Cancer-induced anorexia in tumor-bearing mice is dependent on cyclooxygenase-1

It is well-established that prostaglandins (PGs) affect tumorigenesis, and evidence indicates that PGs also are important for the reduced food intake and body weight loss, the anorexia–cachexia syndrome, in malignant cancer. However, the identity of the PGs and the PG producing cyclooxygenase (COX) species responsible for cancer anorexia–cachexia is unknown. Here, we addressed this issue by transplanting mice with a tumor that elicits anorexia. Meal pattern analysis revealed that the anorexia in the tumor-bearing mice was due to decreased meal frequency. Treatment with a non-selective COX inhibitor attenuated the anorexia, and also tumor growth. When given at manifest anorexia, non-selective COX-inhibitors restored appetite and prevented body weight loss without affecting tumor size. Despite COX-2 induction in the cerebral blood vessels of tumor-bearing mice, a selective COX-2 inhibitor had no effect on the anorexia, whereas selective COX-1 inhibition delayed its onset. Tumor growth was associated with robust increase of PGE₂ levels in plasma – a response blocked both by non-selective COX-inhibition and by selective COX-1 inhibition, but not by COX-2 inhibition. However, there was no increase in PGE₂-levels in the cerebrospinal fluid. Neutralization of plasma PGE₂ with specific antibodies did not ameliorate the anorexia, and genetic deletion of microsomal PGE synthase-1 (mPGES-1) affected neither anorexia nor tumor growth. Furthermore, tumor-bearing mice lacking EP₄ receptors selectively in the nervous system developed anorexia. These observations suggest that COX-enzymes, most likely COX-1, are involved in cancer-elicited anorexia and weight loss, but that these phenomena occur independently of host mPGES-1, PGE₂ and neuronal EP₄ signaling.     

Actions of Prostaglandin E2 on Rat Supraoptic Neurones

Prostaglandins (PGs) have been implicated in the regulation of vasopressin (VP) and oxytocin (OT) release in response to various stimuli. To examine the site and mechanism of actions of PGs, we studied effects of PGE₂ and PG-receptor agonists on supraoptic nucleus (SON) neurones of rat hypothalamic slice preparations using extracellular recording and whole-cell patch-clamp techniques. PGE₂ modulated the electrical activity of more than 80% of the neurones studied. The effects of PGE₂ on both phasic and non-phasic neurones were mostly excitatory, and dose-dependent. The effects of PGE₂ were mimicked by PGF_2α or the FP agonist, fluprostenol, whereas PGD₂ or the selective EP, IP or TP agonist was less effective or had no effect. The effects of PGE₂ were unaffected by the EP₁ antagonist, SC-51322, but reduced to 80% of control by the EP₁/FP/TP antagonist, ONO-NT-012, which reduced the effects of fluprostenol to 32% of control. Moreover, some neurones responsive to PGE₂ did not respond to fluprostenol. Patch-clamp analysis in SON slice preparations revealed that PGE₂ at 10^?6 M depolarized the membrane potential by 3.9±0.3 mV from the resting membrane potential of ?58.4±2.2 mV in the current-clamp mode. In the voltage-clamp mode, PGE₂ induced inward currents at a holding potential of ?70 or ?80 mV, while it did not affect spontaneous excitatory postsynaptic currents. PGE₂ induced currents also in dissociated SON neurones and the reversal potential of the currents was ?35.5±0.9 mV, which was similar to that of currents induced by fluprostenol. These results suggest that SON neurones possess at least two types of PG receptors, FP receptors and EP receptors of a subclass different from EP₁, EP₂, or EP₃, and that activation of these receptors leads to the opening of nonselective cation channels, membrane depolarization and increase of the action potential discharge.     

