prostaglandin-d2 and Fever

The actions of prostanoids in various physiological and pathophysiological conditions have been examined using mice lacking the prostanoid receptors. PGD2 was found to be a mediator of allergic asthma. Prostaglandin (PG) I2 worked not only as a mediator of inflammation but also as an antithrombotic and cardio-protective agent. Several important actions of PGE2 are brought out via the PGE2-receptor subtype EP3; PGE2 participated in the regulation of platelet function, and it worked as a mediator of febrile responses to both endogenous and exogenous pyrogens. These novel findings on the roles of the prostanoids would contribute to the development of drugs targeting the prostanoid receptors.

Topics: Animals; Asthma; Dinoprostone; Drug Design; Epoprostenol; Fever; Humans; Inflammation Mediators; Myocardial Reperfusion Injury; Platelet Activation; Prostaglandin D2; Prostaglandins; Receptors, Prostaglandin; Thrombosis

Body temperature control is a critical brain function. In this issue of Neuron, Wang et al. identify a negative feedback circuit in mouse preoptic area of the hypothalamus that regulates body temperature to counter fever.

Topics: Animals; Body Temperature Regulation; Fever; Hypothalamus; Mice; Preoptic Area; Prostaglandin D2; Temperature

Eicosapentaenoic acid (EPA) has been shown to suppress immune cell responses, such as cytokine production and downstream PG production in vitro. Studies in vivo, however, have used EPA as a minor constituent of fish oil with variable results. We investigated the effects of EPA on systemic inflammatory responses as pure EPA has not been evaluated on immune/inflammatory responses in vivo.. Rabbits were administered polyinosinic: polycytidylic acid (poly I:C) i.v. before and after oral treatment with EPA for 42 days (given daily). The responses to IL-1β and TNF-α were also studied. Immediately following administration of poly I:C, body temperature was continuously monitored and blood samples were taken. Plasma levels of IL-1β, PGE2 (PGE2), and 15-deoxy-Δ(12,14)-PGJ2 (15d-PGJ2) were measured by enzyme immunoassay.. Following EPA treatment, the fever response to poly I:C was markedly suppressed compared with pretreatment responses. This was accompanied by a parallel reduction in the poly I:C-stimulated elevation in plasma levels of IL-1β and PGE2. Paradoxically, the levels of 15d-PGJ2 were higher following EPA treatment. EPA treatment did not significantly alter the fever response or plasma levels of PGE2 in response to either IL-1β or TNF-α.. Oral treatment with EPA can suppress immune/inflammatory responses in vivo via a suppression of upstream cytokine production resulting in a decreased fever response and indirectly reducing circulating levels of PGE2. EPA also enhances the production of the cytoprotective prostanoid 15d-PGJ2 indicating the therapeutic benefit of EPA.

Topics: Animals; Anti-Inflammatory Agents; Eicosapentaenoic Acid; Fever; Immunologic Factors; Interleukin-1beta; Poly I-C; Prostaglandin D2; Rabbits; Tumor Necrosis Factor-alpha

We examined changes in nuclear peroxisome proliferator-activated receptor gamma (PPAR gamma) in the striatum in methamphetamine (METH)-induced dopaminergic neurotoxicity, and also examined effects of treatment with drugs possessing PPAR gamma agonistic properties. The marked reduction of nuclear PPAR gamma-expressed cells was seen in the striatum 3 days after METH injections (4 mg/kg x 4, i.p. with 2-h interval). The reduction of dopamine transporter (DAT)-positive signals and PPAR gamma expression, and accumulation of activated microglial cells were significantly and dose-dependently attenuated by four injections of a nonsteroidal anti-inflammatory drug and a PPAR gamma ligand, ibuprofen (10 or 20 mg/kg x 4, s.c.) given 30 min prior to each METH injection, but not by either a low or high dose of aspirin. Either treatment of ibuprofen or aspirin, that showed no effects on METH-induced hyperthermia, significantly blocked the METH-induced striatal cyclooxygenase (COX) expression. Furthermore, the treatment of an intrinsic PPAR gamma ligand 15d-PG J2 also attenuated METH injections-induced reduction of striatal DAT. Therefore, the present study suggests the involvement of reduction of PPAR gamma expression in METH-induced neurotoxicity. Taken together with the previous report showing protective effects of other PPAR gamma ligand, these results imply that the protective effects of ibuprofen against METH-induced neurotoxicity may be based, in part, on its anti-inflammatory PPAR gamma agonistic properties, but not on its COX-inhibiting property or hypothermic effect.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Aspirin; Body Temperature; Central Nervous System Stimulants; Corpus Striatum; Cyclooxygenase 1; Cyclooxygenase 2; Dopamine Plasma Membrane Transport Proteins; Fever; Ibuprofen; Immunohistochemistry; Male; Membrane Proteins; Methamphetamine; Mice; Mice, Inbred BALB C; Microglia; Neuroprotective Agents; PPAR gamma; Prostaglandin D2

