- Open Access
Brain function in iNOS knock out or iNOS inhibited (l-NIL) mice under endotoxic shock
© Schweighöfer et al.; licensee Springer. 2014
- Received: 5 June 2014
- Accepted: 14 August 2014
- Published: 20 September 2014
Microcirculatory dysfunction due to excessive nitric oxide production by the inducible nitric oxide synthase (iNOS) is often seen as a motor of sepsis-related organ dysfunction. Thus, blocking iNOS may improve organ function. Here, we investigated neuronal functional integrity in iNOS knock out (−/−) or l-NIL-treated wild-type (wt) animals in an endotoxic shock model.
Four groups of each 10 male mice (28 to 32 g) were studied: wt, wt + lipopolysaccharide (LPS) (5 mg/kg body weight i.v.), iNOS(−/−) + LPS, wt + LPS + l-NIL (5 mg/kg body weight i.p. 30 min before LPS). Electric forepaw stimulation was performed before LPS/vehicle and then at fixed time points repeatedly up to 4.5 h. N1-P1 potential amplitudes as well as P1 latencies were calculated from EEG recordings. Additionally, cerebral blood flow was registered using laser Doppler. Blood gas parameters, mean arterial blood pressure, and glucose and lactate levels were obtained at the beginning and the end of experiments. Moreover, plasma IL-6, IL-10, CXCL-5, ICAM-1, neuron-specific enolase (NSE), and nitrate/nitrite levels were determined.
Decline in blood pressure, occurrence of cerebral hyperemia, acidosis, and increase in lactate levels were prevented in both iNOS-blocked groups. SEP amplitudes and NSE levels remained in the range of controls. Effects were related to a blocked nitrate/nitrite level increase whereas IL-6, ICAM-1, and IL-10 were similarly induced in all sepsis groups. Only CXCL-5 induction was lower in both iNOS-blocked groups.
Despite similar hyper-inflammatory responses, iNOS inhibition strategies appeared neurofunctionally protective possibly by stabilizing macro- as well as microcirculation. Overall, our data support modern sepsis guidelines recommending early prevention of microcirculatory failure.
- Somatosensory-evoked potentials
- Neurovascular coupling
- Nitric oxide synthase
- iNOS knock out
Sepsis and systemic inflammatory response syndromes (SIRS) are the leading causes of mortality in intensive care units ,. Excessive production of nitric oxide (NO) by the inducible nitric oxide synthase (iNOS) plays a crucial role in early inflammatory syndromes -.
In the brain, NO triggers several temporally cascaded negative effects. Within minutes to hours, microvascular dysfunction occurs resulting in an inappropriate blood supply of neurons -. As a consequence, levels of hypoxia-induced factor (HIF)-2 alpha increase, somatosensory-evoked potential amplitudes decline, and neuronal (neuron-specific enolase, NSE) and astrocytic (S100B) destruction markers increase 4 h after an endotoxin challenge . After about 6 to 8 h, NO starts to affect mitochondrial function leading to an impaired aerobic glycolysis with energy depletion in neurons . Moreover, NO is also involved in delayed neuronal apoptosis occurring 24 to 48 h following the insult . Systemically, excessive NO levels lead to hypotension ,, microcirculatory dysfunction , and refractoriness to vasopressor catecholamines .
Previously, animals treated with selective iNOS inhibitors or transgenic mice deficient in iNOS had less hypotension and preserved microvascular reactivity under septic conditions ,. Furthermore, iNOS inhibition stabilized also the brain circulation: The neurovascular coupling was stabilized during an endotoxin challenge using 1,400 W as a selective iNOS inhibitor . The neurovascular coupling denotes a brain intrinsic regulative principle, which adapts the local cerebral blood flow in accordance with the metabolic needs (i.e. activity) of underlying neurons . However, results did not clearly favor a 1,400-W therapy since 1,400 W had direct negative effects on somatosensory-evoked potential (SEP) amplitudes . Interestingly, the effect was only seen under LPS challenge but not under control conditions. Thus, the question arises whether the negative effect on SEP was simply an adverse effect of the substance 1,400 W itself, or if it was related to the iNOS inhibition in general. To further address this issue, we studied the effects of endotoxic shock on SEP in iNOS knock out(−/−) or l-NIL inhibited mice.
