Relationship of EP1-4 prostaglandin receptors with rat hypothalamic cell groups involved in lipopolysaccharide fever responses

Oka, Takahiro; Oka, Kae; Scammell, Thomas E.; Lee, Charlotte; Kelly, Joseph F.; Nantel, F.; Elmquist, Joel K.; Saper, Clifford B.

doi:10.1002/1096-9861(20001204)428:1<20::aid-cne3>3.0.co;2-x

Cited by 132 publications

(87 citation statements)

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“…Serotonin has been shown to be involved in LPS-induced anorexia in rats (17), and it is abundant in neurons originating from the midbrain dorsal raphe nucleus and projecting to the hypothalamus, including the paraventricular nucleus. A clear colocalization of c-fos and EP4 mRNA in the paraventricular nucleus and other hypothalamic nuclei has been found after LPS administration in rats (30), and inhibition of PG synthesis by administration of ketorolac abolished the IL-1␤-induced c-fos expression and increase of EP4 mRNA expression in the paraventricular nucleus (42). Taken together, these data suggest a role of EP4 receptors in LPS-and cytokine-induced phenomena, such as fever and anorexia.…”

Section: Discussionsupporting

confidence: 54%

A role for cyclooxygenase-2 in lipopolysaccharide-induced anorexia in rats

Lugarini¹,

Hrupka²,

Schwartz

et al. 2002

American Journal of Physiology-Regulatory, Integrative and Comp

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tion attenuated anorexia after lipopolysaccharide (LPS) administration, we tested the ability of resveratrol (2.5, 10, and 40 mg/kg) and NS-398 (2.5, 10, and 40 mg/kg), selective inhibitors of the two COX isoforms COX-1 and -2, respectively, to attenuate LPS (100 g/kg ip)-induced anorexia. NS-398 (10 and 40 mg/kg) administered with LPS at lights out attenuated LPS-induced anorexia, whereas resveratrol at all doses tested did not. Because prostaglandin (PG) E2 is considered the major metabolite synthesized by COX, we measured plasma and cerebrospinal fluid (CSF) PGE2 levels after LPS administration. LPS induced a time-dependent increase of PGE2 in CSF but not in plasma. NS-398 (5, 10, and 40 mg/kg) blocked the LPS-induced increase in CSF PGE2, whereas resveratrol (10 mg/kg) did not. These results support a role of COX-2 in mediating the anorectic response to peripheral LPS and point at PGE2 as a potential neuromodulator involved in this response.NS-398; resveratrol; prostaglandin E2; food intake; fever LIPOPOLYSACCHARIDE (LPS) and proinflammatory cytokines [e.g., interleukin (IL)-1␤, IL-6, and tumor necrosis factor-␣] induce anorexia and fever (32), two phenomena partly independent of each other. Brain areas involved in feeding and body temperature regulation are activated (5, 40) after peripheral administration of LPS and cytokines. This can be accomplished through neural and/or humoral communications with the central nervous system (CNS). Vagal afferents have been implicated in some of the behavioral effects induced by peripheral LPS or cytokines (3, 16). In our hands, however, subdiaphragmatic vagal deafferentation, alone or in combination with celiac-superior mesenteric ganglionectomy, did not attenuate the anorectic response to peripheral LPS, muramyl dipeptide, and IL-1␤ (33). An alternative route of communication between the periphery and the CNS involves cytokine and LPS receptors on the surface of the cerebral endothelial cells of the brain-blood barrier (1, 39) and subsequent mediators such as prostaglandins (PGs) (6). PGs are synthesized by cyclooxygenase (COX), an enzyme that exists in two different isoforms. COX-1 is constitutively expressed in many tissues, mainly outside the brain, and its levels are relatively insensitive to inflammatory stimulation. COX-1 is scarcely expressed in capillary endothelial and perivascular glial cells (13). COX-2, on the other hand, is constitutively expressed at low levels in neurons of the cortex, hippocampus, and amygdala, but not in the cells of the cerebral vasculature (34). COX-2 is strongly induced in brain vasculature, however, by LPS and IL-1␤ (12,22,34). LPS or cytokines (31) transiently enhance COX-2 mRNA and protein levels via activation of nuclear factor-B (2, 23).In our hands, nonselective pharmacological inhibition of COX by administration of indomethacin or paracetamol attenuated the pyretic and hypophagic effects of peripheral 27). Selective inhibition of COX-2 blocks LPS-induced fever (7). Use of selective inhibitors for COX-1 and -2 could not establ...

