المؤلفون: Li Ming Chen, Yan Huang, Di Wang, Huan Gan Wu, Chun Hui Bao, Lu Yi Wu, Yu Wu, Shi Hua Liang, Hui Rong Liu

المصدر: Journal of Neuroinflammation, Vol 18, Iss 1, Pp 1-13 (2021)
Journal of Neuroinflammation

مصطلحات موضوعية: medicine.medical_specialty, Abdominal pain, Immunology, Population, Review, Disease, Gastroenterology, Inflammatory bowel disease, IDO, 03 medical and health sciences, Cellular and Molecular Neuroscience, chemistry.chemical_compound, 0302 clinical medicine, Internal medicine, Brain-Gut Axis, medicine, The brain-gut axis, Animals, Humans, Indoleamine-Pyrrole 2,3,-Dioxygenase, education, RC346-429, Kynurenine, Depression (differential diagnoses), Inflammation, education.field_of_study, business.industry, Depression, General Neuroscience, Tryptophan, Quinolinic Acid, Inflammatory Bowel Diseases, Prognosis, medicine.disease, Ulcerative colitis, digestive system diseases, Diarrhea, Neurology, chemistry, Quality of Life, 030211 gastroenterology & hepatology, Tryptophan-kynurenine metabolic pathway, Neurology. Diseases of the nervous system, medicine.symptom, business, 030217 neurology & neurosurgery, Signal Transduction, Quinolinic acid

الوصف: Inflammatory bowel disease (IBD), which mainly includes ulcerative colitis (UC) and Crohn's disease (CD), is a group of chronic bowel diseases that are characterized by abdominal pain, diarrhea, and bloody stools. IBD is strongly associated with depression, and its patients have a higher incidence of depression than the general population. Depression also adversely affects the quality of life and disease prognosis of patients with IBD. The tryptophan-kynurenine metabolic pathway degrades more than 90% of tryptophan (TRP) throughout the body, with indoleamine 2,3-dioxygenase (IDO), the key metabolic enzyme, being activated in the inflammatory environment. A series of metabolites of the pathway are neurologically active, among which kynerunic acid (KYNA) and quinolinic acid (QUIN) are molecules of great interest in recent studies on the mechanisms of inflammation-induced depression. In this review, the relationship between depression in IBD and the tryptophan-kynurenine metabolic pathway is overviewed in the light of recent publications.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::29ce81ec4403364b85ec1f950b148097Test
https://doaj.org/article/cfdc3464e622492595479647b25aef24Test

المؤلفون: Chuanzhu Yan, Tong Du, Ruonan Duan, Wenjie Sun, Jiangxia Li, Ai Liu, Qiji Liu, Anran Wang, Xi Li, Chun-Lin Yang

المصدر: Journal of Neuroinflammation, Vol 18, Iss 1, Pp 1-17 (2021)
Journal of Neuroinflammation

مصطلحات موضوعية: Central Nervous System, Indoleamine 2,3-dioxygenase, Encephalomyelitis, Autoimmune, Experimental, Multiple Sclerosis, Immunology, Inflammation, Proinflammatory cytokine, Myelin oligodendrocyte glycoprotein, Suppressor of MEK1, Interleukin 1β, Gene Knockout Techniques, Interferon-gamma, Mice, Cellular and Molecular Neuroscience, Immune system, Phosphoprotein Phosphatases, Animals, Indoleamine-Pyrrole 2,3,-Dioxygenase, Medicine, Myeloid Cells, RC346-429, Neuroinflammation, Experimental autoimmune encephalomyelitis, biology, Microglia, business.industry, Research, General Neuroscience, Multiple sclerosis, medicine.disease, Peptide Fragments, Mice, Inbred C57BL, Disease Models, Animal, medicine.anatomical_structure, Receptors, Aryl Hydrocarbon, Neurology, biology.protein, Cytokines, Myelin-Oligodendrocyte Glycoprotein, Neurology. Diseases of the nervous system, medicine.symptom, business, Spleen, Signal Transduction

