title: Everolimus improves memory and learning while worsening depressive- and anxiety-like behavior in an animal model of depression.
abstract: Everolimus (EVR) is an orally-administered rapamycin analog that selectively inhibits the mammalian target of rapamycin (mTOR) kinase (mainly mTORC1 and likely mTORC2) and the related signaling pathway. mTOR is a serine/threonine protein kinase regulating multiple important cellular functions; dysfunction of mTOR signaling has also been implicated in the pathophysiology of several neurological, neurodegenerative, developmental and cognitive disorders. EVR is widely used as an anti-neoplastic therapy and more recently in children with tuberous sclerosis complex (TSC). However, no clear correlation exists between EVR use and development of central side effects e.g. depression, anxiety or cognitive impairment. We studied the effects of a 3 weeks administration of EVR in mice chronically treated with betamethasone 21-phosphate disodium (BTM) as a model of depression and cognitive decline. EVR treatment had detrimental effects on depressive- and anxiety-like behavior while improving cognitive performance in both control (untreated) and BTM-treated mice. Such effects were accompanied by an increased hippocampal neurogenesis and synaptogenesis. Our results therefore might support the proposed pathological role of mTOR dysregulation in depressive disorders and confirm some previous data on the positive effects of mTOR inhibition in cognitive decline. We also show that EVR, possibly through mTOR inhibition, may be linked to the development of anxiety. The increased hippocampal neurogenesis by EVR might explain its ability to improve cognitive function or protect from cognitive decline. Our findings suggest some caution in the use of EVR, particularly in the developing brain; patients should be carefully monitored for their psychiatric/neurological profiles in any clinical situation where an mTOR inhibitor and in particular EVR is used e.g. cancer treatment, TSC or immunosuppression.
authors.affiliation: Science of Health Department, School of Medicine, University of Catanzaro, Italy. Electronic address: erusso@unicz.it.
authors.forename: Emilio
authors.initials: E
authors.lastname: Russo
authors.affiliation: Science of Health Department, School of Medicine, University of Catanzaro, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Leo
authors.affiliation: Department of Biological and Environmental Science, University of Messina, Italy.
authors.forename: Rosalia
authors.initials: R
authors.lastname: Crupi
authors.affiliation: Science of Health Department, School of Medicine, University of Catanzaro, Italy.
authors.forename: Rossana
authors.initials: R
authors.lastname: Aiello
authors.affiliation: Department of Pharmacy, University of Naples Federico II, Naples, Italy.
authors.forename: Pellegrino
authors.initials: P
authors.lastname: Lippiello
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: Science of Health Department, School of Medicine, University of Catanzaro, Italy.
authors.forename: Serafina
authors.initials: S
authors.lastname: Chimirri
authors.affiliation: Science of Health Department, School of Medicine, University of Catanzaro, Italy.
authors.forename: Rita
authors.initials: R
authors.lastname: Citraro
authors.affiliation: Department of Biological and Environmental Science, University of Messina, Italy.
authors.forename: Salvatore
authors.initials: S
authors.lastname: Cuzzocrea
authors.affiliation: Department of Pharmacology, UCL School of Pharmacy, 29/39 Brunswick Square, London, United Kingdom.
authors.forename: Andrew
authors.initials: A
authors.lastname: Constanti
authors.affiliation: Science of Health Department, School of Medicine, University of Catanzaro, Italy.
authors.forename: Giovambattista
authors.initials: G
authors.lastname: De Sarro
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001007:Anxiety / Q000139:chemically induced / Q000473:pathology / Q000503:physiopathology / Q000523:psychology*; D060825:Cognitive Dysfunction / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology; D003863:Depression / Q000139:chemically induced / Q000473:pathology / Q000503:physiopathology / Q000523:psychology*; D004195:Disease Models, Animal; D000068338:Everolimus / Q000009:adverse effects* / Q000494:pharmacology*; D006624:Hippocampus / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D007858:Learning / Q000187:drug effects*; D008297:Male; D008568:Memory / Q000187:drug effects*; D008811:Mice, Inbred DBA; D055495:Neurogenesis / Q000187:drug effects; D011897:Random Allocation; D013569:Synapses / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D000068338:Everolimus; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases
keywords: Anxiety; Cognitive function; Depression; Mice; Neurogenesis; mTOR