title: A synthetic NCAM-derived mimetic peptide, FGL, exerts anti-inflammatory properties via IGF-1 and interferon-gamma modulation.
abstract: Microglial cell activity increases in the rat hippocampus during normal brain aging. The neural cell adhesion molecule (NCAM)-derived mimetic peptide, FG loop (FGL), acts as an anti-inflammatory agent in the hippocampus of the aged rat, promoting CD200 ligand expression while attenuating glial cell activation and subsequent pro-inflammatory cytokine production. The aim of the current study was to determine if FGL corrects the age-related imbalance in hippocampal levels of insulin-like growth factor-1 (IGF-1) and pro-inflammatory interferon-gamma (IFNgamma), and subsequently attenuates the glial reactivity associated with aging. Administration of FGL reversed the age-related decline in IGF-1 in hippocampus, while abrogating the age-related increase in IFNgamma. FGL robustly promotes IGF-1 release from primary neurons and IGF-1 is pivotal in FGL induction of neuronal Akt phosphorylation and subsequent CD200 ligand expression in vitro. In addition, FGL abrogates both age- and IFNgamma-induced increases in markers of glial cell activation, including major histocompatibility complex class II (MHCII) and CD40. Finally, the proclivity of FGL to attenuate IFNgamma-induced glial cell activation in vitro is IGF-1-dependent. Overall, these findings suggest that FGL, by correcting the age-related imbalance in hippocampal levels of IGF-1 and IFNgamma, attenuates glial cell activation associated with aging. These findings also highlight a novel mechanism by which FGL can impact on neuronal CD200 ligand expression and subsequently on glial cell activation status.
authors.affiliation: Trinity College Institute for Neuroscience, Physiology Department, Trinity College, Dublin, Ireland. Eric.Downer@nuim.ie
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Downer
authors.forename: Thelma R
authors.initials: TR
authors.lastname: Cowley
authors.forename: Fionnuala
authors.initials: F
authors.lastname: Cox
authors.forename: Francis O
authors.initials: FO
authors.lastname: Maher
authors.forename: Vladimir
authors.initials: V
authors.lastname: Berezin
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Bock
authors.forename: Marina A
authors.initials: MA
authors.lastname: Lynch
mesh_terms: D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism; D019013:CD40 Antigens / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000378:metabolism*; D007371:Interferon-gamma / Q000235:genetics / Q000378:metabolism*; D008297:Male; D019006:Neural Cell Adhesion Molecules / Q000494:pharmacology*; D009457:Neuroglia / Q000187:drug effects* / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D051058:Oncogene Protein v-akt / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar
chemical_list: D000893:Anti-Inflammatory Agents; D015703:Antigens, CD; D019013:CD40 Antigens; C488618:NCAM protein (681-695), human; D019006:Neural Cell Adhesion Molecules; D007334:Insulin-Like Growth Factor I; D007371:Interferon-gamma; D051058:Oncogene Protein v-akt; C042739:antigens, CD200