Share this article on:

Bioenergetics, Mitochondrial Dysfunction, and Oxidative Stress in the Pathophysiology of Septic Encephalopathy

Bozza, Fernando A.*†; D’Avila, Joana C.*‡; Ritter, Cristiane§∥; Sonneville, Romain; Sharshar, Tarek; Dal-Pizzol, Felipe§∥

doi: 10.1097/SHK.0b013e31828fade1
Original Article

ABSTRACT Sepsis is a major cause of mortality and morbidity in intensive care units. Acute and long-term brain dysfunctions have been demonstrated both in experimental models and septic patients. Sepsis-associated encephalopathy is an early and frequent manifestation but is underdiagnosed, because of the absence of specific biomarkers and of confounding factors such as sedatives used in the intensive care unit. Sepsis-associated encephalopathy may have acute and long-term consequences including development of autonomic dysfunction, delirium, and cognitive impairment. The mechanisms of sepsis-associated encephalopathy involve mitochondrial and vascular dysfunctions, oxidative stress, neurotransmission disturbances, inflammation, and cell death. Here we review specific evidence that links bioenergetics, mitochondrial dysfunction, and oxidative stress in the setting of brain dysfunctions associated to sepsis.

*Instituto de Pesquisa Clínica Evandro Chagas, Fundação Oswaldo Cruz and Instituto Nacional de Ciência e Tecnologia em Biologia Estrutural; D’Or Institute for Research and Education (IDOR); and Laboratório de Imunofarmacologia, Fundação Oswaldo Cruz (Fiocruz), Rio de Janeiro; and §Laboratório de Fisiopatologia Experimental and Instituto Nacional de Ciência e Tecnologia Translacional em Medicina, Programa de Pós-Graduação em Ciências da Saúde, Unidade Acadêmica de Ciências da Saúde, Universidade do Extremo Sul Catarinense; and Intensive Care Unit, Hospital São José, Criciúma, Santa Catarina, Brazil; and Service de Réanimation Médicale, Hôpital Raymond Poincaré, Garches, France.

Address reprint requests to Fernando A. Bozza, MD, PhD, Intensive Care Unit, Instituto de Pesquisa Clínica Evandro Chagas, Fundação Oswaldo Cruz (Fiocruz), Rio de Janeiro, Rio de Janeiro, Brazil. E-mail:; Or Felipe Dal-Pizzol, MD, PhD, Laboratório de Fisiopatologia Experimental, Unidade Acadêmica de Ciências da Saúde, Universidadedo Extremo Sul Catarinense, Criciúma, Santa Catarina, Brazil. E-mail:

This work was supported by grants from Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Fundação de Amparo a Pesquisa do Estado do Rio de Janeiro (FAPERJ), Instituto Nacional de Ciência e Tecnologia (INCT) em Biologia Estrutural e Bioimagem, e INCT em Translacional em Medicina, Brazil.

Back to Top | Article Outline


Sepsis is associated with multiple organ dysfunctions including acute brain dysfunction, termed here sepsis-associated encephalopathy (SAE), which is an independent predictor of death (1). Recently, a large prospective cohort study associated severe sepsis with long-term cognitive impairment and functional disability among survivors (2). In addition, sepsis, independently of other risk factors, significantly contributes to long-term neurodevelopmental impairment also in preterm infants (3). Thus, it is possible that a large spectrum of disease occurs, going from a mild transitory to irreversible brain dysfunction, progressing from acute delirium to chronic cognitive decline. Despite its importance, SAE has been neglected mainly because there are no precise clinical diagnoses of damage to the brain during sepsis (4). Sepsis-associated encephalopathy pathophysiology is poorly understood, but several mechanisms have been proposed, such as mitochondrial and vascular dysfunction, oxidative damage, neurotransmission disturbances, inflammation, and cellular death (5). Here we review evidence that links bioenergetics, mitochondrial dysfunctions, and oxidative stress in the setting of brain dysfunction associated to sepsis.

Back to Top | Article Outline

Bioenergetics, mitochondrial dysfunctions, and oxidative stress as key mechanisms of septic encephalopathy

Brain bioenergetics

Brain function is almost totally dependent on a continuous supply of glucose and oxygen from the arterial circulation. Although the brain represents only 2% of the body weight, it receives 15% of the cardiac output and consumes 20% of total body oxygen and 25% of total body glucose. As glycogen stores are low (~3 mmol/kg) and exclusive to astrocytes (6), brain glucose supply must be ensured by continuous cerebral blood flow. The brain contains different types of glucose transporters (GLUTs): GLUT 1 is localized on the microvessels and glia, and GLUT 3 is the neuronal isoform (7). Nevertheless, the brain relies on alternative sources of energy substrates, such as phosphocreatine, synthesized by creatine kinase enzymes located at strategic intracellular sites to couple areas of high-energy expenditure to the efficient regeneration of ATP. The creatine kinase/phosphocreatine system plays an important role in energy buffering and cellular bioenergetics because phosphocreatine can rapidly donate a phosphate group to ADP, creating a compartmentalized ATP synthesis, which is particularly important in cells with high and fluctuating energy requirements such as neurons (8).