All procedures performed on the animals were in strict accordance with the National Institutes of Health Guide for Care and Use of Laboratory Animals and approved by the local Animal Care and Use Committee.
Experiments were carried out with wild-type (wt) C57BL6N or iNOS(−/−) C57BL6J adult male mice (28 to 32 g), as given below in detail. In separate experiments with five mice in each group, we tested effects of l-NIL in wt mice and stability of recordings in iNOS(−/−) mice, and studied inflammatory and neurophysiological responses to the LPS challenge in C57BL6J mice.
Mice were initially anesthetized with 1.5% to 3% isoflurane in a 7:3 N2O/O2 mixture of gases, tracheotomized, paralyzed with pancuronium bromide (0.2 mg/kg/h), and artificially ventilated (Minivent, Harvard Apparatus, South Natick, MA, USA). Arterial blood gas analyses and pH were measured at the beginning and the end of experiments (blood gas analyzer model Rapidlab 348, Bayer Vital GmbH, Fernwald, Germany) together with glucose and lactate levels (Glukometer Elite XL, Bayer Vital GmbH, Fernwald, Germany; Lactate pro, Arkray Inc. European Office, Düsseldorf, Germany). Glucose was kept in the physiological range by injections of 0.1 ml 20% glucose i.p. as needed. The right femoral artery and vein were cannulated for blood pressure recording, blood sampling, and drug administration. Rectal body temperature was maintained at 37°C using a feedback-controlled heating pad (Haake, Karlsruhe, Germany).
The head of the animals was fixed in a stereotaxic frame. After a median incision, the bone over the left parietal cortex was exposed allowing EEG and transcranial laser-Doppler flow (LDF) recording. Electric brain activity was recorded monopolarily with an active AgCl-electrode over the somatosensory forepaw area and an indifferent AgCl-electrode placed at the nasal bone . Signals were recorded and amplified (BPA Module 675, HSE, March-Hugstetten, Germany) and SEP was averaged using the Neurodyn acquisition software (HSE, March-Hugstetten, Germany). The LDF probe (BRL-100, Harvard Apparatus, MA, USA) was placed laterally to the cortical electrode.
Approximately 60 min before the stimulation experiments, isoflurane/N2O anesthesia was discontinued and replaced by intravenous application of α-chloralose (60 mg/kg bw i.v. bolus) (Sigma-Aldrich Chemie GmbH, Taufkirchen, Germany). Anesthesia was continued by continuously administrating chloralose intravenously (30 mg/kg/h). During experiments, the animals were ventilated with nitrogen/oxygen mixture of 1/1.
Somatosensory stimulation was carried out with electrical pulses applied using small needle electrodes inserted under the skin of the right forepaw (PSM Module 676, HSE, March-Hugstetten, Germany). The right forepaw was electrically stimulated with rectangular pulses of 0.3 ms width and a repetition frequency of 2 Hz for 30 s. The stimulation current was kept constant at 1.5 mA to prevent systemic blood pressure changes ,. From the averaged typical SEP responses, we calculated the N1-P1 amplitude differences and P1 latencies for further statistical comparisons.
At the end of the experiments, blood samples were collected into tubes containing heparin (Ratiopharm GmbH, Ulm, Germany) and immediately centrifuged, and plasma was stored at −80°C until analyses. The NSE levels were determined using an enzyme-linked immunosorbent assay (NSE EIA kit; Hoffmann-La Roche, Basel, Switzerland). Cytokine analysis was performed for IL-6 and IL-10 using commercial rat ELISA kits (BD Bioscience, Heidelberg, Germany). In addition, CXCL-5, a chemotactic chemokine, and ICAM-1, an endothelial activation marker, were determined according to the recommendation of the manufacturer (R&D Systems, Wiesbaden, Germany).
