Neurotrophins: evolution of concepts on rational therapeutic approaches

Neurotrophins (NT) were "brought to life" by Rita Levi-Montalcini and Stanley Cohen, thanks to their discovery of the nerve growth factor (NGF) isolated from the malignant tumor. A hint got from the cancer studies on the presence of NTs and other molecules like metalloproteases, which control neuronal remodeling and extracellular matrix in tumors, was the stimulus to investigate the role of these molecules in physiology and post-lesion plasticity of the nervous system. NTs have long been identified as drivers of neurogenesis during development and regeneration of the nervous system. Thousands of investigations spanned from early sixties till now provided strong evidence that this small family of molecules is indispensable for central and peripheral nervous system maintenance throughout the whole life of different animal species. In mammals NTs regulate sensation, movement, behavior, and cognition. A problem, which accompanies the majority of experimental therapies using NTs following injury of the nervous system, stems from unspecific and uncontrolled stimulation of the whole circuitry of preserved neurons. Among the already identified causes of clinical trial failure with the use of NT therapy in the treatment of neurodegenerative diseases are: (1) disregarding neuronal preferences to selected NTs; (2) poor knowledge on NT pharmacokinetics (3) uncontrolled spread of NTs when administered systemically, which could have unpredictable effects on other than intended neuronal populations (4) limitations of tissue penetration of some NTs (5) disturbances of the balance between signal transmission through their Trk and LNGTR receptors. I present our contribution to the field and efforts to control spatially and temporally postinjury NT signaling.