Neurotransmission and ionic homeostasis account for most of brain energy expenditure. Glutamate is the major excitatory amino acid, and its extracellular levels must be tightly regulated to maintain brain tissue homeostasis. The uptake of glutamate from the extracellular space is coupled to an inward sodium cotransport that in turn activates the Na+/K+ ATPase pump to normalize ionic gradients across plasma membranes in an ATP-dependent manner. Thus, glutamatergic neurotransmission accounts for a considerable part of energy consumption in the brain. Among the central nervous system (CNS) cell types, neurons are the most oxygen-dependent cells, and numerous studies demonstrate a strong metabolic cooperation between astrocytes and neurons in terms of neurotransmitter reuptake, antioxidant defense, and energy substrate delivery, and all these processes critically depend on energy metabolism (9). Proinflammatory cytokines can modulate astrocytes’ energy metabolism and cellular stress defenses, which may contribute to increased neuronal vulnerability and neurodegeneration (10). In pathological condition associated to neuroinflammation, such as in sepsis, excitatory glutamatergic neurotransmission appears to be increased (5), and this can be both cause and consequence for a bioenergetics crisis and directly affect brain function.

As a major catabolic insult, with disturbances in carbohydrate, lipid, and protein metabolism, sepsis leads to a peripheral bioenergetics crisis and extensive muscle protein breakdown. Classically, altered mental status has been associated to higher levels of plasma aromatic amino acids and normal or low-normal levels of branched-chain amino acids in septic patients. The decrease in branched-chain amino acid/aromatic amino acid ratio has been also associated to an imbalance of neurotransmitters including norepinephrine, dopamine, and serotonin (11). More recently, kynurenine, a product of tryptophan metabolism induced by proinflammatory mediators, was shown to accumulate in the brain in the acute phase of sepsis due to the loss of blood-brain barrier (BBB) integrity common in sepsis. This study showed that increased kynurenine pathway activity was an independent predictor of greater duration of acute brain dysfunction (12). Kynurenine is also an endothelial-relaxing factor that was recently shown to contribute to hypotension in human sepsis (13).

Cerebral blood flow autoregulation and normal mitochondrial function are critical events for the maintenance of brain function and tissue viability. Damage to the mitochondrial respiratory chain is a significant factor in the pathogenesis of many neurodegenerative diseases (14). Following inhibition of mitochondrial respiration, astrocytes respond by increasing their glycolytic metabolism using glycolytically generated ATP to maintain their mitochondrial membrane potential, whereas neurons divert glucose to the pentose phosphate pathway to generate nicotinamide adenine dinucleotide phosphate (NADPH), the cofactor necessary for the regeneration of the antioxidant glutathione (15). It has been suggested that glycolytically generated ATP is more important than that generated by oxidative phosphorylation in providing energy for glutamate uptake both in astrocytes and in neurons (16). Therefore, under systemic inflammatory conditions, especially when combined with hemodynamic instability as in septic shock, where oxygen and glucose delivery usually are limited, neurons seem to be more sensitive than glial cells to metabolic disturbances (17).

Back to Top | Article Outline

Mitochondrial dysfunction

Many evidence points to a critical role of mitochondria activity in the pathogenesis of multiple organ dysfunction syndrome (MODS) (18). Several studies in experimental models and patients have shown the occurrence of mitochondrial dysfunctions in different tissues associated with severity of sepsis and septic shock (18–22). Mitochondrial dysfunctions in sepsis occur by several mechanisms. Although many studies point to dysfunctions in the electron transport chain (ETC) (21), alternative mechanisms include altered mitochondrial structure (swelling) (20), reversible inhibition of ETC complex IV or cytochrome c oxidase (23), oxidative inhibition of mitochondrial dehydrogenases and adenine nucleotide transporters, and decreased cytochrome content and respiratory uncoupling (22, 24) by activities such as uncoupling proteins and the permeability transition pore opening, which increases the permeability of inner mitochondrial membrane leading to proton leak and loss of mitochondrial membrane potential (22, 24). The consequences of mitochondrial dysfunction are numerous and include oxidative stress, cellular Ca2+ dys-homeostasis, promotion of apoptosis, and metabolic failure (Fig. 1). Recently, treatments for mitochondrial dysfunctions have been proposed as an emerging possibility to treat MODS (25).

Fig. 1

Fig. 1

Alterations in mitochondrial function occur in different levels depending on the tissue and on the timing after disease onset. A study with endotoxemic rats showed a rapid onset of mitochondrial dysfunction in the ETC complex I and IV in the rostral ventrolateral medulla, the medullary origin of sympathetic vasomotor tone (26), suggesting that nitric oxide (NO) and proinflammatory cytokines could be inducing mitochondrial reactive oxygen species (ROS) production and dysfunction. In experimental polymicrobial sepsis (cecal ligation and puncture [CLP]) in mice, we demonstrated a reduction in the efficiency of oxidative phosphorylation due to increased permeability of inner mitochondrial membrane and reduction in cytochrome content and complex IV activity in the brain tissue 24 h after sepsis onset (22). In this study, we did not observe increased mitochondrial ROS production, suggesting that other pathways such as the NADPH oxidase (NOX) could be responsible for the oxidative stress observed in the brain tissue of septic rodents (27). In another study with the CLP model in rats, we observed decreased complex I activity late after sepsis induction and increased creatine kinase activity more pronounced 6 h after sepsis onset, in several brain structures (21), corroborating previous finding that early mitochondrial ETC dysfunction and oxidative stress might be associated to acute brain dysfunction in SAE. These studies used fluid resuscitation to avoid hypotension, so it is possible that the mitochondrial dysfunctions observed are secondary to the inflammatory response and not to low blood pressure. Besides its role in energy metabolism, mitochondrion is an important calcium-buffering system in brain cells. Thus, alterations in mitochondrial function may contribute directly to derangements in calcium homeostasis and neurodegeneration (28).

