title: Agmatine induces Nrf2 and protects against corticosterone effects in hippocampal neuronal cell line.
abstract: Hyperactivation of the hypothalamic-pituitary-adrenal axis is a common finding in major depression; this may lead to increased levels of cortisol, which are known to cause oxidative stress imbalance and apoptotic neuronal cell death, particularly in the hippocampus, a key region implicated in mood regulation. Agmatine, an endogenous metabolite of L-arginine, has been proposed for the treatment of major depression. Corticosterone induced apoptotic cell death and increased ROS production in cultured hippocampal neuronal cells, effects that were abolished in a concentration- and time-dependent manner by agmatine. Interestingly, the combination of sub-effective concentrations of agmatine with fluoxetine or imipramine afforded synergic protection. The neuroprotective effect of agmatine was abolished by yohimbine (α2-adrenoceptor antagonist), ketanserin (5-HT2A receptor antagonist), LY294002 (PI3K inhibitor), PD98059 (MEK1/2 inhibitor), SnPP (HO-1 inhibitor), and cycloheximide (protein synthesis inhibitor). Agmatine increased Akt and ERK phosphorylation and induced the transcription factor Nrf2 and the proteins HO-1 and GCLc; induction of these proteins was prevented by yohimbine, ketanserin, LY294002, and PD98059. In conclusion, agmatine affords neuroprotection against corticosterone effects by a mechanism that implicates Nrf2 induction via α2-adrenergic and 5-HT2A receptors, Akt and ERK pathways, and HO-1 and GCLc expression.
authors.affiliation: Instituto Teofilo Hernando, Departamento de Farmacología y Terapéutica, Facultad de Medicina, Universidad Autónoma de Madrid, 4-28029, Madrid, Spain, andiaraef@gmail.com.
authors.forename: Andiara E
authors.initials: AE
authors.lastname: Freitas
authors.forename: Javier
authors.initials: J
authors.lastname: Egea
authors.forename: Izaskun
authors.initials: I
authors.lastname: Buendía
authors.forename: Elisa
authors.initials: E
authors.lastname: Navarro
authors.forename: Patricia
authors.initials: P
authors.lastname: Rada
authors.forename: Antonio
authors.initials: A
authors.lastname: Cuadrado
authors.forename: Ana Lúcia S
authors.initials: AL
authors.lastname: Rodrigues
authors.forename: Manuela G
authors.initials: MG
authors.lastname: López
mesh_terms: D000376:Agmatine / Q000494:pharmacology*; D000818:Animals; D002460:Cell Line; D003345:Corticosterone / Q000378:metabolism*; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051379:Mice; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D044402:Receptor, Serotonin, 5-HT2A / Q000378:metabolism
chemical_list: D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D044402:Receptor, Serotonin, 5-HT2A; D000376:Agmatine; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D003345:Corticosterone
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