A clearance system for prostaglandin D2, a sleep-promoting factor, in cerebrospinal fluid: role of the blood-cerebrospinal barrier transporters.

Although the level of prostaglandin (PG) D(2) in cerebrospinal fluid (CSF) affects the action of D-type prostanoid receptors that promote physiological sleep, the regulatory system of PGD(2) clearance from the CSF is not fully understood. The purpose of this study was to investigate PGD(2) elimination from the CSF via the blood-CSF barrier (BCSFB). The in vivo PGD(2) elimination clearance from the CSF was 16-fold greater than that of inulin, which is considered to reflect CSF bulk flow. This process was inhibited by the simultaneous injection of unlabeled PGD(2). The characteristics of PGD(2) uptake by isolated choroid plexus were, at least partially, consistent with those of PG transporter (PGT) and organic anion transporter 3 (OAT3). Studies using an oocyte expression system showed that PGT and OAT3 were able to mediate PGD(2) transport with a Michaelis-Menten constant of 1.07 and 7.32 µM, respectively. Reverse transcription-polymerase chain reaction and immunohistochemical analyses revealed that PGT was localized on the brush-border membrane of the choroid plexus epithelial cells. These findings indicate that the system regulating the PGD(2) level in the CSF involves PGT- and OAT3-mediated PGD(2) uptake by the choroid plexus epithelial cells, acting as a pathway for PGD(2) clearance from the CSF via the BCSFB.

Prostaglandin D2 produced by hematopoietic prostaglandin D synthase contributes to LPS-induced fever.

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.

Prostaglandin D(2) sustains the pyrogenic effect of prostaglandin E(2).

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.

Carbon monoxide-prostaglandin E2 interaction in the hypothalamic circulation.

The heme oxygenase (HO)-carbon monoxide pathway was earlier shown to increase hypothalamic blood flow after inhibition of nitric oxide synthesis in rats. We hypothesized that this effect is mediated by prostaglandin E2 (PGE2). Inhibition of constitutive HO activity decreased cerebral PGE2 production and simultaneously increased hypothalamic nitric oxide synthase (NOS) activity without changing hypothalamic blood flow. Furthermore, HO blockade induced cyclooxygenase-dependent decrease and NOS-mediated increase of the hypothalamic blood flow after inhibition of NOS and cyclooxygenase, respectively. Therefore, constitutive carbon monoxide release seems to have two indirect effects on the hypothalamic circulation: vasodilation mediated by PGE2 and vasoconstriction as a result of NOS inhibition.

A novel antipyretic action of 15-deoxy-Delta12,14-prostaglandin J2 in the rat brain.

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.

Cerebrospinal fluid prostaglandins and corticotropin releasing factor in schizophrenics and controls: relationship to sleep architecture.

Sleep abnormalities have been consistently observed in patients with schizophrenia. Elevated levels of corticotropin releasing factor (CRF) and prostaglandins (PGs) in the cerebrospinal fluid (CSF) of patients with schizophrenia have been reported, and these neurochemical substances, known to modulate sleep in experimental animals, may play a role in these sleep abnormalities. In this study, we measured PGD2, PGE2, PGF2alpha and CRF levels in the CSF of 14 unmedicated schizophrenic patients and 14 age- and sex-matched control subjects. Polysomnographic recordings were also carried out for each subject. As expected, the sleep of the schizophrenic subjects significantly differed from that of the controls; schizophrenic subjects had a longer sleep onset latency, slept less, spent fewer minutes in stage 2 sleep and had a lower sleep efficiency. We could not, however, detect any differences in CSF CRF and PG levels between normal and schizophrenic subjects, nor could we find any correlation between CSF variables and sleep parameters in the schizophrenic subjects and the non-psychiatric controls. These results do not favor the hypothesis of a role for CRF or PGs in the pathophysiology of sleep disturbances in schizophrenia.

[Beta trace protein in the cerebrospinal fluid and serum in meningoencephalitis]. / Proteína beta traza en líquido cefalorraquídeo y suero en meningoencefalitis.

INTRODUCTION: beta-trace protein or D2 prostaglandin synthase is a dual functional protein. Its role and clinical value in cerebrospinal fluid is under study. MATERIAL AND METHODS: Seventy four pediatric patients suffering from viral meningoencephalitis and 7 with bacterial meningoencephalitis were studied. Sera and cerebrospinal fluid samples were taken. Albumin and beta-trace protein were quantified by immunodiffusion and nephelometry respectively. RESULTS: Increased cerebrospinal fluid beta-trace protein levels in comparison with normal value were observed. Nevertheless such expected increment was no possible seen in bacterial meningoencephalitis. CONCLUSIONS: beta-trace protein may contribute with the etiological diagnosis in meningoencephalitis.

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 PGF2 alpha 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 PGF2 alpha 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 PGF2 alpha 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.

Concentration of prostaglandin D2 in cerebrospinal fluid exhibits a circadian alteration in conscious rats.

Cerebrospinal fluid (CSF) was withdrawn from the cisterna magna of unanesthetized conscious rats (n = 14) through a chronically implanted catheter, and prostaglandins (PGs) D2, E2, and F2 alpha were measured. From each rat, CSF samples were taken at different clock-hours of the day (1000, 1400, and 1800 hr) and night (2200, 0200, and 0600 hr) in succession at 76-hour intervals. The concentration of PGD2 alone exhibited a significant circadian fluctuation, with its peak value at 1400 hr (mean +/- SEM: 1197 +/- 361 pg/ml) and its lowest level at 0600 hr (438 +/- 106 pg/ml). Thus, the mean level of PGD2 during the daytime (903 +/- 162 pg/ml) was significantly higher than that during the night (503 +/- 78 pg/ml). The results obtained are consistent with the postulated role of PGD2, acting in the surface layer of the rostral basal forebrain, as an endogenous factor to promote sleep.