Oxidative stress can impair mitochondrial function by inducing structural changes with ensuing loss of activity of a number of mitochondrial enzymes, compromising ATP synthesis (29). In addition, the direct action of ROS in mitochondrial membrane lipids and proteins may result in the activation of apoptotic cascades. In addition to targets of oxidative stress, mitochondria are also major sources of ROS in the intracellular space. Inducible nitric oxide synthase (iNOS) expression is increased in the brain during sepsis (30), raising the levels of NO and peroxynitrite, which have well-described effects on inhibiting mitochondria ETC (31). Nitric oxide also works as an energy metabolism switch inhibiting mitochondria activity and stimulating glycolysis (32). Figure 2 summarizes the mechanisms and consequences of mitochondrial dysfunction during sepsis.

Fig. 2

Fig. 2

Back to Top | Article Outline

Oxidative stress

Brain tissue has unique characteristics that make it more susceptible to oxidative damage during sepsis, such as low levels of antioxidant defenses compared with other organs (33) and a high rate of oxygen consumption. Experimental and clinical studies demonstrate that MODS in sepsis is associated with increased production of ROS and depletion of antioxidants, leading to oxidative stress (34). Despite the fact that several neuroinflammatory conditions can induce oxidative damage in the brain, these data are mainly from models in which lipopolysaccharide (LPS) is injected directly into the brain, which does not reflect the alterations observed in sepsis. Direct evidence of oxidative damage in the brain in relevant models of sepsis or human patients is limited.

Lipopolysaccharide administered systemically is able to induce oxidative damage as early as 2 h (35), and up to 24 h, and such damage is reversible by the administration of antioxidants (36). In addition, a single injection of LPS induces antioxidant enzyme depletion that can be sustained several hours after LPS administration (37). In the CLP rodent model of sepsis, there is an increase in superoxide (O2 ), nitrite, and lipid peroxidation content in the brain capillaries until 48 h after sepsis induction (38). Glutathione concentration is significantly decreased even at longer times (48 h) (39). In contrast, we observed maximum oxidative damage around 6 h in the course of sepsis (27). At longer times after CLP (10 days), there is some evidence of oxidative damage in the hippocampus, but not the other brain regions (40).

Brain oxidative damage was also determined in septic patients. Ascorbate levels were significantly lower in cerebrospinal fluid (CSF) in patients with septic encephalopathy, being correlated with the severity of neurologic symptoms (41). Postmortem brains of septic patients presented higher expression of iNOS in endothelial cells in septic shock when compared with nonseptic shock patients (30). In septic children, there was a significant increase in the CSF levels of NO and lipid peroxidation, and patients with signs of brain dysfunction have increased levels of these markers compared with sepsis only (42).

Thus, oxidative damage occurs consistently in different models of sepsis as well as in septic humans and is associated with both increase in the production of reactive oxygen and nitrogen species and decrease in antioxidant defense systems. As well as observed in others organs, oxidative damage could be associated with the development of brain dysfunction during sepsis.

Back to Top | Article Outline

Molecular mechanisms of brain dysfunction in sepsis

NO-driven oxidative stress

Nitric oxide is produced by glia under proinflammatory stimuli, and this is associated with increased cellular membrane damage and a marked decrease in the intracellular levels of reduced glutathione and ATP (43). In neuron-glial coculture, LPS-induced NO from glial cells generated oxidative damage in the neurons (44). Reactive oxygen species are involved in the microglial intracellular signaling to induce iNOS (45). Microglia activated with LPS produce more O2 via NOX1-dependent NOX, which enhances iNOS expression and secretion of interleukin 1β (45). Superoxide activates a ROS-dependent PI3-K and p38 MAPK signaling pathways and that NOX-derived ROS functions as an upstream regulator of both these kinases (46). This pathway has dual functions. The NADPH-derived O2 can initiate a cascade of processes that culminates with iNOS expression but can also be involved in the formation of peroxynitrite in LPS-activated microglia (47). In addition to iNOS, there is preliminary evidence that inhibitors of the constitutive isoforms, the calcium/calmodulin controlled isoenzymes eNOS (endothelial NOS) and nNOS (neuronal NOS), protected the brain against oxidative stress evoked by LPS, suggesting involvement of constitutive NOS in septic encephalopathy (48).

Back to Top | Article Outline

Cell death

Inhibition of brain mitochondrial function during sepsis may compromise the tissue bioenergetic efficiency inducing cellular dysfunction and death (29). The role of mitochondria in cell death pathways is broadly acknowledged. A fundamental step in the mitochondrial apoptotic pathway is induction of a mitochondrial permeability transition, with collapse of the transmembrane electrochemical gradient for hydrogen ions stopping the process of oxidative phosphorylation and efflux of cytochrome c from the intermembrane space into the cytosol. There, cytochrome c combines with apoptotic protease activation factor 1 and ATP to form a complex that activates procaspase 9. Subsequent procaspase 3 recruitment forms an “apoptosome” and activates caspase 3. This complex leads to the activation of nucleases that complete the “intrinsic” or mitochondrial-dependent pathway. There is also an “extrinsic” pathway that can initiate caspase activation and apoptosis without involvement of mitochondrial (49).

In neuroinflammatory conditions such as SAE, cell death may occur by apoptosis or by necrosis due to hypoxia, oxidative stress, and other cytotoxic factors (5). Brain imaging studies of septic patients with septic encephalopathy observed sites of tissue ischemia in the brain and lesions predominately in the white matter, suggesting increased BBB permeability, which were associated with poor outcome (50, 51). High levels of NO can induce cell death by two different ways: (i) energy depletion–mediated necrosis and (ii) oxidative/nitrosative stress–mediated apoptosis.