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Section: Discussionsupporting

confidence: 54%

A role for cyclooxygenase-2 in lipopolysaccharide-induced anorexia in rats

Lugarini¹,

Hrupka²,

Schwartz

et al. 2002

American Journal of Physiology-Regulatory, Integrative and Comp

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“…Because of these multiple receptors, PGE 2 commonly has versatile and often opposing actions in many tissues and cells (reviewed in Breyer et al 2001.). In situ probing, immunohistochemistry, and c-fos expression experiments in rats have shown that the EP 1 , EP 2 , and EP 3 receptors are expressed in cerebral cortex and hippocampus (Sugimoto et al 1994;Bhattacharya et al 1998;Ek et al 2000;Nakamura et al 2000;Oka et al 2000), regions of brain affected by the diseases mentioned above. Of these, the EP 3 receptor is predominantly expressed by neurons (Sugimoto et al 1994;Dumont et al 1998;Ek et al 2000;Nakamura et al 2000), whereas the EP 1 and EP 2 receptors are expressed by glia Caggiano and Kraig 1999).…”

mentioning

confidence: 99%

Neuronal oxidative damage from activated innate immunity is EP₂ receptor‐dependent

Montine¹,

Milatović²,

Gupta

et al. 2002

Journal of Neurochemistry

127

143

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Increase in prostaglandin (PG) E 2 levels and oxidative damage are associated with diseases of brain that involve activation of innate immunity. We tested the hypothesis that cerebral oxidative damage resulting from activation of innate immunity with intracerebroventricular (icv) lipopolysaccharide (LPS) is dependent on PGE 2 -mediated signaling. We measured two quantitative in vivo biomarkers of lipid peroxidation: F 2 -isoprostanes (IsoPs) that derive from arachidonic acid (AA) that is uniformly distributed in all cell types in brain, and F 4 -neuroprostanes (NeuroPs) that derive from docosahexaenoic acid (DHA) that is highly concentrated in neuronal membranes. LPS stimulated delayed elevations in cerebral F 2 -IsoPs and F 4 -NeuroPs that were completely suppressed by indomethacin or ibuprofen pre-treatment. LPS-induced cerebral oxidative damage was abolished by disruption of subtype 2 receptor for PGE 2 (EP 2 ). In contrast, initial oxidative damage from icv kainic acid (KA) was more rapid than with LPS also was completely suppressed by indomethacin or ibuprofen pre-treatment but was independent of EP 2 receptor activation. The protective effect of deleting the EP 2 receptor was not associated with changes in cerebral eicosaniod production, but was partially related to reduced induction of nitric oxide synthase (NOS) activity. These results suggest the EP 2 receptor as a therapeutic target to limit oxidative damage from activation of innate immunity in cerebrum. Keywords: excitotoxicityinnate immunity, isoprostanes, neuroprostanes, NSAIDs, prostaglandin E 2 . J. Neurochem. Coincident cerebral oxidative damage and elevated prostaglandin (PG) E 2 levels are characteristic of several degenerative and destructive diseases of brain including stroke, epilepsy, Alzheimer's disease, HIV-associated dementia, and Creutzfeldt-Jakob disease (Griffin et al. 1994;Pace and Leaf 1995;Montine et al. 1998Montine et al. , 1999aMontine et al. , 1999bPaoletti et al. 1998;Thornhill and Smith 1998;Minghetti et al. 2000). PGE 2 potently modulates neurodegeneration and oxidative damage in several model systems; however, some have concluded that PGE 2 is neuroprotective while others have proposed that PGE 2 promotes neuronal damage (Akaike et al. 1994;Cazevielle et al. 1994;Minghetti et al. 1997aMinghetti et al. , 1997bMinghetti et al. , 1998Bezzi et al. 1998; Kraig 1998, 1999;Levi et al. 1998;Paoletti et al. 1998;Thornhill and Smith 1998;Aloisi et al. 1999;Kelley et al. 1999;Sanzgiri et al. 1999;Drachman and Rothstein 2000;Hewett et al. 2000). Most in vivo studies suggest that PGE 2 contributes to oxidative damage and neurodegeneration, while most in vitro studies indicate that PGE 2 has neuroprotective activity. There are several possible explanations for these disparate results.Cell culture models typically are limited by use of supraphysiologic concentrations of PGE 2 , by the absence of some of the PGE 2 receptor (EP) subtypes, and by disruption of paracrine interactions between neurons and glia. In vivo studies have rel...