Circadian variations of prostaglandins D2, E2, and F2 alpha in the cerebrospinal fluid of anesthetized rats.

Circadian variations in the levels of prostaglandins (PGs) D2, E2, and F2 alpha were studied in the cerebrospinal fluid (CSF) of rats. We collected CSF samples from the cisterna magna of anesthetized rats at different clock-hours (1000, 1400, 1800, 2200, 0200, and 0600 hr), and measured the concentrations of the three PGs. PGD2, which appeared to be the most abundant among the three, showed a circadian variation; and the mean of the day-time levels (145 pg/ml) was significantly higher than that of the nighttime ones (111 pg/ml). Day/night variations were also noticed with the levels of PGE2 and PGF2 alpha; however, these levels remained 3-4 times lower than those of PGD2. The general day/night variation seen in the CSF concentration of PGD2 conforms well with the postulated role of PGD2 as an endogenous sleep-promoting factor acting on a certain brain surface area defined as its site of action.

Mediator release in cerebrospinal fluid of human immunodeficiency virus-positive patients with central nervous system involvement.

In this study we evaluated the release of some mediators of inflammatory reactions such as histamine (H), leukotriene B4 (LTB4), leukotriene C4 (LTC4) and prostaglandin D2 (PGD2) in the cerebrospinal fluid (CSF) of 15 patients with acquired immunodeficiency syndrome (AIDS), eight with opportunistic infections of the central nervous system (CNS) and seven without HIV-related neurological pathology, and of 25 HIV-negative control subjects with other neurological diseases. The cerebrospinal LTB4 level was increased in all the AIDS patients (mean 348 pg/ml); the control group revealed normal levels of LTB4 in the CSF (mean 63.2 pg/ml). The PGD2 level in the HIV-positive (mean 264 pg/ml) patients was higher than of the control subjects (mean 50 pg/ml), while low LTC4 levels were found both in the HIV-positive and control groups. We did not find any significant concentration of H in the CSF of either the HIV-positive or the control subjects. These findings may be due to the presence of chronic HIV infection or to the opportunistic infections of the CNS that so often occur in the latest stages of the disease.

Prostaglandin E2 levels in cerebrospinal fluid of normal and narcoleptic dogs.

It has been shown that endogenous prostaglandin D2 and prostaglandin E2 (PGE2) are involved in sleep-wake regulation. Our recent experimental result that exogenously administered PGE2 significantly reduces canine cataplexy (a pathological equivalent of rapid-eye-movement sleep atonia and a symptom of narcolepsy) suggests that PGE2 is involved in the pathophysiology of canine narcolepsy. In order to further investigate the role of prostaglandins (PGs) in this disorder, PG levels in cerebrospinal fluid (CSF) of genetically homozygous narcoleptic, heterozygous (unaffected), and control Doberman pinschers were studied. PGE2 levels were measured by direct radioimmunoassay (RIA) and after high-grade purification using PG affinity columns and high-performance liquid chromatography. PGD2 and PGF2 alpha levels were measured by RIA after high-grade purification. There was no significant difference in PGE2 levels between homozygous narcoleptic and heterozygous or controls dogs, and PGD2 and PGF2 alpha levels were undetectable in most cases. Our results do not favor the hypothesis that central PGE2 levels are modified in canine narcolepsy, assuming that PGE2 levels in cisternal CSF properly reflect PGE2 production in the brain.

The somnogenic T lymphocyte suppressor prostaglandin D2 is selectively elevated in cerebrospinal fluid of advanced sleeping sickness patients.

To help to elucidate the changes induced by Trypanosoma brucei gambiense in the central nervous system (CNS) in advanced sleeping sickness patients, levels of interleukin-1 (IL-1) and prostaglandins D2 (PGD2) and E2 (PGE2) were measured by radioimmunoassay in the cerebrospinal fluid (CSF) from 24 patients diagnosed on the criteria of CSF protein, leucocyte count and parasite presence as having CNS (i.e. late stage) involvement, and from 12 patients without CNS involvement. PGD2 concentrations were selectively and markedly elevated in the late stage patients. The increased PGD2 may in part account for the increased somnolence and the immunosuppression within the CNS. Measurement of PGD2 levels in CSF may be a useful criterion for CNS involvement.

Eicosanoid levels in CSF of premature infants with posthemorrhagic hydrocephalus.

The cerebrospinal fluid (CSF) of 11 premature infants suffering from posthemorrhagic hydrocephalus was examined by radioimmunoassay for prostaglandin (PG) E2, PGF2 alpha, PGD2, 6-keto PGF1 alpha, thromboxane B2 (TxB2) and peptidoleukotrienes (LTC4/LTD4). The LTs were detected in the CSF of more of these patients (70%) than any of the other eicosanoids, and usually in the highest concentration. Among the 11 posthemorrhagic patients CSF eicosanoid levels were highest when determined soon after injury. Moreover, the variety of eicosanoids present, as well as concentrations, in these infants decreased with time. The types of eicosanoids most evident in the CSF of patients who required shunting were TxB2 and LTs, being present together in 5 of 6 (83%) of these infants. In contrast, 1 of 5 (20%) of the patients who did not require this neurosurgical intervention contained both TxB2 and LTs, the remaining having only one or neither eicosanoid. The highest average concentration for each eicosanoid studied was (pg/ml): PGE2, 628; PGF2 alpha, 985; PGD2, 1410; 6-keto PGF1 alpha, 544; TxB2, 486 and LTs, 1229. This study is the first to demonstrate that the CSF of preterm infants may contain a wide variety of eicosanoids and indicates that these lipids are a manifestation of neurological assault.