113 results on '"Nahon JL"'
Search Results
2. THE CONCISE GUIDE TO PHARMACOLOGY 2017/18: Overview
- Author
-
Alexander, Stephen PH, Kelly, Eamonn, Marrion, Neil V, Peters, John A, Faccenda, Elena, Harding, Simon D, Pawson, Adam J, Sharman, Joanna L, Southan, Christopher, Buneman, O Peter, Cidlowski, John A, Christopoulos, Arthur, Davenport, Anthony P, Fabbro, Doriano, Spedding, Michael, Striessnig, Jorg, Davies, Jamie A, Abbracchio, MP, Aldrich, R, Al-Hosaini, K, Arumugam, TV, Attali, B, Back, M, Barnes, NM, Bathgate, R, Beart, PM, Becirovic, E, Bettler, B, Biel, M, Birdsall, NJ, Blaho, V, Boison, D, Brauner-Osborne, H, Broer, S, Bryant, C, Burnstock, G, Calo, G, Catterall, WA, Ceruti, S, Chan, SL, Chandy, KG, Chazot, P, Chiang, N, Chun, JJ, Chung, JJ, Clapham, DE, Clapp, L, Connor, MA, Cox, HM, Davies, P, Dawson, PA, Decaen, P, Dent, G, Doherty, P, Douglas, SD, Dubocovich, ML, Fong, TM, Fowler, CJ, Frantz, A, Fuller, P, Fumagalli, M, Futerman, AH, Gainetdinov, RR, Gershengorn, MA, Goldin, A, Goldstein, S, Goudet, C, Gregory, K, Grissmer, S, Gundlach, AL, Hagenbuch, B, Hamann, J, Hammond, JR, Hancox, JC, Hanson, J, Hanukoglu, I, Hay, DL, Hobbs, AJ, Hollenberg, AN, Holliday, ND, Hoyer, D, Ijzerman, AP, Inui, KI, Irving, AJ, Ishii, S, Jacobson, KA, Jan, LY, Jarvis, MF, Jensen, R, Jockers, R, Kaczmarek, LK, Kanai, Y, Karnik, S, Kellenberger, S, Kemp, S, Kennedy, C, Kerr, ID, Kihara, Y, Kukkonen, J, Larhammar, D, Leach, K, Lecca, D, Leeman, S, Leprince, J, Lolait, SJ, Macewan, D, Maguire, JJ, Marshall, F, Mazella, J, Mcardle, CA, Michel, MC, Miller, LJ, Mizuno, H, Monk, PN, Mouillac, B, Murphy, PM, Nahon, JL, Nerbonne, J, Nichols, CG, Norel, X, Offermanns, S, Palmer, LG, Panaro, MA, Papapetropoulos, A, Perez-Reyes, E, Pertwee, RG, Pisegna, JR, Plant, LD, Poyner, DR, Prossnitz, ER, Pyne, S, Ramachandran, R, Ren, D, Rondard, P, Ruzza, C, Sackin, H, Sanger, G, Sanguinetti, MC, Schild, L, Schioth, H, Schulte, G, Schulz, S, Segaloff, DL, Serhan, CN, Singh, KD, Slesinger, PA, Snutch, TP, Sobey, CG, Stewart, G, Stoddart, LA, Summers, RJ, Szabo, C, Thwaites, D, Toll, L, Trimmer, JS, Tucker, S, Vaudry, H, Verri, T, Vilargada, JP, Waldman, SA, Ward, DT, Waxman, SG, Wei, AD, Willars, GB, Wong, SS, Woodruff, TM, Wulff, H, Ye, RD, Yung, Y, Zajac, JM, and Collaborators, CGTP
- Published
- 2017
3. [Beating frequency of motile cilia lining the third cerebral ventricle is finely tuned by the hypothalamic peptide MCH]
- Author
-
Conductier, G, Viola, A, Le Troter, A, Nahon, JL, Guyon, A, Centre de résonance magnétique biologique et médicale (CRMBM), Assistance Publique - Hôpitaux de Marseille (APHM)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), and Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-Centre National de la Recherche Scientifique (CNRS)
- Subjects
[SPI]Engineering Sciences [physics] ,ComputingMilieux_MISCELLANEOUS - Abstract
International audience
- Published
- 2013
4. Acute and chronic administration of melanin-concentrating hormone enhances food intake and body weight in Wistar and Sprague–Dawley rats
- Author
-
Della-Zuana, O, primary, Presse, F, additional, Ortola, C, additional, Duhault, J, additional, Nahon, JL, additional, and Levens, N, additional
- Published
- 2002
- Full Text
- View/download PDF
5. Des gènes "chimères" sont apparus dans la lignée des hominidés : l'indice d'une spécificité génomique humaine ?
- Author
-
Nahon, JL, primary
- Published
- 2001
- Full Text
- View/download PDF
6. Deux neuropeptides orphelins trouvent enfin leur récepteur.
- Author
-
Vaudry, H, primary, Coulouarn, Y, additional, Lihrmann, I, additional, Tonon, MC, additional, Chartrel, N, additional, Richard, V, additional, Thuillez, C, additional, Nahon, JL, additional, and Beauvillain, JC, additional
- Published
- 2000
- Full Text
- View/download PDF
7. Le récepteur de la MCH (malanin-concentrating hormone) enfin identifié.
- Author
-
Hervieu, G, primary and Nahon, JL, additional
- Published
- 1999
- Full Text
- View/download PDF
8. Invalidation du gène de la melanin-concentrating hormone (MCH) : un " KO " qui n'est pas nul... pour l'équilibre pondéral et énergétique.
- Author
-
Nahon, JL, primary
- Published
- 1999
- Full Text
- View/download PDF
9. Hypocrétines et orexines ne font qu'un : découvertes "simultanées" de deux nouveaux peptides orexigènes.
- Author
-
Nahon, JL, primary
- Published
- 1998
- Full Text
- View/download PDF
10. Dietary fatty acid composition drives neuroinflammation and impaired behavior in obesity.
- Author
-
Sanchez C, Colson C, Gautier N, Noser P, Salvi J, Villet M, Fleuriot L, Peltier C, Schlich P, Brau F, Sharif A, Altintas A, Amri EZ, Nahon JL, Blondeau N, Benani A, Barrès R, and Rovère C
- Subjects
- Animals, Mice, Obesity metabolism, Diet, High-Fat adverse effects, Fatty Acids metabolism, Inflammation, Glucose, Neuroinflammatory Diseases, Insulins
- Abstract
Nutrient composition in obesogenic diets may influence the severity of disorders associated with obesity such as insulin-resistance and chronic inflammation. Here we hypothesized that obesogenic diets rich in fat and varying in fatty acid composition, particularly in omega 6 (ω6) to omega 3 (ω3) ratio, have various effects on energy metabolism, neuroinflammation and behavior. Mice were fed either a control diet or a high fat diet (HFD) containing either low (LO), medium (ME) or high (HI) ω6/ω3 ratio. Mice from the HFD-LO group consumed less calories and exhibited less body weight gain compared to other HFD groups. Both HFD-ME and HFD-HI impaired glucose metabolism while HFD-LO partly prevented insulin intolerance and was associated with normal leptin levels despite higher subcutaneous and perigonadal adiposity. Only HFD-HI increased anxiety and impaired spatial memory, together with increased inflammation in the hypothalamus and hippocampus. Our results show that impaired glucose metabolism and neuroinflammation are uncoupled, and support that diets with a high ω6/ω3 ratio are associated with neuroinflammation and the behavioral deterioration coupled with the consumption of diets rich in fat., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)
- Published
- 2024
- Full Text
- View/download PDF
11. The Concise Guide to PHARMACOLOGY 2023/24: G protein-coupled receptors.
- Author
-
Alexander SPH, Christopoulos A, Davenport AP, Kelly E, Mathie AA, Peters JA, Veale EL, Armstrong JF, Faccenda E, Harding SD, Davies JA, Abbracchio MP, Abraham G, Agoulnik A, Alexander W, Al-Hosaini K, Bäck M, Baker JG, Barnes NM, Bathgate R, Beaulieu JM, Beck-Sickinger AG, Behrens M, Bernstein KE, Bettler B, Birdsall NJM, Blaho V, Boulay F, Bousquet C, Bräuner-Osborne H, Burnstock G, Caló G, Castaño JP, Catt KJ, Ceruti S, Chazot P, Chiang N, Chini B, Chun J, Cianciulli A, Civelli O, Clapp LH, Couture R, Cox HM, Csaba Z, Dahlgren C, Dent G, Douglas SD, Dournaud P, Eguchi S, Escher E, Filardo EJ, Fong T, Fumagalli M, Gainetdinov RR, Garelja ML, de Gasparo M, Gerard C, Gershengorn M, Gobeil F, Goodfriend TL, Goudet C, Grätz L, Gregory KJ, Gundlach AL, Hamann J, Hanson J, Hauger RL, Hay DL, Heinemann A, Herr D, Hollenberg MD, Holliday ND, Horiuchi M, Hoyer D, Hunyady L, Husain A, IJzerman AP, Inagami T, Jacobson KA, Jensen RT, Jockers R, Jonnalagadda D, Karnik S, Kaupmann K, Kemp J, Kennedy C, Kihara Y, Kitazawa T, Kozielewicz P, Kreienkamp HJ, Kukkonen JP, Langenhan T, Larhammar D, Leach K, Lecca D, Lee JD, Leeman SE, Leprince J, Li XX, Lolait SJ, Lupp A, Macrae R, Maguire J, Malfacini D, Mazella J, McArdle CA, Melmed S, Michel MC, Miller LJ, Mitolo V, Mouillac B, Müller CE, Murphy PM, Nahon JL, Ngo T, Norel X, Nyimanu D, O'Carroll AM, Offermanns S, Panaro MA, Parmentier M, Pertwee RG, Pin JP, Prossnitz ER, Quinn M, Ramachandran R, Ray M, Reinscheid RK, Rondard P, Rovati GE, Ruzza C, Sanger GJ, Schöneberg T, Schulte G, Schulz S, Segaloff DL, Serhan CN, Singh KD, Smith CM, Stoddart LA, Sugimoto Y, Summers R, Tan VP, Thal D, Thomas WW, Timmermans PBMWM, Tirupula K, Toll L, Tulipano G, Unal H, Unger T, Valant C, Vanderheyden P, Vaudry D, Vaudry H, Vilardaga JP, Walker CS, Wang JM, Ward DT, Wester HJ, Willars GB, Williams TL, Woodruff TM, Yao C, and Ye RD
- Subjects
- Humans, Ligands, Ion Channels chemistry, Receptors, Cytoplasmic and Nuclear, Databases, Pharmaceutical, Receptors, G-Protein-Coupled
- Abstract
The Concise Guide to PHARMACOLOGY 2023/24 is the sixth in this series of biennial publications. The Concise Guide provides concise overviews, mostly in tabular format, of the key properties of approximately 1800 drug targets, and about 6000 interactions with about 3900 ligands. There is an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source of drug targets and their ligands (https://www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. Although the Concise Guide constitutes almost 500 pages, the material presented is substantially reduced compared to information and links presented on the website. It provides a permanent, citable, point-in-time record that will survive database updates. The full contents of this section can be found at http://onlinelibrary.wiley.com/doi/bph.16177. G protein-coupled receptors are one of the six major pharmacological targets into which the Guide is divided, with the others being: ion channels, nuclear hormone receptors, catalytic receptors, enzymes and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. The landscape format of the Concise Guide is designed to facilitate comparison of related targets from material contemporary to mid-2023, and supersedes data presented in the 2021/22, 2019/20, 2017/18, 2015/16 and 2013/14 Concise Guides and previous Guides to Receptors and Channels. It is produced in close conjunction with the Nomenclature and Standards Committee of the International Union of Basic and Clinical Pharmacology (NC-IUPHAR), therefore, providing official IUPHAR classification and nomenclature for human drug targets, where appropriate., (© 2023 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of The British Pharmacological Society.)
