title: Early molecular and behavioral response to lipopolysaccharide in the WAG/Rij rat model of absence epilepsy and depressive-like behavior, involves interplay between AMPK, AKT/mTOR pathways and neuroinflammatory cytokine release.
abstract: The mammalian target of rapamycin (mTOR) pathway has been recently indicated as a suitable drug target for the prevention of epileptogenesis. The mTOR pathway is known for its involvement in the control of the immune system. Since neuroinflammation is recognized as a major contributor to epileptogenesis, we wished to examine whether the neuroprotective effects of mTOR modulation could involve a suppression of the neuroinflammatory process in epileptic brain. We have investigated the early molecular mechanisms involved in the effects of intracerebral administration of the lipopolysaccharide (LPS) in the WAG/Rij rat model of absence epilepsy, in relation to seizure generation and depressive-like behavior; we also tested whether the effects of LPS could be modulated by treatment with rapamycin (RAP), a specific mTOR inhibitor. We determined, in specific rat brain areas, levels of p-mTOR/p-p70S6K and also p-AKT/p-AMPK as downstream or upstream indicators of mTOR activity and tested the effects of LPS and RAP co-administration. Changes in the brain levels of pro-inflammatory cytokines IL-1β and TNF-α and their relative mRNA expression levels were measured, and the involvement of nuclear factor-κB (NF-κB) was also examined in vitro. We confirmed that RAP inhibits the aggravation of absence seizures and depressive-like/sickness behavior induced by LPS in the WAG/Rij rats through the activation of mTOR and show that this effect is correlated with the ability of RAP to dampen and delay LPS increases in neuroinflammatory cytokines IL-1β and TNF-α, most likely through inhibition of the activation of NF-κB. Our results suggest that such a mechanism could contribute to the antiseizure, antiepileptogenic and behavioral effects of RAP and further highlight the potential therapeutic usefulness of mTOR inhibition in the management of human epilepsy and other neurological disorders. Furthermore, we show that LPS-dependent neuroinflammatory effects are also mediated by a complex interplay between AKT, AMPK and mTOR with specificity to selective brain areas. In conclusion, neuroinflammation appears to be a highly coordinated phenomenon, where timing of intervention may be carefully evaluated in order to identify the best suitable target.
authors.affiliation: Science of Health Department, School of Medicine, University Magna Græcia of Catanzaro, Italy. Electronic address: erusso@unicz.it.
authors.forename: Emilio
authors.initials: E
authors.lastname: Russo
authors.affiliation: Department of Medical and Surgical Sciences, University Magna Græcia of Catanzaro, Catanzaro, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Andreozzi
authors.affiliation: Department of Experimental and Clinical Medicine, School of Medicine, University Magna Græcia of Catanzaro, Italy.
authors.forename: Rodolfo
authors.initials: R
authors.lastname: Iuliano
authors.affiliation: Science of Health Department, School of Medicine, University Magna Græcia of Catanzaro, Italy.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Dattilo
authors.affiliation: Department of Medical and Surgical Sciences, University Magna Græcia of Catanzaro, Catanzaro, Italy.
authors.forename: Teresa
authors.initials: T
authors.lastname: Procopio
authors.affiliation: Department of Experimental and Clinical Medicine, School of Medicine, University Magna Græcia of Catanzaro, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Fiume
authors.affiliation: Department of Experimental and Clinical Medicine, School of Medicine, University Magna Græcia of Catanzaro, Italy.
authors.forename: Selena
authors.initials: S
authors.lastname: Mimmi
authors.affiliation: Science of Health Department, School of Medicine, University Magna Græcia of Catanzaro, Italy.
authors.forename: Nicola
authors.initials: N
authors.lastname: Perrotti
authors.affiliation: Science of Health Department, School of Medicine, University Magna Græcia of Catanzaro, Italy.
authors.forename: Rita
authors.initials: R
authors.lastname: Citraro
authors.affiliation: Department of Medical and Surgical Sciences, University Magna Græcia of Catanzaro, 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, United Kingdom.
authors.forename: Andrew
authors.initials: A
authors.lastname: Constanti
authors.affiliation: Science of Health Department, School of Medicine, University Magna Græcia of Catanzaro, Italy.
authors.forename: Giovambattista
authors.initials: G
authors.lastname: De Sarro
mesh_terms: D000263:Adenylate Kinase / Q000378:metabolism*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology; D001921:Brain / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism*; D003866:Depressive Disorder / Q000276:immunology* / Q000378:metabolism; D004195:Disease Models, Animal; D004569:Electroencephalography; D004832:Epilepsy, Absence / Q000276:immunology* / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008297:Male; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: D016207:Cytokines; D008070:Lipopolysaccharides; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D000263:Adenylate Kinase
keywords: AKT; AMPK; Absence epilepsy; Cytokines; Epileptogenesis; Lipopolysaccharide (LPS); NF-κB; Neuroinflammation; Rapamycin; WAG/Rij rats; mTOR