NO metabolite (nitrite and nitrate) concentrations were determined using NOA Sievers 280 (FMI GmbH, Seeheim, Germany) according to the manufacturer's instructions. Briefly, NO reaction products in plasma samples were reduced by vanadium chloride. Resulting gaseous NO was detected by NOA Sievers 280, which was connected to a computer for data transfer and analysis by NOAWIN32 software (DeMeTec, Langgöns, Germany).
Each mouse (10 per group) was subjected to one of the following groups: wt control, wt + 5 mg/kg LPS (lipopolysaccharide from Escherichia coli, O111:B4, Sigma-Aldrich Chemie GmbH, Germany), wt + l-NIL + LPS, iNOS(−/−) + LPS. LPS was dissolved in 0.1 ml 0.9% NaCl and injected/infused within 2 to 3 min. The control group received 0.1 ml vehicle. A moderate volume therapy of 0.1 to 0.6 ml/kg/h 0.9% NaCl was allowed in all groups. In the l-NIL group, l-NIL was injected after neurophysiological baseline recording and 30 min before sepsis induction at a dose of 5 mg/kg body weight i.p.
SEPs, LDF signal, and blood pressure were measured up to 270 min before and after LPS application. This limited time window was chosen according to previous studies; it was shown that the cerebral autoregulation stays intact and that blood pressure levels remain above the lower limit of the cerebral autoregulative range for this whole time period ,.
If appropriate, a two-way ANOVA was performed to assess differences within and between groups. In case of significance, a Fisher post hoc test was applied. If assumptions of normal distribution and equality of variances could not be assured, a nonparametric Friedman test was undertaken instead (Statview, SAS, Cary, NC, USA). The significance level was set to p < 0.05.
The sample size was calculated with G-Power 3.1.3 (Faul, University of Kiel, Kiel, Germany). Assuming an effect size of 0.7 from previous reports, a total sample size of 40 animals was calculated to determine a significant difference between SEP amplitudes with an alpha error of 0.05 and a power of 0.95 between the four groups.
Hemodynamic and neurophysiological parameters were stable in wt + l-NIL as well as in iNOS(−/−) mice over the entire study window of 4.5 h. Responses to LPS did not differ between C57BL6N or C57BL6J mice (data not shown), and no mouse died from the slow LPS injection.
Gro up-averaged data for glucose, lactate, pH, pO2, pCO2, and hematocrit for all groups
84 ± 12
1.5 ± 1
7.4 ± 0.03
170 ± 12
34 ± 6
46 ± 4
Wt + LPS
83 ± 14
3.2 ± 2*
7.2 ± 0.2****
180 ± 20
35 ± 8
45 ± 6
Wt + LPS + l-NIL
90 ± 17
3.2 ± 2*
7.3 ± 0.1
190 ± 25
36 ± 9
49 ± 6
iNOS(−/−) + LPS
78 ± 8
3.8 ± 2*
7.3 ± 0.1
177 ± 19
33 ± 5
47 ± 4
p < 0.05
p < 0.0005
Cytok ine, chemokine, and endothelial activation markers together with the neuronal destruction marker
10 ± 3
1 ± 0.6
0.2 ± 0.1
84 ± 15
0.3 ± 0.3
120 ± 50
Wt + LPS
14 ± 4 (p = 0.08)
224 ± 81****
3.6 ± 1.5****
156 ± 20****
12 ± 6****
330 ± 130***
Wt + LPS + l-NIL
13 ± 2
175 ± 82****
1.8 ± 0.7*, ##
141 ± 12****
7 ± 2****, ##
150 ± 33
iNOS(−/−) + LPS
14 ± 3
243 ± 32****
2.6 ± 1.5**
145 ± 11****
6 ± 1****, ##
41 ± 10
p < 0.0001
p < 0.0005
p < 0.0001
p < 0.0001
p < 0.0001
Gr oup-averaged data for mean BP, SEP, P1 latencies, and resting LDFV signal
Mean BP (mmHg)
P1 latency (ms)
