Biochemistry Laboratory, Department of Biological Science, Sungkyunkwan University, Jangan-Gu, Suwon, Gyeonggi-Do, Korea.
J Neurochem. 2011 Jan;116(2):205-16. doi: 10.1111/j.1471-4159.2010.07078.x.
Abundant studies have shown possible links between low levels of brain-derived neurotrophic factor (BDNF) and neurological diseases such as Alzheimer's disease, Parkinson's disease, and depression, as well as stress and anxiety; therefore, BDNF could be a therapeutic target for neurological disorders. In the present study, a positional scanning-synthetic peptide combinatorial library was utilized to identify a peptide modulator of BDNF expression in the hippocampal neuronal cell line, H19-7. A novel tripeptide (Neuropep-1) induced a significant increase of BDNF mRNA and protein levels in H19-7 cells. Pre-treatment of TrkB inhibitor (K252a) did not block Neuropep-1-induced BDNF up-regulation. These results indicate that Neuropep-1 may up-regulate BDNF expression that might be independent of the TrkB receptor pathway. Tail vein injection of Neuropep-1 significantly up-regulated BDNF expression, TrkB phosphorylation, and its downstream signals including activation of Akt, ERK, and cAMP response element binding in the rat hippocampus. To evaluate improvement of spatial learning and memory (SLM) by Neuropep-1-induced BDNF up-regulation, the Y-maze and Morris water maze tests were performed. These results showed Neuropep-1 injection improved SLM performance with increase of BDNF and TrkB expression, activation of TrkB downstream signals in rat hippocampus compared with the control group. However, phosphorylation levels of TrkB were not changed when it was normalized to the level of TrkB expression. The difference on TrkB phosphorylation in Neuropep-1-injected rats may be affected by behavioral tests. These results suggest that Neuropep-1 may improve SLM via activation of the BDNF/TrkB signaling pathway in the rat hippocampus. Therefore, our findings represent that Neuropep-1 might be a potential candidate for treatment of learning and memory disorders as well as neurological diseases involving the abnormal expression of BDNF.
大量研究表明，脑源性神经营养因子（BDNF）水平低与阿尔茨海默病、帕金森病、抑郁症以及应激和焦虑等神经疾病之间可能存在关联；因此，BDNF 可能成为神经疾病的治疗靶点。在本研究中，利用定位扫描合成肽组合文库来鉴定在海马神经元细胞系 H19-7 中调节 BDNF 表达的肽调节剂。一种新型三肽（Neuropep-1）可显著增加 H19-7 细胞中 BDNF mRNA 和蛋白水平。预先用 TrkB 抑制剂（K252a）处理并不阻断 Neuropep-1 诱导的 BDNF 上调。这些结果表明，Neuropep-1 可能上调 BDNF 表达，而这可能与 TrkB 受体途径无关。尾静脉注射 Neuropep-1 可显著上调大鼠海马中 BDNF 表达、TrkB 磷酸化及其下游信号，包括 Akt、ERK 和 cAMP 反应元件结合的激活。为了评估 Neuropep-1 诱导的 BDNF 上调对空间学习和记忆（SLM）的改善作用，进行了 Y 迷宫和 Morris 水迷宫测试。与对照组相比，这些结果表明，Neuropep-1 注射可改善 SLM 表现，增加 BDNF 和 TrkB 表达，激活大鼠海马中的 TrkB 下游信号。然而，当 TrkB 磷酸化水平相对于 TrkB 表达水平归一化时，其并未改变。Neuropep-1 注射大鼠中 TrkB 磷酸化的差异可能受行为测试的影响。这些结果表明，Neuropep-1 可能通过激活大鼠海马中的 BDNF/TrkB 信号通路来改善 SLM。因此，我们的研究结果表明，Neuropep-1 可能成为治疗学习和记忆障碍以及涉及 BDNF 异常表达的神经疾病的潜在候选药物。