الوصف: BackgroundExperimental autoimmune encephalomyelitis (EAE) is an animal disease model of multiple sclerosis (MS) that involves the immune system and central nervous system (CNS). However, it is unclear how genetic predispositions promote neuroinflammation in MS and EAE. Here, we investigated how partial loss-of-function of suppressor of MEK1 (SMEK1), a regulatory subunit of protein phosphatase 4, facilitates the onset of MS and EAE.MethodsC57BL/6 mice were immunized with myelin oligodendrocyte glycoprotein 35-55 (MOG35-55) to establish the EAE model. Clinical signs were recorded and pathogenesis was investigated after immunization. CNS tissues were analyzed by immunostaining, quantitative polymerase chain reaction (qPCR), western blot analysis, and enzyme-linked immunosorbent assay (ELISA). Single-cell analysis was carried out in the cortices and hippocampus. Splenic and lymph node cells were evaluated with flow cytometry, qPCR, and western blot analysis.ResultsHere, we showed that partial Smek1 deficiency caused more severe symptoms in the EAE model than in controls by activating myeloid cells and that Smek1 was required for maintaining immunosuppressive function by modulating the indoleamine 2,3-dioxygenase (IDO1)-aryl hydrocarbon receptor (AhR) pathway. Single-cell sequencing and an in vitro study showed that Smek1-deficient microglia and macrophages were preactivated at steady state. After MOG35-55immunization, microglia and macrophages underwent hyperactivation and produced increased IL-1β in Smek1-/+mice at the peak stage. Moreover, dysfunction of the IDO1-AhR pathway resulted from the reduction of interferon γ (IFN-γ), enhanced antigen presentation ability, and inhibition of anti-inflammatory processes in Smek1-/+EAE mice.ConclusionsThe present study suggests a protective role of Smek1 in autoimmune demyelination pathogenesis via immune suppression and inflammation regulation in both the immune system and the central nervous system. Our findings provide an instructive basis for the roles of Smek1 in EAE and broaden the understanding of the genetic factors involved in the pathogenesis of autoimmune demyelination.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::215c9b20f7ee7145b6e581012c1bf596Test
https://doaj.org/article/c9193ccafe52499aaf1c33b9a71e189aTest

المؤلفون: Jiajia Zhang, Lei Chen, Xuefeng Yu, Xi Jiang, Ziwei Chen, Fuhe Liu, Cong Pang, Lexing Xu, Lin Tang

المصدر: Journal of Neuroinflammation, Vol 15, Iss 1, Pp 1-16 (2018)
Journal of Neuroinflammation

مصطلحات موضوعية: Male, 0301 basic medicine, medicine.medical_specialty, Kynurenine pathway, Indoleamine-2,3-dioxygenase (IDO), Immunology, Inflammation, Anxiety, lcsh:RC346-429, Proinflammatory cytokine, Hepatic encephalopathy (HE), 03 medical and health sciences, Cellular and Molecular Neuroscience, chemistry.chemical_compound, 0302 clinical medicine, Kynurenic acid, Downregulation and upregulation, Internal medicine, medicine, Animals, Indoleamine-Pyrrole 2,3,-Dioxygenase, Rats, Wistar, Indoleamine 2,3-dioxygenase, Ligation, Hepatic encephalopathy, Kynurenine, lcsh:Neurology. Diseases of the nervous system, business.industry, Serotonin (5-HT), Depression, Research, General Neuroscience, Tryptophan, medicine.disease, Rats, Disease Models, Animal, 030104 developmental biology, Endocrinology, Neurology, chemistry, Hepatic Encephalopathy, Bile Ducts, Inflammation Mediators, medicine.symptom, business, 030217 neurology & neurosurgery, Signal Transduction

