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- Muhammad Omar Chohan, Olga Bragina, Syed Faraz Kazim, Gloria Statom, Narjes Baazaoui, Denis Bragin, Khalid Iqbal, Edwin Nemoto, and Howard Yonas.
- *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.
- Neurosurgery. 2015 Feb 1; 76 (2): 201-14; discussion 214-5.
BackgroundTraumatic 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.ObjectiveTo describe hippocampal abnormalities in a mouse model of mild to moderate TBI and their reversal by Peptide 6.MethodsTBI 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.ResultsIpsilateral 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.ConclusionLong-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.
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