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Ruud, Johan
Publications (10 of 14) Show all publications
Ruud, J., Nilsson, A., Engström Ruud, L., Wang, W., Nilsberth, C., Iresjo, B.-M., . . . Blomqvist, A. (2013). Cancer-induced anorexia in tumor-bearing mice is dependent on cyclooxygenase-1. Brain, behavior, and immunity, 29, 124-135
Open this publication in new window or tab >>Cancer-induced anorexia in tumor-bearing mice is dependent on cyclooxygenase-1
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2013 (English)In: Brain, behavior, and immunity, ISSN 0889-1591, E-ISSN 1090-2139, Vol. 29, p. 124-135Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
Elsevier, 2013
Keywords
Cancer anorexia-cachexia, Cyclooxygenase, Microsomal prostaglandin E synthase-1, Prostaglandin E2
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-90188 (URN)10.1016/j.bbi.2012.12.020 (DOI)000315365400013 ()
Note

Funding Agencies|Swedish Cancer Foundation||Swedish Research Council||Swedish Brain Foundation||

Available from: 2013-04-04 Created: 2013-03-21 Last updated: 2017-12-06Bibliographically approved
Ruud, J., Björk, D., Nilsson, A., Eskilsson, A., Tang, Y.-j., Stroehle, P., . . . Blomqvist, A. (2013). Inflammation- and tumor-induced anorexia and weight loss require MyD88 in hematopoietic/myeloid cells but not in brain endothelial or neural cells. The FASEB Journal, 27(5), 1973-1980
Open this publication in new window or tab >>Inflammation- and tumor-induced anorexia and weight loss require MyD88 in hematopoietic/myeloid cells but not in brain endothelial or neural cells
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2013 (English)In: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 27, no 5, p. 1973-1980Article in journal (Refereed) Published
Abstract [en]

Loss of appetite is a hallmark of inflammatory diseases. The underlying mechanisms remain undefined, but it is known that myeloid differentiation primary response gene 88 (MyD88), an adaptor protein critical for Toll-like and IL-1 receptor family signaling, is involved. Here we addressed the question of determining in which cells the MyD88 signaling that results in anorexia development occurs by using chimeric mice and animals with cell-specific deletions. We found that MyD88-knockout mice, which are resistant to bacterial lipopolysaccharide (LPS)-induced anorexia, displayed anorexia when transplanted with wild-type bone marrow cells. Furthermore, mice with a targeted deletion of MyD88 in hematopoietic or myeloid cells were largely protected against LPS-induced anorexia and displayed attenuated weight loss, whereas mice with MyD88 deletion in hepatocytes or in neural cells or the cerebrovascular endothelium developed anorexia and weight loss of similar magnitude as wild-type mice. Furthermore, in a model for cancer-induced anorexia-cachexia, deletion of MyD88 in hematopoietic cells attenuated the anorexia and protected against body weight loss. These findings demonstrate that MyD88-dependent signaling within the brain is not required for eliciting inflammation-induced anorexia. Instead, we identify MyD88 signaling in hematopoietic/myeloid cells as a critical component for acute inflammatory-driven anorexia, as well as for chronic anorexia and weight loss associated with malignant disease.

Place, publisher, year, edition, pages
Federation of American Society of Experimental Biology (FASEB), 2013
Keywords
lipopolysaccharide; methylcholanthrene-induced sarcoma; food intake; chimeric mice; Cre-LoxP; inducible cell-specific deletion
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-96147 (URN)10.1096/fj.12-225433 (DOI)000318226100017 ()
Available from: 2013-08-14 Created: 2013-08-14 Last updated: 2017-12-06
Hamzik, N., Tang, Y.-j., Eskilsson, A., Örtegren Kugelberg, U., Ruud, J., Jönsson, J.-I., . . . Nilsberth, C. (2013). Interleukin-6 primarily produced by non-hematopoietic cells mediates the lipopolysaccharide-induced febrile response. Brain, behavior, and immunity, 33, 123-130
Open this publication in new window or tab >>Interleukin-6 primarily produced by non-hematopoietic cells mediates the lipopolysaccharide-induced febrile response
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2013 (English)In: Brain, behavior, and immunity, ISSN 0889-1591, E-ISSN 1090-2139, Vol. 33, p. 123-130Article in journal (Refereed) Published
Abstract [en]

