Prostaglandin E2 Attenuates Preoptic Expression of GABAA Receptors via EP3 Receptors

Tsuchiya, Hiroyoshi; Oka, Takahiro; Nakamura, Kazuhiro; Ichikawa, Atsushi; Saper, Clifford B.; Sugimoto, Yukihiko

doi:10.1074/jbc.m801359200

Cited by 19 publications

(16 citation statements)

References 31 publications

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“…The preoptic region of the anterior hypothalamus was shown to mediate the fever response and to participate to the HPA-activation (Saper et al, 2012;Ulrich-Lai and Herman, 2009) and hyperalgesia (Abe et al, 2001). Despite a high representation of EPs in this region we could not identify any of the inflammation-induced gene expression changes to be regulated by PGE2 (paper IV), which seems to be in line with the sparse evidence in the literature (Tsuchiya et al, 2008), and which suggests that most of the effects of PGE2 are nontranscriptional.…”

Section: Brain Pge2 As a Mediator Of Fever At The Preoptic Regionsupporting

confidence: 77%

“…Nonetheless, even in that model, in which the gene regulatory effects were examined briefly after icv injection of PGE2, few genes were identified that were changed by the stimulus, and these genes generally displayed low fold changes (between 1.5 and 2). However, in that study (Tsuchiya et al, 2008) it was reported that the GABAA transcript was attenuated by PGE2, a finding that could not be verified in our present work.…”

Section: Discussioncontrasting

confidence: 56%

“…The consequence of extracting the entire POA might be that any effect of PGE2 on gene expression in neurons, if present, could be diluted and hence undetected due the presence of a large number of vascular and glial cells. Another approach would have been to dissect individual cells expressing EP receptors like shown for EP3 positive neurons (Tsuchiya et al, 2008). Nonetheless, even in that model, in which the gene regulatory effects were examined briefly after icv injection of PGE2, few genes were identified that were changed by the stimulus, and these genes generally displayed low fold changes (between 1.5 and 2).…”

Section: Discussionmentioning

confidence: 99%

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Talking to the Brain at the Blood-Brain Barrier through Inflammation-Induced Prostaglandin E2

Vasilache¹

2015

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The immune-to-brain signaling is a critical survival factor when the body is confronted by pathogens, and in particular by microorganisms. During infections, the ability of the immune system to engage the central nervous system (CNS) in the management of the inflammatory response is just as important as its ability to mount a specific immune response against the pathogen, since the CNS can provide a systemic negative feed-back to the immune activation by release of stress hormones and also can prioritize the usage of the energy resources by the vital organs. Prostaglandin E2 (PGE2) and pro-inflammatory cytokines were among the first mediators to be identified to participate in the immune-to-brain signaling, a process that is clinically recognized by the development of manifestations of common illness such as fever, anorexia, decreased social interactions, lethargy, sleepiness, and hyperalgesia.In this thesis the contribution of PGE2 to the immune-to-brain signaling was further characterized at the blood-brain-barrier (BBB) and in the anterior preoptic area (POA) of the hypothalamus (i.e. the thermoregulatory region or, in sickness, the fever generating region).BBB is the major interface region between peripheral circulating cytokines and the neuronal parenchyma and a critical source of PGE2. Using chimeric mice lacking the inducible enzyme for PGE2 synthesis, microsomal PGE synthase-1 (mPGES-1), in either hematopoietic or nonhematopoietic cells, we demonstrate in paper I that brain endothelial cells are the critical source of PGE2 in BBB during peripheral inflammation. For the demonstration of the mPGES-1 expression in the BBB cells we developed in paper I a method for enzymatic dissociation of these cells, followed by fluorescence activated cell sorting (FACS). Using the same method, we show in paper II that the BBB response to immune stimuli is towards an increased production of PGE2 in endothelial cells and an increased sensitivity of these cells for proinflammatory cytokines. These changes are supported by decreased PGE2 degradation and decreased synthesis of other prostanoids in perivascular macrophages, which hence respond in concordance with the endothelial cells in enhancing PGE2 signaling.Once released in the neuronal tissue, PGE2 has been shown to be critical for the fever response by acting on the type 3 PGE2 receptors (EP3) within POA. By laser capture microdissection (LCM) we extracted the EP3 receptor expressing region in POA, defined by in situ hybridization histochemistry, from mouse brain sections. We demonstrate in paper III that the predominant subtypes of the EP3 receptor in POA are EP3α and EP3γ. In paper IV we further analyze the effect of PGE2 on the LCM dissected EP-rich POA using gene expression microarrays. We demonstrate that PGE2 has a limited effect on the gene expression changes within POA, suggesting that the neuronal activity is modulated by PGE2 in a transcriptionindependent manner and that the profound gene expression changes that are seen in the CNS during inflammation ...

