Sepsis causes neuroinflammation and concomitant decrease of cerebral metabolism

Journal of Neuroinflammation BioMed Central Research Open Access Sepsis causes neuroinflammation and concomitant decrease of cerebral metabolism Alexander Semmler1, Sven Hermann2, Florian Mormann3, Marc Weberpals1, Stephan A Paxian1, Thorsten Okulla1, Michael Schäfers2, Markus P Kummer1, Thomas Klockgether1 and Michael T Heneka*1 Address: 1University Bonn, Department of Neurology, Bonn, Germany, 2University Münster, Department of Nuclear Medicine, Münster, Germany and 3University Bonn, Department of Epileptology, Bonn, Germany Email: Alexander Semmler - ; Sven Hermann - ; Florian Mormann - ; Marc Weberpals - ; Stephan A Paxian - ; Thorsten Okulla - ; Michael Schäfers - ; Markus P Kummer - ; Thomas Klockgether - ; Michael T Heneka* - * Corresponding author Published: 15 September 2008 Journal of Neuroinflammation 2008, 5:38 doi:10.1186/1742-2094-5-38 Received: 30 July 2008 Accepted: 15 September 2008 This article is available from: http://www.jneuroinflammation.com/content/5/1/38 © 2008 Semmler et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Abstract Background: Septic encephalopathy is a severe brain dysfunction caused by systemic inflammation in the absence of direct brain infection. Changes in cerebral blood flow, release of inflammatory molecules and metabolic alterations contribute to neuronal dysfunction and cell death. Methods: To investigate the relation of electrophysiological, metabolic and morphological changes caused by SE, we simultaneously assessed systemic circulation, regional cerebral blood flow and cortical electroencephalography in rats exposed to bacterial lipopolysaccharide. Additionally, cerebral glucose uptake, astro- and microglial activation as well as changes of inflammatory gene transcription were examined by small animal PET using [18F]FDG, immunohistochemistry, and real time PCR. Results: While the systemic hemodynamic did not change significantly, regional cerebral blood flow was decreased in the cortex paralleled by a decrease of alpha activity of the electroencephalography. Cerebral glucose uptake was reduced in all analyzed neocortical areas, but preserved in the caudate nucleus, the hippocampus and the thalamus. Sepsis enhanced the transcription of several pro- and anti-inflammatory cytokines and chemokines including tumor necrosis factor alpha, interleukin-1 beta, transforming growth factor beta, and monocot chemoattractant protein 1 in the cerebrum. Regional analysis of different brain regions revealed an increase in ED1-positive microglia in the cortex, while total and neuronal cell counts decreased in the cortex and the hippocampus. Conclusion: Together, the present study highlights the complexity of sepsis induced early impairment of neuronal metabolism and activity. Since our model uses techniques that determine parameters relevant to the clinical setting, it might be a useful tool to develop brain specific therapeutic strategies for human septic encephalopathy. Page 1 of 10 (page number not for citation purposes) Journal of Neuroinflammation 2008, 5:38 http://www.jneuroinflammation.com/content/5/1/38 Background Methods Sepsis and its complications are the leading causes of mortality in intensive care units accounting for 10–50% of deaths. Up to 71% of septic patients develop potentially irreversible acute cerebral dysfunction [1-3]. This sepsisinduced encephalopathy is caused by systemic inflammation in the absence of direct brain infection and clinically characterized by slowing of mental processes, impaired attention, disorientation, delirium or coma. Importantly, septic encephalopathy (SE) is an early sign of sepsis and associated with an increased rate of morbidity and mortality [2]. Animals 53 male Wistar rats (Charles River, Sulzfeld, Germany) weighing 250 – 300 g were housed in groups under standard conditions at a temperature of 22°C (± 1°C) and a 12 hour light-dark cycle – with free access to standard food (Altromin, Soest, Germany) and tap water. Animal care and handling were performed according to the Declaration of Helsinki and approved by local ethical committees (approval number 50.203.2 BN 33,34/00). The pathogenesis of SE is unlikely to be directly induced by a pathogenic toxin, as similar encephalopathy can develop as a result of a number of systemic inflammatory response syndromes that lack an infectious etiology (e.g. acute pancreatitis, burns etc.). Clinical and experimental data suggest that a number of factors including the local generation of pro-inflammatory cytokines, impaired cerebral microcirculation, an imbalance of neurotransmitters and a negative impact of peripheral organ failure contribute to the development of SE. Additionally, once inflammation persists, increased excitotoxicity and oxidative stress may further aggravate SE and contribute to neuronal dysfunction and degeneration (for review see [3]). Of note, patients with a pre-existing CNS pathology have a higher risk to develop SE, and a similar predisposing interaction has been reported in an animal model of sepsis [4]. Clinically, the electroencephalogram (EEG) serves as an important diagnostic tool for SE assessment and the majority of patients shows abnormal EEG recordings [5]. Of note, the degree of EEG pathology correlates well with the clinical status and prognosis and has been proven more sensitive than clinical bedside investigation [5]. Likewise, cerebral blood flow (CBF) is another parameter which is routinely analyzed in patients suffering from SE, based on the assumption that sepsis exerts profound and sustained effects on the systemic circulatory function. However, past studies have yielded controversial results and to date, the effects of sepsis on CBF as well as neuronal metabolism and activity remain unclear. To further investigate the relation of potential regional CBF changes, electroencephalography and cerebral metabolism in response to SE, we investigated hemodynamic, electrophysiological and metabolic changes in relation to neuroinflammatory markers and neuronal number in a model of acute SE in rats. Regional cerebral blood flow was reduced in correlation to EEG frequency 24 h after intraperitoneal injection of LPS, whereas brain glucose utilization and neuronal number were reduced concurrent with microgliosis and neuroinflammatory response. Rats were randomized and received either 10 mg/kg of LPS (0127:B8, E. coli; Sigma, München, Germany) dissolved in 1 ml sodium chloride (0.9%) intraperitoneally (i. p.) or the vehicle alone. 24 hours after induction of sepsis, animals were anaesthetized with a combination of ketamine (80 mg/kg) and xylazine (10 mg/kg). The trachea was cannulated to facilitate respiration and rectal temperature was maintained (...truncated)