Interleukin-6 (IL-6) is critical for the lipopolysaccharide (LPS)-induced febrile response. However, the exact source(s) of IL-6 involved in regulating the LPS-elicited fever is still to be identified. One known source of IL-6 is hematopoietic cells, such as monocytes. To clarify the contribution of hematopoietically derived IL-6 to fever, we created chimeric mice expressing IL-6 selectively either in cells of hematopoietic or, conversely, in cells of non-hematopoietic origin. This was performed by extinguishing hematopoietic cells in wild-type (WT) or IL-6 knockout (IL-6 KO) mice by whole-body irradiation and transplanting them with new stem cells. Mice on a WT background but lacking IL-6 in hematopoietic cells displayed normal fever to LPS and were found to have similar levels of IL-6 protein in the cerebrospinal fluid (CSF) and in plasma and of IL-6 mRNA in the brain as WT mice. In contrast, mice on an IL-6 KO background, but with intact IL-6 production in cells of hematopoietic origin, only showed a minor elevation of the body temperature after peripheral LPS injection. While they displayed significantly elevated levels of IL-6 both in plasma and CSF compared with control mice, the increase was modest compared with that seen in LPS injected mice on a WT background, the latter being approximately 20 times larger in magnitude. These results suggest that IL-6 of non-hematopoietic origin is the main source of IL-6 in LPS-induced fever, and that IL-6 produced by hematopoietic cells only plays a minor role.

Place, publisher, year, edition, pages
Elsevier, 2013
Keywords
Interleukin-6, Hematopoietic cells, Bone marrow transplantation, Fever
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-99401 (URN)10.1016/j.bbi.2013.06.006 (DOI)000324788300016 ()
Note

Funding Agencies|Swedish Research Council|33X-0787968X-2053564X-21463|Swedish Cancer Foundation|4095|Swedish Brain Foundation||Tore Nilsson Foundation||Ake Wiberg Foundation||Langmanska Kulturfonden||Lars Hierta Memorial Foundation||Magn. Bergvall Foundation||County Council of Ostergotland||Harald and Greta Jeansson Foundation||Royal Swedish Academy of Sciences||Foundation of the National Board of Health and Welfare||

Available from: 2013-10-17 Created: 2013-10-17 Last updated: 2017-12-06
Ruud, J. (2012). Central Nervous System and Innate Immune Mechanisms for Inflammation- and Cancer-induced Anorexia. (Doctoral dissertation). Linköping: Linköping University Electronic Press
Open this publication in new window or tab >>Central Nervous System and Innate Immune Mechanisms for Inflammation- and Cancer-induced Anorexia
2012 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Anyone who has experienced influenza or a bacterial infection knows what it means to be ill. Apart from feeling feverish, experiencing aching joints and muscles, you lose the desire to eat. Anorexia, defined as loss of appetite or persistent satiety leading to reduced energy intake, is a hallmark of acute inflammatory disease. The anorexia is part of the acute phase response, triggered as the result of activation of the innate immune system with concomitant release of inflammatory mediators, which interact with the central nervous system. A chronic condition, and a severe medical problem, that resembles inflammation-induced anorexia is cachexia. Cachexia, which is commonly associated with malignant cancer, is typified as a cytokine-associated metabolic derangement leading to weight loss, mediated by activation of the immune system. Paradoxically, weight loss in cancer patients is often associated with reduced food intake, indicating that the normal coupling of energy intake to body weight is disarranged. Accumulating evidence indicates that inflammation- and cancer-induced anorexia are associated with Toll-like receptor and cycloxygenase (Cox) activation. However, the nature of these pathways is far from understood, and a series of experiments addressing this issue was therefore undertaken.

In paper I, we injected Morris hepatoma 7777 cells or vehicle into rats, and we analyzed the distribution pattern of the transcription factor Fos, an index of neuronal activity, in the brainstem. We found that the anorexia and weight loss in tumor-bearing rats were associated with extensive expression of Fos in the area postrema and the general visceral region of the nucleus of the solitary tract in the medulla oblongata, as well as in the external lateral pontine parabrachial nucleus, and that the magnitude of the Fos expression correlated positively with tumor weight and negatively with body weight development, respectively. The Fos expression occurred without any obvious signs of peripheral or central inflammation, and was not secondary to alterations in body weight or reduced food intake. Thus, in paper I, we found a tumor-elicited activation of three interconnected autonomic structures, which integrate and transmit afferent visceral and sensory information, and which are known to play vital roles for energy homeostasis.