End (change to baseline)
85 ± 5
73 ± 17
6.6 ± 2.3
5 ± 1.6
9.4 ± 0.5
9.1 ± 0.8
144 ± 30
137 ± 36 (−5%)
Wt + LPS
90 ± 10
56 ± 21*
6.6 ± 3.3
1.2 ± 1.6****
9.3 ± 0.7
9.4 ± 0.1
153 ± 34
180 ± 40*** (+18%)
Wt + LPS + l-NIL
86 ± 8
68 ± 20
6.8 ± 2.2
3.2 ± 3.3
9.4 ± 0.7
9.3 ± 0.1
151 ± 32
137 ± 45 (−10%)
iNOS(−/−) + LPS
92 ± 15
60 ± 21
7.7 ± 2.2
4.7 ± 3.5
9.5 ± 0.6
9.1 ± 0.9
157 ± 30
130 ± 27 (−17%)
p < 0.05
p < 0.001
p < 0.05
This is the first report showing a stabilization of neuronal functioning due to selected iNOS inhibition under an endotoxin challenge: corroborated by iNOS(−/−) experiments, l-NIL stabilized SEP (N2-P1) amplitudes during the first hours of LPS-mediated shock. Previously reported negative effects of 1,400 W on SEP are, therefore, most likely due to a substance/drug-specific effect.
We assume that the stabilization of the macro- as well as microcirculation might best explain the stabilizing effect on SEP amplitudes. Occurrence of cerebral hyperemia and a progressive decline in blood pressure were effectively blocked in the l-NIL and iNOS(−/−) group as nitrate/nitrite levels remained in the range of controls. Cerebral hyperemia is caused by an excessive iNOS-related NO production . NO interferes with the neurovascular coupling, resulting in an unselected widening of resistance vessels leading to an uncontrolled perfusion of the capillary territory and at least to an inappropriate blood supply of active neurons ,,. Neurons react very sensitively towards an inadequate perfusion due to their high-energy demand and strong aerobic metabolism . A mismatch of about 10% to 20% leads to neuronal dysfunction and protein synthesis disturbances in neurons if it lasts for minutes to hours . Similarly, the blood pressure decrease is caused by NO-related interference on the arteriolar resistance vessels ,,. Our data support sepsis guidelines, which focus on an early hemodynamic stabilization within the first 3 h -.
The role of the microcirculation as a motor of sepsis is further strengthened by another interesting finding of the present study. Neither l-NIL nor iNOS(−/−) influenced the induction of the pro-inflammatory cytokine IL-6 or the endothelial activation marker ICAM. The reduced levels of the anti-inflammatory cytokine IL-10 under l-NIL might indicate - if at all - an induced inflammatory response. Therefore, it appears that the early inflammatory process itself (cytokine storm, endothelial activation) did not affect the neuronal function directly. Our findings are in line with reports from rheumatoid arthritis patients who present a normal cognitive function during relapses with significantly increased cytokine levels ,. Later on, starting at 24 to 48 h, cytokines are known to trigger delayed apoptotic pathways -.
The finding of a significantly reduced chemokine CXCL-5 expression indicates reduced parenchymal inflammation and, therefore, reduced neuronal stress. CXCL-5 is significantly induced after cerebral ischemia, indicating a hypoxia-triggered inflammation in the brain ,. An alternative explanation might be an anti-inflammatory effect of iNOS blockade due to an inhibition of the NO-related activation of the prostaglandin synthesis ,. However, further research is needed to investigate this issue in more detail.