- Published
- 2023
- Full Text
- View/download PDF
12. Evidence for Constitutive Microbiota-Dependent Short-Term Control of Food Intake in Mice: Is There a Link with Inflammation, Oxidative Stress, Endotoxemia, and GLP-1?
- Author
-
Ben Fradj S, Nédélec E, Salvi J, Fouesnard M, Huillet M, Pallot G, Cansell C, Sanchez C, Philippe C, Gigot V, Lemoine A, Trompier D, Henry T, Petrilli V, Py BF, Guillou H, Loiseau N, Ellero-Simatos S, Nahon JL, Rovère C, Grober J, Boudry G, Douard V, and Benani A
- Subjects
- Animals, Eating, Glucagon-Like Peptide 1, Inflammation, Mice, Mice, Inbred NOD, Oxidative Stress, Appetite Depressants, Endotoxemia, Microbiota
- Abstract
Aims: Although prebiotics, probiotics, and fecal transplantation can alter the sensation of hunger and/or feeding behavior, the role of the constitutive gut microbiota in the short-term regulation of food intake during normal physiology is still unclear. Results: An antibiotic-induced microbiota depletion study was designed to compare feeding behavior in conventional and microbiota-depleted mice. Tissues were sampled to characterize the time profile of microbiota-derived signals in mice during consumption of either standard or high-fat food for 1 h. Pharmacological and genetic tools were used to evaluate the contribution of postprandial endotoxemia and inflammatory responses in the short-term regulation of food intake. We observed constitutive microbial and macronutrient-dependent control of food intake at the time scale of a meal; that is, within 1 h of food introduction. Specifically, microbiota depletion increased food intake, and the microbiota-derived anorectic effect became significant during the consumption of high-fat but not standard food. This anorectic effect correlated with a specific postprandial microbial metabolic signature, and did not require postprandial endotoxemia or an NOD-, LRR-, and Pyrin domain-containing protein 3-inflammasome-mediated inflammatory response. Innovation and Conclusion: These findings show that the gut microbiota controls host appetite at the time scale of a meal under normal physiology. Interestingly, a microbiota-derived anorectic effect develops specifically with a high-fat meal, indicating that gut microbiota activity is involved in the satietogenic properties of foods. Antioxid. Redox Signal. 37, 349-369.
- Published
- 2022
- Full Text
- View/download PDF
13. THE CONCISE GUIDE TO PHARMACOLOGY 2021/22: G protein-coupled receptors.
- Author
-
Alexander SP, Christopoulos A, Davenport AP, Kelly E, Mathie A, Peters JA, Veale EL, Armstrong JF, Faccenda E, Harding SD, Pawson AJ, Southan C, Davies JA, Abbracchio MP, Alexander W, Al-Hosaini K, Bäck M, Barnes NM, Bathgate R, Beaulieu JM, Bernstein KE, Bettler B, Birdsall NJM, Blaho V, Boulay F, Bousquet C, Bräuner-Osborne H, Burnstock G, Caló G, Castaño JP, Catt KJ, Ceruti S, Chazot P, Chiang N, Chini B, Chun J, Cianciulli A, Civelli O, Clapp LH, Couture R, Csaba Z, Dahlgren C, Dent G, Singh KD, Douglas SD, Dournaud P, Eguchi S, Escher E, Filardo EJ, Fong T, Fumagalli M, Gainetdinov RR, Gasparo M, Gerard C, Gershengorn M, Gobeil F, Goodfriend TL, Goudet C, Gregory KJ, Gundlach AL, Hamann J, Hanson J, Hauger RL, Hay DL, Heinemann A, Hollenberg MD, Holliday ND, Horiuchi M, Hoyer D, Hunyady L, Husain A, IJzerman AP, Inagami T, Jacobson KA, Jensen RT, Jockers R, Jonnalagadda D, Karnik S, Kaupmann K, Kemp J, Kennedy C, Kihara Y, Kitazawa T, Kozielewicz P, Kreienkamp HJ, Kukkonen JP, Langenhan T, Leach K, Lecca D, Lee JD, Leeman SE, Leprince J, Li XX, Williams TL, Lolait SJ, Lupp A, Macrae R, Maguire J, Mazella J, McArdle CA, Melmed S, Michel MC, Miller LJ, Mitolo V, Mouillac B, Müller CE, Murphy P, Nahon JL, Ngo T, Norel X, Nyimanu D, O'Carroll AM, Offermanns S, Panaro MA, Parmentier M, Pertwee RG, Pin JP, Prossnitz ER, Quinn M, Ramachandran R, Ray M, Reinscheid RK, Rondard P, Rovati GE, Ruzza C, Sanger GJ, Schöneberg T, Schulte G, Schulz S, Segaloff DL, Serhan CN, Stoddart LA, Sugimoto Y, Summers R, Tan VP, Thal D, Thomas WW, Timmermans PBMWM, Tirupula K, Tulipano G, Unal H, Unger T, Valant C, Vanderheyden P, Vaudry D, Vaudry H, Vilardaga JP, Walker CS, Wang JM, Ward DT, Wester HJ, Willars GB, Woodruff TM, Yao C, and Ye RD
- Subjects
- Humans, Ion Channels, Ligands, Receptors, Cytoplasmic and Nuclear, Receptors, G-Protein-Coupled, Databases, Pharmaceutical, Pharmacology
- Abstract
The Concise Guide to PHARMACOLOGY 2021/22 is the fifth in this series of biennial publications. The Concise Guide provides concise overviews, mostly in tabular format, of the key properties of nearly 1900 human drug targets with an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. Although the Concise Guide constitutes over 500 pages, the material presented is substantially reduced compared to information and links presented on the website. It provides a permanent, citable, point-in-time record that will survive database updates. The full contents of this section can be found at http://onlinelibrary.wiley.com/doi/bph.15538. G protein-coupled receptors are one of the six major pharmacological targets into which the Guide is divided, with the others being: ion channels, nuclear hormone receptors, catalytic receptors, enzymes and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. The landscape format of the Concise Guide is designed to facilitate comparison of related targets from material contemporary to mid-2021, and supersedes data presented in the 2019/20, 2017/18, 2015/16 and 2013/14 Concise Guides and previous Guides to Receptors and Channels. It is produced in close conjunction with the Nomenclature and Standards Committee of the International Union of Basic and Clinical Pharmacology (NC-IUPHAR), therefore, providing official IUPHAR classification and nomenclature for human drug targets, where appropriate., (© 2021 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of The British Pharmacological Society.)
- Published
- 2021
- Full Text
- View/download PDF
14. Versatile and flexible microfluidic qPCR test for high-throughput SARS-CoV-2 and cellular response detection in nasopharyngeal swab samples.
- Author
-
Fassy J, Lacoux C, Leroy S, Noussair L, Hubac S, Degoutte A, Vassaux G, Leclercq V, Rouquié D, Marquette CH, Rottman M, Touron P, Lemoine A, Herrmann JL, Barbry P, Nahon JL, Zaragosi LE, and Mari B
- Subjects
- Adult, COVID-19 virology, COVID-19 Testing methods, DNA Primers, Diagnostic Tests, Routine methods, Female, Humans, Male, MicroRNAs genetics, RNA, Viral genetics, Real-Time Polymerase Chain Reaction methods, SARS-CoV-2 genetics, Sensitivity and Specificity, COVID-19 diagnosis, Microfluidic Analytical Techniques methods, SARS-CoV-2 isolation & purification, Specimen Handling methods
- Abstract
The emergence and quick spread of SARS-CoV-2 has pointed at a low capacity response for testing large populations in many countries, in line of material, technical and staff limitations. The traditional RT-qPCR diagnostic test remains the reference method and is by far the most widely used test. These assays are limited to a few probe sets, require large sample PCR reaction volumes, along with an expensive and time-consuming RNA extraction step. Here we describe a quantitative nanofluidic assay that overcomes some of these shortcomings, based on the BiomarkTM instrument from Fluidigm. This system offers the possibility of performing 4608 qPCR end-points in a single run, equivalent to 192 clinical samples combined with 12 pairs of primers/probe sets in duplicate, thus allowing the monitoring of SARS-CoV-2 including the detection of specific SARS-CoV-2 variants, as well as the detection other pathogens and/or host cellular responses (virus receptors, response markers, microRNAs). The 10 nL-range volume of BiomarkTM reactions is compatible with sensitive and reproducible reactions that can be easily and cost-effectively adapted to various RT-qPCR configurations and sets of primers/probe. Finally, we also evaluated the use of inactivating lysis buffers composed of various detergents in the presence or absence of proteinase K to assess the compatibility of these buffers with a direct reverse transcription enzymatic step and we propose several protocols, bypassing the need for RNA purification. We advocate that the combined utilization of an optimized processing buffer and a high-throughput real-time PCR device would contribute to improve the turn-around-time to deliver the test results to patients and increase the SARS-CoV-2 testing capacities., Competing Interests: The authors have read the journal’s policy and have the following competing interests: DR is a paid employee of Bayer SAS and VL is employed by LBM Bioesterel (LBM Bioesterel). There are no patents, products in development or marketed products associated with this research to declare. This does not alter our adherence to PLOS ONE policies on sharing data and materials.
- Published
- 2021
- Full Text
- View/download PDF
15. Dietary fat exacerbates postprandial hypothalamic inflammation involving glial fibrillary acidic protein-positive cells and microglia in male mice.
- Author
-
Cansell C, Stobbe K, Sanchez C, Le Thuc O, Mosser CA, Ben-Fradj S, Leredde J, Lebeaupin C, Debayle D, Fleuriot L, Brau F, Devaux N, Benani A, Audinat E, Blondeau N, Nahon JL, and Rovère C
- Subjects
- Animals, Diet, High-Fat adverse effects, Glial Fibrillary Acidic Protein, Hypothalamus, Inflammation, Male, Mice, Mice, Inbred C57BL, Obesity, Dietary Fats, Microglia
- Abstract
In humans, obesity is associated with brain inflammation, glial reactivity, and immune cells infiltration. Studies in rodents have shown that glial reactivity occurs within 24 hr of high-fat diet (HFD) consumption, long before obesity development, and takes place mainly in the hypothalamus (HT), a crucial brain structure for controlling body weight. Here, we sought to characterize the postprandial HT inflammatory response to 1, 3, and 6 hr of exposure to either a standard diet (SD) or HFD. HFD exposure increased gene expression of astrocyte and microglial markers (glial fibrillary acidic protein [GFAP] and Iba1, respectively) compared to SD-treated mice and induced morphological modifications of microglial cells in HT. This remodeling was associated with higher expression of inflammatory genes and differential regulation of hypothalamic neuropeptides involved in energy balance regulation. DREADD and PLX5622 technologies, used to modulate GFAP-positive or microglial cells activity, respectively, showed that both glial cell types are involved in hypothalamic postprandial inflammation, with their own specific kinetics and reactiveness to ingested foods. Thus, recurrent exacerbated postprandial inflammation in the brain might promote obesity and needs to be characterized to address this worldwide crisis., (© 2020 The Authors. Glia published by Wiley Periodicals LLC.)
- Published
- 2021
- Full Text
- View/download PDF
16. Ciliary melanin-concentrating hormone receptor 1 (MCHR1) is widely distributed in the murine CNS in a sex-independent manner.
