title: Transcriptional expression patterns triggered by chemically distinct neuroprotective molecules.
abstract: Glutamate-mediated excitotoxicity has been purported to underlie many neurodegenerative disorders. A subtype of glutamate receptors, namely N-methyl-d-aspartate (NMDA) receptors, has been recognized as potential targets for neuroprotection. To increase our understanding of the mechanisms that underlie this neuroprotection, we employed a mouse model of glutamate receptor-induced excitotoxic injury. Primary cortical neurons derived from postnatal day-0 CD-1 mice were cultured in the presence or absence of neuroprotective molecules and exposed to NMDA. Following a recovery period, whole genome expression was measured by microarray analysis. We used a combination of database and text mining, as well as systems modeling to identify signatures within the differentially expressed genes. While molecules differed in their mechanisms of action, we found significant overlap in the expression of a core group of genes and pathways. Many of these molecules have clear links to neuronal protection and survival, including ion channels, transporters, as well as signaling pathways including the mitogen-activated protein kinase (MAPK), the Toll-like receptor (TLR), and the hypoxic inducible factor (HIF). Within the TLR pathway, we also discovered a significant enrichment of interferon regulatory factor 7 (IRF7)-regulated genes. Knockdown of Irf7 by RNA interference resulted in reduced survival following NMDA treatment. Given the prominent role that IRF7 plays in the transduction of type-I interferons (IFNs), we also tested whether type-I IFNs alone functioned as neuroprotective agents and found that type-I IFNs were sufficient to promote neuronal survival. Our data suggest that the TLR/IRF7/IFN axis plays a significant role in recovery from glutamate-induced excitotoxicity.
authors.affiliation: Department of Neurology, University of California, San Francisco, CA 94158, USA. djpappas75@gmail.com
authors.forename: D J
authors.initials: DJ
authors.lastname: Pappas
authors.forename: P A
authors.initials: PA
authors.lastname: Gabatto
authors.forename: D
authors.initials: D
authors.lastname: Oksenberg
authors.forename: P
authors.initials: P
authors.lastname: Khankhanian
authors.forename: S E
authors.initials: SE
authors.lastname: Baranzini
authors.forename: L
authors.initials: L
authors.lastname: Gan
authors.forename: J R
authors.initials: JR
authors.lastname: Oksenberg
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D002448:Cell Adhesion / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects; D057225:Data Mining; D015723:Gene Library; D055106:Genome-Wide Association Study; D018698:Glutamic Acid / Q000378:metabolism / Q000502:physiology*; D051793:Hypoxia-Inducible Factor 1 / Q000096:biosynthesis; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D018696:Neuroprotective Agents / Q000737:chemistry* / Q000494:pharmacology*; D034622:RNA Interference; D060888:Real-Time Polymerase Chain Reaction; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects / Q000502:physiology; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D051193:Toll-Like Receptors / Q000096:biosynthesis; D014158:Transcription, Genetic / Q000187:drug effects*; D059467:Transcriptome
chemical_list: D051793:Hypoxia-Inducible Factor 1; D018696:Neuroprotective Agents; D016194:Receptors, N-Methyl-D-Aspartate; D051193:Toll-Like Receptors; D018698:Glutamic Acid; D020928:Mitogen-Activated Protein Kinases; D002118:Calcium