Top

Published in:

Open Access 01-12-2012 | Research

Effects of anti-inflammatory vagus nerve stimulation on the cerebral microcirculation in endotoxinemic rats

Authors: Stanka Mihaylova, Anke Killian, Konstantin Mayer, Soni Savai Pullamsetti, Ralph Schermuly, Bernhard Rosengarten

Published in: Journal of Neuroinflammation | Issue 1/2012

Abstract

Background

In sepsis syndromes the severity of the inflammation triggers microvascular dysfunction and early organ failure. We studied the effects of anti-inflammatory vagus nerve stimulation on the cerebral microcirculatory integrity in an endotoxinemic rat model.

Methods

In both control and endotoxinemic (5 mg/kg lipopolysaccharide i.v.) rats, the effect of cervical bilateral vagotomy with or without left-sided distal vagus nerve stimulation were compared to non-vagotomized, nonstimulated group (sham). Neurovascular coupling was analyzed by electrical forepaw stimulation, EEG, and cortical laser-Doppler flow recording. Resting cerebral blood flow, evoked potentials and hemodynamic responses, were obtained over a period of 4.5 hours. Regulation of the nitric oxide system (iNOS expression and nitrite/nitrate measurements), cytokines (IFN-γ, TNF-α, IL-6, IL-10), hypoxic and apoptosis signaling molecules (HIF-2α, Bax) were measured at the end of experiments.

Results

In endotoxinemic rats, vagus nerve stimulation tended to increase anti-inflammatory cytokine levels and resulted in a stabile hemodynamic response (28 ± 13%; versus baseline). Vagotomized animals incurred a pro-inflammatory response (7 ± 4%; P < 0.0001 versus baseline) and produced more HIF-2α than vagotomized vagus nerve stimulated (VNS) animals. Evoked potential amplitudes were stabilized in VNS (15 ± 7 μV; n.s. versus baseline) as compared to vagotomised rats (8 ± 5 μV; P < 0.001 versus baseline). However, no effects were observed on apoptosis markers or nitric oxide levels.

Conclusions

Vagus nerve stimulation in endotoxinemic rats had a positive effect on neurovascular coupling and stabilized evoked potentials.

Martin GS, Mannino DM, Eaton S, Moss M: The epidemiology of sepsis in the United States from 1979 through 2000. N Engl J Med 2003, 348:1546–1554.CrossRefPubMed

Engel C, Brunkhorst FM, Bone HG, Brunkhorst R, Gerlach H, Grond S, Gruendling M, Huhle G, Jaschinski U, John S, Mayer K, Oppert M, Olthoff D, Quintel M, Ragaller M, Rossaint R, Stuber F, Weiler N, Welte T, Bogatsch H, Hartog C, Loeffler M, Reinhart K: Epidemiology of sepsis in Germany: results from a national prospective multicenter study. Intensive Care Med 2007, 33:606–618.CrossRefPubMed

Angus DC, Linde-Zwirble WT, Lidicker J, Clermont G, Carcillo J, Pinsky MR: Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care. Crit Care Med 2001, 29:1303–1310.CrossRefPubMed

Levy MM, Macias WL, Vincent JL, Russell JA, Silva E, Trzaskoma B, Williams MD: Early changes in organ function predict eventual survival in severe sepsis. Crit Care Med 2005, 33:2194–2201.CrossRefPubMed

Ebersoldt M, Sharshar T, Annane D: Sepsis-associated delirium. Intensive Care Med 2007, 33:941–950.CrossRefPubMed

Green R, Scott LK, Minagar A, Conrad S: Sepsis associated encephalopathy (SAE): a review. Frontiers in bioscience: a journal and virtual library 2004, 9:1637–1641.CrossRef

Rosengarten B, Hecht M, Auch D, Ghofrani HA, Schermuly RT, Grimminger F, Kaps M: Microcirculatory dysfunction in the brain precedes changes in evoked potentials in endotoxin-induced sepsis syndrome in rats. Cerebrovasc Dis 2007, 23:140–147.CrossRefPubMed

Rosengarten B, Wolff S, Klatt S, Schermuly RT: Effects of inducible nitric oxide synthase inhibition or norepinephrine on the neurovascular coupling in an endotoxic rat shock model. Crit Care 2009, 13:R139.CrossRefPubMedPubMedCentral

Lundy DJ, Trzeciak S: Microcirculatory dysfunction in sepsis. Crit Care Clin 2009, 25:721–731. viiiCrossRefPubMed

10.

Hotchkiss RS, Coopersmith CM, McDunn JE, Ferguson TA: The sepsis seesaw: tilting toward immunosuppression. Nat Med 2009, 15:496–497.CrossRefPubMedPubMedCentral

11.

De Backer D, Ospina-Tascon G, Salgado D, Favory R, Creteur J, Vincent JL: Monitoring the microcirculation in the critically ill patient: current methods and future approaches. Intensive Care Med 2010, 36:1813–1825.CrossRefPubMed

12.

Wolff S, Klatt S, Wolff JC, Wilhelm J, Fink L, Kaps M, Rosengarten B: Endotoxin-induced gene expression differences in the brain and effects of iNOS inhibition and norepinephrine. Intensive Care Med 2009, 35:730–739.CrossRefPubMed

13.

Denes A, Pinteaux E, Rothwell NJ, Allan SM: Interleukin-1 and stroke: biomarker, harbinger of damage, and therapeutic target. Cerebrovasc Dis 2011, 32:517–527.CrossRefPubMed

14.

