Neuroprotective Efficacy of a Proneurogenic Compound after Traumatic Brain Injury
Neuroprotective Efficacy of a Proneurogenic Compound after Traumatic Brain Injury
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DOI：
10.1089/neu.2013.3135
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发表时间：
2014-03-01
影响因子：
4.2
通讯作者：
Dietrich, W. Dalton
中科院分区：
文献类型：
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作者：
Blaya, Meghan O.;Bramlett, Helen M.;Dietrich, W. Dalton
创伤性脑损伤（Traumatic brain injury，TBI）是一种以组织病理学损害和长期感觉、运动和认知功能障碍为特征的疾病。最近的研究报道了P7 C3类氨丙基咔唑剂的发现，其对成年海马中的新生神经前体细胞和中枢神经系统其他区域中的成熟神经元都具有有效的神经保护特性。这项研究首次测试了高活性P7 C3-A20化合物是否具有神经保护作用，促进海马神经发生，并改善实验性TBI后的功能结果。对中度液压冲击脑损伤的Sprague-Dawley大鼠进行定量免疫组织化学和创伤后行为变化的评价。P7C3-A20（10？mg/kg）或载体开始腹腔注射30？术后10分钟，每天两次，持续7天。P7 C3-A20的管理显着减少总体挫伤体积，保存脆弱的抗神经元核（NeuN）阳性的周挫伤皮质神经元，并改善感觉运动功能创伤后1周。P7 C3-A20治疗还显著增加了TBI后1周同侧齿状回颗粒下区内的溴脱氧尿苷（BrdU）和双皮质素（DCX）阳性细胞。TBI后五周，与TBI对照动物相比，用P7 C3-A20处理的动物在Morris水迷宫中显示出显著增加的BrdU/NeuN双标记神经元和改善的认知功能。这些结果表明，P7 C3-A20是神经保护和促进TBI后的内源性修复策略。我们认为，P7 C3-A20所代表的化学支架为优化和推进新的药理学药物提供了基础，以保护患者免受TBI的早期和慢性后果。
Traumatic brain injury (TBI) is characterized by histopathological damage and long-term sensorimotor and cognitive dysfunction. Recent studies have reported the discovery of the P7C3 class of aminopropyl carbazole agents with potent neuroprotective properties for both newborn neural precursor cells in the adult hippocampus and mature neurons in other regions of the central nervous system. This study tested, for the first time, whether the highly active P7C3-A20 compound would be neuroprotective, promote hippocampal neurogenesis, and improve functional outcomes after experimental TBI. Sprague-Dawley rats subjected to moderate fluid percussion brain injury were evaluated for quantitative immunohistochemical and behavioral changes after trauma. P7C3-A20 (10?mg/kg) or vehicle was initiated intraperitoneally 30?min postsurgery and twice per day every day thereafter for 7 days. Administration of P7C3-A20 significantly reduced overall contusion volume, preserved vulnerable anti-neuronal nuclei (NeuN)-positive pericontusional cortical neurons, and improved sensorimotor function 1 week after trauma. P7C3-A20 treatment also significantly increased both bromodeoxyuridine (BrdU)- and doublecortin (DCX)-positive cells within the subgranular zone of the ipsilateral dentate gyrus 1 week after TBI. Five weeks after TBI, animals treated with P7C3-A20 showed significantly increased BrdU/NeuN double-labeled neurons and improved cognitive function in the Morris water maze, compared to TBI-control animals. These results suggest that P7C3-A20 is neuroprotective and promotes endogenous reparative strategies after TBI. We propose that the chemical scaffold represented by P7C3-A20 provides a basis for optimizing and advancing new pharmacological agents for protecting patients against the early and chronic consequences of TBI.