- Author
-
Diniz GB, Battagello DS, Klein MO, Bono BSM, Ferreira JGP, Motta-Teixeira LC, Duarte JCG, Presse F, Nahon JL, Adamantidis A, Chee MJ, Sita LV, and Bittencourt JC
- Subjects
- Animals, Cilia genetics, Female, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Rats, Rats, Long-Evans, Rats, Sprague-Dawley, Receptors, Somatostatin genetics, Brain metabolism, Cilia metabolism, Receptors, Somatostatin biosynthesis, Sex Characteristics
- Abstract
Melanin-concentrating hormone (MCH) is a ubiquitous vertebrate neuropeptide predominantly synthesized by neurons of the diencephalon that can act through two G protein-coupled receptors, called MCHR1 and MCHR2. The expression of Mchr1 has been investigated in both rats and mice, but its synthesis remains poorly described. After identifying an antibody that detects MCHR1 with high specificity, we employed immunohistochemistry to map the distribution of MCHR1 in the CNS of rats and mice. Multiple neurochemical markers were also employed to characterize some of the neuronal populations that synthesize MCHR1. Our results show that MCHR1 is abundantly found in a subcellular structure called the primary cilium, which has been associated, among other functions, with the detection of free neurochemical messengers present in the extracellular space. Ciliary MCHR1 was found in a wide range of areas, including the olfactory bulb, cortical mantle, striatum, hippocampal formation, amygdala, midline thalamic nuclei, periventricular hypothalamic nuclei, midbrain areas, and in the spinal cord. No differences were observed between male and female mice, and interspecies differences were found in the caudate-putamen nucleus and the subgranular zone. Ciliary MCHR1 was found in close association with several neurochemical markers, including tyrosine hydroxylase, calretinin, kisspeptin, estrogen receptor, oxytocin, vasopressin, and corticotropin-releasing factor. Given the role of neuronal primary cilia in sensing free neurochemical messengers in the extracellular fluid, the widespread distribution of ciliary MCHR1, and the diverse neurochemical populations who synthesize MCHR1, our data indicate that nonsynaptic communication plays a prominent role in the normal function of the MCH system., (© 2020 Wiley Periodicals LLC.)
- Published
- 2020
- Full Text
- View/download PDF
17. Postprandial Hyperglycemia Stimulates Neuroglial Plasticity in Hypothalamic POMC Neurons after a Balanced Meal.
- Author
-
Nuzzaci D, Cansell C, Liénard F, Nédélec E, Ben Fradj S, Castel J, Foppen E, Denis R, Grouselle D, Laderrière A, Lemoine A, Mathou A, Tolle V, Heurtaux T, Fioramonti X, Audinat E, Pénicaud L, Nahon JL, Rovère C, and Benani A
- Subjects
- Animals, Blood Glucose metabolism, Electrophysiological Phenomena, Feeding Behavior, Hyperglycemia blood, Mice, Inbred C57BL, Mice, Transgenic, Postprandial Period, Synapses metabolism, Hyperglycemia physiopathology, Hypothalamus metabolism, Meals, Neuroglia pathology, Neuronal Plasticity, Neurons metabolism, Pro-Opiomelanocortin metabolism
- Abstract
Mechanistic studies in rodents evidenced synaptic remodeling in neuronal circuits that control food intake. However, the physiological relevance of this process is not well defined. Here, we show that the firing activity of anorexigenic POMC neurons located in the hypothalamus is increased after a standard meal. Postprandial hyperactivity of POMC neurons relies on synaptic plasticity that engages pre-synaptic mechanisms, which does not involve structural remodeling of synapses but retraction of glial coverage. These functional and morphological neuroglial changes are triggered by postprandial hyperglycemia. Chemogenetically induced glial retraction on POMC neurons is sufficient to increase POMC activity and modify meal patterns. These findings indicate that synaptic plasticity within the melanocortin system happens at the timescale of meals and likely contributes to short-term control of food intake. Interestingly, these effects are lost with a high-fat meal, suggesting that neuroglial plasticity of POMC neurons is involved in the satietogenic properties of foods., Competing Interests: Declaration of Interests The authors declare no competing interests., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2020
- Full Text
- View/download PDF
18. The weaning period promotes alterations in the orexin neuronal population of rats in a suckling-dependent manner.
- Author
-
Diniz GB, Candido PL, Klein MO, Alvisi RD, Presse F, Nahon JL, Felicio LF, and Bittencourt JC
- Subjects
- Animals, Animals, Suckling, Cell Count, Female, Hypothalamus metabolism, Male, Proto-Oncogene Proteins c-fos metabolism, Rats, Wistar, Hypothalamus growth & development, Lactation, Neurons metabolism, Orexins metabolism, Weaning
- Abstract
The orexin-immunoreactive neurons are part of an important arousal-promoting hypothalamic population. Several groups have investigated these neurons during the lactation period, when numerous physiological alterations occur in the dam's body to cope with the newly acquired metabolic needs of the litter. Although those studies have probed this population during the early and intermediate stages of lactation, few works have examined its response to weaning, including the cessation of the tactile suckling stimulus as the litter stops nursing. Using double immunohistochemistry for orexin and FOS combined with three-dimensional reconstruction techniques, we investigated orexin-synthesizing neurons and their activation at different times during weaning, in addition to the role played by the suckling stimulus. We report here that weaning promoted a decline in the anterior population of orexin-immunoreactive neurons and decreased the number of double orexin-FOS neurons labeled in the central dorsomedial hypothalamus, in addition to reducing the overall number of FOS-immunoreactive cells in the whole tuberal hypothalamus. Disruption of the suckling stimulus from the pups impaired the decrease in the number of anteriorly located orexin-immunoreactive neurons, attenuated the activation of orexin-synthesizing cells in the dorsomedial hypothalamus and reduced the number of FOS-immunoreactive neurons across the tuberal hypothalamus. When taken together, our data suggest that the weaning period is necessary to restore neurochemical pathways altered during the lactation period and that the suckling stimulus plays a significant role in this process.
- Published
- 2018
- Full Text
- View/download PDF
19. Hypothalamic Inflammation and Energy Balance Disruptions: Spotlight on Chemokines.
- Author
-
Le Thuc O, Stobbe K, Cansell C, Nahon JL, Blondeau N, and Rovère C
- Abstract
The hypothalamus is a key brain region in the regulation of energy balance as it controls food intake and both energy storage and expenditure through integration of humoral, neural, and nutrient-related signals and cues. Many years of research have focused on the regulation of energy balance by hypothalamic neurons, but the most recent findings suggest that neurons and glial cells, such as microglia and astrocytes, in the hypothalamus actually orchestrate together several metabolic functions. Because glial cells have been described as mediators of inflammatory processes in the brain, the existence of a causal link between hypothalamic inflammation and the deregulations of feeding behavior, leading to involuntary weight loss or obesity for example, has been suggested. Several inflammatory pathways that could impair the hypothalamic control of energy balance have been studied over the years such as, among others, toll-like receptors and canonical cytokines. Yet, less studied so far, chemokines also represent interesting candidates that could link the aforementioned pathways and the activity of hypothalamic neurons. Indeed, chemokines, in addition to their role in attracting immune cells to the inflamed site, have been suggested to be capable of neuromodulation. Thus, they could disrupt cellular activity together with synthesis and/or secretion of multiple neurotransmitters/mediators involved in the maintenance of energy balance. This review discusses the different inflammatory pathways that have been identified so far in the hypothalamus in the context of feeding behavior and body weight control impairments, with a particular focus on chemokines signaling that opens a new avenue in the understanding of the major role played by inflammation in obesity.
- Published
- 2017
- Full Text
- View/download PDF
20. Central CCL2 signaling onto MCH neurons mediates metabolic and behavioral adaptation to inflammation.
- Author
-
Le Thuc O, Cansell C, Bourourou M, Denis RG, Stobbe K, Devaux N, Guyon A, Cazareth J, Heurteaux C, Rostène W, Luquet S, Blondeau N, Nahon JL, and Rovère C
- Subjects
- Animals, Chemokine CCL2 deficiency, Chemokine CCL2 immunology, Cytokines biosynthesis, Cytokines genetics, Cytokines immunology, Hypothalamic Hormones genetics, Hypothalamic Hormones immunology, Illness Behavior, Lipopolysaccharides immunology, Melanins genetics, Melanins immunology, Mice, Neurons immunology, Pituitary Hormones genetics, Pituitary Hormones immunology, Receptors, CCR2 metabolism, Weight Loss, Chemokine CCL2 genetics, Chemokine CCL2 metabolism, Hypothalamic Hormones metabolism, Hypothalamus metabolism, Inflammation metabolism, Melanins metabolism, Neurons metabolism, Pituitary Hormones metabolism, Signal Transduction
- Abstract
Sickness behavior defines the endocrine, autonomic, behavioral, and metabolic responses associated with infection. While inflammatory responses were suggested to be instrumental in the loss of appetite and body weight, the molecular underpinning remains unknown. Here, we show that systemic or central lipopolysaccharide (LPS) injection results in specific hypothalamic changes characterized by a precocious increase in the chemokine ligand 2 (CCL2) followed by an increase in pro-inflammatory cytokines and a decrease in the orexigenic neuropeptide melanin-concentrating hormone (MCH). We therefore hypothesized that CCL2 could be the central relay for the loss in body weight induced by the inflammatory signal LPS. We find that central delivery of CCL2 promotes neuroinflammation and the decrease in MCH and body weight. MCH neurons express CCL2 receptor and respond to CCL2 by decreasing both electrical activity and MCH release. Pharmacological or genetic inhibition of CCL2 signaling opposes the response to LPS at both molecular and physiologic levels. We conclude that CCL2 signaling onto MCH neurons represents a core mechanism that relays peripheral inflammation to sickness behavior., (© 2016 The Authors.)
- Published
- 2016
- Full Text
- View/download PDF
21. The complex contribution of chemokines to neuroinflammation: switching from beneficial to detrimental effects.
- Author
-
Le Thuc O, Blondeau N, Nahon JL, and Rovère C
- Subjects
- Alzheimer Disease immunology, Brain cytology, Humans, Hypoxia-Ischemia, Brain immunology, Inflammation immunology, Inflammation Mediators immunology, Neuroimmunomodulation immunology, Receptors, Chemokine immunology, Stroke immunology, Alzheimer Disease physiopathology, Brain immunology, Chemokines immunology, Hypoxia-Ischemia, Brain physiopathology, Stroke physiopathology
- Abstract
Inflammation is an innate mechanism that defends organisms against harmful stimuli. Inflammation leads to the production and secretion of proinflammatory mediators that activate and recruit immune cells to damaged tissues, including the brain, to resolve the cause of inflammation. In the central nervous system, inflammation is referred to as neuroinflammation, which occurs in various pathological conditions of the brain. The primary role of neuroinflammation is to protect the brain. However, prolonged and/or inappropriate inflammation can be harmful for the brain, from individual cells to the whole tissue. This review focuses on a particular type of inflammatory mediator, chemokines, and describes their complex effects both under physiological and pathophysiological conditions of the brain. The clinical relevance of the multiple characters of chemokines is highlighted with respect to acute and chronic inflammation of the brain, including their actions in stroke and Alzheimer's disease, respectively., (© 2015 New York Academy of Sciences.)
