title: Signaling pathways underlying the antidepressant-like effect of inosine in mice.
abstract: Inosine is a purine nucleoside formed by the breakdown of adenosine that elicits an antidepressant-like effect in mice through activation of adenosine A1and A2Areceptors. However, the signaling pathways underlying this effect are largely unknown. To address this issue, the present study investigated the influence of extracellular-regulated protein kinase (ERK)1/2, Ca2+/calmoduline-dependent protein kinase (CaMKII), protein kinase A (PKA), phosphoinositide 3-kinase (PI3K)/Akt, and glycogen synthase kinase 3beta (GSK-3β) modulation in the antiimmobility effect of inosine in the tail suspension test (TST) in mice. In addition, we attempted to verify if inosine treatment was capable of altering the immunocontent and phosphorylation of the transcription factor cyclic adenosine monophosphatate (cAMP) response-binding element protein (CREB) in mouse prefrontal cortex and hippocampus. Intracerebroventricular administration of U0126 (5 μg/mouse, MEK1/2 inhibitor), KN-62 (1 μg/mouse, CaMKII inhibitor), H-89 (1 μg/mouse, PKA inhibitor), and wortmannin (0.1 μg/mouse, PI3K inhibitor) prevented the antiimmobility effect of inosine (10 mg/kg, intraperitoneal (i.p.)) in the TST. Also, administration of a sub-effective dose of inosine (0.1 mg/kg, i.p.) in combination with a sub-effective dose of AR-A014418 (0.001 μg/mouse, GSK-3β inhibitor) induced a synergic antidepressant-like effect. None of the treatments altered locomotor activity of mice. Moreover, 24 h after a single administration of inosine (10 mg/kg, i.p.), CREB phosphorylation was increased in the hippocampus. Our findings provided new evidence that the antidepressant-like effect of inosine in the TST involves the activation of PKA, PI3K/Akt, ERK1/2, and CaMKII and the inhibition of GSK-3β. These results contribute to the comprehension of the mechanisms underlying the purinergic system modulation and indicate the intracellular signaling pathways involved in the antidepressant-like effect of inosine in a preclinical test of depression.
authors.affiliation: Biochemistry Graduate Program, Center of Biological Sciences, Universidade Federal de Santa Catarina, Florianópolis, SC, Brazil.
authors.forename: Filipe Marques
authors.initials: FM
authors.lastname: Gonçalves
authors.affiliation: Biochemistry Graduate Program, Center of Biological Sciences, Universidade Federal de Santa Catarina, Florianópolis, SC, Brazil.
authors.forename: Vivian Binder
authors.initials: VB
authors.lastname: Neis
authors.affiliation: Department of Nutrition, Center of Health Science, Universidade Federal de Santa Catarina, Florianópolis, SC, Brazil.
authors.forename: Débora Kurrle
authors.initials: DK
authors.lastname: Rieger
authors.affiliation: Biochemistry Graduate Program, Center of Biological Sciences, Universidade Federal de Santa Catarina, Florianópolis, SC, Brazil.
authors.forename: Mark William
authors.initials: MW
authors.lastname: Lopes
authors.affiliation: Neuroscience Graduate Program, Center of Biological Sciences, Universidade Federal de Santa Catarina, Florianópolis, SC, Brazil.
authors.forename: Isabella A
authors.initials: IA
authors.lastname: Heinrich
authors.affiliation: Neuroscience Graduate Program, Center of Biological Sciences, Universidade Federal de Santa Catarina, Florianópolis, SC, Brazil.
authors.forename: Ana Paula
authors.initials: AP
authors.lastname: Costa
authors.affiliation: Biochemistry Graduate Program, Center of Biological Sciences, Universidade Federal de Santa Catarina, Florianópolis, SC, Brazil.|Neuroscience Graduate Program, Center of Biological Sciences, Universidade Federal de Santa Catarina, Florianópolis, SC, Brazil.
authors.forename: Ana Lúcia S
authors.initials: ALS
authors.lastname: Rodrigues
authors.affiliation: Biochemistry Graduate Program, Center of Biological Sciences, Universidade Federal de Santa Catarina, Florianópolis, SC, Brazil.
authors.forename: Manuella P
authors.initials: MP
authors.lastname: Kaster
authors.affiliation: Biochemistry Graduate Program, Center of Biological Sciences, Universidade Federal de Santa Catarina, Florianópolis, SC, Brazil. rbleal@gmail.com.|Neuroscience Graduate Program, Center of Biological Sciences, Universidade Federal de Santa Catarina, Florianópolis, SC, Brazil. rbleal@gmail.com.|Department of Biochemistry, Universidade Federal de Santa Catarina, Florianópolis, SC, 88040-900, Brazil. rbleal@gmail.com.
authors.forename: Rodrigo Bainy
authors.initials: RB
authors.lastname: Leal
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology; D005106:Exploratory Behavior / Q000187:drug effects; D019417:Hindlimb Suspension; D007288:Inosine / Q000494:pharmacology*; D008297:Male; D051379:Mice; D015398:Signal Transduction / Q000187:drug effects*; D013315:Stress, Psychological
chemical_list: D000928:Antidepressive Agents; D007288:Inosine
keywords: CREB; Depression; Inosine; Protein kinases; Signaling pathways