Effect of Acute Systemic Inflammatory Response and Cytokines on the Transcription of the Genes Encoding Cyclooxygenase Enzymes (COX‐1 and COX‐2) in the Rat Brain

Lacroix, Steve; Rivest, Serge

doi:10.1046/j.1471-4159.1998.70020452.x

Cited by 249 publications

(150 citation statements)

References 76 publications

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“…Prominent induction of COX-2 mRNA has been noted specifically within the parenchyma of the hypothalamic paraventricular nucleus (15). In accord with the effects we observed on food intake after LPS administration, COX-2 has also been demonstrated to be the COX isoform essential for generation of the febrile response after systemic inflammation (20).…”

Section: Discussionsupporting

confidence: 82%

COX-2 inhibition attenuates anorexia during systemic inflammation without impairing cytokine production

Johnson

Vogt

Burney

et al. 2002

American Journal of Physiology-Endocrinology and Metabolism

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Anorexia and weight loss are frequent complications of acute and chronic infections and result from induction of cytokines, prostaglandins, and other inflammatory mediators that are critical for pathogen elimination. Selective attenuation of the hypophagic response to infection and maintenance of the production of factors essential for infection control would be a useful addition to antimicrobial therapy in the treatment of human disease. Here, we evaluate the relative contribution of cyclooxygenase (COX)-1- and COX-2-derived prostaglandins to anorexia and weight loss precipitated by systemic immune activation by lipopolysaccharide (LPS). Using COX isoform-selective pharmacological inhibitors and gene knockout mice, we found that COX-2 inhibition during LPS-induced inflammation results in preserved food intake and maintenance of body weight, whereas COX-1 inhibition results in augmented and prolonged weight loss. Regulation of neuropeptide Y, corticotropin-releasing hormone, leptin, and interleukin-6 does not change as a function of COX-2 inhibition after LPS administration. Our data implicate COX-2 inhibition as a therapeutic target to maintain nutritional status while still allowing a normal cytokine response during infection.

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Section: Discussionsupporting

confidence: 82%

COX-2 inhibition attenuates anorexia during systemic inflammation without impairing cytokine production

Johnson

Vogt

Burney

et al. 2002

American Journal of Physiology-Endocrinology and Metabolism

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“…In this study, we found low brain uptake of [ 11 C]rofecoxib (SUV: 0.26±0.09), supposedly reflecting the low expression levels of COX-2 in the brain. In situ hybridization studies have demonstrated that constitutively expressed COX-2 mRNA is not homogeneously distributed in the brain but predominantly located in cortical areas and hippocampus [17,18]. In this study, we showed that the [ 11 C]rofecoxib distribution corresponds with the known distribution of COX-2 mRNA.…”

Section: Discussionsupporting

confidence: 52%

“…This NS398-induced change in distribution pattern was accompanied by a significant reduction (P b.01) in [ 11 C]rofecoxib accumulation in cingulate/frontopolar cortex (−41%, P=.01), whereas the reduction in hippocampus almost reached significance (−33%, P=.06). These brain regions are known to express significant basal levels of COX-2 in healthy animals [17,18]. Prolongation of the interval between NS398 administration and tracer injection from 5 to 60 min did not result in a significantly greater blockade of tracer binding, indicating that NS398 binding to COX-2 is virtually complete within 5 min.…”

Section: [ 11 C]rofecoxib Distribution In Healthy Rat Brainmentioning

confidence: 90%

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Evaluation of [11C]rofecoxib as PET tracer for cyclooxygenase 2 overexpression in rat models of inflammation

Vries

Doorduin²,

Dierckx

et al. 2008

Nuclear Medicine and Biology

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“…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).…”

mentioning

confidence: 99%

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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Effect of Acute Systemic Inflammatory Response and Cytokines on the Transcription of the Genes Encoding Cyclooxygenase Enzymes (COX‐1 and COX‐2) in the Rat Brain

Cited by 249 publications

References 76 publications

COX-2 inhibition attenuates anorexia during systemic inflammation without impairing cytokine production

COX-2 inhibition attenuates anorexia during systemic inflammation without impairing cytokine production

Evaluation of [11C]rofecoxib as PET tracer for cyclooxygenase 2 overexpression in rat models of inflammation

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

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