- Published
- 2015
- Full Text
- View/download PDF
22. The melanin-concentrating hormone receptors: neuronal and non-neuronal functions.
- Author
-
Presse F, Conductier G, Rovere C, and Nahon JL
- Abstract
Melanin-concentrating hormone (MCH) is a cyclic peptide highly conserved in vertebrates and was originally identified as a skin-paling factor in Teleosts. In fishes, MCH also participates in the regulation of the stress-response and feeding behaviour. Mammalian MCH is a hypothalamic neuropeptide that displays multiple functions, mostly controlling feeding behaviour and energy homeostasis. Transgenic mouse models and pharmacological studies have shown the importance of the MCH system as a potential target in the treatment of appetite disorders and obesity as well as anxiety and psychiatric diseases. Two G-protein-coupled receptors (GPCRs) binding MCH have been characterized so far. The first, named MCH-R1 and also called SLC1, was identified through reverse pharmacology strategies by several groups as a cognate receptor of MCH. This receptor is expressed at high levels in many brain areas of rodents and primates and is also expressed in peripheral organs, albeit at a lower rate. A second receptor, designated MCH-R2, exhibited 38% identity to MCH-R1 and was identified by sequence analysis of the human genome. Interestingly, although MCH-R2 orthologues were also found in fishes, dogs, ferrets and non-human primates, this MCH receptor gene appeared either lacking or non-functional in rodents and lagomorphs. Both receptors are class I GPCRs, whose main roles are to mediate the actions of peptides and neurotransmitters in the central nervous system. However, examples of action of MCH on neuronal and non-neuronal cells are emerging that illustrate novel MCH functions. In particular, the functionality of endogenously expressed MCH-R1 has been explored in human neuroblastoma cells, SK-N-SH and SH-SY5Y cells, and in non-neuronal cell types such as the ependymocytes. Indeed, we have identified mitogen-activated protein kinase (MAPK)-dependent or calcium-dependent signalling cascades that ultimately contributed to neurite outgrowth in neuroblastoma cells or to modulation of ciliary beating in ependymal cells. The putative role of MCH on cellular shaping and plasticity on one side and volume transmission on the other must be now considered.
- Published
- 2014
- Full Text
- View/download PDF
23. Control of ventricular ciliary beating by the melanin concentrating hormone-expressing neurons of the lateral hypothalamus: a functional imaging survey.
- Author
-
Conductier G, Martin AO, Risold PY, Jego S, Lavoie R, Lafont C, Mollard P, Adamantidis A, and Nahon JL
- Abstract
The cyclic peptide Melanin Concentrating Hormone (MCH) is known to control a large number of brain functions in mammals such as food intake and metabolism, stress response, anxiety, sleep/wake cycle, memory, and reward. Based on neuro-anatomical and electrophysiological studies these functions were attributed to neuronal circuits expressing MCHR1, the single MCH receptor in rodents. In complement to our recently published work (1) we provided here new data regarding the action of MCH on ependymocytes in the mouse brain. First, we establish that MCHR1 mRNA is expressed in the ependymal cells of the third ventricle epithelium. Second, we demonstrated a tonic control of MCH-expressing neurons on ependymal cilia beat frequency using in vitro optogenics. Finally, we performed in vivo measurements of CSF flow using fluorescent micro-beads in wild-type and MCHR1-knockout mice. Collectively, our results demonstrated that MCH-expressing neurons modulate ciliary beating of ependymal cells at the third ventricle and could contribute to maintain cerebro-spinal fluid homeostasis.
- Published
- 2013
- Full Text
- View/download PDF
24. [Beating frequency of motile cilia lining the third cerebral ventricle is finely tuned by the hypothalamic peptide MCH].
- Author
-
Conductier G, Viola A, le Troter A, Nahon JL, and Guyon A
- Subjects
- Animals, Cerebral Ventricles physiology, Humans, Movement physiology, Cerebral Ventricles ultrastructure, Cilia physiology, Hypothalamic Hormones physiology, Hypothalamus chemistry, Melanins physiology, Pituitary Hormones physiology
- Published
- 2013
- Full Text
- View/download PDF
25. Baclofen and other GABAB receptor agents are allosteric modulators of the CXCL12 chemokine receptor CXCR4.
- Author
-
Guyon A, Kussrow A, Olmsted IR, Sandoz G, Bornhop DJ, and Nahon JL
- Subjects
- Allosteric Regulation drug effects, Allosteric Regulation physiology, Animals, Baclofen metabolism, Cell Line, Tumor, Female, GABA Agents metabolism, GABA-B Receptor Agonists pharmacology, HEK293 Cells, Humans, Male, Organ Culture Techniques, Protein Binding drug effects, Protein Binding physiology, Rats, Rats, Wistar, Xenopus laevis, Baclofen pharmacology, Chemokine CXCL12 metabolism, GABA-B Receptor Agonists metabolism, Receptors, CXCR4 metabolism
- Abstract
CXCR4, a receptor for the chemokine CXCL12 (stromal-cell derived factor-1α), is a G-protein-coupled receptor (GPCR), expressed in the immune and CNS and integrally involved in various neurological disorders. The GABAB receptor is also a GPCR that mediates metabotropic action of the inhibitory neurotransmitter GABA and is located on neurons and immune cells as well. Using diverse approaches, we report novel interaction between GABAB receptor agents and CXCR4 and demonstrate allosteric binding of these agents to CXCR4. First, both GABAB antagonists and agonists block CXCL12-elicited chemotaxis in human breast cancer cells. Second, a GABAB antagonist blocks the potentiation by CXCL12 of high-threshold Ca(2+) channels in rat neurons. Third, electrophysiology in Xenopus oocytes and human embryonic kidney cell line 293 cells in which we coexpressed rat CXCR4 and the G-protein inward rectifier K(+) (GIRK) channel showed that GABAB antagonist and agonist modified CXCL12-evoked activation of GIRK channels. To investigate whether GABAB ligands bind to CXCR4, we expressed this receptor in heterologous systems lacking GABAB receptors and performed competition binding experiments. Our fluorescent resonance energy transfer experiments suggest that GABAB ligands do not bind CXCR4 at the CXCL12 binding pocket suggesting allosteric modulation, in accordance with our electrophysiology experiments. Finally, using backscattering interferometry and lipoparticles containing only the CXCR4 receptor, we quantified the binding affinity for the GABAB ligands, confirming a direct interaction with the CXCR4 receptor. The effect of GABAergic agents on CXCR4 suggests new therapeutic potentials for neurological and immune diseases.
- Published
- 2013
- Full Text
- View/download PDF
26. Melanin-concentrating hormone regulates beat frequency of ependymal cilia and ventricular volume.
- Author
-
Conductier G, Brau F, Viola A, Langlet F, Ramkumar N, Dehouck B, Lemaire T, Chapot R, Lucas L, Rovère C, Maitre P, Hosseiny S, Petit-Paitel A, Adamantidis A, Lakaye B, Risold PY, Prévot V, Meste O, Nahon JL, and Guyon A
- Subjects
- Adenosine Triphosphate pharmacology, Animals, Brain cytology, Calcium metabolism, Cerebral Ventricles drug effects, Cerebrospinal Fluid drug effects, Cerebrospinal Fluid metabolism, Cilia drug effects, Electric Stimulation, Female, Hormone Antagonists pharmacology, Hypothalamic Hormones deficiency, In Vitro Techniques, Male, Melanins deficiency, Mice, Mice, Inbred C57BL, Mice, Transgenic, Nerve Tissue Proteins metabolism, Neurons drug effects, Neurons metabolism, Pituitary Hormones deficiency, Receptors, Somatostatin deficiency, Receptors, Somatostatin genetics, Serotonin pharmacology, Cerebral Ventricles anatomy & histology, Cilia physiology, Ependyma anatomy & histology, Hypothalamic Hormones pharmacology, Melanins pharmacology, Pituitary Hormones pharmacology
- Abstract
Ependymal cell cilia help move cerebrospinal fluid through the cerebral ventricles, but the regulation of their beat frequency remains unclear. Using in vitro, high-speed video microscopy and in vivo magnetic resonance imaging in mice, we found that the metabolic peptide melanin-concentrating hormone (MCH) positively controlled cilia beat frequency, specifically in the ventral third ventricle, whereas a lack of MCH receptor provoked a ventricular size increase.
- Published
- 2013
- Full Text
- View/download PDF
27. Peripheral injections of melanin-concentrating hormone receptor 1 antagonist S38151 decrease food intake and body weight in rodent obesity models.
- Author
-
Della-Zuana O, Audinot V, Levenez V, Ktorza A, Presse F, Nahon JL, and Boutin JA
- Abstract
The compound S38151 is a nanomolar antagonist that acts at the melanin-concentrating hormone receptor 1 (MCH(1)). S38151 is more stable than its purely peptide counterpart, essentially because of the blockade of its N-terminus. Therefore, its action on various models of obesity was studied. Acute intra-cerebroventricular (i.c.v.) administration of S38151 in wild-type rats counteracted the effect of the stable precursor of melanin-concentrating hormone (MCH), NEI-MCH, in a dose-dependent manner (from 0.5 to 50 nmol/kg). In genetically obese Zucker fa/fa rats, daily i.c.v. administration of S38151 induced dose-dependent (5, 10, and 20 nmol/kg) inhibition of food intake, water intake, and body weight gain, as well as increased motility (maximal effect observed at 20 nmol/kg). In Zucker fa/fa rats, intraperitoneal injection of S38151 (30 mg/kg) induced complete inhibition of food consumption within 1 h. Daily intraperitoneal injection of S38151 (10 and 30 mg/kg) into genetically obese ob/ob mice or diet-induced obese mice is able to limit body weight gain. Furthermore, S38151 administration (10 and 30 mg/kg) does not affect food intake, water intake, or body weight gain in MCHR1-deleted mice, demonstrating that its effects are linked to its interaction with MCH(1). These results validate MCH(1) as a target of interest in obesity. S38151 cannot progress to the clinical phase because it is still too poorly stable in vivo.
- Published
- 2012
- Full Text
- View/download PDF
28. Prion protein is a key determinant of alcohol sensitivity through the modulation of N-methyl-D-aspartate receptor (NMDAR) activity.
- Author
-
Petit-Paitel A, Ménard B, Guyon A, Béringue V, Nahon JL, Zsürger N, and Chabry J
- Subjects
- Animals, Cells, Cultured, Cricetinae, Excitatory Postsynaptic Potentials drug effects, Hippocampus cytology, Hippocampus drug effects, Humans, In Vitro Techniques, Male, Membrane Microdomains drug effects, Mice, Mice, Inbred C57BL, Mice, Transgenic, Phosphorylation, Prion Proteins, Prions genetics, Protein Transport, Proto-Oncogene Proteins c-fyn metabolism, Receptors, N-Methyl-D-Aspartate metabolism, Signal Transduction, src-Family Kinases metabolism, Central Nervous System Depressants pharmacology, Drug Tolerance, Ethanol pharmacology, Prions metabolism, Receptors, N-Methyl-D-Aspartate physiology
- Abstract
The prion protein (PrP) is absolutely required for the development of prion diseases; nevertheless, its physiological functions in the central nervous system remain elusive. Using a combination of behavioral, electrophysiological and biochemical approaches in transgenic mouse models, we provide strong evidence for a crucial role of PrP in alcohol sensitivity. Indeed, PrP knock out (PrP(-/-)) mice presented a greater sensitivity to the sedative effects of EtOH compared to wild-type (wt) control mice. Conversely, compared to wt mice, those over-expressing mouse, human or hamster PrP genes presented a relative insensitivity to ethanol-induced sedation. An acute tolerance (i.e. reversion) to ethanol inhibition of N-methyl-D-aspartate (NMDA) receptor-mediated excitatory post-synaptic potentials in hippocampal slices developed slower in PrP(-/-) mice than in wt mice. We show that PrP is required to induce acute tolerance to ethanol by activating a Src-protein tyrosine kinase-dependent intracellular signaling pathway. In an attempt to decipher the molecular mechanisms underlying PrP-dependent ethanol effect, we looked for changes in lipid raft features in hippocampus of ethanol-treated wt mice compared to PrP(-/-) mice. Ethanol induced rapid and transient changes of buoyancy of lipid raft-associated proteins in hippocampus of wt but not PrP(-/-) mice suggesting a possible mechanistic link for PrP-dependent signal transduction. Together, our results reveal a hitherto unknown physiological role of PrP on the regulation of NMDAR activity and highlight its crucial role in synaptic functions.
