Sepsis Causes Neuroinflammation and Concomitant Decrease of Cerebral Metabolism

Overview

Journal J Neuroinflammation

Publisher Biomed Central

Date 2008 Sep 17

PMID 18793399

Citations 146

Authors

Alexander Semmler

Sven Hermann

Florian Mormann

Marc Weberpals

Stephan A Paxian

Thorsten Okulla

Michael Schafers

Markus P Kummer

Thomas Klockgether

Michael T Heneka

Affiliations

Soon will be listed here.

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.

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References

Nguyen D, Spapen H, Su F, Schiettecatte J, Shi L, Hachimi-Idrissi S . Elevated serum levels of S-100beta protein and neuron-specific enolase are associated with brain injury in patients with severe sepsis and septic shock. Crit Care Med. 2006; 34(7):1967-74. DOI: 10.1097/01.CCM.0000217218.51381.49. View

Soehle M, Heimann A, Kempski O . On the number of measurement sites required to assess regional cerebral blood flow by laser-Doppler scanning during cerebral ischemia and reperfusion. J Neurosci Methods. 2001; 110(1-2):91-4. DOI: 10.1016/s0165-0270(01)00422-8. View

Sharshar T, Annane D, de la GrandMaison G, Brouland J, Hopkinson N, Francoise G . The neuropathology of septic shock. Brain Pathol. 2004; 14(1):21-33. PMC: 8095740. DOI: 10.1111/j.1750-3639.2004.tb00494.x. View

Mori K, Togashi H, UENO K, Matsumoto M, Yoshioka M . Aminoguanidine prevented the impairment of learning behavior and hippocampal long-term potentiation following transient cerebral ischemia. Behav Brain Res. 2001; 120(2):159-68. DOI: 10.1016/s0166-4328(00)00371-5. View

Kelly A, Lynch A, Vereker E, Nolan Y, Queenan P, Whittaker E . The anti-inflammatory cytokine, interleukin (IL)-10, blocks the inhibitory effect of IL-1 beta on long term potentiation. A role for JNK. J Biol Chem. 2001; 276(49):45564-72. DOI: 10.1074/jbc.M108757200. View

Pickering M, Cumiskey D, OConnor J . Actions of TNF-alpha on glutamatergic synaptic transmission in the central nervous system. Exp Physiol. 2005; 90(5):663-70. DOI: 10.1113/expphysiol.2005.030734. View

Boje K, Arora P . Microglial-produced nitric oxide and reactive nitrogen oxides mediate neuronal cell death. Brain Res. 1992; 587(2):250-6. DOI: 10.1016/0006-8993(92)91004-x. View

Rosengarten B, Hecht M, Auch D, Ghofrani H, Schermuly R, Grimminger F . Microcirculatory dysfunction in the brain precedes changes in evoked potentials in endotoxin-induced sepsis syndrome in rats. Cerebrovasc Dis. 2006; 23(2-3):140-7. DOI: 10.1159/000097051. View

Parrillo J . Pathogenetic mechanisms of septic shock. N Engl J Med. 1993; 328(20):1471-7. DOI: 10.1056/NEJM199305203282008. View

10.

Tonnesen J, Pryds A, Larsen E, Paulson O, Hauerberg J, Knudsen G . Laser Doppler flowmetry is valid for measurement of cerebral blood flow autoregulation lower limit in rats. Exp Physiol. 2005; 90(3):349-55. DOI: 10.1113/expphysiol.2004.029512. View

11.

Young G, Bolton C, Archibald Y, Austin T, Wells G . The electroencephalogram in sepsis-associated encephalopathy. J Clin Neurophysiol. 1992; 9(1):145-52. DOI: 10.1097/00004691-199201000-00016. View

12.

Ances B . Coupling of changes in cerebral blood flow with neural activity: what must initially dip must come back up. J Cereb Blood Flow Metab. 2003; 24(1):1-6. DOI: 10.1097/01.WCB.0000103920.96801.12. View

13.

Rosengarten B, Hecht M, Kaps M . Carotid compression: investigation of cerebral autoregulative reserve in rats. J Neurosci Methods. 2005; 152(1-2):202-9. DOI: 10.1016/j.jneumeth.2005.09.003. View

14.

Sprung C, Peduzzi P, Shatney C, Schein R, Wilson M, Sheagren J . Impact of encephalopathy on mortality in the sepsis syndrome. The Veterans Administration Systemic Sepsis Cooperative Study Group. Crit Care Med. 1990; 18(8):801-6. DOI: 10.1097/00003246-199008000-00001. View

15.

Barichello T, Martins M, Reinke A, Feier G, Ritter C, Quevedo J . Cognitive impairment in sepsis survivors from cecal ligation and perforation. Crit Care Med. 2005; 33(1):221-3. DOI: 10.1097/01.ccm.0000150741.12906.bd. View

16.

Wang Q, Rowan M, Anwyl R . Beta-amyloid-mediated inhibition of NMDA receptor-dependent long-term potentiation induction involves activation of microglia and stimulation of inducible nitric oxide synthase and superoxide. J Neurosci. 2004; 24(27):6049-56. PMC: 6729673. DOI: 10.1523/JNEUROSCI.0233-04.2004. View

17.

ODwyer M, Mankan A, Stordeur P, OConnell B, Duggan E, White M . The occurrence of severe sepsis and septic shock are related to distinct patterns of cytokine gene expression. Shock. 2006; 26(6):544-50. DOI: 10.1097/01.shk.0000235091.38174.8d. View

18.

Schafers K, Reader A, Kriens M, Knoess C, Schober O, Schafers M . Performance evaluation of the 32-module quadHIDAC small-animal PET scanner. J Nucl Med. 2005; 46(6):996-1004. View

19.

Tancredi V, DArcangelo G, Grassi F, Tarroni P, Palmieri G, Santoni A . Tumor necrosis factor alters synaptic transmission in rat hippocampal slices. Neurosci Lett. 1992; 146(2):176-8. DOI: 10.1016/0304-3940(92)90071-e. View

20.

Semmler A, Okulla T, Sastre M, Dumitrescu-Ozimek L, Heneka M . Systemic inflammation induces apoptosis with variable vulnerability of different brain regions. J Chem Neuroanat. 2005; 30(2-3):144-57. DOI: 10.1016/j.jchemneu.2005.07.003. View