We conclude that iNOS blocking has a neurofunctionally stabilizing effect in the early phase of endotoxic shock. Effects are most likely explained by microcirculatory stabilization, strengthening modern sepsis concepts recommending early hemodynamic stabilization of septic patients. Additional anti-inflammatory approaches are warranted to maintain the positive effects and to prevent from other negative effects such as a cytokine-related delayed neuronal apoptosis.
- Hotchkiss RS, Karl IE: The pathophysiology and treatment of sepsis. N Engl J Med 2003, 348: 138–150. 10.1056/NEJMra021333PubMedView ArticleGoogle Scholar
- Parrillo JE: Pathogenetic mechanisms of septic shock. N Engl J Med 1993, 328: 1471–1477. 10.1056/NEJM199305203282008PubMedView ArticleGoogle Scholar
- Tureen J: Effect of recombinant human tumor necrosis factor-alpha on cerebral oxygen uptake, cerebrospinal fluid lactate, and cerebral blood flow in the rabbit: role of nitric oxide. J Clin Invest 1995, 95: 1086–1091. 10.1172/JCI117755PubMedPubMed CentralView ArticleGoogle Scholar
- Vincent JL: Microvascular endothelial dysfunction: a renewed appreciation of sepsis pathophysiology. Crit Care 2001, 5: S1-S5. 10.1186/cc1332PubMedPubMed CentralView ArticleGoogle Scholar
- Rees DD: Role of nitric oxide in the vascular dysfunction of septic shock. Biochem Soc Trans 1995, 23: 1025–1029.PubMedView ArticleGoogle Scholar
- 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. 10.1159/000097051PubMedView ArticleGoogle Scholar
- 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. 10.1186/cc8020PubMedPubMed CentralView ArticleGoogle Scholar
- Walton JC, Selvakumar B, Weil ZM, Snyder SH, Nelson RJ: Neuronal nitric oxide synthase and NADPH oxidase interact to affect cognitive, affective, and social behaviors in mice. Behav Brain Res 2013, 256: 320–327. 10.1016/j.bbr.2013.08.003PubMedView ArticleGoogle Scholar
- Mihaylova S, Killian A, Mayer K, Pullamsetti SS, Schermuly R, Rosengarten B: Effects of anti-inflammatory vagus nerve stimulation on the cerebral microcirculation in endotoxinemic rats. J Neuroinflammation 2012, 9: 183. 10.1186/1742-2094-9-183PubMedPubMed CentralView ArticleGoogle Scholar
- Singh S, Zhuo M, Gorgun FM, Englander EW: Overexpressed neuroglobin raises threshold for nitric oxide-induced impairment of mitochondrial respiratory activities and stress signaling in primary cortical neurons. Nitric Oxide 2013, 32: 21–28. 10.1016/j.niox.2013.03.008PubMedView ArticleGoogle Scholar
- Tajes M, Ill-Raga G, Palomer E, Ramos-Fernandez E, Guix FX, Bosch-Morato M, Guivernau B, Jimenez-Conde J, Ois A, Perez-Asensio F, Reyes-Navarro M, Caballo C, Galan AM, Alameda F, Escolar G, Opazo C, Planas A, Roquer J, Valverde MA, Munoz FJ: Nitro-oxidative stress after neuronal ischemia induces protein nitrotyrosination and cell death. Oxidative Med Cell Longev 2013, 2013: 826143. 10.1155/2013/826143View ArticleGoogle Scholar
- Rosselet A, Feihl F, Markert M, Gnaegi A, Perret C, Liaudet L: Selective iNOS inhibition is superior to norepinephrine in the treatment of rat endotoxic shock. Am J Respir Crit Care Med 1998, 157: 162–170. 10.1164/ajrccm.157.1.9701017PubMedView ArticleGoogle Scholar
