamic mRNA expression could involve TNF-α.
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