Identification of prostaglandin D2 as a major prostaglandin in homogenates of rat brain

doi:10.1016/0090-6980(77)90190-3

Prostaglandins

Volume 14, Issue 4, October 1977, Pages 633-643

Prostaglandins

https://doi.org/10.1016/0090-6980(77)90190-3 Get rights and content

Abstract

Prostaglandin (PG) E₂, D₂, F_2α and thromboxane B₂ (TxB₂) were determined in homogenates of rat brain by gas-chromatography - mass spectrometry. The level of PGD₂ was 735 ± 19 ng/g, of PGF_2α 150 ± 13 ng/g, of TxB₂ 112 ng/g and of PGE₂ 86 ± 8 ng/g. The same relative proportions of cyclo-oxygenase products were found in incubates of unstimulated sliced rat brain. ¹⁴C-PGH₂ was converted in high yield into PGD₂ by enzyme(s)_present in the soluble fraction of the homogenate. These results indicate that PGD₂ is the major cyclooxygenase product in the central nervous system of the rat.

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Prostaglandin D2 (PGD2) is a member of the prostaglandin group and is produced from arachidonic acid by cyclooxygenase (COX) and PGD synthase (PGDS) [1].
Prostaglandin D2 (PGD2) is associated with a diverse array of functions in mammals including regulation of appetite, body temperature, sleep, and immune responses. Although much is known about the effects of PGD2 in mammals, there is a lack of information about its effects in birds. Therefore, the purpose of the present study was to determine if intracerebroventricular (ICV) and intraperitoneal (IP) injections of PGD2 affect feeding, voluntary movement, crop-emptying rate, corticosterone release, and cloacal temperature in chicks (Gallus gallus). ICV injection of PGD2 was associated with a reduction in food intake, a reduction in voluntary movement, an increase in the time spent sitting, a decline in crop emptying rate, and also short-term hypothermia. Central injection of PGD2 also decreased the plasma glucose concentration in chicks while it tended to increase the plasma corticosterone concentration. On the other hand, except for crop emptying, such physiological changes are not observed after IP injection of PGD2. In sum, the present study suggests that PGD2 induces anorexia, change in behavior, decline in crop empting rate, hypoglycemia and hypothermia, but most of these effects are exerted via central nervous system in chicks.
PACAP27 prevents Parkinson-like neuronal loss and motor deficits but not microglia activation induced by prostaglandin J2
2014, Biochimica et Biophysica Acta - Molecular Basis of Disease
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In the previous studies we compared in vitro the neurotoxic effects of four different prostaglandins, i.e. A1, D2, E2, and J2, and established that prostaglandin J2 (PGJ2) was the most neurotoxic at the concentrations tested [47]. PGJ2 is derived from PGD2 [87], the principle cyclooxygenase product synthesized in the mammalian CNS [1,14,30]. From all prostaglandins, PGD2 levels change the most under pathological conditions [26,48].
Neuroinflammation is a major risk factor in Parkinson's disease (PD). Alternative approaches are needed to treat inflammation, as anti-inflammatory drugs such as NSAIDs that inhibit cyclooxygenase-2 (COX-2) can produce devastating side effects, including heart attack and stroke. New therapeutic strategies that target factors downstream of COX-2, such as prostaglandin J2 (PGJ2), hold tremendous promise because they will not alter the homeostatic balance offered by COX-2 derived prostanoids. In the current studies, we report that repeated microinfusion of PGJ2 into the substantia nigra of non-transgenic mice, induces three stages of pathology that mimic the slow-onset cellular and behavioral pathology of PD: mild (one injection) when only motor deficits are detectable, intermediate (two injections) when neuronal and motor deficits as well as microglia activation are detectable, and severe (four injections) when dopaminergic neuronal loss is massive accompanied by microglia activation and motor deficits. Microglia activation was evaluated in vivo by positron emission tomography (PET) with [¹¹C](R)PK11195 to provide a regional estimation of brain inflammation. PACAP27 reduced dopaminergic neuronal loss and motor deficits induced by PGJ2, without preventing microglia activation. The latter could be problematic in that persistent microglia activation can exert long-term deleterious effects on neurons and behavior. In conclusion, this PGJ2-induced mouse model that mimics in part chronic inflammation, exhibits slow-onset PD-like pathology and is optimal for testing diagnostic tools such as PET, as well as therapies designed to target the integrated signaling across neurons and microglia, to fully benefit patients with PD.