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Section: Brain Pge2 As a Mediator Of Fever At The Preoptic Regionsupporting

confidence: 77%

Section: Discussioncontrasting

confidence: 56%

Section: Discussionmentioning

confidence: 99%

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Talking to the Brain at the Blood-Brain Barrier through Inflammation-Induced Prostaglandin E2

Vasilache¹

2015

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“…The preoptic area expresses EP 3 receptors that provide direct pyrogenic input to two hyperpyrexia generating sympathoexcitatory brain regions, the dorsomedial hypothalamus (Nakamura et al, 2005), and the rostral raphe pallidus nucleus (Nakamura et al, 2009). It has been suggested that EP 3 receptors cause a decrease in preoptic GABA A expression as a mechanism for PGE 2 -induced fever (Tsuchiya et al, 2008).…”

Section: Distribution and Biological Functionsmentioning

confidence: 99%

International Union of Basic and Clinical Pharmacology. LXXXIII: Classification of Prostanoid Receptors, Updating 15 Years of Progress

Woodward

Jones

Narumiya³

2011

Pharmacol Rev

391

414

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“…LPS-induced febrile response is blunted in mice deficient in mPGES-1 as well as those deficient in COX-2 or the PGE receptor EP3 [13,39,86]. Cerebral vascular endothelial cells express COX-2 and mPGES-1 enabling pro-inflammatory cytokines to stimulate the synthesis of PGE 2 , whose small size and lipophilic property allow it to pass across the blood-brain barrier into CNS neurons, where the PGE 2 /EP3 signaling elicits G i/o activation in preoptic thermocenter neurons by decreasing preoptic GABA type a receptor expression [84]. mPGES-1 expression is induced in neurons, microglia, and endothelial cells in the cerebral cortex after transient focal ischemia.…”

Section: Pain Fever and Nerve Injurymentioning

confidence: 99%

Lipid Mediators in Life Science

2011

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"Lipid mediators" represent a class of bioactive lipids that are produced locally through specific biosynthetic pathways in response to extracellular stimuli. They are exported extracellularly, bind to their cognate G protein-coupled receptors (GPCRs) to transmit signals to target cells, and are then sequestered rapidly through specific enzymatic or non-enzymatic processes. Because of these properties, lipid mediators can be regarded as local hormones or autacoids. Unlike proteins, whose information can be readily obtained from the genome, we cannot directly read out the information of lipids from the genome since they are not genome-encoded. However, we can indirectly follow up the dynamics and functions of lipid mediators by manipulating the genes encoding a particular set of proteins that are essential for their biosynthesis (enzymes), transport (transporters), and signal transduction (receptors). Lipid mediators are involved in many physiological processes, and their dysregulations have been often linked to various diseases such as inflammation, infertility, atherosclerosis, ischemia, metabolic syndrome, and cancer. In this article, I will give an overview of the basic knowledge of various lipid mediators, and then provide an example of how research using mice, gene-manipulated for a lipid mediator-biosynthetic enzyme, contributes to life science and clinical applications.

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Prostaglandin E2 Attenuates Preoptic Expression of GABAA Receptors via EP3 Receptors

Cited by 19 publications

References 31 publications

Talking to the Brain at the Blood-Brain Barrier through Inflammation-Induced Prostaglandin E2

Talking to the Brain at the Blood-Brain Barrier through Inflammation-Induced Prostaglandin E2

International Union of Basic and Clinical Pharmacology. LXXXIII: Classification of Prostanoid Receptors, Updating 15 Years of Progress

Lipid Mediators in Life Science

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