Prostaglandin D2 and sleep/wake regulation

Prostaglandin (PG) D₂ is the most potent endogenous sleep-promoting substance. PGD₂ is produced by lipocalin-type PGD synthase localized in the leptomeninges, choroid plexus, and oligodendrocytes in the brain, and is secreted into the cerebrospinal fluid as a sleep hormone. PGD₂ stimulates DP₁ receptors localized in the leptomeninges under the basal forebrain and the hypothalamus. As a consequence, adenosine is released as a paracrine sleep-promoting molecule to activate adenosine A_2A receptor-expressing sleep-promoting neurons and to inhibit adenosine A₁ receptor-possessing arousal neurons. PGD₂ activates a center of non-rapid eye movement (NREM) sleep regulation in the ventrolateral preoptic area, probably mediated by adenosine signaling, which activation inhibits the histaminergic arousal center in the tuberomammillary nucleus via descending GABAergic and galaninergic projections. The administration of a lipocalin-type PGD synthase inhibitor (SeCl₄), DP₁ antagonist (ONO-4127Na) or adenosine A_2A receptor antagonist (caffeine) suppresses both NREM and rapid eye movement (REM) sleep, indicating that the PGD₂-adenosine system is crucial for the maintenance of physiological sleep.     

Modulatory effects of prostaglandin D2, E2 and F2α on the postsynaptic actions of inhibitory and excitatory amino acids in cerebellar purkinje cell dendrites in vitro

For the purpose of revealing the physiological functions or roles of prostaglandins (PGs), PGD₂ in particular, in the central nervous system, the effects of PGD₂, E₂ and F_2α on the postsynaptic actions of GABA, taurine, l-glutamate and l-aspartate on Purkinje cell dendrites in guinea pig, cerebellar slices were electrophysiologically investigated using intradendritic recording. Iontophoretic application of PGD₂ alone either depolarized or hyperpolarized some Purkinje cell dendrites, while PGE₂ and F_2α induced only depolarizations. All PGs tested showed fairly strong potentiation of the inhibitory action of GABA or taurine and of the excitatory action of l-glutamate or l-aspartate on Purkinje cell dendrites. As a possible mechanism of action, the change of the cyclic nucleotide level induced by PGs was tentatively suggested as being involved in the potentiating action of PGs on excitatory amino acids.     

Lipopolysaccharides enhance the action of bradykinin in enteric neurons via secretion of interleukin‐1β from enteric glial cells

Functional changes of the enteric nervous system have been observed under inflammatory states of inflammatory bowel disease increasing the endotoxin level. The aim of the present study was to determine the effect of lipopolysaccharides (LPS) on myenteric neuron–glia interaction in vitro. We examined the increase of the intracellular Ca²⁺ concentration ([Ca²⁺]_i) and the release of interleukin‐1β (IL‐1β) or prostaglandin E₂ (PGE₂) and COX‐2 expression in myenteric plexus cells from the rat intestine induced by LPS. LPS potentiated BK‐induced [Ca²⁺]_i increases in both myenteric neurons and enteric glial cells, which were suppressed by a B1R antagonist. Only in enteric glial cells, a B1R agonist increased [Ca²⁺]_i. The effects of LPS were blocked by pretreatment with an interleukin‐1 receptor antagonist or by reducing the density of enteric glial cells in culture. LPS prompted the release of IL‐1β from enteric glial cells. The augmenting effects of IL‐1β on the BK‐induced neural [Ca²⁺]_i increase and PGE₂ release from enteric glial cells were abolished by a phospholipase A₂ (PLA₂) inhibitor and a COX inhibitor, and partly suppressed by a COX‐2 inhibitor. IL‐1β up‐regulated the COX‐2 expression in enteric glial cells. LPS promotes IL‐1β secretion from enteric glial cells, resulting in augmentation of the neural response to BK through PGE₂ release via glial PLA₂ and COX‐2. The alteration of the regulatory effect of glial cells may be the cause of the changes in neural function in the enteric nervous system in inflammatory bowel disease. © 2009 Wiley‐Liss, Inc.     

Stimulation of human platelet adenylate cyclase by prostaglandin D2

Prostaglandin D₂ (PGD₂) stimulates the formation of cyclic AMP in human platelets measured as the incorporation of radio-activity from previously labelled intracellular nucleotides. In this action it is similar to, and more powerful than PGE₁. Both inhibition of platelet aggregation and stimulation of cyclic AMP accumulation by PGD₂ and by PGE₁ are potentiated by an inhibitor of platelet phosphodiesterase. A number of minor differences in the response of platelets to PGD₂ and PGE₁ suggest the existence of at least two prostaglandin receptors influencing a single adenylate cyclase.     