الوصف: Background This study aims to explore the role of indoleamine-2,3-dioxygenase (IDO)/kynurenine (KYN) pathway of tryptophan (TRY) metabolism in behavioral alterations observed in hepatic encephalopathy (HE) rats. Methods Expression levels of proinflammatory cytokines were tested by QT-PCR and ELISA, levels of IDOs were tested by QT-PCR and Western blot, and levels of 5-hydroxytryptamine (5-HT), KYN, TRY, 3-hydroxykynurenine (3-HK), and kynurenic acid (KA) in different brain regions were estimated using HPLC. Effects of the IDO direct inhibitor 1-methyl-l-tryptophan (1-MT) on cognitive, anxiety, and depressive-like behavior were evaluated in bile duct ligation (BDL) rats. Results Increased serum TNF-α, IL-1β, and IL-6 levels were shown in rats 7 days after BDL, and these increases were observed earlier than those in the brain, indicating peripheral immune activation may result in central upregulation of proinflammatory cytokines. Moreover, BDL rats showed a progressive decline in memory formation, as well as anxiety and depressive-like behavior. Further study revealed that IDO expression increased after BDL, accompanied by a decrease of 5-HT and an increase of KYN, as well as abnormal expression of 3-HK and KA. The above results affected by BDL surgery were reversed by IDO inhibitor 1-MT treatment. Conclusion Taken together, these findings indicate that (1) behavioral impairment in BDL rats is correlated with proinflammatory cytokines; (2) TRY pathway of KYN metabolism, activated by inflammation, may play an important role in HE development; and (3) 1-MT may serve as a therapeutic agent for HE. Electronic supplementary material The online version of this article (10.1186/s12974-017-1037-9) contains supplementary material, which is available to authorized users.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::49b837ef2f4695ac643d8bbdaff3adedTest
http://link.springer.com/article/10.1186/s12974-017-1037-9Test

المؤلفون: Xiao-Li Li, Heng Li, Min Zhang, Hua Xu, Long-Tao Yue, Xin-Xin Zhang, Shan Wang, Cong-Cong Wang, Yan-Bin Li, Ying-Chun Dou, Rui-Sheng Duan

المصدر: Journal of Neuroinflammation
Journal of Neuroinflammation, Vol 16, Iss 1, Pp 1-2 (2019)

مصطلحات موضوعية: Fas Ligand Protein, Immunology, Exosomes, T-Lymphocytes, Regulatory, lcsh:RC346-429, Cellular and Molecular Neuroscience, Bone Marrow, Animals, Indoleamine-Pyrrole 2,3,-Dioxygenase, fas Receptor, lcsh:Neurology. Diseases of the nervous system, General Neuroscience, Correction, Forkhead Transcription Factors, Dendritic Cells, Flow Cytometry, Myasthenia Gravis, Autoimmune, Experimental, Rats, Up-Regulation, Disease Models, Animal, Microscopy, Electron, Neurology, Rats, Inbred Lew, Cytokines, Female, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Signal Transduction

الوصف: Previously, we have demonstrated that spleen-derived dendritic cells (DCs) modified with atorvastatin suppressed immune responses of experimental autoimmune myasthenia gravis (EAMG). However, the effects of exosomes derived from atorvastatin-modified bone marrow DCs (BMDCs) (statin-Dex) on EAMG are still unknown.Immunophenotypical characterization of exosomes from atorvastatin- and dimethylsulfoxide (DMSO)-modified BMDCs was performed by electron microscopy, flow cytometry, and western blotting. In order to investigate whether statin-DCs-derived exosomes (Dex) could induce immune tolerance in EAMG, we administrated statin-Dex, control-Dex, or phosphate-buffered saline (PBS) into EAMG rats via tail vein injection. The tracking of injected Dex and the effect of statin-Dex injection on endogenous DCs were performed by immunofluorescence and flow cytometry, respectively. The number of Foxp3(+) cells in thymuses was examined using immunocytochemistry. Treg cells, cytokine secretion, lymphocyte proliferation, cell viability and apoptosis, and the levels of autoantibody were also carried out to evaluate the effect of statin-Dex on EAMG rats. To further investigate the involvement of FasL/Fas in statin-Dex-induced apoptosis, the underlying mechanisms were studied by FasL neutralization assays.Our data showed that the systemic injection of statin-Dex suppressed the clinical symptoms of EAMG rats. These statin-Dex had immune regulation functions in immune organs, such as the spleen, thymus, and popliteal and inguinal lymph nodes. Furthermore, statin-Dex exerted their immunomodulatory effects in vivo by decreasing the expression of CD80, CD86, and MHC class II on endogenous DCs. Importantly, the therapeutic effects of statin-Dex on EAMG rats were associated with up-regulated levels of indoleamine 2,3-dioxygenase (IDO)/Treg and partly dependent on FasL/Fas pathway, which finally resulted in decreased synthesis of anti-R97-116 IgG, IgG2a, and IgG2b antibodies.Our data suggest that atorvastatin-induced immature BMDCs are able to secrete tolerogenic Dex, which are involved in the suppression of immune responses in EAMG rats. Importantly, our study provides a novel cell-free approach for the treatment of autoimmune diseases.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::61c101e0947525cb9c184909eb0390c1Test
http://europepmc.org/articles/PMC6554886Test

