A novel trimeric peptide, Neuropep-1-stimulating brain-derived neurotrophic factor expression in rat brain improves spatial learning and memory as measured by the Y-maze and Morris water maze.

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.