Both cyclooxygenase and lipoxygenase inhibitor partially restore the anorexia by interleukin-1β
Abstract
Since the peripheral prostaglandin synthetizing system may at least partly involved in the anorexia that follows central interleukin-1β (IL-1) administration, this study was undertaken to investigate the effect of ibuprofen (ip), selective cyclooxygenase blocker and AA 861, selective lipoxygenase inhibitor, on changes of food and water intake by a single injection of IL-1 (2 μg/rat, ip). We demonstrated that food and water intake were suppressed by peripheral administration of IL-1. Throughout the entire observation periods, suppressed food intake was partially restored to control levels by ibuprofen, while water intake completely restored. In addition, no significant differences about water/food intake were observed in the IL-1 + ibuprofentreated groups, respectively. In the next experiment, IL-1 induced anorexia was also partially restored to the control level following pretreatment with AA 861. These results may suggest that other mechanism including lipoxygenase blocker besides prostaglandin production may be involved in IL-1 induced anorexia.
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Hypothalamic mechanisms in cachexia
2010, Physiology and BehaviorCitation Excerpt :IL-1β has an increasingly recognized role in the regulation of feeding behavior and energy homeostasis. IL-1β potently suppresses food intake when injected peripherally and centrally [140,141] and unlike IL-1β-mediated fever, the anorexic effect of IL-1β is not completely blocked by inhibition of PG synthesis [142,143]. Further, administration of IL-1ra into the lateral ventricle abrogates sickness behavior induced by peripheral IL-1β without affecting the febrile response [141].
The role of nutrition and balanced metabolism in normal growth, development, and health maintenance is well known. Patients affected with either acute or chronic diseases often show disorders of nutrient balance. In some cases, a devastating state of malnutrition known as cachexia arises, brought about by a synergistic combination of a dramatic decrease in appetite and an increase in metabolism of fat and lean body mass. Other common features that are not required for the diagnosis include decreases in voluntary movement, insulin resistance, and anhedonia. This combination is found in a number of disorders including cancer, cystic fibrosis, AIDS, rheumatoid arthritis, renal failure, and Alzheimer's disease. The severity of cachexia in these illnesses is often the primary determining factor in both quality of life, and in eventual mortality. Indeed, body mass retention in AIDS patients has a stronger association with survival than any other current measure of the disease. This has led to intense investigation of cachexia and the proposal of numerous hypotheses regarding its etiology. Most authors suggest that cytokines released during inflammation and malignancy act on the central nervous system to alter the release and function of a number of neurotransmitters, thereby altering both appetite and metabolic rate. This review will discuss the salient features of cachexia in human diseases, and review the mechanisms whereby inflammation alters the function of key brain regions to produce stereotypical illness behavior.
The paper represents an invited review by a symposium, award winner or keynote speaker at the Society for the Study of Ingestive Behavior [SSIB] Annual Meeting in Portland, July 2009.
Homeostatic alterations after IL-1β microinjection into the nucleus accumbens of the rat
2010, AppetiteThe present study investigates the effects of direct administration of interleukin-1β (IL-1β) into the nucleus accumbens (NAcc) on homeostatic regulation. Short- and long-term food intakes (FI), water intakes (WI) and body temperature (BT) were measured before and after bilateral microinjection of IL-1β (with or without paracetamol pretreatment) into the NAcc of Wistar rats, and the effects were compared with those found in vehicle treated control animals. In addition, blood glucose levels, along with a glucose tolerance test (GTT), and plasma concentrations of metabolic parameters, such as total cholesterol, triglycerides, HDL, LDL and uric acid were determined in cytokine treated and control rats. Short-term FI and WI were suppressed after intraaccumbens application of IL-1β. A significant increase of BT was also observed after the cytokine microinjection. Pretreatment with paracetamol failed to influence the anorexigenic, adipsogenic, and pyrogenic effects of IL-1β. A definite glucose intolerance of the cytokine treated animals and their pathologically elevated blood glucose levels became obvious in the acute GTT. Following IL-1β microinjection, plasma levels of triglycerides, total cholesterol and LDL were found increased. Our present findings show that the NAcc is an important site of action of IL-1β mediated processes in central homeostatic regulation.
Prostaglandins and sickness behavior: Old story, new insights
2009, Physiology and BehaviorPrevious evidence has shown that prostaglandins play a key role in the development of sickness behavior observed during inflammatory states. In particular, prostaglandin E2 (PGE2) is produced in the brain by a variety of inflammatory signals such as endotoxins or cytokines. Its injection has been also shown to induce symptoms of sickness behavior. The role of cyclooxygenase enzymes (COX), the rate-limiting enzymes converting arachidonic acid into prostaglandins, in sickness behavior has been extensively studied, and it has been demonstrated that strategies aiming at inhibiting these enzymes limit anorexia, body weight loss and fever in animals with inflammatory diseases. However, inhibiting COX activity may lead to negative gastric or cardiovascular effects, since COX enzymes play a role in the synthesis of others prostanoids with various and sometimes contrasting properties. Recently, prostaglandin E synthases (PGES), which specifically catalyze the final step of PGE2 biosynthesis, were characterized. Among these enzymes, the microsomal prostaglandin E synthase-1 (mPGES-1) was of a particular interest since it was shown to be up-regulated by inflammatory signals in a variety of cell types. Moreover, mPGES-1 was shown to be crucial for correct immune-to-brain communication and induction of fever and anorexia by pro-inflammatory agents. This review takes stock of previous knowledge and recent advances in understanding the role of prostaglandins and of their specific synthesizing enzymes in the molecular mechanisms underlying sickness behavior. The review concludes with a short summary of key questions that remain to be addressed and points out therapeutic developments in this research field.