Intracerebroventricular injection of prostaglandin E2 induces thermal hyperalgesia in rats: the possible involvement of EP3 receptors

To determine what types of prostanoid receptors are involved in the central effect of prostaglandin E₂ (PGE₂) on nociception, we administered PGE₂ and its agonists, i.e., 17-phenyl-ω-trinor PGE₂ (an EP₁ receptor agonist), butaprost (an EP₂ receptor agonists), 11-deoxy PGE₁ (an EP₂/EP₃ receptor agonist, EP₂ EP₃) and M&B28767 (an EP₃ receptor agonist) into the lateral cerebroventricle (LCV) of rats and observed the changes of paw-withdrawal latency on a hot plate. The LCV injection of PGE₂ (10 pg/kg-10 ng/kg), 11-deoxy PGE₁ (100 pg/kg-10 ng/kg) and M&B28767 (1 pg/kg-100 pg/kg) produced a significant reduction in the paw-withdrawal latency. The maximal reduction was observed 15 min after the LCV injection of these drugs. Neither 17-phenyl-ω-trinor PGE₂ (1 pg/kg-1 μg/kg) nor butaprost (1 pg/kg-100 μg/kg) induced any significant changes in the paw-withdrawal latency. The LCV injection of PGE₂ (1 μg/kg) and 17-phenyl-ω-trinor PGE₂ (50 μg/kg) increased the latency only 5 min after LCV injection. These findings indicate that the LCV injection of PGE₂ induces thermal hyperalgesia through EP₃ receptors and analgesia through EP₁ receptors by its central action in rats.     

Up-regulated neuronal COX-2 expression after cortical spreading depression is involved in non-REM sleep induction in rats

Cortical spreading depression is an excitatory wave of depolarization spreading throughout cerebral cortex at a rate of 2-5 mm/min and has been implicated in various neurological disorders, such as epilepsy, migraine aura, and trauma. Although sleepiness or sleep is often induced by these neurological disorders, the cellular and molecular mechanism has remained unclear. To investigate whether and how the sleep-wake behavior is altered by such aberrant brain activity, we induced cortical spreading depression in freely moving rats, monitoring REM and non-REM (NREM) sleep and sleep-associated changes in cyclooxygenase (COX)-2 and prostaglandins (PGs). In such a model for aberrant neuronal excitation in the cerebral cortex, the amount of NREM sleep, but not of REM sleep, increased subsequently for several hours, with an up-regulated expression of COX-2 in cortical neurons and considerable production of PGs. A specific inhibitor of COX-2 completely arrested the increase in NREM sleep. These results indicate that up-regulated neuronal COX-2 would be involved in aberrant brain excitation-induced NREM sleep via production of PGs.     

Prostaglandin E2 protects cultured cortical neurons against receptor-mediated glutamate cytotoxicity

The effects of prostaglandin (PG) E₂ on glutamate-induced cytotoxicity were examined using primary cultures of rat cortical neurons. The cell viability was significantly reduced when cultures were briefly exposed to either glutamate or (NMDA) then incubated with normal medium for 1 h. Similar cytotoxicity was observed with the brief application of ionomycin, a calcium ionophore, and S-nitrosocysteine, a nitric oxide (NO)-generating agent. PGE₂ at concentrations of 0.01–1 μM dose-dependently ameliorated the glutamate-induced cytotoxicity. PGE₁, butaprost, an EP₂ receptor agonist, and 8-bromo-cAMP were also effective in protecting cultures against glutamate cytotoxicity. By contrast, neither 17-phenyl-ω-trinor-PGE₂, an EP₁ receptor agonist, nor M & B 28767, an EP₃ receptor agonist, affected glutamate-induced cytotoxicity. NMDA-induced cytotoxicity was ameliorated by PGE₂, butaprost, MK-801, , a NO synthase inhibitor, and hemoglobin, which binds NO. These agents excluding MK-801 ameliorated the ionomycin-induced cytotoxicity. The cytotoxicity induced by S-nitrosocysteine was prevented only by hemoglobin but not by the other agents including PGE₂. These findings indicate that PGE₂ protects cultured cortical neurons against NMDA receptor-mediated glutamate neurotoxicity via EP₂ receptors. EP₂ receptor stimulation may suppress a step in NO formation triggered by Ca²⁺-influx through NMDA receptors.     

