Neuroprotective effects of novel small peptides in vitro and after brain injury
Neuroprotective effects of novel small peptides in vitro and after brain injury
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DOI：
10.1016/j.neuropharm.2005.04.001
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发表时间：
2005-09-01
影响因子：
4.7
通讯作者：
Cernak, B
中科院分区：
文献类型：
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作者：
Faden, AI;Movsesyan, VA;Cernak, B
据报道，促甲状腺激素释放激素 (TRH) 和 TRH 类似物在脊髓损伤和头部损伤的实验模型中具有神经保护作用。我们之前已经证明，结构上与 TRH 代谢物环组氨酸相关的二酮哌嗪可以在体外和体内减少神经元细胞死亡。在这里，我们报告了其他环状二肽在多种体外神经元损伤模型和小鼠受控皮质冲击（CCI）后的神经保护活性。使用原代神经元培养物，将三种新型二肽与先前报道的二酮哌嗪以及载体对照进行比较；每种化合物都能减少直接身体创伤或营养撤退后的细胞死亡。其中两种肽还可以防止谷氨酸毒性和 P-淀粉样蛋白诱导的损伤；后者还强烈抑制谷氨酸诱导的细胞内钙的增加。使用每种测试化合物进行治疗后，CO 后运动和认知恢复均得到显着改善，并且高场磁共振成像显示病变体积显着减小。大鼠流体冲击诱发创伤性脑损伤 (TBI) 后的 DNA 微阵列研究表明，损伤后用其中一种二肽治疗可显着下调同侧皮质和/或海马中细胞周期蛋白、水通道蛋白、组织蛋白酶和钙蛋白酶的 mRNA 表达，同时上调脑源性神经营养因子、缺氧诱导因子和几种热休克蛋白的表达。许多 mRNA 表达变化在蛋白质水平上是平行的。这些小肽调节有利于神经细胞存活的多种机制，以及它们改善功能结果和减少创伤后病变大小的能力，这一事实表明它们可能在临床头部损伤中具有潜在的用途。 (c) 2005 Elsevier Ltd. 保留所有权利。
Thyrotropin-releasing hormone (TRH) and TRH analogues have been reported to be neuroprotective in experimental models of spinal cord injury and head injury. We have previously shown that a diketopiperazine structurally related to the TRH metabolite cyclo-his-pro reduces neuronal cell death in vitro and in vivo. Here we report the neuroprotective activity of other cyclic dipeptides in multiple in vitro models of neuronal injury and after controlled cortical impact (CCI) in mice. Using primary neuronal cultures, three novel dipeptides were compared to the previously reported diketopiperazine as well as to vehicle controls; each of the compounds reduced cell death after direct physical trauma or trophic withdrawal. Two of these peptides also protected against glutamate toxicity and P-amyloid-induced injury; the latter also strongly inhibited glutamate-induced increases in intracellular calcium. Treatment with each of the test compounds resulted in highly significant improvement of motor and cognitive recovery after CO, as well as markedly reducing lesion volumes as shown by high field magnetic resonance imaging. DNA microarray studies following fluid percussion induced traumatic brain injury (TBI) in rats showed that treatment with one of these dipeptides after injury significantly down-regulated expression of mRNAs for cell cycle proteins, aquaporins, cathepsins and calpain in ipsilateral cortex and/or hippocampus, while up-regulating expression of brain-derived neurotrophic factor, hypoxia-inducible factor and several heat-shock proteins. Many of these mRNA expression changes were paralleled at the protein level. The fact that these small peptides modulate multiple mechanisms favoring neuronal cell survival, as well as their ability to improve functional outcome and reduce posttraumatic lesion size, suggests that they may have potential utility in clinical head injury. (c) 2005 Elsevier Ltd. All rights reserved.