- Scott JA, Mehta S, Duggan M, Bihari A, McCormack DG: Functional inhibition of constitutive nitric oxide synthase in a rat model of sepsis. Am J Respir Crit Care Med 2002, 165: 1426–1432. 10.1164/rccm.2011144PubMedView ArticleGoogle Scholar
- Pullamsetti SS, Maring D, Ghofrani HA, Mayer K, Weissmann N, Rosengarten B, Lehner M, Schudt C, Boer R, Grimminger F, Seeger W, Schermuly RT: Effect of nitric oxide synthase (NOS) inhibition on macro- and microcirculation in a model of rat endotoxic shock. Thromb Haemost 2006, 95: 720–727.PubMedGoogle Scholar
- Gray GA, Schott C, Julou-Schaeffer G, Fleming I, Parratt JR, Stoclet JC: The effect of inhibitors of the L-arginine/nitric oxide pathway on endotoxin-induced loss of vascular responsiveness in anaesthetized rats. Br J Pharmacol 1991, 103: 1218–1224. 10.1111/j.1476-5381.1991.tb12327.xPubMedPubMed CentralView ArticleGoogle Scholar
- Hollenberg SM, Broussard M, Osman J, Parrillo JE: Increased microvascular reactivity and improved mortality in septic mice lacking inducible nitric oxide synthase. Circ Res 2000, 86: 774–778. 10.1161/01.RES.86.7.774PubMedView ArticleGoogle Scholar
- Wei XQ, Charles IG, Smith A, Ure J, Feng GJ, Huang FP, Xu D, Muller W, Moncada S, Liew FY: Altered immune responses in mice lacking inducible nitric oxide synthase. Nature 1995, 375: 408–411. 10.1038/375408a0PubMedView ArticleGoogle Scholar
- Girouard H, Iadecola C: Neurovascular coupling in the normal brain and in hypertension, stroke, and Alzheimer disease. J Appl Physiol 2006, 100: 328–335. 10.1152/japplphysiol.00966.2005PubMedView ArticleGoogle Scholar
- Ullmann JF, Watson C, Janke AL, Kurniawan ND, Reutens DC: A segmentation protocol and MRI atlas of the C57BL/6J mouse neocortex. NeuroImage 2013, 78: 196–203. 10.1016/j.neuroimage.2013.04.008PubMedView ArticleGoogle Scholar
- Rosengarten B, Hecht M, Kaps M: Carotid compression: investigation of cerebral autoregulative reserve in rats. J Neurosci Methods 2006, 152: 202–209. 10.1016/j.jneumeth.2005.09.003PubMedView ArticleGoogle Scholar
- Rosengarten B, Hecht M, Wolff S, Kaps M: Autoregulative function in the brain in an endotoxic rat shock model. Inflamm Res 2008, 57: 542–546. 10.1007/s00011-008-7199-2PubMedView ArticleGoogle Scholar
- Okamoto H, Ito O, Roman RJ, Hudetz AG: Role of inducible nitric oxide synthase and cyclooxygenase-2 in endotoxin-induced cerebral hyperemia. Stroke 1998, 29: 1209–1218. 10.1161/01.STR.29.6.1209PubMedView ArticleGoogle Scholar
- Laranjinha J, Santos RM, Lourenco CF, Ledo A, Barbosa RM: Nitric oxide signaling in the brain: translation of dynamics into respiration control and neurovascular coupling. Ann N Y Acad Sci 2012, 1259: 10–18. 10.1111/j.1749-6632.2012.06582.xPubMedView ArticleGoogle Scholar
- Hossmann KA, Traystman RJ: Cerebral blood flow and the ischemic penumbra. Handb Clin Neurol 2009, 92: 67–92. 10.1016/S0072-9752(08)01904-0PubMedView ArticleGoogle Scholar
- Dellinger RP, Levy MM, Rhodes A, Annane D, Gerlach H, Opal SM, Sevransky JE, Sprung CL, Douglas IS, Jaeschke R, Osborn TM, Nunnally ME, Townsend SR, Reinhart K, Kleinpell RM, Angus DC, Deutschman CS, Machado FR, Rubenfeld GD, Webb S, Beale RJ, Vincent JL, Moreno R: Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock, 2012. Intensive Care Med 2013, 39: 165–228. 10.1007/s00134-012-2769-8PubMedView ArticleGoogle Scholar