Apoptosis of brain cells occurs after systemic LPS administration, and the hippocampus is the most vulnerable region (52). Inhibition of iNOS reduced the number of apoptotic cells in different brain regions, especially hippocampus, after systemic LPS administration (52). In humans, vascular expression of iNOS also correlated (Spearman τ = 0.57) with neuronal apoptosis in autonomic centers (30) and in hippocampus (53). In this study, Polito et al. observed that neuronal apoptosis is associated with endothelial iNOS expression in humans (53).

Necrotic cell death may be initiated by oxidative damage to DNA and activation of the nuclear DNA-repair enzyme poly(ADP-ribose) polymerase 1 (PARP). Activation of PARP-1 contributes to cell necrosis and organ failure in various inflammatory diseases. Overactivation of PARP-1 dramatically lowers the intracellular concentration of its substrate nicotinamide adenine dinucleotide, creating a bioenergetics imbalance that culminates with ATP depletion and necrotic cell death (54). Poly(ADP-ribose) polymerase 1 inhibition is associated with increased resistance to acute septic peritonitis (55). Nitric oxide can be a mediator of PARP-1 activation, and this pathway seems to be an important mechanism of bioenergetics failure in sepsis (56).

Some effects of NO could be associated to glutamate excitotoxicity (57). Nitric oxide–induced excitotoxicity can be associated with alterations in the metabolism of ascorbate, because intracellular ascorbate depletion increases NOS induction followed by inhibition of glutamate uptake (58). These data are reinforced by the fact that CSF ascorbate levels are lower in septic patients, and this correlated with the severity of neurologic symptoms (41). Furthermore, administration of an N-methyl-D-aspartate ionotropic glutamate receptor antagonist prevents the destruction of cholinergic neurons caused by LPS in a chronic inflammation model (59).

Back to Top | Article Outline

Alterations on the BBB permeability

The interface between the CNS and the circulatory system (blood or CSF) is the BBB. The BBB ensures the homeostasis of the microenvironment of the brain parenchyma, regulating ionic balance, managing the transport of nutrients, and preventing the entry of potentially harmful molecules in the system (60). Its structure is dynamic and composed of different cell types, including endothelial cells, the pericytes, astrocytes, microglia, and neurons. The interaction between these cells regulates critical events for the CNS function, such as the permeability of the BBB, cerebral blood flow, and synaptic activity. The endothelial cells of the BBB are maintained together by complex structures, called occlusive junctions (tight junctions). These junctions are formed and maintained by transmembrane proteins (claudin and occludin) connected to cytoskeletal via its cytoplasmic domain.

One major component of systemic inflammation and sepsis is the increase in vascular permeability and edema formation. Recently, we demonstrated by magnetic resonance imaging (MRI) studies that experimental sepsis (CLP) affected brain by distinct mechanisms resulting in cytotoxic and vasogenic edema, as well as in neuronal damage (61). Sharshar and colleges (51) studied by MRI a series of septic patients and identified the presence of leukoencephalopathy surrounding Virchow-Robin spaces, suggesting BBB breakdown in this cases (51).

Compromised barrier integrity has been evidenced in animal models and human sepsis by monitoring the levels or transport of various markers in the brain parenchyma (5, 62). Other studies support the concept that systemic infection can induce an increased production of oxidizing species, tissue damage products, and release of endogenous molecules such as cytokines, complement, or heme, which have the potential to modify the proteins of the endothelial junctions, thus altering the permeability of the BBB. In vitro studies with mouse cerebrovascular endothelial cells challenged with septic plasma demonstrated tight junction instability and increased permeability due to production of ROS and NO (63). Matrix metalloproteinases (MMPs) have been imputed to have a role in several neuronal diseases. The MMPs are molecules involved in tissue injury and repair, and its activity can be induced by cytokines and oxidative stress, resulting in degradation of basal lamina surrounding BBB. Woo et al (64) showed intimate cross-talk between MMPs and ROS, where targeting ROS with inhibitors suppressed the expression and production of MMP-3 and MMP-9, NO, and tumor necrosis factor α, suggesting a possible role of ROS in MMP expression as well as proinflammatory cytokine expression.

Back to Top | Article Outline

Cognitive impairment

There are evidences both from animal models and humans that survivors from sepsis presented long-term cognitive impairment (2, 65). These alterations could be, at least in part, secondary to oxidative stress. Survivors from sepsis presented oxidative damage markers in some brain regions (40), and decreased brain oxidative damage is associated with therapeutic interventions that prevent cognitive impairment (66).

The most convincing evidence linking oxidative damage and long-term cognitive impairment comes from animal studies. Barichello et al. (67) demonstrated that the administration of N-acetyl-cysteine plus deferoxamine in the acute phase of CLP model was able to prevent long-term oxidative damage. This protective effect is robust because it is evident in several different paradigms of cognitive assessment such as the inhibitory avoidance, the open-field task, and the continuous multiple-trials step-down inhibitory avoidance task. This effect is associated with a decrease in brain oxidative damage parameters observed in the early stages of sepsis development, linking early oxidative damage to long-term cognitive impairment.

Back to Top | Article Outline

Mechanisms of long-term cognitive decline

There are two hypotheses of long-term cognitive decline: the neurodegenerative, involving microglial activation, and the vascular, related to diffuse ischemic damage. Both are not exclusive and deserved to be addressed. Indeed, microglial activation has been suggested to be a key mechanism of delirium progress toward cognitive decline (68). This hypothesis is supported by microglial incrimination in neurodegenerative disorders, especially Alzheimer dementia (69). In addition, Weberpals et al. (70) reported that cognitive impairment in endotoxemic mice was associated with activation of glial cells and not neuronal death; Semmler et al. (71) showed septic rats that developed cognitive dysfunction have a reduced cholinergic innervation. According to this hypothesis, the decrease in cholinergic inhibition of the microglial cells would make them neurotoxic (72). However, this hypothesis has been partly refuted by a clinical trial on rivastigmine showing no benefit in terms of prevention of postoperative delirium (73).

It has been recently shown that elevated level of amyloid β in intensive care patients with delirium is correlated with long-term cognitive impairment (74). Neuropathological and neuroradiological reports support the ischemic process. Maybe a thorough and regular assessment of cognitive function would help to discriminate the role of the two main hypotheses (vascular and neurodegenerative). In addition to these mechanisms, insults of axons might be involved. Indeed, one may argue that white matter lesions observed on MRI can partly be due to an axonopathy. Interestingly, a preliminary neuroradiological study suggests that white matter lesions induced by sepsis are associated with cognitive decline (75). Finally, it seems that insults of hippocampus would account for the pattern of long-term psychological disorders and cognitive dysfunction (40, 66, 71). Indeed, hippocampus is involved in posttraumatic stress disorder pathophysiology as well as in attention and memory, which are the two functions the most frequently altered. As aforementioned, it has been shown that reduction of oxidative stress in hippocampus is associated with less cognitive dysfunction in septic rats (67). Other structures can be involved, notably cholinergic innervation of parietal cortex (71). Once again, iNOS seems to be involved as NOS2 gene deficiency protects from sepsis-induced long-term cognitive deficits (70).

Back to Top | Article Outline


There is a large body of evidence supporting the occurrence of oxidative stress, bioenergetics, and mitochondrial dysfunctions in the brain during sepsis. The relationship between these alterations and the cognitive dysfunction is less clear, despite the fact that some information is available in this context. The translation of this experimental knowledge into changes in clinical practice will need novel findings both from animal models and humans.

Back to Top | Article Outline


BBB: blood-brain barrier

GLUT: glucose transporter

iNOS: inducible nitric oxide synthase

MMP: matrix metalloproteinase

NADPH: nicotinamide adenine dinucleotide phosphate

NOX: NADPH oxidase

NO: nitric oxide

O2−: superoxide

PARP-1: poly(ADP-ribose) polymerase 1

ROS: reactive oxygen species

Back to Top | Article Outline


1. Eidelman LA, Putterman D, Putterman C, Sprung CL: The spectrum of septic encephalopathy. Definitions, etiologies, and mortalities. JAMA 275 (6): 470–473, 1996.
2. Iwashyna TJ, Ely EW, Smith DM, Langa KM: Long-term cognitive impairment and functional disability among survivors of severe sepsis. JAMA 304 (16): 1787–1794, 2010.
3. Schlapbach LJ, Aebischer M, Adams M, Natalucci G, Bonhoeffer J, Latzin P, Nelle M, Bucher HU, Latal B: Impact of sepsis on neurodevelopmental outcome in a Swiss National Cohort of extremely premature infants. Pediatrics 128 (2): e348–e357, 2011.
4. Iacobone E, Bailly-Salin J, Polito A, Friedman D, Stevens RD, Sharshar T: Sepsis-associated encephalopathy and its differential diagnosis. Crit Care Med 37 (Suppl 10): S331–S336, 2009.
5. Siami S, Annane D, Sharshar T: The encephalopathy in sepsis. Crit Care Clin 24 (1): 67–82, viii, 2008.
6. Brown AM, Ransom BR: Astrocyte glycogen and brain energy metabolism. Glia 55 (12): 1263–1271, 2007.
7. Simpson IA, Carruthers A, Vannucci SJ: Supply and demand in cerebral energy metabolism: the role of nutrient transporters. J Cereb Blood Flow Metab 27 (11): 1766–1791, 2007.
8. Andres RH, Ducray AD, Schlattner U, Wallimann T, Widmer HR: Functions and effects of creatine in the central nervous system. Brain Res Bull 76 (4): 329–343, 2008.
9. Tsacopoulos M, Magistretti PJ: Metabolic coupling between glia and neurons. J Neurosci 16 (3): 877–885, 1996.
10. Gavillet M, Allaman I, Magistretti PJ: Modulation of astrocytic metabolic phenotype by proinflammatory cytokines. Glia 56 (9): 975–989, 2008.
11. Freund HR, Muggia-Sullam M, Peiser J, Melamed E: Brain neurotransmitter profile is deranged during sepsis and septic encephalopathy in the rat. J Surg Res 38 (3): 267–271, 1985.
12. Adams Wilson JR, Morandi A, Girard TD, Thompson JL, Boomershine CS, Shintani AK, Ely EW, Pandharipande PP: The association of the kynurenine pathway of tryptophan metabolism with acute brain dysfunction during critical illness. Crit Care Med 40 (3): 835–841, 2012.
13. Changsirivathanathamrong D, Wang Y, Rajbhandari D, Maghzal GJ, Mak WM, Woolfe C, Duflou J, Gebski V, dos Remedios CG, Celermajer DS, et al.: Tryptophan metabolism to kynurenine is a potential novel contributor to hypotension in human sepsis. Crit Care Med 39 (12): 2678–2683, 2011.
14. Brown GC, Bal-Price A: Inflammatory neurodegeneration mediated by nitric oxide, glutamate, and mitochondria. Mol Neurobiol 27 (3): 325–355, 2003.
15. Bolanos JP, Almeida A, Moncada S: Glycolysis: a bioenergetic or a survival pathway? Trends Biochem Sci 35 (3): 145–149, 2010.
16. Schousboe A, Sickmann HM, Bak LK, Schousboe I, Jajo FS, Faek SA, Waagepetersen HS: Neuron-glia interactions in glutamatergic neurotransmission: roles of oxidative and glycolytic adenosine triphosphate as energy source. J Neurosci Res 89 (12): 1926–1934, 2011.
17. Marrif H, Juurlink BH: Astrocytes respond to hypoxia by increasing glycolytic capacity. J Neurosci Res 57 (2): 255–260, 1999.
18. Crouser ED: Mitochondrial dysfunction in septic shock and multiple organ dysfunction syndrome. Mitochondrion 4 (5–6): 729–741, 2004.
19. Brealey D, Brand M, Hargreaves I, Heales S, Land J, Smolenski R, Davies NA, Cooper CE, Singer M: Association between mitochondrial dysfunction and severity and outcome of septic shock. Lancet 360 (9328): 219–223, 2002.
20. Crouser ED, Julian MW, Blaho DV, Pfeiffer DR: Endotoxin-induced mitochondrial damage correlates with impaired respiratory activity. Crit Care Med 30 (2): 276–284, 2002.
21. Comim CM, Rezin GT, Scaini G, Di-Pietro PB, Cardoso MR, Petronilho FC, Ritter C, Streck EL, Quevedo J, Dal-Pizzol F: Mitochondrial respiratory chain and creatine kinase activities in rat brain after sepsis induced by cecal ligation and perforation. Mitochondrion 8 (4): 313–318, 2008.
22. d’Avila JC, Santiago AP, Amancio RT, Galina A, Oliveira MF, Bozza FA: Sepsis induces brain mitochondrial dysfunction. Crit Care Med 36 (6): 1925–1932, 2008.
23. Cleeter MW, Cooper JM, Darley-Usmar VM, Moncada S, Schapira AH: Reversible inhibition of cytochrome c oxidase, the terminal enzyme of the mitochondrial respiratory chain, by nitric oxide. Implications for neurodegenerative diseases. FEBS Lett 345 (1): 50–54, 1994.
24. Exline MC, Crouser ED: Mitochondrial mechanisms of sepsis-induced organ failure. Front Biosci 13: 5030–5041, 2008.
25. Dare AJ, Phillips AR, Hickey AJ, Mittal A, Loveday B, Thompson N, Windsor JA: A systematic review of experimental treatments for mitochondrial dysfunction in sepsis and multiple organ dysfunction syndrome. Free Radic Biol Med 47 (11): 1517–1525, 2009.
26. Chuang YC, Tsai JL, Chang AY, Chan JY, Liou CW, Chan SH: Dysfunction of the mitochondrial respiratory chain in the rostral ventrolateral medulla during experimental endotoxemia in the rat. J Biomed Sci 9 (6 Pt 1): 542–548, 2002.
27. Barichello T, Fortunato JJ, Vitali AM, Feier G, Reinke A, Moreira JC, Quevedo J, Dal-Pizzol F: Oxidative variables in the rat brain after sepsis induced by cecal ligation and perforation. Crit Care Med 34 (3): 886–889, 2006.
28. Zhan RZ, Fujiwara N, Shimoji K: Regionally different elevation of intracellular free calcium in hippocampus of septic rat brain. Shock 6 (4): 293–297, 1996.
29. Berg RM, Moller K, Bailey DM: Neuro-oxidative-nitrosative stress in sepsis. J Cereb Blood Flow Metab 31 (7): 1532–1544, 2011.
30. Sharshar T, Gray F, Lorin de la Grandmaison G, Hopkinson NS, Ross E, Dorandeu A, Orlikowski D, Raphael JC, Gajdos P, Annane D: Apoptosis of neurons in cardiovascular autonomic centres triggered by inducible nitric oxide synthase after death from septic shock. Lancet 362 (9398): 1799–1805, 2003.
31. Cassina A, Radi R: Differential inhibitory action of nitric oxide and peroxynitrite on mitochondrial electron transport. Arch Biochem Biophys 328 (2): 309–316, 1996.
32. Almeida A, Moncada S, Bolanos JP: Nitric oxide switches on glycolysis through the AMP protein kinase and 6-phosphofructo-2-kinase pathway. Nat Cell Biol 6 (1): 45–51, 2004.
33. Santiago AP, Chaves EA, Oliveira MF, Galina A: Reactive oxygen species generation is modulated by mitochondrial kinases: correlation with mitochondrial antioxidant peroxidases in rat tissues. Biochimie 90 (10): 1566–1577, 2008.
34. Arvidsson S, Falt K, Marklund S, Haglund U: Role of free oxygen radicals in the development of gastrointestinal mucosal damage in Escherichia coli sepsis. Circ Shock 16 (4): 383–393, 1985.
35. Kheir-Eldin AA, Motawi TK, Gad MZ, Abd-ElGawad HM: Protective effect of vitamin E, beta-carotene and N-acetylcysteine from the brain oxidative stress induced in rats by lipopolysaccharide. Int J Biochem Cell Biol 33 (5): 475–482, 2001.
36. Godbout JP, Berg BM, Kelley KW, Johnson RW: alpha-Tocopherol reduces lipopolysaccharide-induced peroxide radical formation and interleukin-6 secretion in primary murine microglia and in brain. J Neuroimmunol 149 (1–2): 101–109, 2004.
37. Sebai H, Gadacha W, Sani M, Aouani E, Ghanem-Boughanmi N, Ben-Attia M: Protective effect of resveratrol against lipopolysaccharide-induced oxidative stress in rat brain. Brain Inj 23 (13–14): 1089–1094, 2009.
38. Ninkovic M, Malicevic I, Jelenkovic A, Jovanovic DM, Dukic M, Vasiljevic I: Oxidative stress in the rats brain capillaries in sepsis—the influence of 7-nitroindazole. Acta Physiol Hung 93 (4): 315–323, 2006.
39. Ninkovic MB, Malicevic ZM, Jelenkovic A, Dukic MM, Jovanovic MD, Stevanovic ID: Nitric oxide synthase inhibitors partially inhibit oxidative stress development in the rat brain during sepsis provoked by cecal ligation and puncture. Gen Physiol Biophys 28 Spec No: 243–250, 2009.
40. Comim CM, Cassol-Jr OJ, Constantino LS, Felisberto F, Petronilho F, Rezin GT, Scaini G, Daufenbach JF, Streck EL, Quevedo J, et al.: Alterations in inflammatory mediators, oxidative stress parameters and energetic metabolism in the brain of sepsis survivor rats. Neurochem Res 36 (2): 304–311, 2011.
41. Voigt K, Kontush A, Stuerenburg HJ, Muench-Harrach D, Hansen HC, Kunze K: Decreased plasma and cerebrospinal fluid ascorbate levels in patients with septic encephalopathy. Free Radic Res 36 (7): 735–739, 2002.
42. Hamed SA, Hamed EA, Abdella MM: Septic encephalopathy: relationship to serum and cerebrospinal fluid levels of adhesion molecules, lipid peroxides and S-100B protein. Neuropediatrics 40 (2): 66–72, 2009.
43. Moss DW, Bates TE: Activation of murine microglial cell lines by lipopolysaccharide and interferon-gamma causes NO-mediated decreases in mitochondrial and cellular function. Eur J Neurosci 13 (3): 529–538, 2001.
44. Kim EJ, Kwon KJ, Park JY, Lee SH, Moon CH, Baik EJ: Neuroprotective effects of prostaglandin E2 or cAMP against microglial and neuronal free radical mediated toxicity associated with inflammation. J Neurosci Res 70 (1): 97–107, 2002.
45. Cheret C, Gervais A, Lelli A, Colin C, Amar L, Ravassard P, Mallet J, Cumano A, Krause KH, Mallat M: Neurotoxic activation of microglia is promoted by a NOX1-dependent NADPH oxidase. J Neurosci 28 (46): 12039–12051, 2008.
46. Sun HN, Kim SU, Lee MS, Kim SK, Kim JM, Yim M, Yu DY, Lee DS: Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase–dependent activation of phosphoinositide 3-kinase and p38 mitogen-activated protein kinase signal pathways is required for lipopolysaccharide-induced microglial phagocytosis. Biol Pharm Bull 31 (9): 1711–1715, 2008.
47. Yoo BK, Choi JW, Shin CY, Jeon SJ, Park SJ, Cheong JH, Han SY, Ryu JR, Song MR, Ko KH: Activation of p38 MAPK induced peroxynitrite generation in LPS plus IFN-gamma-stimulated rat primary astrocytes via activation of iNOS and NADPH oxidase. Neurochem Int 52 (6): 1188–1197, 2008.
48. Czapski GA, Cakala M, Kopczuk D, Kaminska M, Strosznajder JB: Inhibition of nitric oxide synthase prevents energy failure and oxidative damage evoked in the brain by lipopolysaccharide. Pol J Pharmacol 56 (5): 643–646, 2004.
49. Kroemer G, Dallaporta B, Resche-Rigon M: The mitochondrial death/life regulator in apoptosis and necrosis. Annu Rev Physiol 60: 619–642, 1998.
50. Nguyen DN, Spapen H, Su F, Schiettecatte J, Shi L, Hachimi-Idrissi S, Huyghens L: 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 34 (7): 1967–1974, 2006.
51. Sharshar T, Carlier R, Bernard F, Guidoux C, Brouland JP, Nardi O, de la Grandmaison GL, Aboab J, Gray F, Menon D, et al.: Brain lesions in septic shock: a magnetic resonance imaging study. Intensive Care Med 33 (5): 798–806, 2007.
52. 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 30 (2–3): 144–157, 2005.
53. Polito A, Brouland JP, Porcher R, Sonneville R, Siami S, Stevens RD, Guidoux C, Maxime V, de la Grandmaison GL, Chretien FC, et al.: Hyperglycaemia and apoptosis of microglial cells in human septic shock. Crit Care 15 (3): R131, 2011.
54. Ha HC, Snyder SH: Poly(ADP-ribose) polymerase is a mediator of necrotic cell death by ATP depletion. Proc Natl Acad Sci U S A 96 (24): 13978–13982, 1999.
55. Soriano FG, Liaudet L, Szabo E, Virag L, Mabley JG, Pacher P, Szabo C: Resistance to acute septic peritonitis in poly(ADP-ribose) polymerase-1–deficient mice. Shock 17 (4): 286–292, 2002.
56. Szabo C: Poly (ADP-ribose) polymerase activation and circulatory shock. Novartis Found Symp 280: 92–103; discussion 103–107, 160–164, 2007.
57. Bal-Price A, Brown GC: Inflammatory neurodegeneration mediated by nitric oxide from activated glia-inhibiting neuronal respiration, causing glutamate release and excitotoxicity. J Neurosci 21 (17): 6480–6491, 2001.
58. Korcok J, Wu F, Tyml K, Hammond RR, Wilson JX: Sepsis inhibits reduction of dehydroascorbic acid and accumulation of ascorbate in astroglial cultures: intracellular ascorbate depletion increases nitric oxide synthase induction and glutamate uptake inhibition. J Neurochem 81 (1): 185–193, 2002.
59. Willard LB, Hauss-Wegrzyniak B, Danysz W, Wenk GL: The cytotoxicity of chronic neuroinflammation upon basal forebrain cholinergic neurons of rats can be attenuated by glutamatergic antagonism or cyclooxygenase-2 inhibition. Exp Brain Res 134 (1): 58–65, 2000.
60. Abbott NJ, Patabendige AA, Dolman DE, Yusof SR, Begley DJ: Structure and function of the blood-brain barrier. Neurobiol Dis 37 (1): 13–25, 2010.
61. Bozza FA, Garteiser P, Oliveira MF, Doblas S, Cranford R, Saunders D, Jones I, Towner RA, Castro-Faria-Neto HC: Sepsis-associated encephalopathy: a magnetic resonance imaging and spectroscopy study. J Cereb Blood Flow Metab 30 (2): 440–448, 2010.
62. Jeppsson B, Freund HR, Gimmon Z, James JH, von Meyenfeldt MF, Fischer JE: Blood-brain barrier derangement in sepsis: cause of septic encephalopathy? Am J Surg 141 (1): 136–142, 1981.
63. Handa O, Stephen J, Cepinskas G: Role of endothelial nitric oxide synthase–derived nitric oxide in activation and dysfunction of cerebrovascular endothelial cells during early onsets of sepsis. Am J Physiol Heart Circ Physiol 295 (4): H1712–H1719, 2008.
64. Woo MS, Park JS, Choi IY, Kim WK, Kim HS: Inhibition of MMP-3 or -9 suppresses lipopolysaccharide-induced expression of proinflammatory cytokines and iNOS in microglia. J Neurochem 106 (2): 770–780, 2008.
65. Barichello T, Martins MR, Reinke A, Feier G, Ritter C, Quevedo J, Dal-Pizzol F: Cognitive impairment in sepsis survivors from cecal ligation and perforation. Crit Care Med 33 (1): 221–223; discussion 262–263, 2005.
66. Cassol-Jr OJ, Comim CM, Silva BR, Hermani FV, Constantino LS, Felisberto F, Petronilho F, Hallak JE, De Martinis BS, Zuardi AW, et al.: Treatment with cannabidiol reverses oxidative stress parameters, cognitive impairment and mortality in rats submitted to sepsis by cecal ligation and puncture. Brain Res 1348: 128–138, 2010.
67. Barichello T, Machado RA, Constantino L, Valvassori SS, Reus GZ, Martins MR, Petronilho F, Ritter C, Quevedo J, Dal-Pizzol F: Antioxidant treatment prevented late memory impairment in an animal model of sepsis. Crit Care Med 35 (9): 2186–2190, 2007.
68. Murray C, Sanderson DJ, Barkus C, Deacon RM, Rawlins JN, Bannerman DM, Cunningham C: Systemic inflammation induces acute working memory deficits in the primed brain: relevance for delirium. Neurobiol Aging 33 (3): 603–616, 2012.
69. Perry VH, Nicoll JA, Holmes C: Microglia in neurodegenerative disease. Nat Rev Neurol 6 (4): 193–201, 2010.
70. 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 29 (45): 14177–14184, 2009.
71. Semmler A, Frisch C, Debeir T, Ramanathan M, Okulla T, Klockgether T, Heneka MT: Long-term cognitive impairment, neuronal loss and reduced cortical cholinergic innervation after recovery from sepsis in a rodent model. Exp Neurol 204 (2): 733–740, 2007.
72. van Gool WA, van de Beek D, Eikelenboom P: Systemic infection and delirium: when cytokines and acetylcholine collide. Lancet 375 (9716): 773–775, 2010.
73. van Eijk MM, Roes KC, Honing ML, Kuiper MA, Karakus A, van der Jagt M, Spronk PE, van Gool WA, van der Mast RC, Kesecioglu J, et al.: Effect of rivastigmine as an adjunct to usual care with haloperidol on duration of delirium and mortality in critically ill patients: a multicentre, double-blind, placebo-controlled randomised trial. Lancet 376 (9755): 1829–1837, 2010.
74. van den Boogaard M, Kox M, Quinn KL, van Achterberg T, van der Hoeven JG, Schoonhoven L, Pickkers P: Biomarkers associated with delirium in critically ill patients and their relation with long-term subjective cognitive dysfunction; indications for different pathways governing delirium in inflamed and noninflamed patients. Crit Care 15 (6): R297, 2011.
75. Jackson JC, Hopkins RO, Miller RR, Gordon SM, Wheeler AP, Ely EW: Acute respiratory distress syndrome, sepsis, and cognitive decline: a review and case study. South Med J 102 (11): 1150–1157, 2009.

Sepsis; infection; central nervous system; microglia; neuroinflammation; mitochondrial; energy

©2013The Shock Society