An integrated omics analysis of eicosanoid biology
2009, Journal of Lipid Research
Citation Excerpt :
Whereas the prostane ring on PGE2 has a 9-keto and 11-hydroxy moiety, the positions of these substituents are reversed on PGD2. In the late 1970s, PGD2 was identified as a major product in rat brain homogenates (45) and activated mast cells (46). PGD2 is formed by two evolutionarily distinct, but functionally convergent, prostaglandin D synthases (PGDS): the lipocalin-type (l-PGDS) and hematopoietic-type (h-PGDS).
Eicosanoids have been implicated in a vast number of devastating inflammatory conditions, including arthritis, atherosclerosis, pain, and cancer. Currently, over a hundred different eicosanoids have been identified, with many having potent bioactive signaling capacity. These lipid metabolites are synthesized de novo by at least 50 unique enzymes, many of which have been cloned and characterized. Due to the extensive characterization of eicosanoid biosynthetic pathways, this field provides a unique framework for integrating genomics, proteomics, and metabolomics toward the investigation of disease pathology. To facilitate a concerted systems biology approach, this review outlines the proteins implicated in eicosanoid biosynthesis and signaling in human, mouse, and rat. Applications of the extensive genomic and lipidomic research to date illustrate the questions in eicosanoid signaling that could be uniquely addressed by a thorough analysis of the entire eicosanoid proteome.
Lipocalin-prostaglandin D synthase is a critical beneficial factor in transient and permanent focal cerebral ischemia
2009, Neuroscience
Citation Excerpt :
Consequently, as COX-2 inhibitors are being tested to limit the production of prostaglandins, researchers should keep in mind that a downstream pathway such as the one modulated by L-PGDS could also be beneficial; therefore it would be best if novel drugs did not inhibit this pathway and perhaps should be designed to activate it. PGD2 is considered to be the most abundant prostaglandin present in the brain (Abdel-Halim et al., 1977). It is well known that inflammation increases PGD2 synthesis in the CNS (Hetu and Riendeau, 2005; Mohri et al., 2006b).
Prostaglandin D₂ (PGD₂) is the most abundant prostaglandin produced in the brain. It is a metabolite of arachidonic acid and synthesized by prostaglandin D₂ synthases (PGDS) via the cyclooxygenase pathway. Two distinct types of PGDS have been identified: hematopoietic prostaglandin D synthase (H-PGDS) and lipocalin-type prostaglandin D synthase (L-PGDS). Because relatively little is known about the role of L-PGDS in the CNS, here we examined the outcomes in L-PGDS knockout and wild-type (WT) mice after two different cerebral ischemia models, transient middle cerebral artery (MCA) occlusion (tMCAO) and permanent distal middle cerebral artery occlusion (pMCAO). In the tMCAO model, the MCA was occluded with a monofilament for 90 min and then reperfused for 4 days. In the pMCAO model, the distal part of the MCA was permanently occluded and the mice were sacrificed after 7 days. Percent corrected infarct volume and neurological score were determined after 4 and 7 days, respectively. L-PGDS knockout mice had significantly greater infarct volume and brain edema than did WT mice after tMCAO (P<0.01). Similarly, L-PGDS knockout mice showed greater infarct volume and neurological deficits as compared to their WT counterparts after pMCAO (P<0.01). Using the two models enabled us to study the role of L-PGDS in both early (tMCAO) and delayed (pMCAO) ischemic processes. Our findings suggest that L-PGDS is beneficial for protecting the brain against transient and permanent cerebral ischemia. These results provide a better understanding of the role played by the enzymes that control eicosanoid synthesis and how they can be utilized as potential targets to prevent damage following either acute or potentially chronic neurological disorders.