Tracey KJ: Physiology and immunology of the cholinergic antiinflammatory pathway. J Clin Invest 2007, 117:289–296.CrossRefPubMedPubMedCentral

15.

Borovikova LV, Ivanova S, Zhang M, Yang H, Botchkina GI, Watkins LR, Wang H, Abumrad N, Eaton JW, Tracey KJ: Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxin. Nature 2000, 405:458–462.CrossRefPubMed

16.

Saud B, Nandi J, Ong G, Finocchiaro S, Levine RA: Inhibition of TNF-alpha improves indomethacin-induced enteropathy in rats by modulating iNOS expression. Dig Dis Sci 2005, 50:1677–1683.CrossRefPubMed

17.

Semmler A, Hermann S, Mormann F, Weberpals M, Paxian SA, Okulla T, Schafers M, Kummer MP, Klockgether T, Heneka MT: Sepsis causes neuroinflammation and concomitant decrease of cerebral metabolism. J Neuroinflammation 2008, 5:38.CrossRefPubMedPubMedCentral

18.

Brack KE, Patel VH, Mantravardi R, Coote JH, Ng GA: Direct evidence of nitric oxide release from neuronal nitric oxide synthase activation in the left ventricle as a result of cervical vagus nerve stimulation. J Physiol 2009, 587:3045–3054.CrossRefPubMedPubMedCentral

19.

Le Cras TD, McMurtry IF: Nitric oxide production in the hypoxic lung. Am J Physiol Lung Cell Mol Physiol 2001, 280:L575-L582.PubMed

20.

Robinson MA, Baumgardner JE, Good VP, Otto CM: Physiological and hypoxic O2 tensions rapidly regulate NO production by stimulated macrophages. Am J Physiol Cell Physiol 2008, 294:C1079-C1087.CrossRefPubMed

21.

Ashwal S, Tone B, Tian HR, Cole DJ, Pearce WJ: Core and penumbral nitric oxide synthase activity during cerebral ischemia and reperfusion. Stroke; a journal of cerebral circulation 1998, 29:1037–1046. discussion 1047CrossRefPubMed

22.

Venkatesh B, Morgan TJ: Monitoring tissue gas tensions in critical illness. Critical care and resuscitation: journal of the Australasian Academy of Critical Care Medicine 2002, 4:291–300.

23.

Takeda N, O’Dea EL, Doedens A, Kim JW, Weidemann A, Stockmann C, Asagiri M, Simon MC, Hoffmann A, Johnson RS: Differential activation and antagonistic function of HIF-{alpha} isoforms in macrophages are essential for NO homeostasis. Genes Dev 2010, 24:491–501.CrossRefPubMedPubMedCentral

24.

Sharshar T, Carlier R, Bernard F, Guidoux C, Brouland JP, Nardi O, de la Grandmaison GL, Aboab J, Gray F, Menon D, Annane D: Brain lesions in septic shock: a magnetic resonance imaging study. Intensive Care Med 2007, 33:798–806.CrossRefPubMed

25.

Iwashyna TJ, Ely EW, Smith DM, Langa KM: Long-term cognitive impairment and functional disability among survivors of severe sepsis. JAMA 2010, 304:1787–1794.CrossRefPubMedPubMedCentral

26.

Devine SA, Kirkley SM, Palumbo CL, White RF: MRI and neuropsychological correlates of carbon monoxide exposure: a case report. Environ Health Perspect 2002, 110:1051–1055.CrossRefPubMedPubMedCentral

27.

Harve H, Tiainen M, Poutiainen E, Maunu M, Kajaste S, Roine RO, Silfvast T: The functional status and perceived quality of life in long-term survivors of out-of-hospital cardiac arrest. Acta Anaesthesiol Scand 2007, 51:206–209.CrossRefPubMed

Title: Effects of anti-inflammatory vagus nerve stimulation on the cerebral microcirculation in endotoxinemic rats
Authors: Stanka Mihaylova
Anke Killian
Konstantin Mayer
Soni Savai Pullamsetti
Ralph Schermuly
Bernhard Rosengarten
Publication date: 01-12-2012
Publisher: BioMed Central
Published in: Journal of Neuroinflammation / Issue 1/2012
Electronic ISSN: 1742-2094
DOI: https://doi.org/10.1186/1742-2094-9-183

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Effects of anti-inflammatory vagus nerve stimulation on the cerebral microcirculation in endotoxinemic rats

Abstract

Background

Methods

Results

Conclusions

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 1/2012

Inhibition of P2X7 receptor ameliorates transient global cerebral ischemia/reperfusion injury via modulating inflammatory responses in the rat hippocampus

Inducible nitric oxide synthase is involved in the modulation of depressive behaviors induced by unpredictable chronic mild stress

DQB1*0602 rather than DRB1*1501 confers susceptibility to multiple sclerosis-like disease induced by proteolipid protein (PLP)

Variability in detection and quantification of interferon β-1b–induced neutralizing antibodies

Proteolytic activation of proapoptotic kinase protein kinase Cδ by tumor necrosis factor α death receptor signaling in dopaminergic neurons during neuroinflammation

Can the benefits of cannabinoid receptor stimulation on neuroinflammation, neurogenesis and memory during normal aging be useful in AD prevention?

DQB10602 rather than DRB11501 confers susceptibility to multiple sclerosis-like disease induced by proteolipid protein (PLP)