المؤلفون: Hasan Yousefi-Manesh, Razieh Mohammad Jafari, Mohammad Amin Sadeghi, Sara Hemmati, Ahmad Reza Dehpour

المصدر: Journal of Neuroinflammation
Journal of Neuroinflammation, Vol 16, Iss 1, Pp 1-10 (2019)

مصطلحات موضوعية: 0301 basic medicine, Male, Kynurenine pathway, Lipopolysaccharide, Immunology, Gene Expression, Inflammation-induced depression, Pharmacology, Hippocampus, lcsh:RC346-429, Indoleamine 2, 3-dioxygenase, NF-ĸB, 03 medical and health sciences, Cellular and Molecular Neuroscience, chemistry.chemical_compound, Mice, 0302 clinical medicine, Granulocyte-macrophage stimulating factor, Downregulation and upregulation, Neuroinflammation, Medicine, Animals, Indoleamine-Pyrrole 2,3,-Dioxygenase, Indoleamine 2,3-dioxygenase, lcsh:Neurology. Diseases of the nervous system, business.industry, Depression, General Neuroscience, Research, NF-kappa B, Granulocyte-Macrophage Colony-Stimulating Factor, Antidepressive Agents, Toll-Like Receptor 4, 030104 developmental biology, Neurology, chemistry, TLR4, Antidepressant, Forced swim test, business, 030217 neurology & neurosurgery, Behavioural despair test

الوصف: Background Indoleamine 2, 3-dioxygenase 1 (IDO) is responsible for the progression of the kynurenine pathway. This pathway has been implicated in the pathophysiology of inflammation-induced depression in which conventional antidepressants are not effective. It has been reported that granulocyte-macrophage stimulating factor (GM-CSF) could interfere with the induction of IDO in septic patients. We hypothesized that GM-CSF could exert antidepressant effects through IDO downregulation in a model for acute inflammation-induced depression. Methods To produce the model, lipopolysaccharide (LPS) (0.83 mg/kg) was administered intraperitoneally to mice. It has been well documented that LPS mediates IDO overexpression through TLR4/NF-ĸB signaling. In the treatment group, mice received GM-CSF (30 μg/kg, i.p.) thirty minutes prior to LPS injection. A validated selective serotonin reuptake inhibitor, fluoxetine (30 mg/kg i.p.), was also administered to an experimental group 30 min prior to LPS. Depressive-like behaviors were evaluated based on the duration of immobility in the forced swim test. To confirm that GM-CSF interferes with IDO induction in LPS treated mice, real-time PCR was used to quantify IDO mRNA expression. Furthermore, in order to study whether GM-CSF inhibits the TLR4/NF-ĸB signaling pathway, we measured levels ofpNF-ĸB and TLR4 by western blotting. Results GM-CSF demonstrated significant antidepressant activity in the presence of LPS on immobility (p < .001) and latency (p = .010) times in the forced swim test. In contrast, fluoxetine did not show any antidepressant activity on either immobility (p = .918) or latency (p = .566) times. Furthermore, GM-CSF inhibited the increase in IDO mRNA (p = .032) and protein (p = .016) expression as a result of LPS administration. A similar trend was observed for TLR4 (p = .042) and pNF-ĸB (p = .026) expression as both proteins showed reduced expression levels in the GM-CSF-pretreated group compared to the untreated (LPS) group. Conclusion Our results propose a promising antidepressant effect for GM-CSF possibly through the downregulation of IDO expression. This remedying effect of GM-CSF could be attributed to decreased amounts of TLR4 and active NF-ĸB in the treated mice.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::aab1559713097fce779bff43e0d24b0aTest
https://pubmed.ncbi.nlm.nih.gov/31153376Test