Prostaglandin D(2) (PGD(2)) is involved in a variety of physiological and pathophysiological processes, but its role in fever is poorly understood. Here we investigated the effects of central PGD(2) administration on body temperature and prostaglandin levels in the cerebrospinal fluid (CSF) of rats. Administration of PGD(2) into the cisterna magna (i.c.m) evoked a delayed fever response that was paralleled by increased levels of prostaglandin E(2) (PGE(2)) in the CSF. The elevated PGE(2) levels were not caused by an increased expression of cyclooxygenase 2 or microsomal prostaglandin E synthase-1 in the hypothalamus. Interestingly, i.c.m. pretreatment of animals with PGD(2) considerably sustained the pyrogenic effects of i.c.m. administered PGE(2). These data indicate that PGD(2) might control the availability of PGE(2) in the CSF and suggest that centrally produced PGD(2) may play a role in the maintenance of fever.

Topics: Animals; Body Temperature; Cisterna Magna; Dinoprostone; Dose-Response Relationship, Drug; Fever; Male; Prostaglandin D2; Rats; Rats, Sprague-Dawley

A large body of evidence has implicated prostaglandin E(2) (PGE(2)) in fever production. However, the role of PGD(2) in this context is only poorly understood. We therefore determined by LC-MS/MS analyses the content of PGD(2) and PGE(2) in cerebrospinal fluid (CSF), plasma and lungs of rats over 5 hours after fever induction by intraperitoneal injection of lipopolysaccharide (LPS, 50 microg/kg). Both PGD(2) and PGE(2) were detected in CSF, plasma and lungs of saline-treated control animals. The injection of LPS evoked fever and an increase of PGE(2) in the CSF, while the CSF content of PGD(2) was not significantly altered. However, both PGE(2) and PGD(2) levels were elevated in plasma and lungs after LPS injection. Interestingly, pretreatment with a novel selective inhibitor of hematopoietic prostaglandin D synthase (H-PGDS), EDJ300520 (10-40 mg/kg p.o.), selectively and dose-dependently prevented the LPS-induced increase of PGD(2) in plasma and lungs but did not affect the PGE(2) content. Most remarkably, EDJ300520 pretreatment led to an hypothermic response after LPS injection during the first 3 h and prevented fever induction. These data indicate that PGD(2) produced peripherally by H-PGDS essentially contributes to LPS-induced fever.

Topics: Animals; Body Temperature; Chromatography, High Pressure Liquid; Dinoprostone; Dose-Response Relationship, Drug; Fever; Hematopoiesis; Injections, Intraperitoneal; Intramolecular Oxidoreductases; Lipocalins; Lipopolysaccharides; Lung; Male; Prostaglandin D2; Rats; Rats, Sprague-Dawley; Tandem Mass Spectrometry

Near-term pregnant rats show a suppressed fever response to LPS that is associated with reduced induction of cyclooxygenase (COX)-2 in the hypothalamus. The objective of this study is to explore whether the LPS-activated signaling pathways in the fever-controlling region of the hypothalamus are specifically altered at near term. Three rat groups consisting of 15-day pregnant rats, near-term 21- to 22-day pregnant rats, and day 5 lactating rats were injected with a febrile dose of LPS (50 mug/kg ip). The hypothalamic preoptic area and the organum vasculosum of the lamina terminalis (OVLT) were collected 2 h after LPS injection. The activation of three transcription modulators, nuclear factor-kappaB (NF-kappaB), extracellular signal-regulated kinase 1/2 (ERK1/2), and signal transducer and activator of transcription 5 (STAT5), was assessed using semiquantitative Western blot analysis. LPS activated the NF-kappaB pathway in all rat groups, and this response was not altered at near term. ERK1/2 and STAT5 were constitutively activated during all reproductive stages, and their levels were not significantly affected by LPS injection. Plasma levels of the proinflammatory cytokines (IL-1beta, IL-6, TNF-alpha, and IFN-gamma), anti-inflammatory cytokines (IL-4, IL-10, and IL-1 receptor antagonist), and corticosterone were unaffected during the three reproductive stages after LPS challenge. We observed a sharp decrease in the expression of a prostaglandin-producing enzyme called lipocalin-prostaglandin D2 synthase in near-term pregnant and lactating rats. Thus fever suppression at near term is not due to an alteration in either LPS-activated intracellular signaling pathways or LPS-induced pro- and anti-inflammatory cytokine production.

Topics: Animals; Corticosterone; Cytokines; Enzyme Activation; Female; Fever; Lipopolysaccharides; MAP Kinase Kinase 1; MAP Kinase Kinase 2; NF-kappa B; Pregnancy; Prostaglandin D2; Rats; Rats, Sprague-Dawley; Signal Transduction

Fever is an important part of the host defense response, yet fever can be detrimental if it is uncontrolled. We provide the first evidence that 15-deoxy-Delta12,14-prostaglandin J2 (15d-PGJ2), an endogenous ligand for peroxisome proliferator-activated receptor gamma (PPARgamma), can attenuate the febrile response to lipopolysaccharide (LPS) in rats via an action on the brain. Furthermore, we show that PPARgamma is expressed in the hypothalamus, an important locus in the brain for fever generation. In addition, 15d-PGJ2 and its synthesizing enzyme (PGD2 synthase) were present in rat cerebrospinal fluid, and their levels were enhanced in response to systemic injection of LPS. The antipyretic effect of 15d-PGJ2 was associated with reduction in LPS-stimulated cyclooxygenase-2 expression in the hypothalamus but not in p44/p42 mitogen-activated protein kinase phosphorylation or in the expression of the PPARgamma. Thus it is likely that there is a parallel induction of an endogenous prostanoid pathway in the brain capable of limiting deleterious actions of the proinflammatory prostaglandin E2-dependent pathway.

