Neurotrophins: The therapeutic potential and concept of minipeptides

Neurotrophins belong to a family of polypeptides that exert control over many aspects of the survival, development, and functioning of structures within the central and peripheral nervous system. Neurotrophins, the nerve growth factor (NGF), the brain derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3), as well as extracellular tyrosine kinase receptors (TrkA, TrkB, and TrkC) are specific targets for therapeutic intervention during different diseases. All these neurotrophins also bind to the p75 receptor, which has many functions depending on the type of cell where it is present. The diversity of neurotrophin effects is determined by ligand-receptor binding and the type of signaling responses that are specific for this interaction. NGF and other neurotrophins are involved in many pathological conditions. It has been shown that an insufficient level of neurotrophins in certain brain structures may be not only an initial cause of Alzheimer's disease but also may be typical for cerebrovascular dysfunction, brain trauma, cognitive impairments, etc. The therapeutic potential of neurotrophins has been shown in many studies in the last decade but the effectiveness of neurotrophic therapy is limited by the poor diffusion of molecules across the blood-brain barrier and toxic adverse effects. The solution to this problem may be the creation of minipeptides and peptidomimetics that affect the activity of tyrosine-kinase receptors. Some of these structures are combinations of cyclic pentapeptides that facilitate interaction with Trk receptors and exert neuroprotective activity. In this review, we discuss the clinical and experimental data on the results of an alternative strategy that uses these peptidomimetics. These compounds comprise a new group of perspective agents in the therapy of neurodegenerative disorders.