المؤلفون: Jennifer M. Parrott, Jason C. O'Connor, Laney Redus

المصدر: Journal of Neuroinflammation

مصطلحات موضوعية: Lipopolysaccharides, Male, 0301 basic medicine, Time Factors, Kynurenine pathway, Hippocampus, Mass Spectrometry, Mice, chemistry.chemical_compound, Kynurenine 3-monooxygenase, 0302 clinical medicine, Neuroinflammation, Indoleamine 2,3-dioxygenase, Kynurenine 3-Monooxygenase, Kynurenine, Microglia, General Neuroscience, Microfilament Proteins, Brain, Cell biology, medicine.anatomical_structure, Neurology, Cytokines, Neurogenic Inflammation, Cell activation, Brain regions, Signal Transduction, Pro-inflammatory cytokines, Immunology, Biology, Proinflammatory cytokine, 03 medical and health sciences, Cellular and Molecular Neuroscience, Glial Fibrillary Acidic Protein, medicine, Animals, Indoleamine-Pyrrole 2,3,-Dioxygenase, RNA, Messenger, Research, Calcium-Binding Proteins, Mice, Inbred C57BL, Disease Models, Animal, 030104 developmental biology, chemistry, 030217 neurology & neurosurgery, Chromatography, Liquid

الوصف: Background Inflammation increases the risk of developing depression-related symptoms, and tryptophan metabolism is an important mediator of these behavior changes. Peripheral immune activation results in central up-regulation of pro-inflammatory cytokine expression, microglia activation, and the production of neurotoxic kynurenine metabolites. The neuroinflammatory and kynurenine metabolic response to peripheral immune activation has been largely characterized at the whole brain level. It is unknown if this metabolic response exhibits regional specificity even though the unique indoleamine 2,3-dioxygenase (IDO)-dependent depressive-like behaviors are known to be controlled by discrete brain regions. Therefore, regional characterization of neuroinflammation and kynurenine metabolism might allow for better understanding of the potential mechanisms that mediate inflammation-associated behavior changes. Methods Following peripheral immune challenge with lipopolysaccharide (LPS), brain tissue from behaviorally relevant regions was analyzed for changes in mRNA of neuroinflammatory targets and kynurenine pathway enzymes. The metabolic balance of the kynurenine pathway was also determined in the peripheral circulation and these brain regions. Results Peripheral LPS treatment resulted in region-independent up-regulation of brain expression of pro-inflammatory cytokines and glial cellular markers indicative of a neuroinflammatory response. The expression of kynurenine pathway enzymes was also largely region-independent. While the kynurenine/tryptophan ratio was elevated significantly in both the plasma and in each brain regions evaluated, the balance of kynurenine metabolism was skewed toward production of neurotoxic metabolites in the hippocampus. Conclusions The upstream neuroinflammatory processes, such as pro-inflammatory cytokine production, glial cell activation, and kynurenine production, may be similar throughout the brain. However, it appears that the balance of downstream kynurenine metabolism is a tightly regulated brain region-dependent process.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::bcd91e6968ff965593dee7389afa26c9Test
https://doi.org/10.1186/s12974-016-0590-yTest

المؤلفون: May Tan, Chai K. Lim, Tony Frugier, Gayathri Sundaram, David W. Walker, Gilles J. Guillemin, Edwin BingBing Yan, Maria Cristina Morganti-Kossmann, Benjamin Heng, Jeffrey V. Rosenfeld

المصدر: Journal of Neuroinflammation

مصطلحات موضوعية: Male, Kynurenine pathway, Excitotoxicity, Glasgow Outcome Scale, medicine.disease_cause, chemistry.chemical_compound, 0302 clinical medicine, Kynurenic acid, Cerebrospinal fluid, Traumatic brain injury, Quinolinic acid, Kynurenine, 0303 health sciences, General Neuroscience, Tryptophan, Brain, Middle Aged, Prognosis, Neurology, Female, medicine.symptom, Signal Transduction, Adult, medicine.medical_specialty, Patients, Adolescent, Immunology, Neurotoxins, Brain damage, Biology, 03 medical and health sciences, Cellular and Molecular Neuroscience, Young Adult, Internal medicine, medicine, Humans, Indoleamine-Pyrrole 2,3,-Dioxygenase, RNA, Messenger, Tryptophan metabolism, 030304 developmental biology, Aged, Research, Neurotoxicity, medicine.disease, Endocrinology, chemistry, Brain Injuries, Case-Control Studies, 030217 neurology & neurosurgery, Biomarkers

