Proposed mechanism of action of BDNF peptides.

<p>BDNF peptides B-5 and B-3 may interact with or compete for the binding site of BDNF to its transmembrane receptor TrkB. Depending on the concentration or the cellular state or condition (i.e. during stress, like in the presence of H<sub>2</sub>O<sub>2</sub>), the peptides could act as partial agonists or partial antagonists. Fig. 8A shows the partial agonistic role of the peptides. In this case, the peptides favor the activation of the TrkB receptor, and in the presence of BDNF, they synergize with it. Once the TrkB receptor gets activated, it is dimerized and autophosphorylated (one of the residues that gets phosphorylated is the Tyr 706) and the signal is transduced. The cascades that could be activated by the peptides include the differentiation pathway through MAPK and pCREB regulating gene expression of markers of neuronal phenotype and plasticity, and also the expression of BDNF and TrkB, giving the possibility of a feedback mechanism. The other cascade that could be activated by the peptides is the survival one, in which PI3K and AKT participate to enhance survival and inhibit cell death. Fig. 8B represents the partial antagonistic role of the peptides where the peptides compete with BDNF for the activation of the receptor blocking the TrkB activation by BDNF and its signal transduction pathway. The sites where the TrkB inhibitor K252a and the protein synthesis inhibitor CHX can block the pathway are shown with a grey and red bar, respectively.</p>