PMID- 24998197 OWN - NLM STAT- MEDLINE DCOM- 20151214 LR - 20211203 IS - 1090-2139 (Electronic) IS - 0889-1591 (Linking) VI - 42 DP - 2014 Nov TI - 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. PG - 157-68 LID - S0889-1591(14)00181-0 [pii] LID - 10.1016/j.bbi.2014.06.016 [doi] AB - 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-1beta and TNF-alpha and their relative mRNA expression levels were measured, and the involvement of nuclear factor-kappaB (NF-kappaB) 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-1beta and TNF-alpha, most likely through inhibition of the activation of NF-kappaB. 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. CI - Copyright (c) 2014 Elsevier Inc. All rights reserved. FAU - Russo, Emilio AU - Russo E AD - Science of Health Department, School of Medicine, University Magna Graecia of Catanzaro, Italy. Electronic address: erusso@unicz.it. FAU - Andreozzi, Francesco AU - Andreozzi F AD - Department of Medical and Surgical Sciences, University Magna Graecia of Catanzaro, Catanzaro, Italy. FAU - Iuliano, Rodolfo AU - Iuliano R AD - Department of Experimental and Clinical Medicine, School of Medicine, University Magna Graecia of Catanzaro, Italy. FAU - Dattilo, Vincenzo AU - Dattilo V AD - Science of Health Department, School of Medicine, University Magna Graecia of Catanzaro, Italy. FAU - Procopio, Teresa AU - Procopio T AD - Department of Medical and Surgical Sciences, University Magna Graecia of Catanzaro, Catanzaro, Italy. FAU - Fiume, Giuseppe AU - Fiume G AD - Department of Experimental and Clinical Medicine, School of Medicine, University Magna Graecia of Catanzaro, Italy. FAU - Mimmi, Selena AU - Mimmi S AD - Department of Experimental and Clinical Medicine, School of Medicine, University Magna Graecia of Catanzaro, Italy. FAU - Perrotti, Nicola AU - Perrotti N AD - Science of Health Department, School of Medicine, University Magna Graecia of Catanzaro, Italy. FAU - Citraro, Rita AU - Citraro R AD - Science of Health Department, School of Medicine, University Magna Graecia of Catanzaro, Italy. FAU - Sesti, Giorgio AU - Sesti G AD - Department of Medical and Surgical Sciences, University Magna Graecia of Catanzaro, Catanzaro, Italy. FAU - Constanti, Andrew AU - Constanti A AD - Department of Pharmacology, UCL School of Pharmacy, 29/39 Brunswick Square, London, United Kingdom. FAU - De Sarro, Giovambattista AU - De Sarro G AD - Science of Health Department, School of Medicine, University Magna Graecia of Catanzaro, Italy. LA - eng PT - Journal Article DEP - 20140703 PL - Netherlands TA - Brain Behav Immun JT - Brain, behavior, and immunity JID - 8800478 RN - 0 (Cytokines) RN - 0 (Lipopolysaccharides) RN - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) RN - EC 2.7.4.3 (Adenylate Kinase) SB - IM MH - Adenylate Kinase/*metabolism MH - Animals MH - Behavior, Animal/drug effects/physiology MH - Brain/drug effects/immunology/metabolism MH - Cytokines/*metabolism MH - Depressive Disorder/*immunology/metabolism MH - Disease Models, Animal MH - Electroencephalography MH - Epilepsy, Absence/*immunology/metabolism MH - Lipopolysaccharides/*pharmacology MH - Male MH - Proto-Oncogene Proteins c-akt/*metabolism MH - Rats MH - Rats, Wistar MH - Signal Transduction/drug effects/*immunology MH - TOR Serine-Threonine Kinases/*metabolism OTO - NOTNLM OT - AKT OT - AMPK OT - Absence epilepsy OT - Cytokines OT - Epileptogenesis OT - Lipopolysaccharide (LPS) OT - NF-kappaB OT - Neuroinflammation OT - Rapamycin OT - WAG/Rij rats OT - mTOR EDAT- 2014/07/08 06:00 MHDA- 2015/12/15 06:00 CRDT- 2014/07/08 06:00 PHST- 2014/04/17 00:00 [received] PHST- 2014/06/16 00:00 [revised] PHST- 2014/06/24 00:00 [accepted] PHST- 2014/07/08 06:00 [entrez] PHST- 2014/07/08 06:00 [pubmed] PHST- 2015/12/15 06:00 [medline] AID - S0889-1591(14)00181-0 [pii] AID - 10.1016/j.bbi.2014.06.016 [doi] PST - ppublish SO - Brain Behav Immun. 2014 Nov;42:157-68. doi: 10.1016/j.bbi.2014.06.016. Epub 2014 Jul 3.