Topics: Analgesics, Non-Narcotic; Animals; Body Temperature; Brain; Cyclooxygenase 2; Disease Models, Animal; Fever; Hypothalamus; Intramolecular Oxidoreductases; Isoenzymes; Lipocalins; Lipopolysaccharides; Male; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Mitogen-Activated Protein Kinases; Prostaglandin D2; Prostaglandin-Endoperoxide Synthases; Rats; Rats, Sprague-Dawley; Receptors, Cytoplasmic and Nuclear; Transcription Factors

Experiments compared the hemispheric neural damage resulting from global hemispheric hypoxic ischemia (GHHI, ligation of right common carotid artery plus 35 min of 12% O2) in groups of anesthetized, male Long Evans rats, 9-10 weeks of age, kept at 37 degrees C, and previously given an intracerebroventricular (i.c.v., 2.5 microl) injection of 28 or 70 pmoles of PGE2, PGF2alpha or PGD2 or sterile saline (SS) 30 min beforehand. Mean arterial pressure (MAP), ipsilateral cortical capillary blood flow (CBF), colonic (Tc), ipsilateral (Tipsi) and contralateral (Tcontra), temporalis muscle temperatures were measured before, during and for 15 min after GHHI. Necrotic neural damage was assessed 7 days post-GHHI. All groups given GHHI + PGs showed increased ipsilateral hemispheric damage to GHHI especially due to enhanced neocortical damage, compared to the saline control group given the same insult. PGD2 was the most potent PG to cause further damage to the global insult. Tc, Tipsi, Tcontra and MAP increased following the i.c.v. injection of PGE2. I.c.v. PGF2alpha transiently decreased MAP, PGD2 tended to decrease cerebral blood flow and neither evoked changes in temperature compared to respective pre-injection control values. Results demonstrate increased neural damage to GHHI with prior i.c.v. PGE2, PGF2alpha or PGD2 administration.

Topics: Animals; Body Temperature; Brain; Brain Ischemia; Dinoprost; Dinoprostone; Fever; Hemodynamics; Hypoxia, Brain; Male; Prostaglandin D2; Rats

1. The effects of microinjection of prostaglandin D2, E2 and F2 alpha and of endogenous pyrogen on the rectal temperature of rabbits were extensively examined in sixty-eight brain regions and in the third cerebral ventricle. 2. Intracerebroventricular injection of both prostaglandins E2 and F2 alpha produced dose-dependent fever over a range of 100-1000 ng. The selective brain regions, the nucleus broca ventralis, preoptic area, anterior hypothalamus and the ventromedial hypothalamus, responded to microinjections of a small dose (less than 200 ng) of prostaglandins E2 and F2 alpha by producing fever. Furthermore, the lateral hypothalamus, ventral thalamus, substantia nigra and the trigeminal nucleus were also sensitive to high concentrations of prostaglandins E2 and F2 alpha, fever being produced. It is likely that prostaglandin D2 is not involved in fever induction. 3. The ventricular injection of endogenous pyrogen also produced fever. However, brain regions sensitive to microinjection of endogenous pyrogen were exclusively localized to regions near the organum vasculosum laminae terminalis (OVLT), such as the nucleus broca ventralis and the preoptic area. In contrast to the monophasic fever induced by prostaglandins E2 and F2 alpha, about 30 min after ventricular or cerebral injection of endogenous pyrogen the rectal temperature gradually started to rise and the fever was prolonged over 4 h. 4. We investigated the effect of an inhibitor of prostaglandin synthesis, sodium salicylate, on biphasic fever induced by intravenous injection of bacterial endotoxin. The microinjections of sodium salicylate into the bilateral regions near the OVLT suppressed the second peak but had no effect on the first peak. 5. The present study clarifies that there exist two separate mechanisms of induction of biphasic fever. Correlating with the first peak of biphasic fever, prostaglandins synthesized outside the blood-brain barrier act on multiple sites in the central nervous system to induce fever. Correlating with the second peak, endogenous pyrogen acts on regions near the OVLT to synthesize and release pyrogenic prostaglandins.

Topics: Animals; Body Temperature; Brain; Cerebral Ventricles; Dinoprost; Dinoprostone; Dose-Response Relationship, Drug; Fever; Injections, Intraventricular; Interleukin-1; Male; Prostaglandin D2; Prostaglandins; Prostaglandins D; Prostaglandins E; Prostaglandins F; Rabbits; Time Factors