title: Neuroprotective and Anti-Apoptotic Effects of CSP-1103 in Primary Cortical Neurons Exposed to Oxygen and Glucose Deprivation.
abstract: CSP-1103 (formerly CHF5074) has been shown to reverse memory impairment and reduce amyloid plaque as well as inflammatory microglia activation in preclinical models of Alzheimer's disease. Moreover, it was found to improve cognition and reduce brain inflammation in patients with mild cognitive impairment. Recent evidence suggests that CSP-1103 acts through a single molecular target, the amyloid precursor protein intracellular domain (AICD), a transcriptional regulator implicated in inflammation and apoptosis. We here tested the possible anti-apoptotic and neuroprotective activity of CSP-1103 in a cell-based model of post-ischemic injury, wherein the primary mouse cortical neurons were exposed to oxygen-glucose deprivation (OGD). When added after OGD, CSP-1103 prevented the apoptosis cascade by reducing cytochrome c release and caspase-3 activation and the secondary necrosis. Additionally, CSP-1103 limited earlier activation of p38 and nuclear factor κB (NF-κB) pathways. These results demonstrate that CSP-1103 is neuroprotective in a model of post-ischemic brain injury and provide further mechanistic insights as regards its ability to reduce apoptosis and potential production of pro-inflammatory cytokines. In conclusion, these findings suggest a potential use of CSP-1103 for the treatment of brain ischemia.
authors.affiliation: Department of Molecular and Translational Medicine, University of Brescia, Viale Europa 11, 25123 Brescia, Italy. v.porrini@unibs.it.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Porrini
authors.affiliation: Department of Molecular and Translational Medicine, University of Brescia, Viale Europa 11, 25123 Brescia, Italy. ilesar@libero.it.
authors.forename: Ilenia
authors.initials: I
authors.lastname: Sarnico
authors.affiliation: Department of Molecular and Translational Medicine, University of Brescia, Viale Europa 11, 25123 Brescia, Italy. marina.benarese@unibs.it.
authors.forename: Marina
authors.initials: M
authors.lastname: Benarese
authors.affiliation: Department of Molecular and Translational Medicine, University of Brescia, Viale Europa 11, 25123 Brescia, Italy. c.branca@unibs.it.
authors.forename: Caterina
authors.initials: C
authors.lastname: Branca
authors.affiliation: Department of Molecular and Translational Medicine, University of Brescia, Viale Europa 11, 25123 Brescia, Italy. m.coelhodamota@unibs.it.
authors.forename: Mariana
authors.initials: M
authors.lastname: Mota
authors.affiliation: Department of Molecular and Translational Medicine, University of Brescia, Viale Europa 11, 25123 Brescia, Italy. annamaria.lanzillotta@unibs.it.
authors.forename: Annamaria
authors.initials: A
authors.lastname: Lanzillotta
authors.affiliation: Department of Molecular and Translational Medicine, University of Brescia, Viale Europa 11, 25123 Brescia, Italy. arianna.bellucci@unibs.it.
authors.forename: Arianna
authors.initials: A
authors.lastname: Bellucci
authors.affiliation: Department of Molecular and Translational Medicine, University of Brescia, Viale Europa 11, 25123 Brescia, Italy. edoardo.parrella@unibs.it.
authors.forename: Edoardo
authors.initials: E
authors.lastname: Parrella
authors.affiliation: Department of Molecular and Translational Medicine, University of Brescia, Viale Europa 11, 25123 Brescia, Italy. lara.faggi@unibs.it.
authors.forename: Lara
authors.initials: L
authors.lastname: Faggi
authors.affiliation: Department of Molecular and Translational Medicine, University of Brescia, Viale Europa 11, 25123 Brescia, Italy. pierfranco.spano@unibs.it.|Department of Neurorehabilitation, IRCCS San Camillo, Via Alberoni 70, 30126 Venice, Italy. pierfranco.spano@unibs.it.
authors.forename: Pierfranco
authors.initials: P
authors.lastname: Spano
authors.affiliation: Research & Development, Chiesi Farmaceutici, Via Palermo 26/A, 43100 Parma, Italy. b.imbimbo@chiesi.com.
authors.forename: Bruno Pietro
authors.initials: BP
authors.lastname: Imbimbo
authors.affiliation: Department of Molecular and Translational Medicine, University of Brescia, Viale Europa 11, 25123 Brescia, Italy. marina.pizzi@unibs.it.|Department of Neurorehabilitation, IRCCS San Camillo, Via Alberoni 70, 30126 Venice, Italy. marina.pizzi@unibs.it.
authors.forename: Marina
authors.initials: M
authors.lastname: Pizzi
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3 / Q000378:metabolism; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D002540:Cerebral Cortex / Q000473:pathology; D003521:Cyclopropanes / Q000494:pharmacology*; D045304:Cytochromes c / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D005480:Flurbiprofen / Q000031:analogs & derivatives* / Q000494:pharmacology; D005947:Glucose / Q000172:deficiency*; D000071679:Glycogen Synthase Kinase 3 beta / Q000378:metabolism; D007052:Ibuprofen / Q000494:pharmacology; D008810:Mice, Inbred C57BL; D009336:Necrosis; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010100:Oxygen / Q000494:pharmacology*; D051996:Transcription Factor RelA / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: C522246:1-(3',4'-dichloro-2-fluoro(1,1'-biphenyl)-4-yl)cyclopropanecarboxylic acid; D003521:Cyclopropanes; D018696:Neuroprotective Agents; D051996:Transcription Factor RelA; D005480:Flurbiprofen; D045304:Cytochromes c; D000071679:Glycogen Synthase Kinase 3 beta; D048051:p38 Mitogen-Activated Protein Kinases; D053148:Caspase 3; D005947:Glucose; D010100:Oxygen; D007052:Ibuprofen
keywords: CHF5074; CSP-1103; amyloid precursor protein intracellular domain (AICD); caspase-3; ischemia; nuclear factor κB (NF-κB); oxygen-glucose deprivation; p38