title: Modulatory effects of vagal stimulation on neurophysiological parameters and the cellular immune response in the rat brain during systemic inflammation.
abstract: BACKGROUND
  Stimulation of the vagus nerve has modulating, anti-inflammatory effects on the cellular immune response in the blood and the spleen, stabilizing brain function. Here, we aimed to investigate its potential effects on immune-to-brain communication focusing on neurophysiological readouts and leukocyte migration to the brain during severe sepsis-like endotoxemia.
  
  
  METHODS
  Systemic inflammation was induced by intravenous administration of lipopolysaccharide (LPS; 5 mg/kg). Animals received either no manipulation of the vagus nerve, vagotomy, or vagotomy plus vagus nerve stimulation of the distal trunk. Somatosensory evoked potentials and evoked flow velocity response were measured for 4.5 h as indicators of brain function and neurovascular coupling, respectively. In addition, brain areas with (cortex) and without (hypothalamus) tight blood-brain barrier were studied separately using immunohistochemistry and RT-PCR. Moreover, plasma cytokine and leptin levels were analyzed by ELISA.
  
  
  RESULTS
  LPS induced a decline of both neurophysiological parameters, which was prevented by vagus nerve stimulation. As for peripheral organs, LPS-stimulated neutrophil counts increased in the brain and colocalized in the brain with endothelial intercellular adhesion molecule (ICAM)-1. Interestingly, vagal stimulation reduced this colocalization and decreased nuclear translocation of the brain cell activation marker nuclear factor interleukin 6 (NF-IL6). Furthermore, it reduced the gene expression of inflammatory markers and extravasation signals (IL-6, CXCL-1, ICAM-1) in the hypothalamus but not the cortex linked to a moderate decrease in circulating cytokine levels (interleukin 6, tumor necrosis factor alpha) as well as lower plasma leptin concentration.
  
  
  CONCLUSIONS
  Our data suggest beneficial effects of anti-inflammatory vagus nerve stimulation on brain function by reducing the interaction of neurotrophil granulocytes with the brain endothelium as well as attenuating inflammatory responses in brain areas lacking a blood-brain barrier.
authors.affiliation: Department of Neurology, Justus-Liebig-University Giessen, Klinikstr. 33, 35392, Giessen, Germany.|Institute of Veterinary Physiology and Biochemistry, Justus-Liebig-University Giessen, 35392, Giessen, Germany.
authors.forename: Hanna
authors.initials: H
authors.lastname: Schweighöfer
authors.affiliation: Institute of Veterinary Physiology and Biochemistry, Justus-Liebig-University Giessen, 35392, Giessen, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Rummel
authors.affiliation: Institute of Veterinary Physiology and Biochemistry, Justus-Liebig-University Giessen, 35392, Giessen, Germany.
authors.forename: Joachim
authors.initials: J
authors.lastname: Roth
authors.affiliation: Department of Neurology, Justus-Liebig-University Giessen, Klinikstr. 33, 35392, Giessen, Germany. Bernhard.Rosengarten@neuro.med.uni-giessen.de.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Rosengarten
keywords: Cytokines; Immune-to-brain signaling; Leptin; Neurovascular coupling; Nuclear factor interleukin 6; Nuclear factor kappa B; Prostaglandins; Sepsis; Vagus nerve stimulation