In paper II we evaluated the effects of tumor growth on feeding behaviour in mice as well as the role of Cox-1 and Cox-2, and prostaglandin E2 (PGE2) for the decreased appetite. We implanted mice with a MCG 101 tumor, which resulted in decreased meal frequency but not decreased meal size or meal duration. We found that indomethacin, a non-selective Cox-inhibitor, attenuated the anorexia as well as the tumor growth. When given acutely at manifest anorexia, Cox-inhibitors rescued the loss of appetite and prevented body weight loss without affecting tumor weight. Despite Cox-2 gene induction in the brain and Cox-2 protein induction in cells associated to the blood-brain barrier in tumor-bearing mice, a Cox-2 inhibitor had no impact on tumor-induced anorexia. By contrast, manipulating Cox-1 activity with a selective Cox-1 inhibitor delayed the onset of the anorexic response. Tumor growth was associated with large elevations in plasma PGE2, a response that was prevented by indomethacin. In contrast, however, PGE2 levels in liquor were largely unaffected, in line with tumor-bearing mice being afebrile. Neutralisation of peripheral PGE2 with anti-PGE2 antibodies did not temper the anorexia, and deletion of host mPGES-1 did not affect the anorexia or tumor growth. Furthermore, we found that tumor-bearing mice lacking EP4 receptors in the nervous system, created by Cre-LoxP-targeted mutagenesis, developed anorexia. The most important conclusions from paper II are that decreased meal frequency caused the anorexia, and that Cox-enzymes, most likely Cox-1, are critical for cancer-elicited anorexia and weight loss and that these changes occur independently of host mPGES-1, PGE2 and neuronal EP4 receptor signaling.

In paper III, we investigated whether the inflammatory response critical for tumor-induced anorexia (paper II) was a result of innate immune signaling mechanisms. In paper IV, we also included measurements of food intake in mice injected with bacterial endotoxin, lipopolysaccharide (LPS; a Toll-like receptor 4 ligand), and aimed at identifying at which site(s) the activation of the innate immune system occurs during acute (LPS) as well as chronic (tumor) inflammation. To do so we examined the anorexic response in mice ubiquitously lacking (born without the gene in every cell) MyD88, the intracellular adaptor for Toll-like receptor and IL-1/18 receptor signalling, or lacking MyD88 in specific cell types. We found that a ubiquitous null deletion conferred complete resistance to LPS- and tumor-induced anorexia, as well as protected against weight loss. MyD88 knock-out mice, which had been subjected to whole-body irradiation to delete hematopoietic cells, and then transplanted with wild-type bone-marrow, developed anorexia when challenged with LPS. In line with this, mice lacking MyD88 in hematopoietic cells were largely protected against LPS-induced anorexia. Similarly, inactivation of MyD88 in hematopoietic cells attenuated the tumor-induced anorexia development and protected from body weight loss. In contrast, genetic disruption of MyD88 signaling in neural cells or cerebrovascular endothelial cells affected neither LPS- or tumor-induced anorexia, nor weight loss. Thus, the key findings in paper III and IV are that genetic inactivation of MyD88 protects mice from developing cancer- and LPS-induced anorexia, indicating that innate immune signaling mechanisms are critical for this response. The findings also identify hematopoietic cells, but not neural cells or cerebrovascular endothelial cells, as a critical nexus for inflammatory driven anorexia and weight loss associated with acute (LPS) and chronic (malignant) disease.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2012. p. 111
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1311
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-77754 (URN)978-91-7519-879-8 (ISBN)
Public defence
2012-06-08, Berzeliussalen, ingång 64, plan 9, Campus US, Linköpings universitet, Linköping, 09:00 (Swedish)
Opponent
Supervisors
Available from: 2012-05-28 Created: 2012-05-28 Last updated: 2019-12-10Bibliographically approved
Engström, L., Ruud, J., Eskilsson, A., Larsson, A., Mackerlova, L., Kugelberg, U., . . . Blomqvist, A. (2012). Lipopolysaccharide-Induced Fever Depends on Prostaglandin E2 Production Specifically in Brain Endothelial Cells. Endocrinology, 153(10), 4849-4861
Open this publication in new window or tab >>Lipopolysaccharide-Induced Fever Depends on Prostaglandin E2 Production Specifically in Brain Endothelial Cells
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2012 (English)In: Endocrinology, ISSN 0013-7227, E-ISSN 1945-7170, Vol. 153, no 10, p. 4849-4861Article in journal (Refereed) Published
Abstract [en]