الوصف: During inflammation, the kynurenine pathway (KP) metabolises the essential amino acid tryptophan (TRP) potentially contributing to excitotoxicity via the release of quinolinic acid (QUIN) and 3-hydroxykynurenine (3HK). Despite the importance of excitotoxicity in the development of secondary brain damage, investigations on the KP in TBI are scarce. In this study, we comprehensively characterised changes in KP activation by measuring numerous metabolites in cerebrospinal fluid (CSF) from TBI patients and assessing the expression of key KP enzymes in brain tissue from TBI victims. Acute QUIN levels were further correlated with outcome scores to explore its prognostic value in TBI recovery. Methods Twenty-eight patients with severe TBI (GCS ≤ 8, three patients had initial GCS = 9–10, but rapidly deteriorated to ≤8) were recruited. CSF was collected from admission to day 5 post-injury. TRP, kynurenine (KYN), kynurenic acid (KYNA), QUIN, anthranilic acid (AA) and 3-hydroxyanthranilic acid (3HAA) were measured in CSF. The Glasgow Outcome Scale Extended (GOSE) score was assessed at 6 months post-TBI. Post-mortem brains were obtained from the Australian Neurotrauma Tissue and Fluid Bank and used in qPCR for quantitating expression of KP enzymes (indoleamine 2,3-dioxygenase-1 (IDO1), kynurenase (KYNase), kynurenine amino transferase-II (KAT-II), kynurenine 3-monooxygenase (KMO), 3-hydroxyanthranilic acid oxygenase (3HAO) and quinolinic acid phosphoribosyl transferase (QPRTase) and IDO1 immunohistochemistry. Results In CSF, KYN, KYNA and QUIN were elevated whereas TRP, AA and 3HAA remained unchanged. The ratios of QUIN:KYN, QUIN:KYNA, KYNA:KYN and 3HAA:AA revealed that QUIN levels were significantly higher than KYN and KYNA, supporting increased neurotoxicity. Amplified IDO1 and KYNase mRNA expression was demonstrated on post-mortem brains, and enhanced IDO1 protein coincided with overt tissue damage. QUIN levels in CSF were significantly higher in patients with unfavourable outcome and inversely correlated with GOSE scores. Conclusion TBI induced a striking activation of the KP pathway with sustained increase of QUIN. The exceeding production of QUIN together with increased IDO1 activation and mRNA expression in brain-injured areas suggests that TBI selectively induces a robust stimulation of the neurotoxic branch of the KP pathway. QUIN’s detrimental roles are supported by its association to adverse outcome potentially becoming an early prognostic factor post-TBI.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::f2f6d229542479b0216573762572d84dTest
http://europepmc.org/articles/PMC4457980Test

المؤلفون: Robert Dantzer, Keith W. Kelley, S. Park, Robert H. McCusker, Marcus A. Lawson

المصدر: Journal of Neuroinflammation, Vol 8, Iss 1, p 179 (2011)
Journal of Neuroinflammation

مصطلحات موضوعية: Lipopolysaccharides, Male, medicine.medical_specialty, Lipopolysaccharide, medicine.medical_treatment, Immunology, Motor Activity, lcsh:RC346-429, Eating, Mice, Cellular and Molecular Neuroscience, Insulin-like growth factor, chemistry.chemical_compound, sickness, Neurotrophic factors, Internal medicine, medicine, Animals, Indoleamine-Pyrrole 2,3,-Dioxygenase, Nerve Growth Factors, Insulin-Like Growth Factor I, lcsh:Neurology. Diseases of the nervous system, Sickness behavior, Depression (differential diagnoses), chemistry.chemical_classification, depression-like behavior, Behavior, Animal, Depression, business.industry, Research, General Neuroscience, Growth factor, Body Weight, lipopolysaccharide, Tryptophan, Brain, IGF-I, Endocrinology, Enzyme, Neurology, chemistry, Exploratory Behavior, Cytokines, Peptides, business, Biomarkers, Injections, Intraperitoneal