- Published
- 2012
- Full Text
- View/download PDF
29. Variations in circulating inflammatory factors are related to changes in calorie and carbohydrate intakes early in the course of surgery-induced weight reduction.
- Author
-
Dalmas E, Rouault C, Abdennour M, Rovere C, Rizkalla S, Bar-Hen A, Nahon JL, Bouillot JL, Guerre-Millo M, Clément K, and Poitou C
- Subjects
- Adult, Diabetes Mellitus, Type 2 immunology, Female, Gastric Bypass, Humans, Middle Aged, Obesity surgery, Cytokines blood, Dietary Carbohydrates administration & dosage, Energy Intake, Obesity immunology, Surgical Procedures, Operative, Weight Loss
- Abstract
Background: Obesity is considered a low-grade inflammatory state that improves with weight loss. In addition to acute-phase proteins, other cytokines might contribute to systemic inflammation., Objective: Our objective was to compare serum concentrations of a large panel of inflammation-related factors in obese and normal-weight subjects and to determine kinetic changes induced by caloric restriction., Design: The cohort comprised 14 normal-weight women and 51 obese women who were followed over 2 y after Roux-en-Y gastric bypass. Multiplexed proteomics were used to simultaneously assay 27 cytokines and growth factors in serum., Results: Concentrations of interleukin (IL)-9, IL-1-receptor antagonist, IL-10, interferon-γ-inducible protein 10, macrophage inflammatory protein 1β, monocyte chemoattractant protein 1, IL-8, RANTES (regulated upon activation, normal T cell expressed and secreted), monokine induced by interferon-γ, and vascular endothelial growth factor were found to be elevated in obesity. IL-10 was further elevated in diabetic obese patients, whereas eotaxin was found to be higher only in diabetic subjects. After surgery, many factors showed a biphasic pattern of variation, decreasing sharply at month 3 before rising back to presurgical values at month 6; these changes closely tracked similar kinetic changes in calorie and carbohydrate intake. After 1 y, an overall reduction in cytokines accompanied the reduction in body mass index and an amelioration in metabolic status., Conclusions: Obesity is associated with elevated circulating concentrations of a large panel of cytokines. Coordinated kinetic changes during weight loss suggest an early influence of calorie and carbohydrate intakes, whereas a longer-term reduction in corpulence might prevail in regulating circulating cytokine concentrations. This trial is registered at clincaltrials.gov as NCT00476658.
- Published
- 2011
- Full Text
- View/download PDF
30. Dopamine depresses melanin concentrating hormone neuronal activity through multiple effects on α2-noradrenergic, D1 and D2-like dopaminergic receptors.
- Author
-
Conductier G, Nahon JL, and Guyon A
- Subjects
- Action Potentials drug effects, Action Potentials physiology, Animals, Dopamine pharmacology, Dose-Response Relationship, Drug, Hypothalamic Hormones genetics, Hypothalamus drug effects, Hypothalamus physiology, Male, Melanins genetics, Membrane Potentials drug effects, Mice, Mice, Inbred C57BL, Mice, Transgenic, Neurons metabolism, Patch-Clamp Techniques, Pituitary Hormones genetics, Synaptic Transmission drug effects, Synaptic Transmission physiology, Dopamine physiology, Hypothalamic Hormones metabolism, Melanins metabolism, Membrane Potentials physiology, Neurons physiology, Pituitary Hormones metabolism, Receptors, Adrenergic, alpha-2 physiology, Receptors, Dopamine D1 physiology, Receptors, Dopamine D2 physiology
- Abstract
Two neuronal populations of the lateral hypothalamus that, respectively, produce melanin-concentrating hormone (MCH) and orexin peptides are crucially involved in control of metabolism, feeding and related goal-oriented behaviors. In contrast to orexin neurons, mainly involved in short-term regulation of feeding, MCH neurons participate in long-term control of energy storage and body weight. Beyond its effect on feeding, MCH has also been shown to be involved in regulation of seeking behavior and addiction through modulation of dopamine (DA) metabolism. This regulation is essential for reinforcement-associated behaviors. Moreover, drugs of abuse, which increase extracellular DA levels, are known to decrease food intake. Consistent with this observation, DA has been shown to modulate orexin neurons of the lateral hypothalamus. However, no study is available concerning the effects of DA on MCH neurons. Whole-cell patch-clamp recordings were done in hypothalamic mouse brain slices. MCH neurons were identified by Tau-Cyan-GFP labeling using a transgenic mouse model (MCH-GFP). First, we show that DA (10-200 μM) induces an outward current in MCH neurons. However, this current is not due to activation of DA receptors, but mediated through activation of α2-noradrenergic receptors and subsequent opening of G-protein activated inward rectifier K+ (GIRK) channels. Current-clamp experiments revealed that this GIRK-activation leads to hyperpolarization, thus decreasing excitability of MCH neurons. Furthermore, we confirm that MCH neurons receive mainly GABAergic inputs rather than glutamatergic ones. We show that DA modulates these inputs in a complex manner: at low concentrations, DA activates D1-like receptors, promoting presynaptic activity, whereas, at higher concentrations (100 μM), D2-like receptor activation inhibits presynaptic activity. Overall, DA should lead to a decrease in MCH neuron excitability, likely resulting in down-regulation of MCH release and feeding behavior., (Copyright © 2011 IBRO. Published by Elsevier Ltd. All rights reserved.)
- Published
- 2011
- Full Text
- View/download PDF
31. Development of posterior hypothalamic neurons enlightens a switch in the prosencephalic basic plan.
- Author
-
Croizier S, Amiot C, Chen X, Presse F, Nahon JL, Wu JY, Fellmann D, and Risold PY
- Subjects
- Animals, Axons metabolism, Bromodeoxyuridine metabolism, Cell Differentiation, Embryo, Mammalian metabolism, Gene Expression Regulation, Developmental, Green Fluorescent Proteins metabolism, Hedgehog Proteins metabolism, Homeobox Protein Nkx-2.2, Hypothalamic Hormones metabolism, Intercellular Signaling Peptides and Proteins metabolism, Melanins metabolism, Mesencephalon cytology, Mesencephalon metabolism, Mice, Models, Biological, Nerve Growth Factors metabolism, Nerve Tissue Proteins metabolism, Netrin-1, Neurons cytology, Phenotype, Pituitary Hormones metabolism, Rats, Receptors, Immunologic metabolism, Telencephalon cytology, Telencephalon metabolism, Time Factors, Tumor Suppressor Proteins metabolism, Hypothalamus cytology, Hypothalamus metabolism, Neurons metabolism
- Abstract
In rats and mice, ascending and descending axons from neurons producing melanin-concentrating hormone (MCH) reach the cerebral cortex and spinal cord. However, these ascending and descending projections originate from distinct sub-populations expressing or not "Cocaine-and-Amphetamine-Regulated-Transcript" (CART) peptide. Using a BrdU approach, MCH cell bodies are among the very first generated in the hypothalamus, within a longitudinal cell cord made of earliest delaminating neuroblasts in the diencephalon and extending from the chiasmatic region to the ventral midbrain. This region also specifically expresses the regulatory genes Sonic hedgehog (Shh) and Nkx2.2. First MCH axons run through the tractus postopticus (tpoc) which gathers pioneer axons from the cell cord and courses parallel to the Shh/Nkx2.2 expression domain. Subsequently generated MCH neurons and ascending MCH axons differentiate while neurogenesis and mantle layer differentiation are generalized in the prosencephalon, including telencephalon. Ascending MCH axons follow dopaminergic axons of the mesotelencephalic tract, both being an initial component of the medial forebrain bundle (mfb). Netrin1 and Slit2 proteins that are involved in the establishment of the tpoc and mfb, respectively attract or repulse MCH axons.We conclude that first generated MCH neurons develop in a diencephalic segment of a longitudinal Shh/Nkx2.2 domain. This region can be seen as a prosencephalic segment of a medial neurogenic column extending from the chiasmatic region through the ventral neural tube. However, as the telencephalon expends, it exerts a trophic action and the mfb expands, inducing a switch in the longitudinal axial organization of the prosencephalon.
- Published
- 2011
- Full Text
- View/download PDF
32. The role of monocyte chemoattractant protein MCP1/CCL2 in neuroinflammatory diseases.
- Author
-
Conductier G, Blondeau N, Guyon A, Nahon JL, and Rovère C
- Subjects
- Alzheimer Disease immunology, Alzheimer Disease metabolism, Animals, Brain metabolism, Chemokine CCL2 biosynthesis, Chemokine CCL2 genetics, Humans, Multiple Sclerosis immunology, Multiple Sclerosis metabolism, Receptors, CCR2 biosynthesis, Receptors, CCR2 genetics, Stroke immunology, Stroke metabolism, Alzheimer Disease pathology, Brain immunology, Brain pathology, Chemokine CCL2 physiology, Chemotaxis, Leukocyte immunology, Multiple Sclerosis pathology, Receptors, CCR2 physiology, Stroke pathology
- Abstract
Inflammatory response represents one of the first immune processes following injury. It is characterized by the production of various molecules that initiate the recruitment of immune cells to the lesion sites, including in the brain. Accordingly, in acute brain trauma, such as stroke, as well as during chronic affections like multiple sclerosis or Alzheimer's disease, inflammation occurs in order to "clean up" the lesion and to limit its area. Nevertheless, prolonged and sustained inflammation may have cytotoxic effects, aggravating the incidence and the severity of the disease. Among molecules produced during inflammation associated to neuronal death, monocyte chemoattractant proteins (MCPs) seem to be particularly important. This review will focus on the current knowledge about one of the MCPs, CCL2, and its cognate receptor, CCR2, both expressed in physiological conditions and during neurodegenerative diseases., ((c) 2010 Elsevier B.V. All rights reserved.)
- Published
- 2010
- Full Text
- View/download PDF
33. Genes regulated in MPTP-treated macaques and human Parkinson's disease suggest a common signature in prefrontal cortex.
- Author
-
Storvik M, Arguel MJ, Schmieder S, Delerue-Audegond A, Li Q, Qin C, Vital A, Bioulac B, Gross CE, Wong G, Nahon JL, and Bezard E
- Subjects
- Aged, Aged, 80 and over, Alzheimer Disease genetics, Alzheimer Disease metabolism, Animals, Disease Models, Animal, Female, Globus Pallidus metabolism, Humans, Macaca fascicularis, Male, Middle Aged, Models, Neurological, Oligonucleotide Array Sequence Analysis, Polymerase Chain Reaction, Putamen metabolism, RNA, Messenger metabolism, Species Specificity, Thalamus metabolism, Parkinson Disease genetics, Parkinson Disease metabolism, Parkinsonian Disorders genetics, Parkinsonian Disorders metabolism, Prefrontal Cortex metabolism
- Abstract
The presymptomatic phase of Parkinson's disease (PD) is now recognized as a prodromal phase, with compensatory mechanism masking its progression and non-motor early manifestations, such as depression, cognitive disturbances and apathy. Those mechanisms were thought to be strictly dopamine-mediated until recent advances have shed light upon involvement of putative outside-basal ganglia, i.e. cortical, structures. We took advantage of our progressive 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated macaque model to monitor whole genome transcriptional changes in several brain areas. Our data reveals that transcriptomic activity changes take place from early stages, suggesting very early compensatory mechanisms or pathological activity outside the basal ganglia, including the PFC. Specific transcriptomic changes occurring in the PFC of fully parkinsonian MPTP-treated macaques have been identified. Interestingly, a large part of these transcriptomic changes were also observed in human post-mortem samples of patients with neurodegenerative diseases analysed by quantitative PCR. These results suggest that the PFC is able to detect the progression of dopamine denervation even at very early time points. There are therefore mechanisms, within the PFC, leading to compensatory alterations and/or participating to pathophysiology of prodromal PD manifestations.