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“…In the brain, EPs were mostly found to be associated with neuronal and glial cells (Batshake et al, 1995;Ek et al, 2000;Nakamura et al, 2000;Oka et al, 2000;Sugimoto et al, 1993;Zhang and Rivest, 1999). However, EP2 and EP4 were but recently reported to be expressed in the endothelium, and to be induced after stroke .…”

Section: Pge2 Receptorsmentioning

confidence: 99%

“…Accordingly, the four EPs have distinct distribution patterns (Batshake et al, 1995;Ek et al, 2000;Nakamura et al, 2000;Oka et al, 2000;Sugimoto et al, 1993;Zhang and Rivest, 1999). Hence they are not restricted to the typical CNS immune-responsive regions Ericsson et al, 1994;Herkenham et al, 1998) but are also present in structures like the cerebral cortex, hippocampus, thalamus or cerebellar nuclei.…”

Section: The Bbb As An Interface For Immune Signal-transductionmentioning

confidence: 99%

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Talking to the Brain at the Blood-Brain Barrier through Inflammation-Induced Prostaglandin E2

Vasilache¹

2015

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The immune-to-brain signaling is a critical survival factor when the body is confronted by pathogens, and in particular by microorganisms. During infections, the ability of the immune system to engage the central nervous system (CNS) in the management of the inflammatory response is just as important as its ability to mount a specific immune response against the pathogen, since the CNS can provide a systemic negative feed-back to the immune activation by release of stress hormones and also can prioritize the usage of the energy resources by the vital organs. Prostaglandin E2 (PGE2) and pro-inflammatory cytokines were among the first mediators to be identified to participate in the immune-to-brain signaling, a process that is clinically recognized by the development of manifestations of common illness such as fever, anorexia, decreased social interactions, lethargy, sleepiness, and hyperalgesia.In this thesis the contribution of PGE2 to the immune-to-brain signaling was further characterized at the blood-brain-barrier (BBB) and in the anterior preoptic area (POA) of the hypothalamus (i.e. the thermoregulatory region or, in sickness, the fever generating region).BBB is the major interface region between peripheral circulating cytokines and the neuronal parenchyma and a critical source of PGE2. Using chimeric mice lacking the inducible enzyme for PGE2 synthesis, microsomal PGE synthase-1 (mPGES-1), in either hematopoietic or nonhematopoietic cells, we demonstrate in paper I that brain endothelial cells are the critical source of PGE2 in BBB during peripheral inflammation. For the demonstration of the mPGES-1 expression in the BBB cells we developed in paper I a method for enzymatic dissociation of these cells, followed by fluorescence activated cell sorting (FACS). Using the same method, we show in paper II that the BBB response to immune stimuli is towards an increased production of PGE2 in endothelial cells and an increased sensitivity of these cells for proinflammatory cytokines. These changes are supported by decreased PGE2 degradation and decreased synthesis of other prostanoids in perivascular macrophages, which hence respond in concordance with the endothelial cells in enhancing PGE2 signaling.Once released in the neuronal tissue, PGE2 has been shown to be critical for the fever response by acting on the type 3 PGE2 receptors (EP3) within POA. By laser capture microdissection (LCM) we extracted the EP3 receptor expressing region in POA, defined by in situ hybridization histochemistry, from mouse brain sections. We demonstrate in paper III that the predominant subtypes of the EP3 receptor in POA are EP3α and EP3γ. In paper IV we further analyze the effect of PGE2 on the LCM dissected EP-rich POA using gene expression microarrays. We demonstrate that PGE2 has a limited effect on the gene expression changes within POA, suggesting that the neuronal activity is modulated by PGE2 in a transcriptionindependent manner and that the profound gene expression changes that are seen in the CNS during inflammation ...

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Relationship of EP1-4 prostaglandin receptors with rat hypothalamic cell groups involved in lipopolysaccharide fever responses

Cited by 132 publications

References 50 publications

A role for cyclooxygenase-2 in lipopolysaccharide-induced anorexia in rats

A role for cyclooxygenase-2 in lipopolysaccharide-induced anorexia in rats

Neuronal oxidative damage from activated innate immunity is EP₂ receptor‐dependent

Talking to the Brain at the Blood-Brain Barrier through Inflammation-Induced Prostaglandin E2

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Relationship of EP1-4 prostaglandin receptors with rat hypothalamic cell groups involved in lipopolysaccharide fever responses

Cited by 132 publications

References 50 publications

A role for cyclooxygenase-2 in lipopolysaccharide-induced anorexia in rats

A role for cyclooxygenase-2 in lipopolysaccharide-induced anorexia in rats

Neuronal oxidative damage from activated innate immunity is EP2 receptor‐dependent

Talking to the Brain at the Blood-Brain Barrier through Inflammation-Induced Prostaglandin E2

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Product

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Neuronal oxidative damage from activated innate immunity is EP₂ receptor‐dependent