title: Melanocortin 4 receptor activation induces brain-derived neurotrophic factor expression in rat astrocytes through cyclic AMP-protein kinase A pathway.
abstract: Melanocortin 4 receptors (MC4R) are mainly expressed in the brain. We previously showed that the anti-inflammatory action of α-melanocyte-stimulating hormone (α-MSH) in rat hypothalamus and in cultured astrocytes involved MC4R activation. However, MC4R mechanisms of action remain undetermined. Since brain-derived neurotrophic factor (BDNF) may be mediating MC4R hypothalamic anorexigenic actions, we determined melanocortin effects on BDNF expression in rat cultured astrocytes and certain mechanisms involved in MC4R signaling. α-MSH and its analogue NDP-MSH, induced production of cAMP in astrocytes. This effect was completely blocked by the MC4R antagonist, HS024. We found that NDP-MSH increased BDNF mRNA and protein levels in astrocytes. The effect of NDP-MSH on BDNF expression was abolished by the adenylate cyclase inhibitor SQ22536, and decreased by the PKA inhibitor Rp-cAMP. Since melanocortins are immunomodulators, we investigated their actions with bacterial lipopolysaccharide (LPS) and interferon-γ (IFN-γ) stimulus. Although both α-MSH and LPS+IFN-γ increased cAMP responding element binding protein (CREB) activation, LPS+IFN-γ did not modify BDNF expression. On the other hand, α-MSH did not modify basal or LPS+IFN-γ-induced nuclear factor-κB activation. Our results show for the first time that MC4R activation in astrocytes induces BDNF expression through cAMP-PKA-CREB pathway without involving NF-κB.
authors.affiliation: Research Institute for Reproduction, School of Medicine, University of Buenos Aires, Buenos Aires, Argentina.
authors.forename: Carla
authors.initials: C
authors.lastname: Caruso
authors.forename: Lila
authors.initials: L
authors.lastname: Carniglia
authors.forename: Daniela
authors.initials: D
authors.lastname: Durand
authors.forename: Patricia V
authors.initials: PV
authors.lastname: Gonzalez
authors.forename: Teresa N
authors.initials: TN
authors.lastname: Scimonelli
authors.forename: Mercedes
authors.initials: M
authors.lastname: Lasaga
mesh_terms: D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D001253:Astrocytes / Q000378:metabolism*; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism*; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D015870:Gene Expression; D007371:Interferon-gamma / Q000494:pharmacology / Q000502:physiology; D008070:Lipopolysaccharides / Q000494:pharmacology; D016328:NF-kappa B / Q000378:metabolism; D010456:Peptides, Cyclic / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D044105:Receptor, Melanocortin, Type 4 / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction; D000521:alpha-MSH / Q000031:analogs & derivatives / Q000494:pharmacology / Q000502:physiology
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D017362:Cyclic AMP Response Element-Binding Protein; C116098:HS 024; D008070:Lipopolysaccharides; D016328:NF-kappa B; D010456:Peptides, Cyclic; D044105:Receptor, Melanocortin, Type 4; D000521:alpha-MSH; C027756:MSH, 4-Nle-7-Phe-alpha-; D007371:Interferon-gamma; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D000262:Adenylyl Cyclases