Immune-induced prostaglandin E2 (PGE2) synthesis is critical for fever and other centrally elicited disease symptoms. The production of PGE2 depends on cyclooxygenase-2 and microsomal prostaglandin E synthase-1 (mPGES-1), but the identity of the cells involved has been a matter of controversy. We generated mice expressing mPGES-1 either in cells of hematopoietic or nonhematopoietic origin. Mice lacking mPGES-1 in hematopoietic cells displayed an intact febrile response to lipopolysaccharide, associated with elevated levels of PGE2 in the cerebrospinal fluid. In contrast, mice that expressed mPGES-1 only in hematopoietic cells, although displaying elevated PGE2 levels in plasma but not in the cerebrospinal fluid, showed no febrile response to lipopolysaccharide, thus pointing to the critical role of brain-derived PGE2 for fever. Immunohistochemical stainings showed that induced cyclooxygenase-2 expression in the brain exclusively occurred in endothelial cells, and quantitative PCR analysis on brain cells isolated by flow cytometry demonstrated that mPGES-1 is induced in endothelial cells and not in vascular wall macrophages. Similar analysis on liver cells showed induced expression in macrophages and not in endothelial cells, pointing at the distinct role for brain endothelial cells in PGE2 synthesis. These results identify the brain endothelial cells as the PGE2-producing cells critical for immune-induced fever.

Place, publisher, year, edition, pages
Endocrine Society, 2012
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-84885 (URN)10.1210/en.2012-1375 (DOI)000309210200027 ()
Note

Funding Agencies|Swedish Research Council|7879|Swedish Cancer Foundation|100533|Swedish Brain Foundation||Gustav V:s 80-ars Fond||

Available from: 2012-11-01 Created: 2012-10-26 Last updated: 2017-12-07
Elander, L., Ruud, J., Korotkova, M., Jakobsson, P.-J. & Blomqvist, A. (2010). Cyclooxygenase-1 mediates the immediate corticosterone response to peripheral immune challenge induced by lipopolysaccharide. Neuroscience letters, 470(1), 10-2
Open this publication in new window or tab >>Cyclooxygenase-1 mediates the immediate corticosterone response to peripheral immune challenge induced by lipopolysaccharide
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2010 (English)In: Neuroscience letters, ISSN 1872-7972, Vol. 470, no 1, p. 10-2Article in journal (Refereed) Published
Abstract [en]

Immune-induced activation of the hypothalamus-pituitary-adrenal axis is mediated by cyclooxygenase derived prostaglandins. Here we examined the role of cyclooxygenase-1 in this response, by using genetically modified mice as well as pharmacological inhibition. We found that mice with a deletion of the gene encoding cyclooxygenase-1, in contrast to wild type mice, did not show increased plasma corticosterone at 1h after immune challenge by peripheral injection of bacterial wall lipopolysaccharide, whereas the corticosterone levels were similarly elevated in both genotypes at 6h post-injection. Pretreatment of mice with the selective cyclooxygenase-1 inhibitor SC-560, given orally, likewise inhibited the rapid corticosterone response. These findings, taken together with our recent demonstration that the delayed stress hormone response to immune challenge is dependent on cyclooxygenase-2, show that the two cyclooxygenase isoforms play distinct, but temporally supplementary roles for the stress hormone response to inflammation.

Keywords
Corticosterone; Hypothalamus–pituitary–adrenal axis; Mouse; Cyclooxygenase; Lipopolysaccharide
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-53911 (URN)10.1016/j.neulet.2009.12.036 (DOI)000274947500003 ()20034541 (PubMedID)
Available from: 2010-02-11 Created: 2010-02-11 Last updated: 2010-03-12
Ruud, J., Backhed, F., Engblom, D. & Blomqvist, A. (2010). Deletion of the gene encoding MyD88 protects from anorexia in a mouse tumor model. Brain, behavior, and immunity, 24(4), 554-557
Open this publication in new window or tab >>Deletion of the gene encoding MyD88 protects from anorexia in a mouse tumor model
2010 (English)In: Brain, behavior, and immunity, ISSN 0889-1591, E-ISSN 1090-2139, Vol. 24, no 4, p. 554-557Article in journal (Refereed) Published
Abstract [en]

