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

Johnson, Peter; Vogt, Sherri K.; Burney, Mary W.; Muglia, Louis J.

doi:10.1152/ajpendo.00388.2001

Cited by 72 publications

(57 citation statements)

References 43 publications

(49 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…These results extend previous findings in which nonselective COX inhibitors attenuated intraperitoneal LPS-induced anorexia in rats (26), mice (38), chickens (20), and pigs (21). Our results are consistent with a recent study in which either pharmacological inhibition or genetic ablation of COX-2 in mice also attenuated the body weight loss and anorectic response of intraperitoneal LPS (100 g/mouse) (19). Here we extend these findings by providing evidence for a role of central PGE 2 in LPS-induced anorexia.…”

Section: Discussionsupporting

confidence: 93%

See 1 more Smart Citation

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

View full text Add to dashboard Cite

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...

show abstract

Section: Discussionsupporting

confidence: 93%

“…This may reflect a COX-1-related protective role of PGs in response to LPS. A potentiation of LPS anorexia by COX-1 inhibition was recently found in mice (19). Under certain conditions, such as when exogenous IL-1␤ reduces milk intake in mice, COX-1 may be important in mediating the early (first 30 min) period of anorexia (11).…”

Section: Discussionmentioning

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

View full text Add to dashboard Cite

show abstract

“…However, d ‐Trp(8)‐γMSH, unlike αMSH, was unable to prevent the increased expression of COX‐2 in the hypothalamus of arthritic rats. Taking into account the role of COX‐2 in inflammatory anorexia,34, 35 the lack of effect of d ‐Trp(8)‐γMSH treatment on hypothalamic COX‐2 induction can explain the different effects of both melanocortins on inflammatory anorexia.…”

Section: Discussionmentioning

confidence: 99%

The melanocortin receptor type 3 agonistd-Trp(8)-γMSH decreases inflammation and muscle wasting in arthritic rats

Gómez-SanMiguel

Martín

Nieto-Bona

et al. 2015

Journal of Cachexia, Sarcopenia and Muscle

View full text Add to dashboard Cite

BackgroundChronic inflammatory diseases induce cachexia that increases mortality and morbidity of the illness. Adjuvant‐induced arthritis is an experimental model of rheumatoid arthritis that is associated with body weight loss and muscle wasting. Alpha‐melanocyte stimulating hormone has an anti‐inflammatory effect in arthritic rats and decreases muscle wasting. The aim of this work was to elucidate whether the anti‐cachectic action of alpha‐melanocyte stimulating hormone is mediated by the melanocortin receptor type 3 pathway.MethodsArthritis was induced in male Wistar rats by intradermal injection of Freund's adjuvant, and 6 days afterwards, arthritic rats were injected with the selective melanocortin receptor type 3 agonist d‐Trp(8)‐gammaMSH ( d‐Trp(8)‐γMSH) 500 µg/kg subcutaneously. or saline twice a day, for 10 days.Results d‐Trp(8)‐γMSH decreased the external signs of inflammation and body weight loss, but it was not able to modify the anorexigenic effect of arthritis or the increase in hypothalamic cyclooxygenase‐2 (COX‐2) expression. In contrast, d‐Trp(8)‐γMSH prevented arthritis‐induced increase in hypothalamic IL‐1β and serum corticosterone levels and the decrease in serum IGF‐I levels. d‐Trp(8)‐γMSH treatment also prevented arthritis‐induced NF‐kB(p65) phosphorylation and tumour necrosis factor‐α mRNA increase in the gastrocnemius. d‐Trp(8)‐γMSH administration to arthritic rats increased gastrocnemius mass, its cross‐sectional area, and mean fast fibre area. Those effects of d‐Trp(8)‐γMSH were associated with a decreased expression of atrogin‐1 and muscle ring‐finger protein‐1 in the gastrocnemius. In rats treated with saline, arthritis increased the expression of autophagy marker genes LC3b, Bnip‐3, and Gabarap1 as well as the conversion of LC3b I to LC3b II by lipidation in the gastrocnemius. d‐Trp(8)‐γMSH decreased gastrocnemius LC3b, Bnip‐3, and Gabarap1 mRNA expression and prevented the increase in LC3b II in arthritic rats.ConclusionThese data suggest that d‐Trp(8)‐γMSH administration prevents the effect of arthritis on corticosterone and insulin‐like growth factor‐I serum levels and decreases muscle wasting, by down‐regulating atrogenes and autophagy through modifying the NF‐kB(p65)/tumour necrosis factor‐α signalling transduction pathway.

show abstract

“…Ainsi, au niveau central, la synthèse de la prostaglandine de type E2 (PGE2) à partir de l'acide arachidonique augmente de façon considérable lors d'une infection et son rôle causal dans la mise en place des symptômes du illness behavior a été établi voilà plusieurs années par différents groupes [2,3,13]. Une des stratégies théra-peutiques anti-inflammatoires parmi les plus anciennes consiste à bloquer la production de ces composés via l'inhibition des enzymes cyclo-oxygénases (COX) dont deux principales isoformes sont actuellement identifiées : COX-1 et COX-2.…”

Section: Magazineunclassified

“…Présent de manière constitutive dans le cytosol, l'hétérodimère NF-κB (le plus souvent p65/p50) est séques-tré par son inhibiteur IκBα qui masque sa séquence de localisation nucléaire [2,3]. L'activation de NF-κB repose sur la mise en place de plates-formes multiprotéiques spécifiques d'un stimulus dont la fonction est de recruter et rendre compétent le complexe IKK (inhibitor of NF-kB kinase).…”

Section: Nouvelleunclassified