Prostaglandins are powerful inducers of NGF and BDNF production in mouse astrocyte cultures
2004, FEBS Letters
We found that prostaglandin (PG) D₂ and PGE₂, which are major PGs in the brain of mammals, powerfully induced the secretion of nerve growth factor (NGF) from cultured mouse astrocytes; PGE₂ or PGD₂ induced an approximately 12- or 19-fold increase in NGF secretion after a 24-h incubation, respectively. Moreover, it was found that the sequential metabolites of PGD₂, PGJ₂, Δ¹²-PGJ₂, and 15-deoxy-Δ^12,14-PGJ₂, induced the NGF secretion to the culture medium strikingly (60–98-fold of the control after a 24-h incubation). NGF secretion induced by the J₂ series of PGs was accompanied by the increased expression of NGF mRNA. These PGs also stimulated the secretion/synthesis of brain-derived neurotrophic factor (BDNF). Our findings suggest that PGs play a neuroprotective role by inducing NGF and BDNF production in the central nervous system.
Effect of endotoxin treatment on the expression on cyclooxygenase-2 and prostaglandin synthases in spinal cord, dorsal root ganglia, and skin of rats
2003, Neuroscience
Peripheral inflammation causes upregulation of cyclooxygenase in the spinal cord and subsequent increase in prostaglandin biosynthesis. However, prostaglandin synthases, which are downstream of cyclooxygenase control the type of prostaglandin that is formed predominantly. Since there is little known about the regulation of prostaglandin synthases, the present study was conducted in order to determine the effect of endotoxin treatment on the expression of messenger RNA encoding interleukin 1β, cyclooxygenase-2, and prostaglandin synthases mediating the formation of prostaglandin E₂ (membrane bound prostaglandin E synthase) and prostaglandin D₂ (lipocalin prostaglandin D synthase) in spinal cord, dorsal root ganglia and skin of rats.
Endotoxin (2 mg/kg i.p.) induced the expression of interleukin-1β, cyclooxygenase-2, and membrane bound prostaglandin E synthase messenger RNA in spinal cord, dorsal root ganglia, and skin as determined by reverse transcription polymerase chain reaction. In contrast, basal expression of lipocalin prostaglandin D synthase messenger RNA in spinal cord and dorsal root ganglia was not significantly altered by endotoxin. Dexamethasone (1 mg/kg s.c. at −18 h and −1 h) attenuated the effect endotoxin on the expression of interleukin-1β, cyclooxygenase-2, and membrane bound prostaglandin E synthase messenger RNA in all tissues investigated, but did not significantly influence expression of lipocalin prostaglandin D synthase mRNA in spinal cord and dorsal root ganglia. In situ hybridisation histochemistry showed endotoxin-induced expression of cyclooxygenase-2 and membrane bound prostaglandin E synthase messenger RNA throughout gray and white matter of spinal cord sections. In dorsal root ganglia, expression of membrane bound prostaglandin E synthase seemed primarily located to non-neuronal cells, while cyclooxygenase-2 messenger RNA was not detectable.
The results show that the immune response elicited by endotoxin induced cyclooxygenase-2 and membrane bound prostaglandin E synthase, but not lipocalin prostaglandin D synthase messenger RNA in spinal cord and dorsal root ganglia of rats. The distribution of cyclooxygenase-2 and membrane bound prostaglandin E synthase messenger RNA expressing cells suggests major involvement of non-neuronal cells in spinal prostaglandin biosynthesis. Determination of the regulation of enzymes downstream of cyclooxygenase at the messenger RNA level may represent a valuable tool to investigate effects of analgesic/anti-inflammatory drugs on the regulation of spinal prostaglandin biosynthesis.

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Identification of prostaglandin D2 as a major prostaglandin in homogenates of rat brain

Abstract

Prostaglandins

Biochem. Biophys. Res. Comm.

J. Biol. Chemistry

Biochim. Biophys. Acta

Biochim. Biophys. Acta

Biochim. Biophys. Acta

Identification of a smooth muscle-stimulating factor in bovine brain, prostaglandins and related factors 25

Biochim. Biophys. Acta

Identification of prostaglandin D₂ as a major prostaglandin in homogenates of rat brain