title: Liraglutide prevents cognitive decline in a rat model of streptozotocin-induced diabetes independently from its peripheral metabolic effects.
abstract: Diabetes has been identified as a risk factor for cognitive dysfunctions. Glucagone like peptide 1 (GLP-1) receptor agonists have neuroprotective effects in preclinical animal models. We evaluated the effects of GLP-1 receptor agonist, liraglutide (LIR), on cognitive decline associated with diabetes. Furthermore, we studied LIR effects against hippocampal neurodegeneration induced by streptozotocin (STZ), a well-validated animal model of diabetes and neurodegeneration associated with cognitive decline. Diabetes and/or cognitive decline were induced in Wistar rats by intraperitoneal or intracerebroventricular injection of STZ and then rats were treated with LIR (300μg/kg daily subcutaneously) for 6 weeks. Rats underwent behavioral tests: Morris water maze, passive avoidance, forced swimming (FST), open field, elevated plus maze, rotarod tests. Furthermore, LIR effects on hippocampal neurodegeneration and mTOR pathway (AKT, AMPK, ERK and p70S6K) were assessed. LIR improved learning and memory only in STZ-treated animals. Anxiolytic effects were observed in all LIR-treated groups but pro-depressant effects in CTRL rats were observed. At a cellular/molecular level, intracerebroventricular STZ induced hippocampal neurodegeneration accompanied by decreased phosphorylation of AMPK, AKT, ERK and p70S6K. LIR reduced hippocampal neuronal death and prevented the decreased phosphorylation of AKT and p70S6K; AMPK was hyper-phosphorylated in comparison to CTRL group, while LIR had no effects on ERK. LIR reduced animal endurance in the rotarod test and this effect might be also linked to a reduction in locomotor activity during only the last two minutes of the FST. LIR had protective effects on cognitive functions in addition to its effects on blood glucose levels. LIR effects in the brain also comprised anxiolytic and pro-depressant actions (although influenced by reduced endurance). Finally, LIR protected from diabetes-dependent hippocampal neurodegeneration likely through an effect on mTOR pathway.
authors.affiliation: Science of Health Department, School of Medicine, University "Magna Graecia" of Catanzaro, Italy.
authors.forename: Caterina
authors.initials: C
authors.lastname: Palleria
authors.affiliation: Science of Health Department, School of Medicine, University "Magna Graecia" of Catanzaro, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Leo
authors.affiliation: Department of Medical and Surgical Sciences, University Magna Graecia of Catanzaro, 88100, Viale Europa, Catanzaro, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Andreozzi
authors.affiliation: Science of Health Department, School of Medicine, University "Magna Graecia" of Catanzaro, Italy.
authors.forename: Rita
authors.initials: R
authors.lastname: Citraro
authors.affiliation: CNR, Institute of Neurological Sciences, Pharmacology Section, Roccelletta di Borgia, Catanzaro, Italy.
authors.forename: Michelangelo
authors.initials: M
authors.lastname: Iannone
authors.affiliation: Department of Medical and Surgical Sciences, University Magna Graecia of Catanzaro, 88100, Viale Europa, Catanzaro, Italy.
authors.forename: Rosangela
authors.initials: R
authors.lastname: Spiga
authors.affiliation: Department of Medical and Surgical Sciences, University Magna Graecia of Catanzaro, 88100, Viale Europa, Catanzaro, Italy.
authors.forename: Giorgio
authors.initials: G
authors.lastname: Sesti
authors.affiliation: Department of Pharmacology, UCL School of Pharmacy, 29/39 Brunswick Square, London, UK.
authors.forename: Andrew
authors.initials: A
authors.lastname: Constanti
authors.affiliation: Science of Health Department, School of Medicine, University "Magna Graecia" of Catanzaro, Italy.
authors.forename: Giovambattista
authors.initials: G
authors.lastname: De Sarro
authors.affiliation: Department of Medical and Surgical Sciences, University Magna Graecia of Catanzaro, 88100, Viale Europa, Catanzaro, Italy.
authors.forename: Franco
authors.initials: F
authors.lastname: Arturi
authors.affiliation: Science of Health Department, School of Medicine, University "Magna Graecia" of Catanzaro, Italy. Electronic address: erusso@unicz.it.
authors.forename: Emilio
authors.initials: E
authors.lastname: Russo
mesh_terms: D000818:Animals; D001007:Anxiety / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D001362:Avoidance Learning / Q000187:drug effects; D001786:Blood Glucose / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D060825:Cognitive Dysfunction / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D003863:Depression / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000523:psychology*; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D000069450:Liraglutide / Q000494:pharmacology*; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D009043:Motor Activity / Q000187:drug effects; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D011897:Random Allocation; D017208:Rats, Wistar
chemical_list: D001786:Blood Glucose; D007004:Hypoglycemic Agents; D018696:Neuroprotective Agents; D000069450:Liraglutide
keywords: Cognitive functions; Diabetes mellitus; GLP-1 receptors; Liraglutide; Neurodegeneration; Rats; Streptozotocin; mTOR signaling