title: Neuroprotective effects of hesperetin in mouse primary neurones are independent of CREB activation.
abstract: Dietary flavonoids, including the citrus flavanone hesperetin, may have stimulatory effects on cytoprotective intracellular signalling pathways. In primary mouse cortical neurone cultures, but not SH-SY5Y human neuroblastoma cells or human primary dermal fibroblasts (Promocells), hesperetin (100-300nM, 15min) caused significant increases in the level of ERK1/2 phosphorylation, but did not increase CREB phosphorylation. Administration of hesperetin for 18h did not alter gene expression driven by the cyclic AMP response element (CRE), assessed using a luciferase reporter system, but 300nM hesperetin partially reversed staurosporine-induced cell death in primary neurones. Our data show that hesperetin is a neuroprotective compound at concentrations where antioxidant effects are unlikely to predominate. The effects of hesperetin are cell-type dependent and, unlike the flavanol (-)epicatechin, neuroprotection in vitro is not associated with enhanced CREB phosphorylation or CRE-mediated gene expression.
authors.affiliation: King's College London, The Wolfson Centre for Age-Related Diseases, Guy's Hospital Campus, London SE1 1UL, UK.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Rainey-Smith
authors.forename: Lars-Wilhelm
authors.initials: LW
authors.lastname: Schroetke
authors.forename: Parmvir
authors.initials: P
authors.lastname: Bahia
authors.forename: Ahmed
authors.initials: A
authors.lastname: Fahmi
authors.forename: Rachel
authors.initials: R
authors.lastname: Skilton
authors.forename: Jeremy P E
authors.initials: JP
authors.lastname: Spencer
authors.forename: Catherine
authors.initials: C
authors.lastname: Rice-Evans
authors.forename: Marcus
authors.initials: M
authors.lastname: Rattray
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Williams
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology / Q000627:therapeutic use; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D017362:Cyclic AMP Response Element-Binding Protein / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000187:drug effects / Q000378:metabolism; D005419:Flavonoids / Q000494:pharmacology / Q000627:therapeutic use; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D006569:Hesperidin / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D051379:Mice; D019636:Neurodegenerative Diseases / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology* / Q000627:therapeutic use; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D010766:Phosphorylation / Q000187:drug effects; D015533:Transcriptional Activation / Q000187:drug effects / Q000235:genetics; D014407:Tumor Cells, Cultured
chemical_list: D000975:Antioxidants; C492004:Creb1 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; D004791:Enzyme Inhibitors; D005419:Flavonoids; D018696:Neuroprotective Agents; D006569:Hesperidin; D048049:Extracellular Signal-Regulated MAP Kinases; C013015:hesperetin