الوصف: Centrally administered insulin-like growth factor (IGF)-I has anti-depressant activity in several rodent models, including lipopolysaccharide (LPS)-induced depression. In this study we tested the ability of IGF-I and GPE (the N-terminal tri-peptide derived from IGF-I) to alter depression-like behavior induced by intraperitoneal (i.p.) administration of LPS in a preventive and curative manner. In the first case, IGF-I (1 μg) or GPE (5 μg) was administered i.c.v. to CD-1 mice followed 30 min later by 330 μg/kg body weight i.p. LPS. In the second case, 830 μg/kg body weight LPS was given 24 h prior to either IGF-I or GPE. When administered i.p., LPS induced full-blown sickness assessed as a loss of body weight, decrease in food intake and sickness behavior. None of these indices were affected by IGF-I or GPE. LPS also induced depression-like behavior; assessed as an increased duration of immobility in the tail suspension and forced swim tests. When administered before or after LPS, IGF-I and GPE abrogated the LPS response; attenuating induction of depression-like behaviors and blocking preexistent depression-like behaviors. Similar to previous work with IGF-I, GPE decreased brain expression of cytokines in response to LPS although unlike IGF-I, GPE did not induce the expression of brain-derived neurotrophic factor (BDNF). LPS induced expression of tryptophan dioxygenases, IDO1, IDO2 and TDO2, but expression of these enzymes was not altered by GPE. Thus, both IGF-I and GPE elicit specific improvement in depression-like behavior independent of sickness, an action that could be due to their anti-inflammatory properties.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::870acdf0721155cebef97c6eadc37fa2Test
https://doi.org/10.1186/1742-2094-8-179Test

المؤلفون: Keith W. Kelley, Marcus A. Lawson, Robert Dantzer, Xin Fu

المصدر: Journal of Neuroinflammation, Vol 8, Iss 1, p 88 (2011)
Journal of Neuroinflammation

مصطلحات موضوعية: MAPK/ERK pathway, Lipopolysaccharides, Male, medicine.medical_treatment, Nitric Oxide Synthase Type II, HIV Infections, Comorbidity, Neuropsychological Tests, Hippocampus, p38 Mitogen-Activated Protein Kinases, lcsh:RC346-429, Mice, 0302 clinical medicine, Interferon gamma, Indoleamine 2,3-dioxygenase, Serotonin Plasma Membrane Transport Proteins, 0303 health sciences, medicine.diagnostic_test, Behavior, Animal, Depression, General Neuroscience, 3. Good health, Nitric oxide synthase, Cytokine, Infusions, Intraventricular, Neurology, tat Gene Products, Human Immunodeficiency Virus, medicine.drug, MAP Kinase Signaling System, p38 mitogen-activated protein kinases, Immunology, Biology, 03 medical and health sciences, Cellular and Molecular Neuroscience, Interferon-gamma, Western blot, medicine, Animals, Humans, Indoleamine-Pyrrole 2,3,-Dioxygenase, Protein kinase A, lcsh:Neurology. Diseases of the nervous system, 030304 developmental biology, Interleukin-6, Tumor Necrosis Factor-alpha, Research, Molecular biology, Enzyme Activation, Mice, Inbred C57BL, biology.protein, HIV-1, 030217 neurology & neurosurgery

الوصف: Background We have established that activation of the tryptophan degrading enzyme indoleamine 2,3 dioxygenase (IDO) mediates the switch from cytokine-induced sickness behavior to depressive-like behavior. Because human immunodeficiency virus type 1 (HIV-1) Tat protein causes depressive-like behavior in mice, we investigated its ability to activate IDO in organotypic hippocampal slice cultures (OHSCs) derived from neonatal C57BL/6 mice. Methods Depressive-like behavior in C57BL/6J mice was assessed by the forced swim test. Expression of cytokines and IDO mRNA in OHSCs was measured by real-time RT-PCR and cytokine protein was measured by enzyme-linked immunosorbent assays (ELISAs). p38 MAPK phosphorylation was analyzed by western blot. Results Intracerebroventricular (i.c.v.) administration of Tat (40 ng) induced depressive-like behavior in the absence of sickness. Addition of Tat (40 ng/slice) to the medium of OHSCs induced IDO steady-state mRNA that peaked at 6 h. This effect was potentiated by pretreatment with IFNγ. Tat also induced the synthesis and release of TNFα and IL-6 protein in the supernatant of the slices and increased expression of the inducible isoform of nitric oxide synthase (iNOS) and the serotonin transporter (SERT). Tat had no effect on endogenous synthesis of IFNγ. To explore the mechanisms of Tat-induced IDO expression, slices were pretreated with the p38 mitogen-activated protein kinase (MAPK) inhibitor SB 202190 for 30 min before Tat treatment. SB 202190 significantly decreased IDO expression induced by Tat, and this effect was accompanied by a reduction of Tat-induced expression of TNFα, IL-6, iNOS and SERT. Conclusion These data establish that Tat induces IDO expression via an IFNγ-independent mechanism that depends upon activation of p38 MAPK. Targeting IDO itself or the p38 MAPK signaling pathway could provide a novel therapy for comorbid depressive disorders in HIV-1-infected patients.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::7264b83911984c711fe6462d54eb46f6Test
http://www.jneuroinflammation.com/content/8/1/88Test