Activation of EP2 receptor suppresses poly(I: C) and LPS‐mediated inflammation in primary microglia and organotypic hippocampal slice cultures: Contributing role for MAPKs

Brain inflammation is a critical factor involved in neurodegeneration. Recently, the prostaglandin E₂ (PGE₂) downstream members were suggested to modulate neuroinflammatory responses accompanying neurodegenerative diseases. In this study, we investigated the protective effects of prostaglandin E₂ receptor 2 (EP₂) during TLR3 and TLR4‐driven inflammatory response using in vitro primary microglia and ex vivo organotypic hippocampal slice cultures (OHSCs). Depletion of microglia from OHSCs differentially affected TLR3 and TLR4 receptor expression. Poly(I:C) induced the production of prostaglandin E₂ in OHSCs by increasing cyclooxygenase (COX‐2) and microsomal prostaglandin E synthase (mPGES)‐1. Besides, stimulation of OHSCs and microglia with Poly(I:C) upregulated EP₂ receptor expression. Co‐stimulation of OHSCs and microglia with the EP₂ agonist butaprost reduced inflammatory mediators induced by LPS and Poly(I:C). In Poly(I:C) challenged OHSCs, butaprost almost restored microglia ramified morphology and reduced Iba1 immunoreactivity. Importantly, microglia depletion prevented the induction of inflammatory mediators following Poly(I:C) or LPS challenge in OHSCs. Activation of EP₂ receptor reversed the Poly(I:C)/LPS‐induced phosphorylation of the mitogen activated protein kinases (MAPKs) ERK, p38 MAPK and c‐Jun N‐terminal kinase (JNK) in microglia. Collectively, these data identify an anti‐inflammatory function for EP₂ signaling in diverse innate immune responses, through a mechanism that involves the mitogen‐activated protein kinases pathway.     

Characterization of the EP receptor types that mediate longitudinal smooth muscle contraction of human colon,mouse colon and mouse ileum

Background Prostaglandin E₂ (PGE₂) is an inflammatory mediator implicated in several gastrointestinal pathologies that affect normal intestinal transit. The aim was to establish the contribution of the four EP receptor types (EP_1–4), in human colon, that mediate PGE₂‐induced longitudinal smooth muscle contraction. Methods Changes in isometric muscle tension of human colon, mouse colon and mouse ileum were measured in organ baths in response to receptor‐specific agonists and antagonists. In addition, lidocaine was used to block neurogenic activity to investigate whether EP receptors were pre‐ or post‐junctional. Key Results PGE₂ contracted longitudinal muscle from human and mouse colon and mouse ileum. These contractions were inhibited by the EP₁ receptor antagonist, EP₁A in human colon, whereas a combination of EP₁A and the EP₃ antagonist, L798106 inhibited agonist responses in both mouse preparations. The EP₃ agonist, sulprostone also increased muscle tension in both mouse tissues, and these responses were inhibited by lidocaine in the colon but not in the ileum. Although PGE₂ consistently contracted all three muscle preparations, butaprost decreased tension by activating smooth muscle EP₂ receptors in both colonic tissues. Alternatively, in mouse ileum, butaprost responses were lidocaine‐sensitive, suggesting that it was activating prejunctional EP₂ receptors on inhibitory motor neurons. Conversely, EP₄ receptors were not functional in all the intestinal muscle preparations tested. Conclusions & Inferences PGE₂‐induced contraction of longitudinal smooth muscle is mediated by EP₁ receptors in human colon and by a combination of EP₁ and EP₃ receptors in mouse intestine, whereas EP₂ receptors modulate relaxation in all three preparations.     