Homeostatic alterations induced by interleukin-1β microinjection into the orbitofrontal cortex in the rat
2005, AppetiteThe present experiments were designed to elucidate the effect of direct orbitofrontal cortical administration of interleukin-1β (IL-1β) on the homeostatic regulation. Short- and long-term food intakes (FI), water intakes and body temperature (BT) were measured before and after a bilateral microinjection of IL-1β (with or without paracetamol /P/ pretreatment) into the orbitofrontal cortex (OBF) of Wistar rats, and the effects were compared with those found in vehicle-treated and i.p. injected IL-1β, IL-1β+P or control animals. In addition, blood glucose levels (BGLs), along a glucose tolerance test, and plasma concentrations of insulin, leptin, cholesterol, triglycerides and urate were determined in cytokine treated and control rats. Short-term FI was suppressed after orbitofrontal cortical or peripheral application of IL-1β. In the long-term FI, however, there was no significant difference among the groups. Cytokine microinjection into the OBF, similar to the i.p. administration, was also followed by a significant increase in BT. Pretreatment with P failed to influence the anorexigenic and hyperthermic effects of the centrally administered IL-1β. The sugar load led to a diabetes-like prolonged elevation of BGL in the IL-1β treated animals. Following cytokine administration, plasma levels of insulin and that of triglycerides were found decreased, whereas that of uric acid increased. The present findings confirm that the OBF is one of the neural routes through which IL-1β exerts modulatory effect on the central homeostatic regulation.
EP<inf>3</inf> and EP<inf>4</inf> receptor mRNA expression in peptidergic cell groups of the rat parabrachial nucleus
2004, NeuroscienceThis study examines the distribution of prostaglandin E2 receptors of subtype EP3 and EP4 among brain stem parabrachial neurons that were characterized with respect to their neuropeptide expression. By using a dual-labeling in situ hybridization method, we show that preprodynorphin mRNA expressing neurons in the dorsal and central lateral subnuclei express EP3 receptor mRNA. Such receptors are also expressed in preproenkephalin, calcitonin gene related peptide and preprotachykinin mRNA positive neurons in the external lateral subnucleus, whereas preprodynorphin mRNA expressing neurons in this subnucleus are EP receptor negative. In addition, EP3 receptor expression is seen among some enkephalinergic neurons in the Kölliker-Fuse nucleus. Neurons in the central part of the cholecystokininergic population in the regions of the superior lateral subnucleus express EP4 receptor mRNA, whereas those located more peripherally express EP3 receptors. Taken together with previous findings showing that discrete peptidergic cell groups mediate nociceptive and/or visceral afferent information to distinct brain stem and forebrain regions, the present results suggest that the processing of this information in the parabrachial nucleus is influenced by prostaglandin E2. Recent work has shown that prostaglandin E2 is released into the brain following peripheral immune challenge; hence, the parabrachial nucleus may be a region where humoral signaling of peripheral inflammatory events may interact with neuronal signaling elicited by the same peripheral processes.
The role of cyclooxygenases in endotoxin- and interleukin-1-induced hypophagia
2000, Brain, Behavior, and ImmunityEndotoxin (lipopolysaccharide, LPS) and interleukin-1 (IL-1) reduce food intake in rodents. Cyclooxygenase (COX) inhibitors have long been known to attenuate these responses, but recent work has revealed the existence of two distinct isoforms of the enzyme, COX1 and COX2, with different characteristics and functions. Therefore, we reassessed the COX involvement using inhibitors with different selectivities for COX1 and COX2. Feeding was assessed in nondeprived mice by measuring the intake of sweetened milk in a 30-minute period, as well as daily food pellet intake. LPS and IL-1β consistently reduced milk intake. Treatment of the mice with the selective COX1 inhibitor, piroxicam, attenuated the hypophagic responses to IL-1 and LPS. Similar results were obtained with diclofenac. The hypophagic responses to LPS and IL-1β were not affected by the COX2-selective inhibitors nimesulide and NS-398 at doses considered selective for COX2, but were inhibited by higher doses. Pretreatment of the mice with aspirin, an irreversible inhibitor of COX1 and COX2, prevented the hypophagic response to IL-1, 16 h, but not 40 h later. Taken together, these results suggest that COX1 may be the major isozyme involved in the hypophagic responses to LPS and IL-1, but a role for COX2 cannot be excluded. We also studied the combination of a COX inhibitor with the IL-1 receptor antagonist protein. Consistent with earlier results, both the IL-1 receptor antagonist (IL-1ra) and indomethacin attenuated the hypophagic responses to LPS. Combination of the two treatments produced additive results almost completely preventing the hypophagic response. Because indomethacin almost completely prevented the hypophagic response to IL-1, this additivity suggests that there are multiple mechanisms by which LPS induces hypophagia.