title: Administration of the inverse benzodiazepine agonist MRK-016 rescues acquisition and memory consolidation following peripheral administration of bacterial endotoxin.
abstract: Recent evidence suggests that inflammation-induced decrements in cognitive function can be mitigated via manipulation of excitatory or inhibitory transmission. We tested the ability of the inverse benzodiazepine agonist, MRK-016 (MRK) to protect against LPS-induced deficits in memory acquisition and consolidation, using a contextual fear conditioning (CFC) paradigm. In Experiment One, mice received lipopolysaccharide (LPS) and/or MRK injections prior to CFC training, and were then tested 24h after training. In Experiment Two, animals received similar treatment injections immediately after training, and were tested 24h later. Additionally, hippocampal samples were collected 4h after LPS injections and immediately after testing, to evaluate brain-derived neurotrophic factor (BDNF) and insulin-like growth factor 1 (IGF-1) mRNA expression. Results indicate that MRK can protect against LPS-induced learning/memory decrements in both paradigms. We also found, in both paradigms, that animals treated with LPS/Saline expressed significantly less BDNF mRNA when compared to Saline/Saline-treated animals 4h after LPS administration, but that MRK did not restore BDNF expression levels. Further, treatment administrations had no effect on IGF-1 mRNA expression at any collection time-point. In summary, MRK-016 can protect against LPS-induced deficits in memory acquisition and consolidation, in this hippocampus-dependent paradigm, though this protection occurs independently of recovery of BDNF expression.
authors.affiliation: Department of Psychology, Neurobiology of Aging Collaborative, Texas Christian University, Fort Worth, TX 76129, USA.
authors.forename: M J
authors.initials: MJ
authors.lastname: Eimerbrink
authors.affiliation: Department of Psychology, Neurobiology of Aging Collaborative, Texas Christian University, Fort Worth, TX 76129, USA.
authors.forename: J D
authors.initials: JD
authors.lastname: White
authors.affiliation: Department of Psychology, Neurobiology of Aging Collaborative, Texas Christian University, Fort Worth, TX 76129, USA.
authors.forename: R J
authors.initials: RJ
authors.lastname: Pendry
authors.affiliation: Department of Psychology, Neurobiology of Aging Collaborative, Texas Christian University, Fort Worth, TX 76129, USA.
authors.forename: S L
authors.initials: SL
authors.lastname: Hodges
authors.affiliation: Department of Psychology, Neurobiology of Aging Collaborative, Texas Christian University, Fort Worth, TX 76129, USA.
authors.forename: L N
authors.initials: LN
authors.lastname: Sadler
authors.affiliation: Department of Psychology, Neurobiology of Aging Collaborative, Texas Christian University, Fort Worth, TX 76129, USA.
authors.forename: J D
authors.initials: JD
authors.lastname: Wiles
authors.affiliation: Department of Psychology, Neurobiology of Aging Collaborative, Texas Christian University, Fort Worth, TX 76129, USA.
authors.forename: M K
authors.initials: MK
authors.lastname: Weintraub
authors.affiliation: Department of Biology, Neurobiology of Aging Collaborative, Texas Christian University, Fort Worth, TX 76129, USA.
authors.forename: M J
authors.initials: MJ
authors.lastname: Chumley
authors.affiliation: Department of Psychology, Neurobiology of Aging Collaborative, Texas Christian University, Fort Worth, TX 76129, USA. Electronic address: g.boehm@tcu.edu.
authors.forename: G W
authors.initials: GW
authors.lastname: Boehm
mesh_terms: D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D003213:Conditioning, Psychological / Q000187:drug effects / Q000502:physiology; D005239:Fear / Q000187:drug effects / Q000502:physiology; D046352:Freezing Reaction, Cataleptic / Q000187:drug effects / Q000502:physiology; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D007249:Inflammation / Q000188:drug therapy* / Q000378:metabolism / Q000523:psychology; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D007555:Isoxazoles / Q000494:pharmacology*; D007858:Learning / Q000187:drug effects* / Q000502:physiology; D008070:Lipopolysaccharides / Q000633:toxicity*; D008297:Male; D008568:Memory / Q000187:drug effects* / Q000502:physiology; D008810:Mice, Inbred C57BL; D015213:Neuroimmunomodulation / Q000187:drug effects / Q000502:physiology; D018697:Nootropic Agents / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D013997:Time Factors; D014227:Triazines / Q000494:pharmacology*
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D007555:Isoxazoles; D008070:Lipopolysaccharides; C494554:MRK 016; D018697:Nootropic Agents; D012333:RNA, Messenger; D014227:Triazines; C519530:insulin-like growth factor-1, mouse; D007334:Insulin-Like Growth Factor I
keywords: BDNF; Hippocampus; IGF-1; Inflammation; LPS; Lipopolysaccharide