The anorexia-cachexia syndrome, characterized by a rise in energy expenditure and loss of body weight that paradoxically are associated with loss of appetite and decreased food intake, contributes significantly to the morbidity and mortality in cancer. While the pathophysiology of cancer anorexia-cachexia is poorly understood, evidence indicates that pro-inflammatory cytokines are key mediators of this response. Although inflammation hence is recognized as an important component of cancer anorexia-cachexia, the molecular pathways involved are largely unknown. We addressed this issue in mice carrying a deletion of the gene encoding MyD88, the key intracellular adaptor molecule in Toll-like and interleukin-1 family receptor signaling. Wild-type and MyD88-deficient mice were transplanted subcutaneously with a syngenic methylcholanthrene-induced tumor (MCG 101) and daily food intake and body weight were recorded. Wild-type mice showed progressively reduced food intake from about 5 days after tumor transplantation and displayed a slight body weight loss after 10 days when the experiment was terminated. In contrast, MyD88-deficient mice did not develop anorexia, and displayed a positive body weight development during the observation period. While the MyD88-deficient mice on average developed somewhat smaller tumors than wild-type mice, this did not explain the absence of anorexia, because anorexia was seen in wild-type mice with similar tumor mass as non-anorexic knock-out mice. These data suggest that MyD88-dependent mechanisms are involved in the metabolic derangement during cancer anorexia-cachexia and that innate immune signaling is important for the development of this syndrome.

Place, publisher, year, edition, pages
Amsterdam: Elsevier Science B.V., 2010
Keywords
Anorexia, Cachexia, Cancer, MyD88, Mice, Innate immunity
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-56458 (URN)10.1016/j.bbi.2010.01.006 (DOI)000277206600006 ()
Available from: 2010-05-17 Created: 2010-05-17 Last updated: 2017-12-12Bibliographically approved
Bjartmar, L., Alkhori, L., Ruud, J., Marcusson, J. & Hallbeck, M. (2010). Long-term treatment with antidepressants, but not environmental stimulation, induces expression of NP2 mRNA in hippocampus and medial habenula. Brain Research, 1328, 24-33
Open this publication in new window or tab >>Long-term treatment with antidepressants, but not environmental stimulation, induces expression of NP2 mRNA in hippocampus and medial habenula
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2010 (English)In: Brain Research, ISSN 0006-8993, E-ISSN 1872-6240, Vol. 1328, p. 24-33Article in journal (Refereed) Published
Abstract [en]

Neuronal Pentraxin 2 (NP2, Narp), known to mediate clustering of glutamatergic AMPA receptors at synapses, is involved in activity-dependent synaptogenesis and synaptic plasticity. In experimental settings, antidepressant treatment as well as a stimulating environment has a positive influence on cognition and hippocampal plasticity. This study demonstrates that NP2 mRNA is robustly expressed in the hippocampus and the medial habenula (MHb), both regions implicated in cognitive functions. Furthermore, NP2 mRNA expression is enhanced in the hippocampal subregions as well as in the MHb after long-term treatment with antidepressant drugs of various monoaminergic profiles, indicating a common mode of action of different antidepressant drugs. This effect occurs at the time frame where clinical response is normally achieved. In contrast, neither environmental enrichment nor deprivation has any influence on long-term NP2 mRNA expression. These findings support an involvement of NP2 in the pathway of antidepressant induced plasticity, but not EE induced plasticity; that NP2 might constitute a common link for the action of different types of antidepressant drugs and that the MHb could be a putative region for further studies of NP2.

Place, publisher, year, edition, pages
Elsevier, 2010
Keywords
Neuronal pentraxins, narp, habenula, hippocampus, synaptic plasticity, antidepressant
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-51408 (URN)10.1016/j.brainres.2010.03.004 (DOI)000277682400003 ()
Note
On the day of the defence day the status of this article was: Submitted.Available from: 2009-10-30 Created: 2009-10-30 Last updated: 2019-10-14Bibliographically approved
Elander, L., Engström, L., Ruud, J., Mackerlova, L., Jakobsson, P.-J., Engblom, D., . . . Blomqvist, A. (2009). Inducible Prostaglandin E-2 Synthesis Interacts in a Temporally Supplementary Sequence with Constitutive Prostaglandin-Synthesizing Enzymes in Creating the Hypothalamic-Pituitary-Adrenal Axis Response to Immune Challenge. Journal of Neuroscience, 29(5), 1404-1413
Open this publication in new window or tab >>Inducible Prostaglandin E-2 Synthesis Interacts in a Temporally Supplementary Sequence with Constitutive Prostaglandin-Synthesizing Enzymes in Creating the Hypothalamic-Pituitary-Adrenal Axis Response to Immune Challenge
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2009 (English)In: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 29, no 5, p. 1404-1413Article in journal (Refereed) Published
Abstract [en]