- De Backer D, Donadello K, Sakr Y, Ospina-Tascon G, Salgado D, Scolletta S, Vincent JL: Microcirculatory alterations in patients with severe sepsis: impact of time of assessment and relationship with outcome. Crit Care Med 2013, 41: 791–799. 10.1097/CCM.0b013e3182742e8bPubMedView ArticleGoogle Scholar
- Leone M, Blidi S, Antonini F, Meyssignac B, Bordon S, Garcin F, Charvet A, Blasco V, Albanese J, Martin C: Oxygen tissue saturation is lower in nonsurvivors than in survivors after early resuscitation of septic shock. Anesthesiology 2009, 111: 366–371. 10.1097/ALN.0b013e3181aae72dPubMedView ArticleGoogle Scholar
- Kozora E, Laudenslager M, Lemieux A, West SG: Inflammatory and hormonal measures predict neuropsychological functioning in systemic lupus erythematosus and rheumatoid arthritis patients. J Int Neuropsychol Soc 2001, 7: 745–754. 10.1017/S1355617701766106PubMedView ArticleGoogle Scholar
- Shimizu M, Nakagishi Y, Yachie A: Distinct subsets of patients with systemic juvenile idiopathic arthritis based on their cytokine profiles. Cytokine 2013, 61: 345–348. 10.1016/j.cyto.2012.11.025PubMedView ArticleGoogle Scholar
- Semmler A, Widmann CN, Okulla T, Urbach H, Kaiser M, Widman G, Mormann F, Weide J, Fliessbach K, Hoeft A, Jessen F, Putensen C, Heneka MT: Persistent cognitive impairment, hippocampal atrophy and EEG changes in sepsis survivors. J Neurol Neurosurg Psychiatry 2013, 84: 62–69. 10.1136/jnnp-2012-302883PubMedView ArticleGoogle Scholar
- Weberpals M, Hermes M, Hermann S, Kummer MP, Terwel D, Semmler A, Berger M, Schafers M, Heneka MT: NOS2 gene deficiency protects from sepsis-induced long-term cognitive deficits. J Neurosci 2009, 29: 14177–14184. 10.1523/JNEUROSCI.3238-09.2009PubMedView ArticleGoogle Scholar
- Semmler A, Okulla T, Sastre M, Dumitrescu-Ozimek L, Heneka MT: Systemic inflammation induces apoptosis with variable vulnerability of different brain regions. J Chem Neuroanat 2005, 30: 144–157. 10.1016/j.jchemneu.2005.07.003PubMedView ArticleGoogle Scholar
- Mirabelli-Badenier M, Braunersreuther V, Viviani GL, Dallegri F, Quercioli A, Veneselli E, Mach F, Montecucco F: CC and CXC chemokines are pivotal mediators of cerebral injury in ischaemic stroke. Thromb Haemost 2011, 105: 409–420. 10.1160/TH10-10-0662PubMedView ArticleGoogle Scholar
- Zaremba J, Skrobanski P, Losy J: The level of chemokine CXCL5 in the cerebrospinal fluid is increased during the first 24 hours of ischaemic stroke and correlates with the size of early brain damage. Folia Morphol (Warsz) 2006, 65: 1–5.Google Scholar
- Salvemini D, Misko TP, Masferrer JL, Seibert K, Currie MG, Needleman P: Nitric oxide activates cyclooxygenase enzymes. Proc Natl Acad Sci U S A 1993, 90: 7240–7244. 10.1073/pnas.90.15.7240PubMedPubMed CentralView ArticleGoogle Scholar
- Salvemini D, Seibert K, Masferrer JL, Settle SL, Misko TP, Currie MG, Needleman P: Nitric oxide and the cyclooxygenase pathway. Adv Prostaglandin Thromboxane Leukot Res 1995, 23: 491–493.PubMedGoogle Scholar
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited.