Oxidative stress and pyrogenic fever pathogenesis

European Journal of Pharmacology 667 (2011) 6–12

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European Journal of Pharmacology j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / e j p h a r

Perspective

Oxidative stress and pyrogenic fever pathogenesis Ching-Cheng Hou a, 1, Hung Lin b, 1, Ching-Ping Chang c, Wu-Tein Huang d, Mao-Tsun Lin e,⁎ a

Department of Intensive Care Medicine, Chi Mei Medical Center, Tainan 710, Taiwan Department of Surgery, Chi Mei Medical Center, Tainan 710, Taiwan c Department of Biotechnology, Southern Taiwan University, Tainan 710, Taiwan d Department of Recreation and Health Care Management, Chia-Nan University of Pharmacy and Science, Tainan 710, Taiwan e Department of Emergency and Critical Care Medicine, Landseed Hospital, Tao-Yuan 330, Taiwan b

a r t i c l e

i n f o

Article history: Received 2 March 2011 Received in revised form 16 May 2011 Accepted 23 May 2011 Available online 7 June 2011 Keywords: Pyrogen Fever Glutamate Nitric oxide metabolite Hydroxyl radical

a b s t r a c t The causative/regulatory connections between changes in tissue redox state and fever induction were investigated herein. Wherefore, LPS, the primary element of bacterial cell wall, in addition to inducing proinflammatory cytokines, activated macrophages and other leukocytes to secrete hydroxyl radical (OH), nitric oxide metabolites (NOx−), superoxide (O2•) and other reactive oxygen/nitrogen species. Furthermore, inflammation response-associated hypoxia stimulated glutamate release, which caused excitotoxicity of cells by increasing extracellular Ca2+. Cytokines and glutamate in turn also triggered the release of large amounts of NOx−, OH, O2•, and other radicals. Those reactive nitrogen species in turn caused cellular injury via the peroxidation of membrane lipids and oxidative damage of proteins and DNA. Glutamate, NOx−, OH and antioxidants participated in the pathogenesis and regulation of LPS- or cytokines-induced fever. In particular, to highlight the role of glutamate, prostaglandin E2, NOx− and OH generated in the hypothalamus during pyrogenic fever was attempted hereby. To find the link among the signaling with the glutamate, NOx− and OH•/prostaglandin E2 in the hypothalamus during pyrogenic fever will be challenging and could now clinically suppress pyrogenic fever. © 2011 Elsevier B.V. All rights reserved.

1. Lipopolysaccharide (LPS)- or cytokine-caused fever It was described that the most frequent and serious global problem was sepsis, which was a systemic inflammatory process mostly endotoxin- or lipopolysaccharide (LPS)-caused (Bhattacharyya et al., 2004; Rangel-Frausto et al., 1995). LPS triggered the production of tumor necrosis factor-alpha (TNF-α), interleukin-1 (IL-1), IL-6, prostaglandin E2 (PGE2), interferon gamma, leukemia inhibitory factor, migration inhibitory factor, platelet activating factor, products of the complement and clotting cascades, in addition to activating macrophages and other leukocytes to secrete hydroxyl radical (OH•), nitric oxide metabolites (NOx−), superoxide (O2•) and other reactive oxygen/nitrogen species. Also in experimental and clinical studies, infection, trauma, or tissue anoxia stimulated macrophages and monocytes to secrete IL-1β, TNF-α, and others (Wu et al., 2008); hypoxia, glutamate release, which caused cell excitotoxicity by increasing extracellular Ca 2+ (Cassina et al., 2002). These cytokines and glutamate in turn released large amounts of NOx−, OH•, O2•, and others and resulted in cellular injury via the peroxidation of

⁎ Corresponding author. Tel./fax: + 886 6 2517850. E-mail address: [email protected] (M.-T. Lin). 1 These authors contributed equally to this work. 0014-2999/$ – see front matter © 2011 Elsevier B.V. All rights reserved. doi:10.1016/j.ejphar.2011.05.075

membrane lipids and oxidative damage of proteins and DNA (Cassina et al., 2002; Feihl et al., 2001). The organum vasculosum laminae terminalis (OVLT), a circumventricular organ in the anterior wall of the third cerebral ventricle, was a site through which signaled that increased body temperatures were transferred from the blood to the hypothalamus in animals (Hashimoto et al., 1994; Stitt, 1985). According to Dinarello (2004), Gram-positive or Gram-negative organisms released endotoxins in local or systemic infection. Pyrogenic cytokines IL-1, TNF-α, IL-6 and other cytokines which were synthesized and processed accessed the circulation and were bound to the respective cytokine receptors in the OVLT. Activated Toll-like receptors (TLR) and other cytokine receptors induced cyclooxygenase-2 (COX-2), which resultantly synthesized PGE2 on the brain side (the OVLT). Increases in hypothalamic PGE2 released cyclic adenosine monophosphate (cAMP) and other neurotransmitters triggering thermosensitive neurons in the hypothalamus to raise the thermostatic set point. Hypothalamic signals activated peripheral efferent nerves to increase heat production and decrease heat loss. The resulting increase in blood temperature was detected by the thermoregulatory center in the hypothalamus. This review was to update the role of glutamate, NOx− and OH• and antioxidants in the pathogenesis of LPS- or cytokines-induced fever, particularly to focus the role of glutamate, PGE2, NOx− and OH• in the hypothalamus generated during pyrogenic fever.

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2. Glutamate in pyrogenic fever The amino acid glutamate, the major excitatory neurotransmitter in the central nervous system, was important in learning, memory, development, and other forms of synaptic plasticity (Said et al., 1996). The ionotropic N-methyl-D-aspartate (NMDA) receptor was the focus of much attention because of its implication in heat injury, strokes, epileptic seizure, Alzheimer disease, Huntington disease, Parkinson disease, amyotrophic lateral sclerosis and dementia. The aspirin neuroprotective effect by inhibiting glutamate release after permanent focal cerebral ischemia in rats was also shown (De Cristobal et al., 2002). Cyclooxygenase-2 was implicated in excitotoxic cell death and, currently, this inducible enzyme is regarded as a potential therapeutic target for neuroprotection (Pepicelli et al., 2005). In vivo activation of NMDA receptors in the rat hippocampus immediately and transiently increased the PGE2 basal levels (Pepicelli et al., 2002). The increased PGE2 caused by NMDA receptor activation was prevented to a similar extent by the specific NMDA antagonist MK801 and by selective/non-selective COX-2 inhibitors, indicating that the NMDA-evoked PGE2 synthesis largely depended on COX-2 activity. LPS activated the hypothalamic–pituitary–adreno-cortical axis and brain stem nuclei (Ericsson et al., 1994) and affected norepinephrine, dopamine, serotonin (Molina-Holgado and Gauza 1996) and glutamate activities (Lin et al., 1999). It was likely that LPS might cause fever via stimulating NMDA-dependent hydroxyl radical–PGE2 pathway in the hypothalamus. Intravenous staphylococcal enterotoxin A produced fever accompanied by increasingly released glutamate in the rabbit hypothalamus (Huang et al., 2001). Applied NMDA receptor antagonists significantly attenuated the staphylococcal enterotoxin A and induced augmenting glutamate release in the hypothalamus and fever which could be induced by directly administrated glutamate into the hypothalamus and greatly reduced by pretreatment with intrahypothalamic NMDA receptor antagonist (Huang et al., 2001). Both the fever and augmented glutamate release in the hypothalamus after intravenous staphylococcal enterotoxin A were significantly reduced by pretreatment with intravenous cyclooxygenase inhibitors such as aspirin, sodium salicylate, acetaminophen, or diclofenac (Huang et al., 2004a,b). Intrahypothalamically administrated aspirin or sodium salicylate significantly suppressed the glutamate-induced fever (Huang et al., 2004a,b). Several in vivo findings also demonstrated that glutamatergic neuron discharge promoted the extracellular release of hydroxyl radicals (Yang et al., 1995). Intravenous LPS elicited a biphasic febrile response, with the core temperature maxima at 80 and 200 min post-injection. Each core temperature rise was accompanied by a distinct wave of cellular concentrations of 2,3-DHBA (an index of the level of hydroxyl radicals) in the hypothalamus (Huang et al., 2006). The rise (following systemic injection of LPS) in both the core temperature (early or late fever) and hypothalamic 2,3-DHBA could be induced by directly injected glutamate into the cerebroventricular fluid system, and was significantly antagonized by pretherapeutic injection of α-lipoic acid, N-acetyl-L-cysteine, MK-801, or LY235959 1 h before LPS injection. The LPS-increased PGE2 in the hypothalamus could be suppressed by free radical scavengers like α-lipoic acid or N-acetyl-L-cysteine. In these findings, an NMDA receptor-dependent hydroxyl radical–PGE2 pathway in the hypothalamus of rabbit brain could mediate the LPS-induced fever (Huang et al., 2006). Indeed, lipopolysaccharide- and glutamate-elevated hypothalamic hydroxyl radical and fever could be NMDA receptor antagonismsuppressed (Kao et al., 2007). 3. Nitric oxide in pyrogenic fever Nitric oxide metabolites (NOx−) were generated by three isoforms of nitric oxide synthase (NOS), two of which were expressed constitutively (in endothelium: endothelial NOS, eNOS; brain: neuronal

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NOS, nNOS), while the other one was endotoxin- or cytokine-induced (inducible NOS, iNOS) (Thiemermann, 1997). Expressed iNOS in many organs or tissues in Gram-negative or Gram-positive bacteria-caused septic shock resulted in an enhanced NOx− that contributed to hypotension, vascular hyperactivity to vasoconstrictors, organ injury and dysfunction as well as host defense. The inhibited iNOS (e.g., with dexamethasone) or iNOS (e.g., with selective inhibitors of iNOS activity) exerted beneficial effects in septic shock animal models; the inhibited eNOS, excessive vasoconstriction (adverse effects) plausibly. LPS stimulated the acute early release of pro-inflammatory cytokines like TNF-α, IL-1β, and others from macrophages and leukocytes (Bhattacharyya et al., 2004); these pro-inflammatory cytokines, the expression and activation of iNOS; NOx−, the biosynthesis of PGE2, so it could be propyretic in the hypothalamic mediation of the pyrogenic fever (Gerstberger, 1999; Schmidt et al., 1998; Simon, 1998; Steiner and Branco, 2003; Steiner and Branco, 2001). NOx−-dependent cyclic GMP production in glial cells could be LPS- or cytokines-modulated (Simmons and Murphy, 1993). Blockaded NOx− production promoted down-regulation of COX-2 activity and decreased PGE2 production (Perkins and Kniss, 1999). According to Dinarello (2004), fever induced by IL-1, TNF-α, IL-6 or Toll-like receptor ligands required COX-2, production of PGE2 and activation of hypothalamic PGE2 receptors. It was likely that iNOS-dependent NOx− might be in the hypothalamic mediation of PGE2-related fever. In the light of the above, Lin and Lin (1996b) were to ascertain whether iNOS-dependent NOx− in the hypothalamus (or OVLT) participated in hypothalamic mediation of pyrogenic fever. In conscious rabbits, microinjected LPS, several chemically different NOx− donors, the cyclic GMP analog-8-Br-cyclic GMP, or PGE2 into the OVLT caused a dose-related fever, which appeared secondary to decreased heat loss (due to peripheral vasoconstriction) and/or increased heat production (thermogenesis) secondary to shivering (Lin and Lin, 1996b). Dexamethasone [a potent inhibitor of the iNOS transcription as well as the protein synthesis, anisomycin, iNOS inhibitors like aminoguanidine, L-NMMA, and L-NIO, but not eNOS inhibitor like L-NAME (Rees et al., 1990; Szabó et al., 1994; Wu et al., 1995)] significantly attenuated the LPS-induced fever in rabbits. (Lin and Lin, 1996a,b). Pretreatment with an iNOS inhibitor like dexamethasone not only reduced the fever but also attenuated the iNOSdependent NOx− production in the OVLT following an intra-OVLT dose of LPS (Lin et al., 1997), which indicated that iNOS-dependent NOx− in the hypothalamus played a pyretic role in rabbits. Inhibited iNOS was also to suppress LPS-, psychological stress- (Soszynski, 2001), and IL1β-induced fever (Roth et al., 1998) in rats. In these observations, LPS or pro-inflammatory cytokines might act on the COX-2-dependent PGE2–cAMP pathway in the OVLT (Dinarello, 2004) to induce fever via stimulating iNOS-dependent NOx− production in situ. On the contrary, other lines of evidence indicated that NOx− inhibited LPS-induced COX-2 activity (Clancy et al., 2000; D'Acquisto et al., 2001; Deeb et al., 2006; Tanaka et al., 2001) and therefore was antipyretic (Feleder et al., 2007; Mathai et al., 2004). It should be mentioned that eNOS-dependent NOx− mediated peripheral vasodilation (Corbett et al., 1992). Activated eNOS-dependent NOx− caused by some certain circumstances might increase heat loss and decrease body core temperature. Other lines of evidence proposed a role of NOx− as a signal transducing agent in febrile response by early decreased NOx− production in the plasma following LPS, as evaluated by falling plasma nitrate levels, which inversely correlated with the fever height (Riedel, 1997). Likewise, conversely, in methylene blue-pretreated rabbits, plying LPS was followed by rising plasma nitrate levels and abolishing oxygen radical formation, and fever was completely prevented despite elevated PGE2 and TNF-α in the plasma (Weihrauch and Riedel, 1997). As mentioned, eNOS-dependent NOx− mediated vasodilation (Corbett et al., 1992). Administrated LPS might reduce heat loss (vasoconstriction) via getting decreased and releasing eNOS-dependent NO in the plasma.

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Again, methylene blue might prevent LPS-induced fever by getting increased and releasing eNOS-dependent NOx−. 4. Oxygen free radicals in pyrogenic fever

baseline after 120 min, but core temperature significantly increased after 30 min, and then lasted for 300 min. Apparently, both the early and the late fever were associated with the increased TNF-α plus IL-1β and IL-6 serum, respectively. The rise of IL-6 might be by both TNF-α and IL-1β (Pedersen et al., 2001); that of TNF-α (Tsai et al., 2006) and IL-6 (Niu et al., 2009) by LPS administration, greatly reduced by hyperbaric oxygen pretreatment or post-treatment, either of which thus might reduce LPS-induced fever by attenuating increased TNF-α, IL-1β, IL-6, or other pro-inflammatory cytokines. This contention was many investigators-supported; hyperbaric oxygen treatment attenuated IL-1, TNF-α, and IL-6 release from monocytes-macrophages in rodents (Inamoto et al., 1991; Lahat et al., 1995) and humans (Benson et al., 2003; Weisz et al., 1997), besides protecting against LPS-overproduced TNF-α and mortality in endotoxic rats (Lin et al., 2005), and attenuating cytokine induction in rats (Yamashita and Yamashita, 2000). In addition, the therapy inhibited the LPS- or IL-6-increased glutamate, hydroxyl radicals and PGE2 in the OVLT (Niu et al., 2009). Furthermore, simultaneously administrated N-acetyl-L-cysteine (an antioxidant) (Farr et al., 2003) 1 h before the LPS injection significantly enhanced the hyperbaric oxygen-exerted antipyretic effects. Ensuantly, hyperbaric oxygen might prevent and suppress fever by inhibiting the glutamate–hydroxyl radicals–PGE2 pathways in OVLT and circulating pro-inflammatory cytokine accumulation during LPSfever in rabbits (Niu et al., 2009), which was in part other disease models-supported, and for example, inhibited diet-induced atherosclerosis in New Zealand white rabbits (Kudchodhar et al., 2000). These changes were accompanied by significantly reduced auto antibodies against oxidatively-modified LDL, asides from the profound ones in the redox state of the liver and aortic tissues (Kudchodkar et al., 2007). A 10-week hyperbaric oxygen therapy significantly reduced hepatic levels of lipid peroxidation and oxidized glutathione, while significantly increasing the reduced glutathione, glutathione reductase, transferase, Se-dependent glutathione peroxidase and catalase. Consequently, hyperbaric oxygen therapy affected the redox state of relevant tissues powerfully and inhibited oxidation.

Free radicals were atoms or molecules that had an unpaired electron in the outer orbit, and whose major species derived from oxygen were oxygen free radicals or reactive oxygen species. The sequential univalent reduction of molecular oxygen resulted in forming superoxide anion, hydrogen peroxide and hydroxyl radical. In accumulated evidence, reactive oxygen species was important in the pathogenesis of endotoxemia or sepsis (Bhattacharya et al., 2004). In sepsis, increasingly activated neutrophils increased reactive oxygen species leading to tissue damage, which itself uncoupled electron transport system and thus, generated even more reactive oxygen species. Systemically administrated LPS or intracerebroventricularly injected glutamate caused a dose-dependent increase in both the OVLT levels of hydroxyl radicals and core temperature (Huang et al., 2006). After LPS or glutamate injection, the changed OVLT levels of hydroxyl radicals were correlated with the increased core temperature. In addition, pretreatment with hydroxyl radical scavengers such as α-lipoic acid or N-acetyl-L-cysteine significantly attenuated the LPS-induced augmented hydroxyl radical production and fever. Furthermore, both the fever and increased hydroxyl radicals in the OVLT after LPS injection were significantly attenuated by pretreatment with NMDA receptor antagonists including MK-801 and LY235959. Thus, both glutamatergic and hydroxyl radical pathways were in the pyrogenic fever inhibition of oxygen radical formation in the plasma by potent radical scavengers such as methylene blue (Kelner et al., 1988); α-lipoic acid (Han et al., 1997), or aspirin (Shi et al., 1999) was also to prevent LPS-induced fever in rabbits (Riedel et al., 2003). Consequently, LPS might excessively accumulate hydroxyl radicals in both the peripheral blood stream and the cerebrospinal fluid system that could be suppressed by pretreatment of rabbits with hydroxyl radical scavengers or NMDA receptor antagonists. Reactive oxygen species could be second messengers to activate NFkB (Asehnoune et al., 2004), and abolished by a broad range of antioxidants (Blackwell et al., 1996). Accordingly, both overproduced iNOS and COX-2 could be NF-kB-activated (Oh et al., 2004). Pyrogens such as LPS, or IL-1β might act via iNOS–COX-2 pathways in OVLT to induce fever in rabbits (Huang et al., 1997; Lin and Lin, 1996a; Lin and Lin, 1996b; Lin and Lin, 2000). The induced fever could be attenuated by administrated several NF-kB inhibitors in rabbits or rats (Lee et al., 2003b; Shao et al., 2004). Therefore, after LPS injection, the induced reactive oxygen species overproduction in OVLT might activate both iNOS-dependent NOx− and COX-2-dependent PGE2 which induced fever (Ajmone-Cat et al., 2003; Wang et al., 2004). Indeed, the LPSoverproduced hypothalamic PGE2 could be reduced by antioxidants such as α-lipoic acid and N-acetyl-L-cysteine (Huang et al., 2004b), both of which were recognized as hydroxyl radical scavengers and used to combat oxidative stress-induced tissue damage (Farr et al., 2003). Both acetaminophen and aspirin caused antipyresis by reducing excessively accumulated glutamate in the rabbit hypothalamus (Huang et al., 2004a; Huang et al., 2004b). Directly injected glutamate into the cerebrospinal fluid system raised the hypothalamic levels of hydroxyl radicals (Kao et al., 2007).

Baicalin (7-D-glucuronic acid, 5,6-dihydroxyflavone), a flavonoid compound derived from the root of Scutellaria baicalensis Georgi (Huang Qin in Chinese), has been widely used in traditional Chinese herbal medicine for upper respiratory and gastrointestinal tract infection, viral hepatitis, and allergic disease (Huang, 1999). In RAW 264.7 mouse macrophage, the LPS-induced iNOS and COX-2 were baicalin-suppressed (Chen et al., 2001). In addition, the carrageenanoverproduced nitric oxide, PGE2, and inflammatory cytokines were also baicalin-reduced (Chou et al., 2003; Krakauer et al., 2001). In addition to possessing antioxidant activities (Shieh et al., 2000), baicalin protected against cerebral ischemia injury by attenuating glutamate production (Lee et al., 2003a; Li et al., 2003). Systemically administrated baicalin (2–20 mg/k, intravenous) 1 h before intravenous LPS significantly reduced the LPS-overproduced circulating TNF-α and glutamate and hydroxyl radicals (Tsai et al., 2006) and might exert its antipyresis by inhibiting the N-methyl-D-aspartate receptor-dependent hydroxyl radicals–PGE2 pathways in OVLT and circulating TNF-α accumulation in rabbits during LPS-fever.

5. The hyperbaric oxygen antipyretic effects

7. The interleukin-1 receptor antagonist antipyretic effects

It was demonstrated that intravenous 2 μg/kg LPS raised the biphasic body temperature, with the core temperature maxima at 80–90 and 180–210 min post-injection (Huang et al., 2008). The early fever was associated with both elevated TNF-α and IL-1β in the serum; the late fever, with the elevated IL-6 serum levels. Both IL-1β and TNF-α peaked at 90 min after LPS injection and returned to

The pro-inflammatory cytokine interleukin-1β (IL-1β), a major mediator of LPS-induced fever, elicited febrile responses via COX-2dependent PGE2 in the brain (Kluger, 1995; Li et al., 2001). In studiesprovided considerable evidence, IL-1 directly caused fever in the brain. For example, peripherally injected LPS synthesized and produced IL-1 in the brain (mainly in the hypothalamus) (Ban et al.,

6. The baicalin antipyretic effects

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1992; Bandtlow et al., 1990; Nguyen et al., 1998). Intracerebrally injected recombinant IL-1 elicited marked fever in rodents (Anforth et al., 1998). The activity of hypothalamic thermosensitive neurons was altered by IL-1 administration in vivo and in vitro, the characteristics of which were consistent with the fever development (Hori et al., 1988). The observed fever could be attenuated by central administration of neutralizing anti-IL-1β antiserum (Gourine et al., 1998; Klir et al., 1994) or naturally occurring interleukin-1 receptor antagonist (Luheshi et al., 1996; Miller et al., 1997). Furthermore, IL-1 receptor antagonists inhibited the released glutamate, hydroxyl radicals, and PGE2 in the hypothalamus during LPS-induced fever in rabbits (Huang et al., 2010).

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Focus of Infection

Gram negative bacteria Gram positive bacteria (+) Endotoxemia, sepsis (+) Endotoxin (LPS) (+) Hypotension

8. The central interleukin-10 antipyretic effects Interleukin-10 (IL-10), an endogenous anti-inflammatory cytokine, inhibited: many actions of LPS (Berg et al., 1995; Moore et al., 2001; Oberholzer et al., 2002; Strle et al., 2001; Ward et al., 2001); the production of tumor necrosis factor-alpha (TNF-α), IL-1, and IL-6, while upregulating IL-1 receptor antagonists (Howard and O'Garra, 1992; Jenkins et al., 1994). Moreover, IL-10-knockout mice likely increased inflammatory bowel disease (Rennick et al., 1997), mortality rates after sepsis (Berg et al., 1995), and an exacerbated and prolonged fever in response to systemically administered LPS (Leon et al., 1999). Central IL-10 attenuated the febrile response to central LPS in rats (Ledeboer et al., 2002). Systemically injected LPS increased the core temperature, and extracellular glutamate, hydroxyl radicals, and PGE2 in the hypothalamus accompanied by increased plasma levels of TNF-α (Kao et al., 2011). Pretreatment with IL-10 (10–100 ng, intracerebroventricular) 1 h before intravenous LPS significantly reduced the LPS-induced changes in extracellular glutamate, hydroxyl radicals, and PGE2 in the hypothalamus and fever, but not the increased TNF-α in rabbits. Hence, directly injected IL-10 into the lateral cerebral ventricle 1 h before intravenous LPS exerted its antipyresis by inhibiting the changes in extracellular glutamate, hydroxyl radicals, and PGE2 in the hypothalamus during LPS fever in rabbits. 9. The aspirin antipyretic effects Both the core temperature elevation and the augmented glutamate release in the hypothalamus after an intravenous staphylococcal enterotoxin A were significantly reduced by pretreatment with intravenous aspirin (Huang et al., 2004b). Systemically injected aspirin 1 h before intrahypothalamic glutamate also significantly suppressed the glutamate-induced fever in rabbits (Huang et al., 2004a,b). Intravenous aspirin was also to prevent LPS-induced fever by inhibiting oxygen radical formation in plasma (Riedel et al., 2003). Further, systemically administrated aspirin, in addition to reducing PGE2, exerted its antipyresis by inhibiting the NMDA receptordependent hydroxyl radical-PGE2 pathways in the OVLT during LPS fever in rabbits (Kao et al., 2007). 10. Pathogenic sequence during pyrogen fever Fig. 1 depicted the proposed pathogenic sequence during pyrogen fever. As reviewed by Kluger (1995), Bhattacharyya et al., (2004), and Dinarello (2004), LPS activated blood monocytes and/or hepatic macrophages (Kupffer cells) and released TNF-α, IL-1β, IL-6, and others. Blood-borne pro-inflammatory cytokines could activate meningeal macrophages, cerebral endothelial cells, and perivascular microglial cells, thereby locally producing PGE2 and IL-6 which were both implicated in fever (Cao et al., 1999; Elmquist et al., 1997; Van Dam et al., 1996). Circulating cytokines could also act on cells in the organum vasculosum laminae terminalis and the area postrema of the anterior hypothalamus (Blatteis, 1992; Saper and Breder, 1994). Additionally,

(+)

(+)

Splanchnic

Brain ischemia

Vasoconstriction and

and hypoxia

hypoxia

OVLT and others: Macrophages, Leukocytes, Microglia (+)

(+)

Reactive oxygen /nitrogen species: Hydroxyl radical (OH ) Nitric oxide (NOx-) prostaglandin

Other factors: Glutamate

E2 (PGE2)

Interleukin-1β (IL-1β), IL-6

others

others

Thermoregulatory center

(-) Heat loss

(+) Heat production

Tumor necrosis factor-α (TNF-α)

cortex

Behavior changes

Fever

Fig. 1. Pathogenic sequence during pyrogenic fever (modified from both Bhattacharyya et al., 2004 and Dinarello, 2004). 1. LPS activated blood monocytes and/or hepatic macrophages (Kupffer cells) and released TFN-α, IL-1β, IL-6, and others 2. Blood-borne pro-inflammatory cytokines could activate meningeal macrophages, cerebral endothelial cells, and macrophages (Kupffer cells), thereby locally producing IL-6 and PGE2 in the organum vasculosum laminal terminalis (OVLT) of the hypothalamus. 3. Increases in brain PGE2 released cAMP and other neurotransmitters triggering thermosensitive neurons in the thermoregulatory center to raise the hypothalamic set point. 4. Neuronal signals to the cortex initiated behavioral thermoregulation. 5. Hypothalamic signals activated autonomic reactions. (+) stimulated; (−) inhibited.

peripherally produced cytokines could activate vagal afferent nerves that innervated the nucleus of the solitary tract in the brain stem, from which catecholaminergic projections led to the hypothalamus (Blatteis and Sehie, 1997; Ericsson et al., 1994; Simons et al., 1998). As evidenced, TNF-α, IL-1β, IL-6 mRNA and protein expressed in microglial cells and/ or neurons in the brain after peripheral LPS (Breder et al., 1994; Buttini and Boddeke, 1995; Gatti and Bartfai, 1993; Laye et al., 1994; Tilders et al., 1994; Vallieres and Rivest, 1997; Van Dam et al., 1992) induced a fever within minutes and required COX-2 and synthesis of PGE2 in the hypothalamus (Dinarello, 2004). In rabbits, intravenous LPS increased the circulating TNF-α (Tsai et al., 2006) and IL-6 (Niu et al., 2009), and core temperature. Systemically administrated LPS or centrally injected TNF-α or IL-6 increased hypothalamic levels of glutamate, hydroxyl radicals, and PGE2 and core temperature in rabbits (Niu et al., 2009; Tsai et al., 2006). 11. General conclusions and prospective perspectives Table 1 summarized the components of the immunoinflammatory system in the thermoregulatory center (hypothalamus) and potential

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Table 1 Components of the immunoinflammatory system in the thermoregulatory center (hypothalamus) and summary of potential antipyretic approaches in pyrogenic fever. 1. Participating cells: Activated microglia and monocytic macrophages (Kluger, 1995; Bhattacharyya et al., 2004; Dinarello, 2004) Activated astrocytes (Cao et al., 1999; Elmquist et al., 1997; Simmons and Murphy, 1993; Van Dam et al., 1996) BBB and endothelial cells (Cao et al., 1999; Elmquist et al., 1997; Van Dam et al., 1996) 2. Major known immunoinflammatory mediators in the hypothalamus: Cytokines (Bhattacharyya et al., 2004; Dinarello, 2004; Niu et al., 2009; Tsai et al., 2006) Glutamate (De Cristóbal et al., 2002; Huang et al., 2001; Huang et al., 2004a,b; Lin et al., 1999) COX-2/PGE2 system (Pepiceli et al., 2002; Huang et al., 2004a,b; Huang et al., 2006; Kao et al., 2007) NO–iNOS system (Gersberger, 1999; Schmidt et al., 1998; Simon, 1998; Steiner and Branco, 2003; 2001; Perkin and Kniss, 1999; Lin and Lin, 1996b; Lin et al., 1997; Roth et al., 1998) Reactive oxygen species system (Huang et al., 2006; Kao et al., 2007; Yang et al., 1995) 3. Potential therapeutic approaches: Anticytokines (e.g., IL-1 receptor antagonist, TNF-α antagonist IL-10) (Kao et al., 2011; Huang et al., 2010; Gourine et al., 1998; Luhesi et al., 1996) NMDA receptor antagonists (Huang et al., 2001, 2004a,b; Lin et al., 1999) iNOS inhibitors (Lin and Lin, 1996a,b) NSAID (Huang et al., 2004a,b; Kao et al., 2007; Riedel et al., 2003) COX-2 inhibitors (Huang et al., 2004a,b, 2006; Kao et al., 2007) Hyperbaric oxygen (Farr et al., 2003; Lin et al., 2005; Niu et al., 2009; Niu et al., 2009; Tsai et al., 2006; Yamashita and Yamashita, 2000) Flavonoid compounds (e.g., baicalin) (Chen et al., 2001; Chou et al., 2003; Lee et al., 2003a; Li et al., 2003; Tsai et al., 2006) NOTES: PGE2 = prostaglandin E2; COX-2 = cyclooxygenase-2; NOx− = nitric oxide metabolites; iNOS = inducible nitric oxide synthase; BBB = blood–brain-barrier; NSAID = nonsteroid anti-inflammatory drugs.

antipyretic approaches in pyrogenic fever. In the table, the major known immunoinflammatory mediators in the hypothalamus contained cytokines, glutamate, PGE2, NOx−, and reactive oxygen species; the principal cells in this part, microglia, macrophages, astrocytes, BBB, and endothelial cells; potential therapeutic approaches in antipyresis, anti-cytokines, NMDA receptor antagonists, iNOS inhibitors, COX-2 inhibitors, hyperbaric oxygen, and flavonoid compounds. In particular, the glutamate–hydroxyl radicals–PGE 2 pathways in the hypothalamus were the target for treating fever. However, the interrelationships among glutamate, reactive oxygen species, NOx−, PGE2, and many neurotransmitters deserve to be clarified. References Ajmone-Cat, M.A., Nicolini, A., Minghetti, L., 2003. Prolonged exposure of microglia to lipopolysaccharide modifies the intracellular signaling pathways and selectively promotes prostaglandin E2 synthesis. J. Neurochem. 87, 1193–1203. Anforth, H.R., Bluthe, R.M., Bristow, A., Hopkins, S., Lenczowski, M.J., Luheshi, G., Lundkvist, J., Michaud, B., Mistry, Y., Van Dam, A.M., Zhen, C., Dantzer, R., Poole, S., Rothwell, N.J., Tilders, F.J., Wollman, E.E., 1998. Biological activity and brain actions of recombinant rat interleukin-1alpha and interleukin-1beta. Eur. Cytokine Netw. 9, 279–288. Asehnoune, K., Strassheim, D., Mitra, S., Kim, J.Y., Abraham, E., 2004. Involvement of reactive oxygen species in Toll-like receptor 4-dependent activation of NF-kappa B. J. Immunol. 172, 2522–2529. Ban, E., Haour, F., Lenstra, R., 1992. Brain interleukin 1 gene expression induced by peripheral lipopolysaccharide administration. Cytokine 4, 48–54. Bandtlow, C.E., Meyer, M., Lindholm, D., Spranger, M., Heumann, R., Thoenen, H., 1990. Regional and cellular codistribution of interleukin 1 beta and nerve growth factor mRNA in the adult rat brain: possible relationship to the regulation of nerve growth factor synthesis. J. Cell Biol. 111, 1707–1711. Benson, R.M., Minter, L.M., Osborne, B.A., Granowitz, E.V., 2003. Hyperbaric oxygen inhibits stimulus-induced proinflammatory cytokine synthesis by human bloodderived monocyte-macrophages. Clin. Exp. Immunol. 134, 57–62. Berg, D.J., Kühn, R., Rajewsky, K., Müller, W., Menon, S., Davidson, N., Grünig, G., Rennick, D., 1995. Interleukin-10 is a central regulator of the response to LPS in murine models of endotoxic shock and the Shwartzman reaction but not endotoxin tolerance. J. Clin. Invest. 96, 2339–2347.

Bhattacharyya, J., Biswas, S., Datta, A.G., 2004. Mode of action of endotoxin: role of free radicals and antioxidants. Curr. Med. Chem. 11, 35–368. Blackwell, T.S., Blackwell, T.R., Holden, E.P., Christman, B.W., Christman, J.W., 1996. In vivo antioxidant treatment suppresses nuclear factor-kappa B activation and neutrophilic lung inflammation. J. Immunol. 157, 1630–1637. Blatteis, C.M., 1992. Role of the OVLT in the febrile response to circulating pyrogens. Prog. Brain Res. 91, 409–412. Blatteis, C.M., Sehie, E., 1997. Fever: how may circulating pyrogens signal the brain? News. Physiol. Soc. 12, 1–9. Breder, C.D., Hazuka, C., Ghayur, T., Klug, C., Huginin, M., Yasuda, K., Teng, M., Saper, C.B., 1994. Regional induction of tumor necrosis factor alpha expression in the mouse brain after systemic lipopolysaccharide administration. Proc. Natl. Acad. U.S.A. 91, 11393–11397. Buttini, M., Boddeke, H., 1995. Peripheral lipopolysaccharide stimulation induces interleukin-1 beta messenger RNA in rat brain microglial cells. Neuroscience 65, 523–530. Cao, C., Matsumura, K., Ozaki, M., Watanabe, Y., 1999. Lipopolysaccharide injected into the cerebral ventricle evokes fever through induction of cyclooxygenase-2 in brain endothelial cells. J. Neurosci. 19, 716–725. Cassina, P., Peluffo, H., Pehar, M., Martinez-Palma, L., Rssia, A., Beckman, J.S., Estevez, A.G., Barbeito, L., 2002. Peroxynitrite triggers a phenotypic transformation in spinal cord astrocytes that induces motor neuron apoptosis. J. Neurosci. Res. 67, 21–29. Chen, Y.C., Shen, S.C., Chen, L.G., Lee, T.J., Yang, L.L., 2001. Wogonin, baicalin, and baicalein inhibition of inducible nitric oxide synthase and cyclooxygenase-2 gene expressions induced by nitric oxide synthase inhibitors and lipopolysaccharide. Biochem. Pharmacol. 61, 1417–1427. Chou, T.C., Chang, L.P., Li, C.Y., Wong, C.S., Yang, S.P., 2003. The anti-inflammatory and analgesic effects of baicalin in carrageenan-evoked thermal hyperalgesia. Anesth. Analg. 97, 1724–1729. Clancy, R., Varenika, B., Huang, W., Ballou, L., Attur, M., Amin, A.R., Abramson, S.B., 2000. Nitric oxide synthase/COX cross-talk: nitric oxide activates COX-1 but inhibits COX-2-derived prostaglandin production. J. Immunol. 165, 1528–1587. Corbett, J.A., Tilton, R.G., Chang, K., Hasan, K.S., Ido, Y., Wang, J.L., Sweetland, M.A., Lancaster Jr., J.R., Williamson, J.R., McDaniel, M.L., 1992. Aminoguanidine, a novel inhibitor of nitric oxide formation, prevents diabetic vascular dysfunction. Diabetes 41, 552–556. D'Acquisto, F., Maiuri, M.C., de Cristofaro, F., Carnuccio, R., 2001. Nitric oxide prevents inducible cyclooxygenase expression by inhibiting nuclear factor-kappa B and nuclear factor-interleukin-6 activation. Naunyn Schmiedebergs Arch. Pharmacol. 364, 157–165. De Cristóbal, J., Cárdenas, A., Lizasoain, I., Leza, J.C., Fernández-Tomé, P., Lorenzo, P., Moro, M.A., 2002. Inhibition of glutamate release via recovery of ATP levels accounts for a neuroprotective effect of aspirin in rat cortical neurons exposed to oxygen-glucose deprivation. Stroke 33, 261–267. Deeb, R.S., Shen, H., Gamss, C., Gavrilova, T., Summers, B.D., Kraemer, R., Hao, G., Gross, S.S., Lainé, M., Maeda, N., Hajjar, D.P., Upmacis, R.K., 2006. Inducible nitric oxide synthase mediates prostaglandin h2 synthase nitration and suppresses eicosanoid production. Am. J. Pathol. 168, 349–362. Dinarello, C.A., 2004. Infection, fever, and exogenous and endogenous pyrogens: some concepts have changed. J. Endotoxin Res. 10, 201–222. Elmquist, J.K., Breder, C.D., Sherin, J.E., Scammell, T.E., Hickey, W.F., Dewitt, D., Saper, C.B., 1997. Intravenous lipopolysaccharide induces cyclooxygenase 2-like immunoreactivity in rat brain periovascular microglia and meningeal macrophages. J. Comp. Neurol. 381, 119–129. Ericcson, A., Kovacs, K.J., Sawchenko, P.E., 1994. A functional anatomical analysis of central pathways subserving the effects of interleukin-1 on stress-related neuroendocrine neurons. J. Neurosci. 14, 897–913. Farr, S.A., Poon, H.F., Dogrukol-Ak, D., Drake, J., Banks, W.A., Eyerman, E., Butterfield, D.A., Morley, J.E., 2003. The antioxidants alpha-lipoic acid and N-acetylcysteine reverse memory impairment and brain oxidative stress in aged SAMP8 mice. J. Neurochem. 84, 1173–1183. Feihl, F., Waeber, B., Liaudet, L., 2001. Is nitric oxide overproduction the target of choice for the management of septic shock? Pharmacol. Ther. 91, 179–213. Feleder, C., Perlik, V., Blatteis, C.M., 2007. Preoptic nitric oxide attenuates endotoxic fever in guinea pigs by inhibiting the POA release of norepinephrine. Am. J. Physiol. Regul. Integr. Comp. Physiol. 293, R1144–R1151. Gatti, S., Bartfai, T., 1993. Induction of tumor necrosis factor-alpha mRNA in the brain after peripheral endotoxin treatment: comparison with interleukin-1 family and interleukin-6. Brain Res. 624, 291–294. Gerstberger, R., 1999. Nitric oxide and body temperature control. News Physiol. Sci. 14, 30–36. Gourine, A.V., Rudolph, K., Tesfaigzi, J., Kluger, M.J., 1998. Role of hypothalamic interleukin-1beta in fever induced by cecal ligation and puncture in rats. Am. J. Physiol. 275, R754–R761. Han, D., Sen, C.K., Roy, S., Kobayashi, M.S., Tritschler, H.J., Packer, L., 1997. Protection against glutamate-induced cytotoxicity in C6 glial cells by thiol antioxidants. Am. J. Physiol. 273, R1771–R1778. Hashimoto, M., Ueno, T., Iriki, M., 1994. What roles does the organum vasculosum laminae terminalis play in fever in rabbits? Pflugers Arch Eur. J. Physiol. 429, 50–57. Hori, T., Shibata, M., Nakashima, T., Yamasaki, M., Asami, A., Asami, T., Koga, H., 1988. Effects of interleukin-1 and arachidonate on the preoptic and anterior hypothalamic neurons. Brain Res. Bull. 20, 75–82. Howard, M., O'Garra, A., 1992. Biological properties of interleukin-10. Immunol. Today 13, 198–200. Huang, K.C., 1999. Antibacterial, antiviral, and antifungal herbs. In: Huang, K.C. (E.d.). The Pharmacology of Chinese Herbs, CRC press, Boca Raton, Florida, pp. 385–386.

C.-C. Hou et al. / European Journal of Pharmacology 667 (2011) 6–12 Huang, K.F., Huang, W.T., Lin, K.C., Lin, M.T., Chang, C.P., 2010. Interleukin-1 receptor antagonist inhibits the release of glutamate, hydroxyl radicals, and prostaglandin E2 in the hypothalamus during pyrogen-induced fever in rabbits. Eur. J. Pharmacol. 629, 125–131. Huang, W.T., Lin, M.T., Chang, C.P., 2006. A NMDA receptor-dependent hydroxyl radical pathway in the rabbit hypothalamus may mediate lipopolysaccharide fever. Neuropharmacology 50, 504–511. Huang, W.T., Lin, M.T., Won, S.J., 1997. Staphylococcal enterotoxin A-induced fever is associated with increased circulating levels of cytokines in rabbits. Infect. Immun. 65, 2656–2662. Huang, W.T., Niu, K.C., Chang, C.K., Lin, M.T., Chang, C.P., 2008. Curcumin inhibits the increase of glutamate, hydroxyl radicals and PGE2 in the hypothalamus and reduces fever during LPS-induced systemic inflammation in rabbits. Eur. J. Pharmacol. 593, 105–111. Huang, W.T., Tsai, S.M., Lin, M.T., 2001. Involvement of brain glutamate release in pyrogenic fever. Neuropharmacology 41, 811–818. Huang, W.T., Wang, J.J., Lin, M.T., 2004a. Antipyretic effect of acetaminophen by inhibition of glutamate release after staphylococcal enterotoxin A fever in rabbits. Neurosci. Lett. 355, 33–36. Huang, W.T., Wang, J.J., Lin, M.T., 2004b. Cyclooxygenase inhibitors attenuate augmented glutamate release in organum vasculosum laminae terminalis and fever induced by staphylococcal enterotoxin A. J. Pharmacol. Sci. 94, 192–196. Inamoto, Y., Okuno, F., Saito, K., Tanaka, Y., Watanabe, K., Morimoto, I., Yamashita, U., Eto, S., 1991. Effect of hyperbaric oxygenation on macrophage function in mice. Biochem. Biophys. Res. Commun. 179, 886–891. Jenkins, J.K., Malyak, M., Arend, W.P., 1994. The effects of interleukin-10 on interleukin1 receptor antagonist and interleukin-1 beta production in human monocytes and neutrophils. Lymphokine Cytokine Res. 13, 47–54. Kao, C.H., Huang, W.T., Lin, M.T., Wu, W.S., 2011. Central interleukin-10 attenuated lipopolysaccharide-induced changes in core temperature and hypothalamic glutamate, hydroxyl radicals and prostaglandin-E(2). Europ. J. Pharmacol. 654, 187–193. Kao, C.H., Kao, T.Y., Huang, W.T., Lin, M.T., 2007. Lipopolysaccharide- and glutamateinduced hypothalamic hydroxyl radical elevation and fever can be suppressed by N-methyl-D-aspartate-receptor antagonists. J. Pharmacol. Sci. 104, 130–136. Kelner, M.J., Bagnell, R., Hale, B., Alexander, N.M., 1988. Potential of methylene blue to block oxygen radical generation in reperfusion injury. Basic Life Sci. 49, 895–898. Klir, J.J., McClellan, J.L., Kluger, M.J., 1994. Interleukin-1 beta causes the increase in anterior hypothalamic interleukin-6 during LPS-induced fever in rats. Am. J. Physiol. 266, R1845–R1848. Kluger, M.J., 1995. Fever: role of pyrogens and cryogens. Physiol. Rev. 71, 93–127. Krakauer, T., Li, B.G., Young, H.A., 2001. The flavonoid baicalin inhibits superantigeninduced inflammatory cytokines and chemokines. FEBS Letter 500, 52–55. Kudchodkar, B.J., Pierce, A., Dory, L., 2007. Chronic hyperbaric oxygen treatment elicits an anti-oxidant response and attenuates atherosclerosis in apoE knockout mice. Atheroscleresis 193, 28–35. Kudchodkar, B.J., Wilson, J., Lacko, A., Dory, L., 2000. Hyperbaric oxygen reduces the progression and accelerates the regression of atherosclerosis in rabbits. Arterioscler. Thromb. Vasc. Biol. 20, 1637–1643. Lahat, N., Bitterman, H., Yaniv, N., Kinarty, A., Bitterman, N., 1995. Exposure to hyperbaric oxygen induces tumour necrosis factor-alpha (TNF-alpha) secretion from rat macrophages. Clin. Exp. Immunol. 102, 655–659. Laye, S., Parnet, P., Goujon, E., Dantzer, R., 1994. Peripheral administration of lipopolysacchride induces the expression of cytokine transcripts in the brain and pituitary of mice. Brain Res. Mol. Brain Res. 27, 157–162. Ledeboer, A., Binnekade, R., Brevé, J.J., Bol, J.G., Tilders, F.J., Van Dam, A.M., 2002. Sitespecific modulation of LPS-induced fever and interleukin-1 beta expression in rats by interleukin-10. Am. J. Physiol. Regul. Integr. Comp. Physiol. 282, R1762–R1772. Lee, H.H., Yang, L.L., Wang, C.C., Hu, S.Y., Chang, S.F., Lee, Y.H., 2003a. Differential effects of natural polyphenols on neuronal survival in primary cultured central neurons against glutamate- and glucose deprivation-induced neuronal death. Brain Res. 986, 103–113. Lee, J.J., Huang, D.Z., Liao, J.F., Lin, M.T., 2003b. Blocking NF-kappa B activation may be an effective strategy in the fever therapy. Jpn. J. Physiol. 53, 367–375. Leon, L.R., Kozak, W., Rudolph, K., Kluger, M.J., 1999. An antipyretic role for interleukin10 in LPS fever in mice. Am. J. Physiol. 276, R81–R89. Li, H., Wang, H., Chen, J.H., Wang, L.H., Zhang, H.S., Fan, Y., 2003. Determination of amino acid neurotransmitters in cerebral cortex of rats administered with baicalin prior to cerebral ischemia by capillary electrophoresis-laser-induced fluorescence detection. J. Chromatogr. B Analyt. Technol. Biomed. Life Sci. 788, 93–101. Li, S., Ballou, L.R., Morham, S.G., Blatteis, C.M., 2001. Cyclooxygenase-2 mediates the febrile response of mice to interleukin-1 beta. Brain Res. 910, 163–173. Lin, H.C., Wan, F.J., Kang, B.H., Wu, C.C., Tseng, C.J., 1999. Systemic administration of lipopolysaccharide induces release of nitric oxide and glutamate and c-fos expression in the nucleus tractus solitarii of rats. Hypertension 33, 1218–1224. Lin, H.C., Wan, F.J., Wu, C.C., Tung, C.S., Wu, T.H., 2005. Hyperbaric oxygen protects against lipopolysaccharide-stimulated oxidative stress and mortality in rats. Eur. J. Pharmacol. 508, 249–254. Lin, J.H., Lin, M.T., 1996a. Inhibition of nitric oxide synthase or cyclooxygenase pathways in organum vasculosum lamiane terminalis attenuates interleukin-1β fever in rabbits. Neurosci. Lett. 208, 55–158. Lin, J.H., Lin, M.T., 1996b. Nitric oxide synthase–cyclooxygenase pathways in organum vasoculosum laminae terminalis: possible role in pyrogenic fever in rabbit. Br. J. Pharmacol. 118, 179–185. Lin, M.T., Lin, J.H., 2000. Involvement of tyrosine hydroxylase in pyrogenic fever exerted by NOS pathways in organum vasculosum laminae terminalis. Neuropharmacology 39, 347–351.

11

Lin, M.T., Lin, J.H., Yang, Y.L., 1997. Dexamethasone administered into organum vasculosum laminase terminalis of rabbits induced antipyresis via inhibiting nitric oxide pathway in situ. Neurosci. Lett. 230, 53–56. Luheshi, G., Miller, A.J., Brouwer, S., Dascombe, M.J., Rothwell, N.J., Hopkins, S.J., 1996. Interleukin-1 receptor antagonist inhibits endotoxin fever and systemic interleukin-6 induction in the rat. Am. J. Physiol. 270, E91–E95. Mathai, L.M., Arnold, I., Febbraio, M.A., Mckinley, M.J., 2004. Central blockade of nitric oxide synthase induces hyperthermia that is prevented by indomethacin in rats. J. Therm. Biol. 29, 401–405. Miller, A.J., Hopkins, S.J., Luheshi, G.N., 1997. Sites of action of IL-1 in the development of fever and cytokine responses to tissue inflammation in the rat. Br. J. Pharmacol. 120, 1274–1276. Molina-Holgado, F., Guaza, C., 1996. Endotoxin administration induced differential neurochemical activation of the rat brain stem nuclei. Brain Res. Bull. 40, 151–156. Moore, K.W., de Waal Malefyt, R., Coffman, R.L., O'Garra, A., 2001. Interleukin-10 and the interleukin-10 receptor. Annu. Rev. Immunol. 19, 683–765. Nguyen, K.T., Deak, T., Owens, S.M., Kohno, T., Fleshner, M., Watkins, L.R., Maier, S.F., 1998. Exposure to acute stress induces brain interleukin-1beta protein in the rat. J. Neurosci. 18, 2239–2246. Niu, K.C., Huang, W.T., Lin, M.T., Huang, K.F., 2009. Hyperbaric oxygen causes both antiinflammation and antipyresis in rabbits. Fur. J. Pharmacol. 6060, 240–245. Oberholzer, A., Oberholzer, C., Moldawer, L.L., 2002. Interleukin-10: a complex role in the pathogenesis of sepsis syndromes and its potential as an anti-inflammatory drug. Crit. Care Med. 30, S58–S63. Oh, G.S., Pae, H.O., Choi, B.M., Seo, E.A., Kim, D.H., Shin, M.K., Kim, J.D., Kim, J.B., Chung, H.T., 2004. 20(S)-Protopanaxatriol, one of ginsenoside metabolites, inhibits inducible nitric oxide synthase and cyclooxygenase-2 expressions through inactivation of nuclear factor-kappaB in RAW 264.7 macrophages stimulated with lipopolysaccharide. Cancer Lett. 205, 23–29. Pedersen, B.K., Steensberg, A., Schjerling, P., 2001. Exercise and interleukin-6. Curr. Opin. Hematol. 8, 137–141. Pepicelli, O., Fedele, E., Berardi, M., Raiteri, M., Levi, G., Greco, A., Ajmone-Cat, M.A., Minghetti, L., 2005. Cyclo-oxygenase-1 and -2 differently contribute to prostaglandin E2 synthesis and lipid peroxidation after in vivo activation of N-methyl-D-aspartate receptors in rat hippocampus. J. Neurochem. 93, 1561–1567. Pepicelli, O., Fedele, E., Bonanno, G., Raiteri, M., Ajmone-Cat, M.A., Greco, A., Levi, G., Minghetti, L., 2002. In vivo activation of N-methyl-D-aspartate receptors in the rat hippocampus increases prostaglandin E(2) extracellular levels and triggers lipid peroxidation through cyclooxygenase-mediated mechanisms. J. Neurochem. 81, 1028–1034. Perkins, D.J., Kniss, D.A., 1999. Blockade of nitric oxide formation down-regulates cyclooxygenase-2 and decreases PGE2 biosynthesis in macrophages. J. Leukoc. Biol. 65, 792–799. Rangel-Frausto, M.S., Pittet, D., Costigan, M., Hwang, T., Davis, C.S., Wenzel, R.P., 1995. The natural history of the systemic inflammatory response syndrome (SIRS). A prospective study. JAMA 273, 117–123. Rees, D.D., Cellek, S., Palmer, R.M., Moncada, S., 1990. Dexamethasone prevents the induction by endotoxin of a nitric oxide synthase and the associated effects on vascular tone: an insight into endotoxin shock. Biochem. Biophys. Res. Commun. 173, 541–547. Rennick, D.M., Fort, M.M., Davidson, N.J., 1997. Studies with IL-10−/− mice: an overview. J. Leukoc. Biol. 61, 389–396. Riedel, W., 1997. Antipyretic role of nitric oxide during endotoxin-induced fever in rabbits. Int. J. Tissue React. 19, 171–178. Riedel, W., Lang, U., Oetjen, U., Schlapp, U., Shibata, M., 2003. Inhibition of oxygen radical formation by methylene blue, aspirin, or alpha-lipoic acid, prevents bacterial-lipopolysaccharide-induced fever. Mol. Cell. Biochem. 247, 83–94. Roth, J., Störr, B., Voigt, K., Zeisberger, E., 1998. Inhibition of nitric oxide synthase results in a suppression of interleukin-1beta-induced fever in rats. Life Sci. 22, 345–350. Said, S.I., Berisha, H.I., Pakbaz, H., 1996. Excitotoxicity in the lung: N-methyl-D-aspartateinduced, nitric oxide-dependent, pulmonary edema is attenuated by vasoactive intestinal peptide and by inhibitors of poly (ADP-ribose) polymerase. Proc. Natl. Acad. Sci. USA 93, 4688–4692. Saper, C.B., Breder, C.D., 1994. The neurologic basis of fever. N. Engl. J. Med. 330, 1880–1886. Schmid, H.A., Riedel, W., Simon, E., 1998. Role of nitric oxide in temperature regulation. Prog. Brain Res. 115, 25–49. Shao, D.Z., Lee, J.J., Huang, W.T., Liao, J.F., Lin, M.T., 2004. Inhibition of nuclear factorkappa B prevents staphylococcal enterotoxin A-induced fever. Mol. Cell. Biochem. 262, 177–185. Shi, X., Ding, M., Dong, Z., Chen, F., Ye, J., Wang, S., Leonard, S.S., Castranova, V., Vallyathan, V., 1999. Antioxidant properties of aspirin: characterization of the ability of aspirin to inhibit silica-induced lipid peroxidation, DNA damage, NF-kappaB activation, and TNF-alpha production. Mol. Cell. Biochem. 199, 93–102. Shieh, D.E., Liu, L.T., Lin, C.C., 2000. Antioxidant and free radical scavenging effects of baicalein, baicalin, and wogonin. Anticancer 20, 2861–2865. Simmons, M.L., Murphy, S., 1993. Cytokines regulate L-arginine-dependent cyclic GMP production in rat glial cells. Eru. J. Neurosci. 5, 825–831. Simon, E., 1998. Nitric oxide as a peripheral and central mediator in temperature regulation. Amino Acids 14, 87–93. Simons, C.T., Kulchitsky, V.A., Sugimoto, N., Homer, L.D., Szekely, M., Romanovsky, A.A., 1998. Signaling the brain in systemic inflammation: which vagal branch is involved in fever genesis? Am. J. Physiol. 275, R63–R68. Soszynski, D., 2001. The inhibition of nitric oxide synthase suppresses LPS- and psychological-stress-induced fever in rats. Physiol. Behav. 72, 65–72. Steiner, A.A., Branco, L.G., 2001. Nitric oxide in the regulation of body temperature and fever. J. Thermal Boil. 26, 325–330.

12

C.-C. Hou et al. / European Journal of Pharmacology 667 (2011) 6–12

Steiner, A.A., Branco, L.G., 2003. Fever and anapyrexia in systemic inflammation: intracellular signaling by cyclic nucleotides. Front. Biosci. 8, 1398–1408. Stitt, J.T., 1985. Evidence for the involvement of the organum vasculosum laminae terminalis in the febrile response of rabbits and rats. J. Physiol. (London). 368, 501–511. Strle, K., Zhou, J.H., Shen, W.H., Broussard, S.R., Johnson, R.W., Freund, G.G., Dantzer, R., Kelley, K.W., 2001. Interleukin-10 in the brain. Crit. Rev. Immunol. 21, 427–449. Szabó, C., Thiemermann, C., Wu, C.C., Perretti, M., Vane, J.R., 1994. Attenuation of the induction of nitric oxide synthase by endogenous glucocorticoids accounts for endotoxin tolerance in vivo. Proc Natl Acad Sci. USA 91, 271–275. Tanaka, Y., Igimi, S., Amano, F., 2001. Inhibition of prostaglandin synthesis by nitric oxide in RAW 264.7 macrophages. Arch. Biochem. Biophys. 391, 207–217. Thiemermann, C., 1997. Nitric oxide and septic shock. Gen. Pharmacol. 29, 159–166. Tilders, F.J., DeRijk, R.H., van Dam, A.M., Vinent, V.A., Schotanus, K., Persoons, J.H., 1994. Activation of the hypothalamic–pituitary–adrenal axis by bacterial endotoxins: routes and intermediate signals. Psychoneuroendocrinology 19, 209–232. Tsai, C.C., Lin, M.T., Wang, J.J., Liao, J.F., Huang, W.T., 2006. The antipyretic effects of baicalin in lipopolysaccharide-evoked fever in rabbits. Neuropharmacology 51, 709–717. Vallieres, L., Rivest, S., 1997. Regulation of the genes encoding interleukin-6, its receptor, and gp130 in the rat brain in response to the immune activator lipopolysaccharide and the proinflammatory cytokine interleukin-1beta. J. Neurochem. 69, 1668–1683. van Dam, A.M., Brouns, M., Louisse, S., Berkenbosch, F., 1992. Appearance of interleukin1 in macrophages and in ramified microglia in the brain of endotoxin-treated rats: a pathway for the induction of non-specific symptoms of sickness? Brain Res. 588, 291–296. Van Dam, A.M., De Vries, H.E., Kuiper, J., Zijlstra, F.J., De Boer, A.G., Tilders, F.J., Berkenbosch, F., 1996. Interleukin-1 receptors on rat brain endothelial cells: a role in neuroimmune interaction? FASEB J. 10, 351–356.

Wang, T., Qin, L., Liu, B., Liu, Y., Wilson, B., Eling, T.E., Langenbach, R., Taniura, S., Hong, J.S., 2004. Role of reactive oxygen species in LPS-induced production of prostaglandin E2 in microglia. J. Neurochem. 88, 939–947. Ward, H., Vigues, S., Poole, S., Bristow, A.F., 2001. The rat interleukin 10 receptor: cloning and sequencing of cDNA coding for the alpha-chain protein sequence, and demonstration by western blotting of expression in the rat brain. Cytokine 15, 237–240. Weihrauch, D., Riedel, W., 1997. Nitric oxide (NO) and oxygen radicals, but not prostaglandins, modulate fever. Ann. N. Y. Acad. Sci. 813, 373–382. Weisz, G., Lavy, A., Adir, Y., Melamed, Y., Rubin, D., Eidelman, S., Pollack, S., 1997. Modification of in vivo and in vitro TNF-alpha, IL-1, and IL-6 secretion by circulating monocytes during hyperbaric oxygen treatment in patients with perianal Crohn's disease. J. Clin. Immunol. 17, 154–159. Wu, C.C., Croxtall, J.D., Perretti, M., Bryant, C.E., Thiemermann, C., Flower, R.J., Vane, J.R., 1995. Lipocortin 1 mediates the inhibition by dexamethasone of the induction by endotoxin of nitric oxide synthase in the rat. Proc Natl Acad Sci. USA 92, 3473–3477. Wu, J.Y., Tsou, M.Y., Chen, T.H., Chen, S.J., Tsao, C.M., Wu, C.C., 2008. Therapeutic effects of melatonin on peritonitis-induced septic shock with multiple organ dysfunction syndrome in rat. J. Pineal Res. 45, 106–116. Yamashita, M., Yamashita, M., 2000. Hyperbaric oxygen treatment attenuates cytokine induction after massive hemorrhage. Am. J. Physiol. Endocrinol Metal 278, E811–E816. Yang, C.S., Tsai, P.J., Lin, N.N., Liu, L., Kuo, J.S., 1995. Elevated extracellular glutamate levels increased the formation of hydroxyl radical in the striatum of anesthetized rat. Free Rad. Biol. Med. 19, 453–459.