المؤلفون: Yuan-Yuan Xie, Qijin Zhao, Chen-yang Dai, An-Jing Kang, Yan Liang, Tong Xie, Xin Xiao Zheng, Guangji Wang, Xiaolan Wu, Haiping Hao, Lin Xie

المصدر: Journal of Neuroinflammation
Journal of Neuroinflammation, Vol 8, Iss 1, p 100 (2011)

مصطلحات موضوعية: Lipopolysaccharides, Male, Serotonin, Ginsenosides, Immunology, Central nervous system, Anti-Inflammatory Agents, Panax, Pharmacology, Neuropsychological Tests, Blood–brain barrier, lcsh:RC346-429, Proinflammatory cytokine, Cell Line, Cellular and Molecular Neuroscience, Ginseng, chemistry.chemical_compound, Mice, Weight Loss, medicine, Animals, Humans, Indoleamine-Pyrrole 2,3,-Dioxygenase, Tissue Distribution, lcsh:Neurology. Diseases of the nervous system, Neuroinflammation, Kynurenine, Behavior, Animal, business.industry, Depression, General Neuroscience, Research, Tryptophan, Brain, Tail suspension test, Antidepressive Agents, Anorexia, medicine.anatomical_structure, Neurology, chemistry, Blood-Brain Barrier, Cytokines, Encephalitis, business, Behavioural despair test

الوصف: Background The effectiveness of ginseng in preventing and treating various central nervous system (CNS) diseases has been widely confirmed. However, ginsenosides, the principal components of ginseng, are characterized by poor accessibility to the brain, and this pharmacokinetic-pharmacological paradox remains poorly explained. Anti-inflammatory approaches are becoming promising therapeutic strategies for depression and other CNS diseases; however, previous studies have focused largely on anti-inflammatory therapies directed at the central nervous system. It is thus of interest to determine whether ginsenosides, characterized by poor brain distribution, are also effective in treating lipopolysaccharide- (LPS) induced depression-like behavior and neuroinflammation. Methods In an LPS-induced depression-like behavior model, the antidepressant effects of ginseng total saponins (GTS) were assessed using a forced swimming test, a tail suspension test, and a sucrose preference test. The anti-inflammatory efficacies of GTS in brain, plasma, and LPS-challenged RAW264.7 cells were validated using ELISA and quantitative real-time PCR. Moreover, indoleamine 2,3-dioxygenase (IDO) activity in the periphery and brain were also determined by measuring levels of kynurenine/tryptophan. Results GTS significantly attenuated LPS-induced depression-like behavior. Moreover, LPS-induced increases in 5-HT and tryptophane turnover in the brain were significantly reduced by GTS. IDO activities in brain and periphery were also suppressed after pretreatment with GTS. Furthermore, GTS-associated recovery from LPS-induced depression-like behavior was paralleled with reduced mRNA levels for IL-1β, IL-6, TNF-α, and IDO in hippocampus. Poor brain distribution of ginsenosides was confirmed in LPS-challenged mice. GTS treatment significantly decreased production of various proinflammatory cytokines in both LPS-challenged mice and RAW264.7 cells. Conclusion This study suggests that the anti-depression efficacy of GTS may be largely attributable to its peripheral anti-inflammatory activity. Our study also strengthens an important notion that peripheral anti-inflammation strategies may be useful in the therapy of inflammation-related depression and possibly other CNS diseases.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::b8a392a65ddf8deacefe51cb3fab0ef8Test
https://pubmed.ncbi.nlm.nih.gov/21843370Test