title: Identification of potentially neuroprotective genes upregulated by neurotrophin treatment of CA3 neurons in the injured brain.
abstract: Specific neurotrophic factors mediate histological and/or functional improvement in animal models of traumatic brain injury (TBI). In previous work, several lines of evidence indicated that the mammalian neurotrophin NT-4/5 is neuroprotective for hippocampal CA3 pyramidal neurons after experimental TBI. We hypothesized that NT-4/5 neuroprotection is mediated by changes in the expression of specific sets of genes, and that NT-4/5-regulated genes are potential therapeutic targets for blocking delayed neuronal death after TBI. In this study, we performed transcription profiling analysis of CA3 neurons to identify genes regulated by lateral fluid percussion injury, or by treatment with the trkB ligands NT-4/5 or brain-derived neurotrophic factor (BDNF). The results indicate extensive overlap between genes upregulated by neurotrophins and genes upregulated by injury, suggesting that the mechanism behind neurotrophin neuroprotection may mimic the brain's endogenous protective response. A subset of genes selected for further study in vitro exhibited neuroprotection against glutamate excitotoxicity. The neuroprotective genes identified in this study were upregulated at 30 h post-injury, and are thus expected to act during a clinically useful time frame of hours to days after injury. Modulation of these factors and pathways by genetic manipulation or small molecules may confer hippocampal neuroprotection in vivo in preclinical models of TBI.
authors.affiliation: Department of Neurosurgery and Center for Brain Injury and Repair, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Saafan Z
authors.initials: SZ
authors.lastname: Malik
authors.forename: Shahab
authors.initials: S
authors.lastname: Motamedi
authors.forename: Nicolas C
authors.initials: NC
authors.lastname: Royo
authors.forename: David
authors.initials: D
authors.lastname: LeBold
authors.forename: Deborah J
authors.initials: DJ
authors.lastname: Watson
mesh_terms: D000818:Animals; D001930:Brain Injuries / Q000235:genetics* / Q000473:pathology; D056654:CA3 Region, Hippocampal / Q000187:drug effects* / Q000293:injuries* / Q000378:metabolism / Q000473:pathology; D005786:Gene Expression Regulation / Q000187:drug effects*; D008297:Male; D042282:Microdissection; D009414:Nerve Growth Factors / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D009414:Nerve Growth Factors