Biphasic modulation in the trigeminal nociceptive neuronal responses by the intracerebroventricular prostaglandin E2 may be mediated through different EP receptors subtypes in rats

To determine which prostaglandin E₂ (PGE₂) receptor subtypes are involved in the brain-derived PGE₂-induced changes in nociception, we injected synthetic EP₁, EP₂ and EP₃ receptor agonists (0.01 fmol to 10 nmol) into the lateral cerebroventricle (LCV) of urethane-anesthetized rats and observed the changes in the responses of the wide dynamic range (WDR) neurons in the trigeminal nucleus caudalis to noxious pinching of facial skin. The enhancement and suppression of the nociceptive responses of the WDR neurons were observed after the LCV injection of MB28767 (an EP₃ receptor agonist) at a low dose range (1–100 fmol) and 17-phenyl-ω-trinor PGE₂ (an EP₁ receptor agonist) at high doses (1–10 nmol), respectively. Furthermore, the suppression of nociceptive neuronal responses after the LCV injection of PGE₂ (1 nmol) was completely blocked by SC19220 (an EP₁ receptor antagonist, 300 nmol). On the other hand, butaprost (an EP₂ receptor agonist) at any doses tested (0.1 fmol to 1 nmol) had no effect on the nociceptive responses. The LCV injection of MB28767 (10 fmol) and 17-phenyl-ω-trinor PGE₂ (1 nmol), which respectively enhanced and suppressed the nociceptive neuronal responses, did not affect the responses of the low threshold mechanoreceptive neurons to innocuous tactile stimuli. These results provide electrophysiological evidence that brain-derived PGE₂ induces mechanical hyperalgesia and hypoalgesia through EP₃ and EP₁ receptors, respectively, in the rat.     

Molecular species of prostaglandins involved in modulating luteinising hormone pulses of female rats under infectious stress conditions

Mammalian reproductive function is controlled by the hypothalamic‐pituitary‐gonadal (HPG) axis, which is suppressed under infectious stress conditions. By analysing the pulsatility of luteinising hormone (LH), we have previously demonstrated that prostaglandins (PGs) in the central nervous system mediate infectious stress to suppress the activity of the HPG axis. The present study aimed to characterise the types of PGs responsible for suppression of the HPG axis. We focused on three major types of PGs: PGE₂, PGD₂ and PGF_2α. We used female rats overiectomised bilaterally 1 week before the experiments. Lipopolysaccharide (100 μg kg^–1) suppressed LH pulses at the same time as enhancing the concentration of all three PGs in the cerebrospinal fluid, which was restored by indomethacin (10 mg kg^–1). Subsequently, we observed LH pulsatility after a single injection of each PG and after co‐injection of PGE₂ with PGF_2α into the third cerebral ventricle. A single injection of PGE₂ dose‐dependently induced a transient increase in mean LH concentration and LH pulse amplitude, and PGD₂ significantly increased the amplitude of LH pulses, wereas PGF_2α did not affect LH pulsatility. On the other hand, co‐injection of PGE₂ and PGF_2α induced a significant suppression of both the frequency and amplitude of LH pulses. These results suggest that PGE₂ and PGF_2α can represent two of the mediators that suppress the HPG axis in situations of infectious stress. Moreover, the results imply that there are two contradictory effects of PGE₂ on LH pulsatility: (i) enhancive when working alone and (ii) suppressive when working together with PGF_2α.     

Effect of NMDA receptor antagonists on prostaglandin E2-induced hyperalgesia in conscious mice

Intrathecal (i.t.) injection of prostaglandin E₂ (PGE₂) to conscious mice produced a hyperalgesic action over a wide range of dosages with two apparent peaks at 100 pg and 10 ng per mouse, which may be mediated through EP₃ and EP₂ subtypes of the PGE receptor. In the present study, the effects of NMDA receptor antagonists on hyperalgesia induced by PGE₂ were evaluated by the hot plate test at 30 min after i.t. injection. Hyperalgesia induced by a higher dose of PGE₂ (10 ng/mouse) was relieved byd-AP5 (a competitive antagonist), 7-Cl-KynA (a glycine site antagonist), and ketamine and MK801 (non-competitive channel blockers). Intrathecal injection of butaprost (10 ng/mouse), an EP₂ agonist, induced hyperalgesia, and this hyperalgesia was blocked byd-AP5, 7-Cl-KynA, ketamine, and MK801, similar to that induced by 10 ng of PGE₂. On the other hand, hyperalgesia induced by a lower dose of PGE₂ (100 pg/mouse) was blocked byd-AP5 and 7-Cl-KynA, but not by ketamine and MK801. Intrathecal injection of sulprostone (100 pg/mouse), an EP₁ and EP₃ agonist, induced hyperalgesia, and this hyperalgesia was blocked byd-AP5 and 7-Cl-KynA, but not by ketamine and MK801, similar to that induced by 100 pg of PGE₂. These results first demonstrate that the NMDA receptor is involved in the PGE₂-induced hyperalgesia and suggest that the hyperalgesic action by lower and higher doses of PGE₂ may be mediated through EP₃ and EP₂ subtypes, respectively.     

