Chohan Muhammad Omar, Bragina Olga, Kazim Syed Faraz, Statom Gloria, Baazaoui Narjes, Bragin Denis, Iqbal Khalid, Nemoto Edwin, Yonas Howard
*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;76(2):201-14; discussion 214-5. doi: 10.1227/NEU.0000000000000577.
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.
To describe hippocampal abnormalities in a mouse model of mild to moderate TBI and their reversal by Peptide 6.
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.
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.
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.
创伤性脑损伤（TBI）是阿尔茨海默病（AD）的一个风险因素，AD是一种具有相似细胞异常的神经认知障碍。我们最近发现了一种对应于人睫状神经营养因子活性区域的小分子（肽6），在AD和唐氏综合征小鼠模型中具有神经发生和神经营养特性。
描述轻度至中度TBI小鼠模型中的海马异常情况以及肽6对其的逆转作用。
使用控制皮层撞击法，使成年C57Bl6小鼠皮层穿透1.5毫米，诱导TBI。动物接受50 nmol/d的肽6或盐溶液治疗30天。对齿状回神经发生、树突和突触密度以及AD生物标志物进行定量分析，并进行行为测试。
TBI小鼠中可见CA1和顶叶皮质同侧神经元丢失，以及阿尔茨海默病型高磷酸化tau和A-β增加。与盐溶液相比，肽6治疗使齿状回新生神经元数量增加了80%，但未分化祖细胞数量未增加。肽6治疗还逆转了TBI诱导的树突和突触密度损失，同时增加了三突触海马回路的活性，最终导致行为测试中的记忆回忆改善。
肽6长期治疗可增加齿状回新生神经元池，防止CA1和顶叶皮质神经元丢失，保留海马中的树突和突触结构，并改善TBI小鼠在依赖海马的记忆任务中的表现。这些发现有必要进一步探究基于神经营养因子的小分子的治疗潜力。
