title: Enhancement of neurogenesis and memory by a neurotrophic peptide in mild to moderate traumatic brain injury.
abstract: BACKGROUND
  Traumatic brain injury (TBI) is a risk factor for Alzheimer disease (AD), a neurocognitive disorder with similar cellular abnormalities. We recently discovered a small molecule (Peptide 6) corresponding to an active region of human ciliary neurotrophic factor, with neurogenic and neurotrophic properties in mouse models of AD and Down syndrome.
  
  
  OBJECTIVE
  To describe hippocampal abnormalities in a mouse model of mild to moderate TBI and their reversal by Peptide 6.
  
  
  METHODS
  TBI was induced in adult C57Bl6 mice using controlled cortical impact with 1.5 mm of cortical penetration. The animals were treated with 50 nmol/d of Peptide 6 or saline solution for 30 days. Dentate gyrus neurogenesis, dendritic and synaptic density, and AD biomarkers were quantitatively analyzed, and behavioral tests were performed.
  
  
  RESULTS
  Ipsilateral neuronal loss in CA1 and the parietal cortex and increase in Alzheimer-type hyperphosphorylated tau and A-β were seen in TBI mice. Compared with saline solution, Peptide 6 treatment increased the number of newborn neurons, but not uncommitted progenitor cells, in dentate gyrus by 80%. Peptide 6 treatment also reversed TBI-induced dendritic and synaptic density loss while increasing activity in tri-synaptic hippocampal circuitry, ultimately leading to improvement in memory recall on behavioral testing.
  
  
  CONCLUSIONS
  Long-term treatment with Peptide 6 enhances the pool of newborn neurons in the dentate gyrus, prevents neuronal loss in CA1 and parietal cortex, preserves the dendritic and synaptic architecture in the hippocampus, and improves performance on a hippocampus-dependent memory task in TBI mice. These findings necessitate further inquiry into the therapeutic potential of small molecules based on neurotrophic factors.
authors.affiliation: *Department of Neurosurgery, University of New Mexico Hospital, Albuquerque, New Mexico; ‡Department of Neurochemistry, Inge Grundke-Iqbal Floor, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, New York; §Neural and Behavioral Science Graduate Program, State University of New York (SUNY) Downstate Medical Center, Brooklyn, New York.
authors.forename: Muhammad Omar
authors.initials: MO
authors.lastname: Chohan
authors.forename: Olga
authors.initials: O
authors.lastname: Bragina
authors.forename: Syed Faraz
authors.initials: SF
authors.lastname: Kazim
authors.forename: Gloria
authors.initials: G
authors.lastname: Statom
authors.forename: Narjes
authors.initials: N
authors.lastname: Baazaoui
authors.forename: Denis
authors.initials: D
authors.lastname: Bragin
authors.forename: Khalid
authors.initials: K
authors.lastname: Iqbal
authors.forename: Edwin
authors.initials: E
authors.lastname: Nemoto
authors.forename: Howard
authors.initials: H
authors.lastname: Yonas
mesh_terms: D000818:Animals; D001930:Brain Injuries / Q000473:pathology / Q000503:physiopathology*; D002454:Cell Differentiation / Q000187:drug effects; D020934:Ciliary Neurotrophic Factor / Q000494:pharmacology*; D004195:Disease Models, Animal; D006624:Hippocampus / Q000187:drug effects* / Q000502:physiology; D008297:Male; D008568:Memory / Q000187:drug effects* / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018613:Microscopy, Confocal; D058953:Neural Stem Cells / Q000187:drug effects; D055495:Neurogenesis / Q000187:drug effects*; D010455:Peptides / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D020934:Ciliary Neurotrophic Factor; D010455:Peptides