Prostaglandin E2, a postulated astrocyte-derived neurovascular coupling agent,constricts rather than dilates parenchymal arterioles

It has been proposed that prostaglandin E₂ (PGE₂) is released from astrocytic endfeet to dilate parenchymal arterioles through activation of prostanoid (EP₄) receptors during neurovascular coupling. However, the direct effects of PGE₂ on isolated parenchymal arterioles have not been tested. Here, we examined the effects of PGE₂ on the diameter of isolated pressurized parenchymal arterioles from rat and mouse brain. Contrary to the prevailing assumption, we found that PGE₂ (0.1, 1, and 5 μmol/L) constricted rather than dilated parenchymal arterioles. Vasoconstriction to PGE₂ was prevented by inhibitors of EP₁ receptors. These results strongly argue against a direct role of PGE₂ on arterioles during neurovascular coupling.     

Prostaglandin E2 may induce hyperthermia through EP1 receptor in the anterior wall of the third ventricle and neighboring preoptic regions

We have previously reported that intracerebroventricular injection of prostaglandin E₂ (PGE₂) induces hyperthermia possibly through EP₁ receptors in the rat. In the present study, to determine the sites in the brain where PGE₂ induces hyperthermia through EP₁ receptors, we microinjected an EP₁ receptor agonist, 17-phenyl-ω-trinor PGE₂ (17-Ph-PGE₂, 100 ng) into different sites in the rat brain and observed the colonic temperature (T_co) for 2 h in a 23±1°C environment. Responsive sites where 17-Ph-PGE₂ (100 ng) produced a rise in the T_co of more than 1.1°C within 60 min after injection were found in the medial preoptic area, the subchiasmatic portion of the median preoptic nucleus, the anterior wall of the third ventricle (A3V) and the ventral portion of the diagonal band of Broca. Among these sites, the A3V was the most responsive. In contrast, microinjection of neither butaprost (an EP₂ agonist, 100 ng) nor M&B28767 (an EP₃ agonist, 100 ng) into these four sites had any effect on the T_co. Intracerebroventricular pretreatment with SC-19220 (an EP₁ antagonist, 100 μg) inhibited the rise in the T_co which was induced by microinjection of PGE₂ (50 ng) into the A3V. These results thus suggest that PGE₂ induces hyperthermia by stimulating EP₁ receptors in the A3V and the neighboring preoptic region.     

Sickness behaviour after lipopolysaccharide treatment in ghrelin deficient mice

Ghrelin is an orexigenic hormone produced mainly by the gastrointestinal system and the brain. Much evidence also indicates a role for ghrelin in sleep and thermoregulation. Further, ghrelin was recently implicated in immune system modulation. Administration of bacterial lipopolysaccharide (LPS) induces fever, anorexia, and increased non-rapid-eye movement sleep (NREMS) and these actions are mediated primarily by proinflammatory cytokines. Ghrelin reduces LPS-induced fever, suppresses circulating levels of proinflammatory cytokines and reduces the severity and mortality of various models of experimental endotoxemia. In the present study, we determined the role of intact ghrelin signaling in LPS-induced sleep, feeding, and thermoregulatory responses in mice. Sleep-wake activity was determined after intraperitoneal, dark onset administration of 0.4, 2 and 10 μg LPS in preproghrelin knockout (KO) and wild-type (WT) mice. In addition, body temperature, motor activity and changes in 24-h food intake and body weight were measured. LPS induced dose-dependent increases in NREMS, and suppressed rapid-eye movement sleep, electroencephalographic slow-wave activity, motor activity, food intake and body weight in both Ppg KO and WT mice. Body temperature changes showed a biphasic pattern with a decrease during the dark period followed by an increase in the light phase. The effects of the low and middle doses of LPS were indistinguishable between the two genotypes. Administration of 10 μg LPS, however, induced significantly larger changes in NREMS and wakefulness amounts, body temperature, food intake and body weight in the Ppg KO mice. These findings support a role for ghrelin as an endogenous modulator of inflammatory responses and a central component of arousal and feeding circuits.     