Inflammation-induced activation of the hypothalamic-pituitary-adrenal (HPA) axis has been suggested to depend on prostaglandins, but the prostaglandin species and the prostaglandin-synthesizing enzymes that are responsible have not been fully identified. Here, we examined HPA axis activation in mice after genetic deletion or pharmacological inhibition of prostaglandin E-2-synthesizing enzymes, including cyclooxygenase-1 (Cox-1), Cox-2, and microsomal prostaglandin E synthase-1 (mPGES-1). After immune challenge by intraperitoneal injection of lipopolysaccharide, the rapid stress hormone responses were intact after Cox-2 inhibition and unaffected by mPGES-1 deletion, whereas unselective Cox inhibition blunted these responses, implying the involvement of Cox-1. However, mPGES-1-deficient mice showed attenuated transcriptional activation of corticotropin-releasing hormone (CRH) that was followed by attenuated plasma concentrations of adrenocorticotropic hormone and corticosterone. Cox-2 inhibition similarly blunted the delayed corticosterone response and further attenuated corticosterone release in mPGES-1 knock-out mice. The expression of the c-fos gene, an index of synaptic activation, was maintained in the paraventricular hypothalamic nucleus and its brainstem afferents both after unselective and Cox-2 selective inhibition as well as in Cox-1, Cox-2, and mPGES-1 knock-out mice. These findings point to a mechanism by which ( 1) neuronal afferent signaling via brainstem autonomic relay nuclei and downstream Cox-1-dependent prostaglandin release and ( 2) humoral, CRH transcription-dependent signaling through induced Cox-2 and mPGES-1 elicited PGE(2) synthesis, shown to occur in brain vascular cells, play distinct, but temporally supplementary roles for the stress hormone response to inflammation.

Keywords
CRH, ACTH, corticosterone, mPGES-1, LPS, Fos
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-16849 (URN)10.1523/JNEUROSCI.5247-08.2009 (DOI)
Available from: 2009-02-21 Created: 2009-02-20 Last updated: 2017-12-13
Sepehr, A., Ruud, J. & Mohseni, S. (2009). Neuron survival in vitro is more influenced by the developmental age of the cells than by glucose condition. Cytotechnology (Dordrecht), 61(1-2), 73-79
Open this publication in new window or tab >>Neuron survival in vitro is more influenced by the developmental age of the cells than by glucose condition
2009 (English)In: Cytotechnology (Dordrecht), ISSN 0920-9069, E-ISSN 1573-0778, Vol. 61, no 1-2, p. 73-79Article in journal (Refereed) Published
Abstract [en]

The objective of this study was to determine whether the sensitivity to varying glucose conditions differs for the peripheral and central nervous system neurons at different developmental stages. Ventral horn neurons (VHN) and dorsal root ganglion neurons (DRG) from rats of different postnatal ages were exposed to glucose-free or glucose-rich culture conditions. Following 24 h at those conditions, the number of protein gene product 9.5 positive (PGP(+)) DRG neurons and choline acetyltransferase positive (ChAT(+)) VHN were counted and their neurite lengths and soma diameters were measured. For both DRG and VHN, the highest number of cells with and without neurite outgrowth was seen when cells from postnatal day 4 donors were cultured, while the lowest cell numbers were when neurons were from donors early after birth and grown under glucose-free conditions. The length of the neurites and the soma diameter for VHN were not affected by either glucose level or age. DRG neurons, however, exhibited the shortest neurites and smallest soma diameter when neurons were obtained and cultured early after birth. Our results indicate that survival of neurons in vitro is more influenced by the developmental stage than by glucose concentrations.

Keywords
Age; DRG; Glucose; In vitro; Neurite outgrowth; Ventral horn neuron
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-52897 (URN)10.1007/s10616-009-9234-8 (DOI)
Note
The original publication is available at www.springerlink.com: Arian Sepehr, Johan Ruud and Simin Mohseni, Neuron survival in vitro is more influenced by the developmental age of the cells than by glucose condition, 2009, Cytotechnology (Dordrecht), (61), 1-2, 73-79. http://dx.doi.org/10.1007/s10616-009-9234-8 Copyright: Springer Science Business Media http://www.springerlink.com/ Available from: 2010-01-13 Created: 2010-01-12 Last updated: 2017-12-12
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