- Published
- 2010
- Full Text
- View/download PDF
34. Spadin, a sortilin-derived peptide, targeting rodent TREK-1 channels: a new concept in the antidepressant drug design.
- Author
-
Mazella J, Pétrault O, Lucas G, Deval E, Béraud-Dufour S, Gandin C, El-Yacoubi M, Widmann C, Guyon A, Chevet E, Taouji S, Conductier G, Corinus A, Coppola T, Gobbi G, Nahon JL, Heurteaux C, and Borsotto M
- Subjects
- Adaptor Proteins, Vesicular Transport chemistry, Adaptor Proteins, Vesicular Transport genetics, Adaptor Proteins, Vesicular Transport pharmacology, Animals, Antidepressive Agents metabolism, Antidepressive Agents therapeutic use, COS Cells, Chlorocebus aethiops, Cyclic AMP Response Element-Binding Protein metabolism, Depressive Disorder drug therapy, Drug Design, Humans, Male, Mice, Mice, Inbred C57BL, Motor Activity drug effects, Patch-Clamp Techniques, Peptides chemistry, Peptides genetics, Peptides pharmacology, Peptides therapeutic use, Potassium Channel Blockers metabolism, Potassium Channels, Tandem Pore Domain antagonists & inhibitors, Potassium Channels, Tandem Pore Domain genetics, Raphe Nuclei drug effects, Serotonin metabolism, Synaptic Transmission drug effects, Adaptor Proteins, Vesicular Transport metabolism, Antidepressive Agents chemistry, Peptides metabolism, Potassium Channels, Tandem Pore Domain metabolism
- Abstract
Current antidepressant treatments are inadequate for many individuals, and when they are effective, they require several weeks of administration before a therapeutic effect can be observed. Improving the treatment of depression is challenging. Recently, the two-pore domain potassium channel TREK-1 has been identified as a new target in depression, and its antagonists might become effective antidepressants. In mice, deletion of the TREK-1 gene results in a depression-resistant phenotype that mimics antidepressant treatments. Here, we validate in mice the antidepressant effects of spadin, a secreted peptide derived from the propeptide generated by the maturation of the neurotensin receptor 3 (NTSR3/Sortilin) and acting through TREK-1 inhibition. NTSR3/Sortilin interacted with the TREK-1 channel, as shown by immunoprecipitation of TREK-1 and NTSR3/Sortilin from COS-7 cells and cortical neurons co-expressing both proteins. TREK-1 and NTSR3/Sortilin were colocalized in mouse cortical neurons. Spadin bound specifically to TREK-1 with an affinity of 10 nM. Electrophysiological studies showed that spadin efficiently blocked the TREK-1 activity in COS-7 cells, cultured hippocampal pyramidal neurons, and CA3 hippocampal neurons in brain slices. Spadin also induced in vivo an increase of the 5-HT neuron firing rate in the Dorsal Raphe Nucleus. In five behavioral tests predicting an antidepressant response, spadin-treated mice showed a resistance to depression as found in TREK-1 deficient mice. More importantly, an intravenous 4-d treatment with spadin not only induced a strong antidepressant effect but also enhanced hippocampal phosphorylation of CREB protein and neurogenesis, considered to be key markers of antidepressant action after chronic treatment with selective serotonin reuptake inhibitors. This work also shows the development of a reliable method for dosing the propeptide in serum of mice by using AlphaScreen technology. These findings point out spadin as a putative antidepressant of new generation with a rapid onset of action. Spadin can be regarded as the first natural antidepressant peptide identified. It corresponds to a new concept to address the treatment of depression., Competing Interests: The authors have declared that no competing interests exist.
- Published
- 2010
- Full Text
- View/download PDF
35. Dietary supplementation of alpha-linolenic acid in an enriched rapeseed oil diet protects from stroke.
- Author
-
Nguemeni C, Delplanque B, Rovère C, Simon-Rousseau N, Gandin C, Agnani G, Nahon JL, Heurteaux C, and Blondeau N
- Subjects
- Animals, Fatty Acids, Monounsaturated, Lipid Peroxidation drug effects, Lipid Peroxidation physiology, Male, Mice, Mice, Inbred C57BL, Rapeseed Oil, Stroke metabolism, Stroke pathology, Dietary Fats, Unsaturated administration & dosage, Dietary Supplements, Plant Oils administration & dosage, Stroke prevention & control, alpha-Linolenic Acid administration & dosage
- Abstract
Populations of Western countries are severely deficient in omega-3 intake, both in the form of alpha-linolenic acid (ALA) and the Long Chain derivatives (LC-n-3), Eicosa-Pentaenoic-Acid and Docosa-Hexaenoic-Acid. Omega-3 insufficiency is a risk factor for cardiovascular and cerebral diseases such as coronary heart disease and stroke. Stroke is a major cause of mortality and morbidity, and induces a significant socioeconomic cost and a marked increase in patient/family burden. To date, preventive treatments and neuroprotective drugs identified in preclinical studies failed in clinical trials, in part because of an inability to tolerate drugs at neuroprotective concentrations. Therefore testing alternative protective strategies, such as functional foods/nutraceuticals, are of considerable interest. We have previously demonstrated that a single injection of ALA reduced ischemic damage by limiting glutamate-mediated neuronal death, whereas repeated injections displayed additive protective benefits as a result of increased neurogenesis, synaptogenesis and neurotrophin expression. Because intravenous injections are not a suitable long-term strategy in humans, the present study investigated the effect of ALA supplementation by an experimental diet containing rapeseed oil (RSO, a rich source of ALA) as the only source of lipids for stroke prevention. We tested several experimental diets which included 5, 10, and 20% RSO-enriched diet and feeding paradigms (fresh diet was provided once or twice a week for 4 or 6 weeks). Our results showed that ALA supplemented diets are more sensitive to lipid peroxidation than a regular chow diet. Because the diet affected feeding behavior and animal growth, we defined concrete guidelines to investigate the effect of omega-3 supplementation on neuropathology. Among the different sets of experiments, animals fed with 10% and 20% RSO-enriched diet displayed a reduced mortality rate, infarct size and increased probability of spontaneous reperfusion in the post-ischemic period. In addition, a drastic reduction of lipid peroxidation levels was observed in the ischemic brain of RSO-fed animals. Overall, our findings provide new insights into the potential of employing rapeseed oil as a functional food/nutraceutical aiding in stroke prevention and protection., (2009 Elsevier Ltd. All rights reserved.)
- Published
- 2010
- Full Text
- View/download PDF
36. Melanin-concentrating hormone producing neurons: Activities and modulations.
- Author
-
Guyon A, Conductier G, Rovere C, Enfissi A, and Nahon JL
- Subjects
- Animals, Electrophysiology, Feeding Behavior physiology, Humans, Hypothalamic Hormones metabolism, Hypothalamic Hormones physiology, Hypothalamus cytology, Melanins metabolism, Melanins physiology, Pituitary Hormones metabolism, Pituitary Hormones physiology, Hypothalamic Hormones biosynthesis, Melanins biosynthesis, Neurons metabolism, Pituitary Hormones biosynthesis
- Abstract
Regulation of energy homeostasis in animals involves adaptation of energy intake to its loss, through a perfect regulation of feeding behavior and energy storage/expenditure. Factors from the periphery modulate brain activity in order to adjust food intake as needed. Particularly, "first order" neurons from arcuate nucleus are able to detect modifications in homeostatic parameters and to transmit information to "second order" neurons, partly located in the lateral hypothalamic area. These "second order" neurons have widespread projections throughout the brain and their proper activation leads them to a coordinated response associated to an adapted behavior. Among these neurons, melanin-concentrating hormone (MCH) expressing neurons play an integrative role of the various factors arising from periphery, first order neurons and extra-hypothalamic arousal systems neurons and modulate regulation of feeding, drinking and seeking behaviors. As regulation of MCH release is correlated to regulation of MCH neuronal activity, we focused this review on the electrophysiological properties of MCH neurons from the lateral hypothalamic area. We first reviewed the knowledge on the endogenous electrical properties of MCH neurons identified according to various criteria which are described. Then, we dealt with the modulations of the electrical activity of MCH neurons by different factors such as glucose, glutamate and GABA, peptides and hormones regulating feeding and transmitters of extra-hypothalamic arousal systems. Finally, we described the current knowledge on the modulation of MCH neuronal activity by cytokines and chemokines. Because of such regulation, MCH neurons are some of the best candidate to account for infection-induced anorexia, but also obesity.
- Published
- 2009
- Full Text
- View/download PDF
37. Melanin-concentrating hormone induces neurite outgrowth in human neuroblastoma SH-SY5Y cells through p53 and MAPKinase signaling pathways.
- Author
-
Cotta-Grand N, Rovère C, Guyon A, Cervantes A, Brau F, and Nahon JL
- Subjects
- Blotting, Southern, Blotting, Western, Cell Line, Cell Line, Tumor, Early Growth Response Protein 1 metabolism, Flavonoids pharmacology, Humans, Immunohistochemistry, Mitogen-Activated Protein Kinase 1 metabolism, Mitogen-Activated Protein Kinase 3 metabolism, Patch-Clamp Techniques, Phosphorylation drug effects, Receptors, Pituitary Hormone genetics, Receptors, Pituitary Hormone metabolism, Reverse Transcriptase Polymerase Chain Reaction, Tumor Suppressor Protein p53 metabolism, ets-Domain Protein Elk-1 metabolism, Hypothalamic Hormones pharmacology, Melanins pharmacology, Neurites drug effects, Neuroblastoma metabolism, Pituitary Hormones pharmacology, Signal Transduction drug effects
- Abstract
Melanin-concentrating hormone (MCH) peptide plays a major role in energy homeostasis regulation. Little is known about cellular functions engaged by endogenous MCH receptor (MCH-R1). Here, MCH-R1 mRNA and cognate protein were found expressed in human neuroblastoma SH-SY5Y cells. Electrophysiological experiments demonstrated that MCH modulated K(+) currents, an effect depending upon the time of cellular growth. MCH treatments induced a transient phosphorylation of MAPKinases, abolished by PD98059, and partially blocked by PTX, suggesting a Galphai/Galphao protein contribution. MCH stimulated expression and likely nuclear localization of phosphorylated p53 proteins, an effect fully dependent upon MAPKinase activities. MCH treatment also increased phosphorylation of Elk-1 and up-regulated Egr-1, two transcriptional factors targeted by the MAPKinase pathway. Finally, MCH provoked neurite outgrowth after 24h-treatment of neuroblastoma cells. This effect and transcriptional factors activation were partly prevented by PD98059. Collectively, our results provide the first evidence for a role of MCH in neuronal differentiation of endogenously MCH-R1-expressing cells via non-exclusive MAPKinase and p53 signaling pathways.
- Published
- 2009
- Full Text
- View/download PDF
38. Melanin-concentrating hormone. Editorial.
- Author
-
Vaudry H and Nahon JL
- Subjects
- Animals, Feeding Behavior, Humans, Hypothalamic Hormones genetics, Hypothalamic Hormones metabolism, Melanins genetics, Melanins metabolism, Pituitary Hormones genetics, Pituitary Hormones metabolism, Receptors, Pituitary Hormone metabolism, Hypothalamic Hormones physiology, Melanins physiology, Neuropeptides metabolism, Pituitary Hormones physiology
- Published
- 2009
- Full Text
- View/download PDF
39. Long term exposure to the chemokine CCL2 activates the nigrostriatal dopamine system: a novel mechanism for the control of dopamine release.
- Author
-
Guyon A, Skrzydelski D, De Giry I, Rovère C, Conductier G, Trocello JM, Daugé V, Kitabgi P, Rostène W, Nahon JL, and Mélik Parsadaniantz S
- Subjects
- Animals, Cell Membrane physiology, Chemokine CCL2 pharmacology, Corpus Striatum drug effects, In Vitro Techniques, Ion Channel Gating, Male, Microdialysis, Motor Activity drug effects, Neurons drug effects, Neurons physiology, Patch-Clamp Techniques, Potassium Channels physiology, Rats, Rats, Wistar, Stereotyped Behavior drug effects, Substantia Nigra drug effects, Time Factors, Chemokine CCL2 physiology, Corpus Striatum metabolism, Dopamine metabolism, Substantia Nigra metabolism
- Abstract
Accumulating evidence show that chemokines can modulate the activity of neurons through various mechanisms. Recently, we demonstrated that CCR2, the main receptor for the chemokine CCL2, is constitutively expressed in dopamine neurons in the rat substantia nigra. Here we show that unilateral intranigral injections of CCL2 (50 ng) in freely moving rats increase extracellular concentrations of dopamine and its metabolites and decrease dopamine content in the ipsilateral dorsal striatum. Furthermore, these CCL2 injections are responsible for an increase in locomotor activity resulting in contralateral circling behavior. Using patch-clamp recordings of dopaminergic neurons in slices of the rat substantia nigra, we observed that a prolonged exposure (>8 min) to 10 nM CCL2 significantly increases the membrane resistance of dopaminergic neurons by closure of background channels mainly selective to potassium ions. This leads to an enhancement of dopaminergic neuron discharge in pacemaker or burst mode necessary for dopamine release. We provide here the first evidence that application of CCL2 on dopaminergic neurons increases their excitability, dopamine release and related locomotor activity.
- Published
- 2009
- Full Text
- View/download PDF
40. Glucose inhibition persists in hypothalamic neurons lacking tandem-pore K+ channels.
- Author
-
Guyon A, Tardy MP, Rovère C, Nahon JL, Barhanin J, and Lesage F
- Subjects
- Animals, Barium pharmacology, Hydrogen-Ion Concentration, In Vitro Techniques, Intracellular Signaling Peptides and Proteins metabolism, Male, Membrane Potentials drug effects, Membrane Potentials genetics, Mice, Mice, Inbred C57BL, Mice, Knockout, Nerve Tissue Proteins deficiency, Neural Inhibition physiology, Neurons physiology, Neuropeptides metabolism, Orexins, Patch-Clamp Techniques methods, Potassium Channels deficiency, Potassium Channels, Tandem Pore Domain classification, Glucose pharmacology, Hypothalamus cytology, Neural Inhibition drug effects, Neurons drug effects, Potassium Channels, Tandem Pore Domain deficiency, Sweetening Agents pharmacology
- Abstract
Glucose sensing by hypothalamic neurons triggers adaptive metabolic and behavioral responses. In orexin neurons, extracellular glucose activates a leak K(+) current promoting electrical activity inhibition. Sensitivity to external acidification and halothane, and resistance to ruthenium red designated the tandem-pore K(+) (K(2P)) channel subunit TASK3 as part of the glucose-induced channel. Here, we show that glucose inhibition and its pH sensitivity persist in mice lacking TASK3 or TASK1, or both subunits. We also tested the implication of another class of K(2P) channels activated by halothane. In the corresponding TREK1/2/TRAAK triple knock-out mice, glucose inhibition persisted in hypothalamic neurons ruling out a major contribution of these subunits to the glucose-activated K(+) conductance. Finally, block of this glucose-induced hyperpolarizing current by low Ba(2+) concentrations was consistent with the conclusion that K(2P) channels are not required for glucosensing in hypothalamic neurons.
- Published
- 2009
- Full Text
- View/download PDF
41. Primate-specific spliced PMCHL RNAs are non-protein coding in human and macaque tissues.
- Author
-
Schmieder S, Darré-Toulemonde F, Arguel MJ, Delerue-Audegond A, Christen R, and Nahon JL
- Subjects
- Adult, Amino Acid Sequence, Animals, Brain metabolism, Chromosomes, Human, Pair 5 genetics, Evolution, Molecular, Exons, Humans, Introns, Macaca genetics, Male, Molecular Sequence Data, Phylogeny, Primates, RNA, Untranslated metabolism, Sequence Alignment, Testis metabolism, Hypothalamic Hormones genetics, Protein Precursors genetics, RNA Splicing, RNA, Untranslated genetics
- Abstract
Background: Brain-expressed genes that were created in primate lineage represent obvious candidates to investigate molecular mechanisms that contributed to neural reorganization and emergence of new behavioural functions in Homo sapiens. PMCHL1 arose from retroposition of a pro-melanin-concentrating hormone (PMCH) antisense mRNA on the ancestral human chromosome 5p14 when platyrrhines and catarrhines diverged. Mutations before divergence of hylobatidae led to creation of new exons and finally PMCHL1 duplicated in an ancestor of hominids to generate PMCHL2 at the human chromosome 5q13. A complex pattern of spliced and unspliced PMCHL RNAs were found in human brain and testis., Results: Several novel spliced PMCHL transcripts have been characterized in human testis and fetal brain, identifying an additional exon and novel splice sites. Sequencing of PMCHL genes in several non-human primates allowed to carry out phylogenetic analyses revealing that the initial retroposition event took place within an intron of the brain cadherin (CDH12) gene, soon after platyrrhine/catarrhine divergence, i.e. 30-35 Mya, and was concomitant with the insertion of an AluSg element. Sequence analysis of the spliced PMCHL transcripts identified only short ORFs of less than 300 bp, with low (VMCH-p8 and protein variants) or no evolutionary conservation. Western blot analyses of human and macaque tissues expressing PMCHL RNA failed to reveal any protein corresponding to VMCH-p8 and protein variants encoded by spliced transcripts., Conclusion: Our present results improve our knowledge of the gene structure and the evolutionary history of the primate-specific chimeric PMCHL genes. These genes produce multiple spliced transcripts, bearing short, non-conserved and apparently non-translated ORFs that may function as mRNA-like non-coding RNAs.
- Published
- 2008
- Full Text
- View/download PDF
42. Stromal-cell-derived factor 1alpha /CXCL12 modulates high-threshold calcium currents in rat substantia nigra.
- Author
-
Guyon A, Skrzydelski D, Rovère C, Apartis E, Rostène W, Kitabgi P, Mélik Parsadaniantz S, and Nahon JL
- Subjects
- Animals, Calcium Channels, N-Type drug effects, Calcium Channels, N-Type metabolism, Calcium Signaling drug effects, Cells, Cultured, Chemokine CXCL12 pharmacology, Conotoxins pharmacology, Dose-Response Relationship, Drug, Male, Membrane Potentials drug effects, Membrane Potentials physiology, Neurons drug effects, Patch-Clamp Techniques, Presynaptic Terminals drug effects, Presynaptic Terminals physiology, Rats, Rats, Wistar, Substantia Nigra cytology, Substantia Nigra drug effects, Synaptic Transmission drug effects, Synaptic Transmission physiology, Calcium Signaling physiology, Chemokine CXCL12 metabolism, Dopamine metabolism, Neurons metabolism, Substantia Nigra metabolism
- Abstract
Dopaminergic neurons of the substantia nigra constitutively express the CXCR4 receptor for the chemokine stromal-cell-derived factor 1alpha (CXCL12) but, to date, no direct effect of CXCR4 activation by CXCL12 on membrane conductance of dopaminergic neurons has been demonstrated. We tested the effects of CXCL12 on whole-cell currents of dopaminergic neurons recorded in patch clamp in substantia nigra slices and showed that CXCL12 (0.01-10 nm) increased the amplitude of total high-voltage-activated (HVA) Ca currents through CXCR4 activation. This effect was reversibly reduced by varpi-conotoxin-GVIA, suggesting that CXCL12 acted on N-type Ca currents, known to be involved in dopamine (DA) release. We therefore investigated the effects of CXCL12 on DA release from cultured dopaminergic neurons from the rat mesencephalon. In basal conditions, CXCL12 alone had no effect on DA release. When neurons were depolarized with KCl (20 mm), and thus when HVA Ca currents were activated, low CXCL12 concentrations (1-50 nm) increased DA release via CXCR4 stimulation. These data strongly suggest that the chemokine CXCL12 can act directly as a neuromodulator of dopaminergic neuronal electrical activity through the modulation of HVA currents.
- Published
- 2008
- Full Text
- View/download PDF
43. How cytokines can influence the brain: a role for chemokines?
- Author
-
Guyon A, Massa F, Rovère C, and Nahon JL
- Subjects
- Afferent Pathways physiology, Animals, Brain cytology, Hormones metabolism, Humans, Models, Biological, Neurons, Afferent physiology, Brain physiology, Chemokines physiology, Cytokines physiology
- Abstract
Following inflammation or infection, cytokines are released in the blood. Besides their effect on the immune system, cytokines can also act in the brain to modulate our behaviors, inducing for example anorexia when produced in large amount. This review focuses on our current knowledge on how cytokines can influence the brain and the behaviors through several possible pathways: modulating peripheral neurons which project to the brain through the vagus nerve, modulating the levels of hormones such as leptin which can act to the brain through the humoral pathway and possibly acting directly in the brain, through the local production of cytokines and chemokines such as SDF-1alpha/CXCL12.
- Published
- 2008
- Full Text
- View/download PDF
44. Effect of ppMCH derived peptides on PBMC proliferation and cytokine expression.
- Author
-
Coumans B, Grisar T, Nahon JL, and Lakaye B
- Subjects
- Cells, Cultured, Humans, Interferon-gamma metabolism, Interleukin-2 metabolism, Interleukin-2 pharmacology, Interleukin-4 metabolism, Leukocytes, Mononuclear cytology, Leukocytes, Mononuclear metabolism, Peptide Fragments pharmacology, Tumor Necrosis Factor-alpha metabolism, Cell Proliferation drug effects, Cytokines metabolism, Hypothalamic Hormones pharmacology, Leukocytes, Mononuclear drug effects, Melanins pharmacology, Pituitary Hormones pharmacology
- Abstract
The mRNA encoding prepro-Melanin concentrating hormone (ppMCH) is mainly expressed in the central nervous system but has also been detected at lower amount in many peripheral tissues including spleen and thymus. At the peptide level however, several forms of the precursor can be detected in these tissues and are sometimes expressed at similar levels compared to brain. In the present work, we have studied the in vitro action of a wide range of concentration (1 nM to 1 microM) of the different peptides encoded by ppMCH i.e. neuropeptide glycine-glutamic acid (NGE), neuropeptide glutamic acid-isoleucine (NEI), Melanin concentrating hormone (MCH) and the dipeptide NEI-MCH on peripheral blood mononuclear cells (PBMC) proliferation and cytokine production following anti-CD3 stimulation. Among them only MCH decreased PBMC proliferation with a maximal effect of 35% at 100 nM. Moreover as demonstrated by using ELISA, MCH significantly decreases IL-2 production by 25% but not IL-4, INF-gamma or TNF-alpha expression. Interestingly, exogenous IL-2 decreases significantly MCH-mediated inhibition, suggesting that it is an important downstream mediator of MCH action. Finally, we showed that after 7 to 9 days of incubation, MCH also inhibits proliferation of non-stimulated PBMC. Altogether, these data demonstrate that fully mature MCH modulates proliferation of anti-CD3 stimulated PBMC partially through regulation of IL-2 production.
- Published
- 2007
- Full Text
- View/download PDF
45. The chemokine stromal cell-derived factor-1/CXCL12 activates the nigrostriatal dopamine system.
- Author
-
Skrzydelski D, Guyon A, Daugé V, Rovère C, Apartis E, Kitabgi P, Nahon JL, Rostène W, and Parsadaniantz SM
- Subjects
- Action Potentials drug effects, Animals, Behavior, Animal drug effects, Brain Chemistry drug effects, Chemokine CXCL12, Dose-Response Relationship, Drug, Functional Laterality, Male, Microdialysis methods, Motor Activity drug effects, Rats, Rats, Wistar, Receptors, CCR4, Receptors, Chemokine metabolism, Tyrosine 3-Monooxygenase metabolism, Chemokines, CXC pharmacology, Corpus Striatum drug effects, Dopamine metabolism, Substantia Nigra drug effects
- Abstract
We recently demonstrated that dopaminergic (DA) neurons of the rat substantia nigra constitutively expressed CXCR4, receptor for the chemokine stromal cell-derived factor-1 (SDF-1)/CXCL12 (SDF-1). To check the physiological relevance of such anatomical observation, in vitro and in vivo approaches were used. Patch clamp recording of DA neurons in rat substantia nigra slices revealed that SDF-1 (10 nmol/L) induced: (i) a depolarization and increased action potential frequency; and (ii) switched the firing pattern of depolarized DA neurons from a tonic to a burst firing mode. This suggests that SDF-1 could increase DA release from neurons. Consistent with this hypothesis, unilateral intranigral injection of SDF-1 (50 ng) in freely moving rat decreased DA content and increased extracellular concentrations of DA and metabolites in the ipsilateral dorsal striatum, as shown using microdialysis. Furthermore, intranigral SDF-1 injection induced a contralateral circling behavior. These effects of SDF-1 were mediated via CXCR4 as they were abrogated by administration of a selective CXCR4 antagonist. Altogether, these data demonstrate that SDF-1, via CXCR4, activates nigrostriatal DA transmission. They show that the central functions of chemokines are not restricted, as originally thought, to neuroinflammation, but extend to neuromodulatory actions on well-defined neuronal circuits in non-pathological conditions.
- Published
- 2007
- Full Text
- View/download PDF
46. Multiple actions of the chemokine stromal cell-derived factor-1alpha on neuronal activity.
- Author
-
Guyon A and Nahon JL
- Subjects
- Animals, Chemokine CXCL12, Chemokines, CXC chemistry, Chemokines, CXC metabolism, Dimerization, Humans, Mice, Neurotransmitter Agents metabolism, Chemokines, CXC physiology, Neurons physiology
- Abstract
The chemokine SDF-1alpha and its cognate receptor CXCR4 are expressed in several neuronal populations. This review focuses on our current knowledge about the actions of this chemokine on neuronal excitability, through CXCR4 or other yet unknown pathways. In various neuronal populations (CA1 neurons of the hippocampus, granular and Purkinje cells of the cerebellum, melanin-concentrating hormone neurons of the lateral hypothalamus, vasopressinergic neurons of the supraoptic and the paraventricular nucleus of the hypothalamus, and dopaminergic neurons of the substantia nigra), SDF-1alpha can modulate the activity of neurons by multiple regulatory pathways including and often combining: (i) modulation of voltage-dependent channels (sodium, potassium, and calcium), (ii) activation of the G-protein-activated inward rectifier potassium current, and (iii) increase in neurotransmitter release (gamma-amino butyric acid (GABA), glutamate, and dopamine), often through Ca-dependent mechanisms. The possible mechanisms underlying these effects and their consequences in terms of modulation of neuroendocrine systems and physiopathology are discussed.
- Published
- 2007
- Full Text
- View/download PDF
47. The melanocortins and melanin-concentrating hormone in the central regulation of feeding behavior and energy homeostasis.
- Author
-
Nahon JL
- Subjects
- Agouti Signaling Protein, Animals, Hormones physiology, Humans, Intercellular Signaling Peptides and Proteins physiology, Pro-Opiomelanocortin physiology, Receptor, Melanocortin, Type 4 physiology, Signal Transduction, Energy Metabolism physiology, Feeding Behavior physiology, Homeostasis physiology, Hypothalamic Hormones physiology, Melanins physiology, Pituitary Hormones physiology, alpha-MSH physiology
- Abstract
A number of different neuropeptides exert powerful concerted controls on feeding behavior and energy balance, most of them being produced in hypothalamic neuronal networks under stimulation by anabolic and catabolic peripheral hormones such as ghrelin and leptin, respectively. These peptide-expressing neurons interconnect extensively to integrate the multiple opposing signals that mediate changes in energy expenditure. In the present review I have summarized our current knowledge about two key peptidic systems involved in regulating appetite and energy homeostasis, the melanocortin system (alpha-MSH, agouti and Agouti-related peptides, MC receptors and mahogany protein) and the melanin-concentrating hormone system (proMCH-derived peptides and MCH receptors) that contribute to satiety and feeding-initiation, respectively, with concurrent effects on energy expenditure. I have focused particularly on recent data concerning transgenic mice and the ongoing development of MC/MCH receptor antagonists/agonists that may represent promising drugs to treat human eating disorders on both sides of the energy balance (anorexia, obesity).
- Published
- 2006
- Full Text
- View/download PDF
48. Stromal cell-derived factor-1alpha modulation of the excitability of rat substantia nigra dopaminergic neurones: presynaptic mechanisms.
- Author
-
Guyon A, Skrzydelsi D, Rovère C, Rostène W, Parsadaniantz SM, and Nahon JL
- Subjects
- Animals, Benzylamines, Chemokine CXCL12, Chemokines, CXC pharmacology, Cyclams, G Protein-Coupled Inwardly-Rectifying Potassium Channels drug effects, G Protein-Coupled Inwardly-Rectifying Potassium Channels metabolism, GABA Antagonists pharmacology, Glutamic Acid metabolism, Heterocyclic Compounds pharmacology, Ion Channels drug effects, Ion Channels metabolism, Male, Membrane Potentials drug effects, Membrane Potentials physiology, Neural Inhibition drug effects, Organ Culture Techniques, Patch-Clamp Techniques, Presynaptic Terminals drug effects, Rats, Rats, Wistar, Receptors, CXCR4 drug effects, Receptors, CXCR4 metabolism, Receptors, GABA-A drug effects, Receptors, GABA-A metabolism, Sodium Channel Blockers pharmacology, Substantia Nigra drug effects, Synaptic Transmission drug effects, Up-Regulation drug effects, Up-Regulation physiology, Chemokines, CXC metabolism, Dopamine metabolism, Neural Inhibition physiology, Presynaptic Terminals metabolism, Substantia Nigra metabolism, Synaptic Transmission physiology
- Abstract
In rat substantia nigra (SN), Chemokine (CXC motif) receptor 4 (CXCR4) for the chemokine stromal cell-derived factor (SDF)-1alpha is expressed on dopaminergic (DA) neurones, but also on non-DA cells, suggesting presynaptic actions. Using whole-cell patch-clamp recordings in DA neurones of rat SN slices at a holding potential of -60 mV, we showed here that SDF-1alpha exerts multiple presynaptic effects. First, SDF-1alpha (10 nm) induced an increase in the frequency of spontaneous and miniature GABA(A) postsynaptic currents by presynaptic mechanisms, consistent with the presence of CXCR4 on GABAergic neurones of the SN, as revealed by immunocytochemistry. Second, SDF-1alpha (0.1-1 nm) induced a glutamatergic inward current resistant to tetrodotoxin (TTX), most probably the result of glutamate release from non-neuronal cells. This inward current was not blocked by the CXCR4 antagonist AMD 3100 (1 microm), consistent with the lack of CXCR4 on astrocytes as shown by immunocytochemistry under basal conditions. Finally, SDF-1alpha (10 nm) induced, via CXCR4, an outward G protein-activated inward rectifier (GIRK) current, which was TTX sensitive and prevented by application of the GABA(B) antagonist CGP55845A, suggesting GABA spillover on to GABA(B) receptors. Our results show that SDF-1alpha induces, via presynaptic mechanisms, alterations in the excitability of DA neurones as confirmed by current-clamp experiments.
- Published
- 2006
- Full Text
- View/download PDF
49. [Inflammation mediators and control of food intake].
- Author
-
Guyon A and Nahon JL
- Subjects
- Anorexia etiology, Cytokines physiology, Humans, Hypothalamic Hormones physiology, Hypothalamus physiology, Melanins physiology, Neurons physiology, Pituitary Hormones physiology, Eating physiology, Inflammation Mediators physiology
- Published
- 2006
50. Stromal cell-derived factor-1alpha directly modulates voltage-dependent currents of the action potential in mammalian neuronal cells.
- Author
-
Guyon A, Rovère C, Cervantes A, Allaeys I, and Nahon JL
- Subjects
- Animals, Benzylamines, Cadmium Chloride pharmacology, Cells, Cultured, Chemokine CXCL12, Cyclams, Dose-Response Relationship, Drug, Drug Interactions, Gene Expression Regulation drug effects, Glycine pharmacology, Guanosine 5'-O-(3-Thiotriphosphate) pharmacology, Heterocyclic Compounds pharmacology, Humans, Hypothalamus cytology, Immunohistochemistry methods, Mice, Neuroblastoma, Neurons metabolism, Patch-Clamp Techniques methods, Porins drug effects, Potassium Channel Blockers pharmacology, RNA, Messenger biosynthesis, Receptors, CXCR4 antagonists & inhibitors, Reverse Transcriptase Polymerase Chain Reaction methods, Sodium Channel Blockers pharmacology, Tetraethylammonium pharmacology, Tetrodotoxin pharmacology, Voltage-Dependent Anion Channels, Action Potentials drug effects, Chemokines, CXC pharmacology, Glycine analogs & derivatives, Neurons drug effects, Porins metabolism
- Abstract
Stromal cell-derived factor-1alpha (SDF-1alpha) is a chemokine whose receptor, CXCR4, is distributed in specific brain areas including hypothalamus. SDF-1alpha has recently been found to play important roles in neurons, although direct modulation of voltage-gated ionic channels has never been shown. In order to clarify this issue, we performed patch-clamp experiments in fetal mouse hypothalamic neurons in culture. SDF-1alpha (10 nm) decreased the peak and rising slope of the action potentials and spike discharge frequency in 22% of hypothalamic neurons tested. This effect was blocked by the CXCR4 antagonist AMD 3100 (1 microm) but not by the metabotropic glutamate receptor antagonist MCPG (500 microm), indicating a direct action of SDF-1alpha on its cognate receptor. This effect involved a depression of both inward and outward voltage-dependent currents of the action potential. We confirmed these effects in the human neuroblastoma cell line SH-SY5Y, which endogenously expresses CXCR4. Voltage-clamp experiments revealed that SDF-1alpha induced a 20% decrease in the peak of the tetrodotoxin-sensitive sodium current and tetraethylammonium-sensitive delayed rectifier potassium current, respectively. Both effects were concentration dependent, and blocked by AMD 3100 (200 nm). This dual effect was reduced or blocked by 0.4 mm GTPgammaS G-protein pre-activation or by pre-treatment with the G-protein inhibitor pertussis toxin (200 ng/mL), suggesting that it is mediated via activation of a G(i/o) protein. This study extends the functions of SDF-1alpha to a direct modulation of voltage-dependent membrane currents of neuronal cells.
- Published
- 2005
- Full Text
- View/download PDF
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.