The effect of non-steroidal anti-inflammatory agents on behavioural changes and cytokine production following systemic inflammation: Implications for a role of COX-1

Systemic inflammation gives rise to metabolic and behavioural changes, largely mediated by pro-inflammatory cytokines and prostaglandin production (PGE₂) at the blood–brain barrier. Despite numerous studies, the exact biological pathways that give rise to these changes remains elusive. This study investigated the mechanisms underlying immune-to-brain communication following systemic inflammation using various anti-inflammatory agents.Mice were pre-treated with selective cyclo-oxygenase (COX) inhibitors, thromboxane synthase inhibitors or dexamethasone, followed by intra-peritoneal injection of lipopolysaccharide (LPS). Changes in body temperature, open-field activity, and burrowing were assessed and mRNA and/or protein levels of inflammatory mediators measured in serum and brain.LPS-induced systemic inflammation resulted in behavioural changes and increased production of IL-6, IL-1β and TNF-α, as well as PGE₂ in serum and brain. Indomethacin and ibuprofen reversed the effect of LPS on behaviour without changing peripheral or central IL-6, IL-1β and TNF-α mRNA levels. In contrast, dexamethasone did not alter LPS-induced behavioural changes, despite complete inhibition of cytokine production. A selective COX-1 inhibitor, piroxicam, but not the selective COX-2 inhibitor, nimesulide, reversed the LPS-induced behavioural changes without affecting IL-6, IL-1β and TNF-α protein expression levels in the periphery or mRNA levels in the hippocampus.Our results suggest that the acute LPS-induced changes in burrowing and open-field activity depend on COX-1. We further show that COX-1 is not responsible for the induction of brain IL-6, IL-1β and TNF-α synthesis or LPS-induced hypothermia. Our results may have implications for novel therapeutic strategies to treat or prevent neurological diseases with an inflammatory component.     

CSF levels of prostaglandins, especially the level of prostaglandin D2, are correlated with increasing propensity towards sleep in rats

The concentration of PGD₂, PGE₂, and of PGF_2α was measured in the cerebrospinal fluid (CSF) collected from the cisterna magna of conscious rats (n=29), which, chronically implanted with a catheter for the CSF sampling, underwent deprivation of daytime sleep. Significant elevation of the CSF level of PGD₂ was observed following 2.5-h sleep deprivation (SD), and the elevation became more marked following 5- and 10-h SD, apparently reaching the maximum at 5-h SD (703±140 pg/ml (mean±S.E.M.) for baseline vs. 1734±363 pg/ml for SD, n=10). The levels of PGE₂ and PGF_2α also significantly increased following 5- and 10-h SD, but not following 2.5-h SD. It is unlikely that these changes were simply caused by some responses of the animals to stress stimuli, because stress stimuli derived from restraint of the animal at the supine position to a board for 1 h did not produce any acute responses in the CSF levels of prostaglandins (n=13). In a different group of animals (n=11) implanted with electrodes for recording electroencephalogram (EEG) and electromyogram (EMG) in addition to the catheter, the levels of the prostaglandins in CSF were determined for slow-wave sleep (SWS) and wakefulness in the day and for SWS and wakefulness in the night. The highest PGD₂ value was obtained at daytime SWS, whereas the lowest was at night wakefulness; furthermore, a significant difference was observed between SWS and wakefulness rather than between day and night. The CSF level of PGE₂ also showed a similar tendency. In an additional group of animals (n=6), not only PGD₂ but also PGE₂ and PGF_2α significantly increased the sleeping time of the animal when applied into the subarachnoid space underlying the ventral surface area of the rostral basal forebrain, the previously defined site of action for the sleep-promoting effect of PGD₂. The promotion of sleep by PGE₂ applied to the subarachnoid space was an effect completely opposite to the well-established awaking effect of the same prostaglandin demonstrated in the hypothalamic region in a series of previous studies. Based on these results, we conclude that increases in CSF levels of prostaglandins, especially that of PGD₂, are correlated in rats with heightened propensity towards sleep and further with the depth of sleep under normal as well as SD conditions. © 1997 Elsevier Science B.V. All rights reserved.