NEUROTROPHIC MOLECULES - STRATEGIES FOR DESIGNING EFFECTIVE THERAPEUTIC MOLECULES IN NEURODEGENERATION

Over the past several years, neurotrophic factors-a description genera lly applied to naturally occurring polypeptides that support the devel opment and survival of neurons-have made considerable progress from th e laboratory into the clinic. Evidence from preclinical and clinical s tudies indicates that it may be possible to use neurotrophic factors t o prevent, slow the progression of, or even reverse the effects of a n umber of neurodegenerative diseases and other types of insults in both the central nervous system (CNS) and the peripheral nervous system. I nitially, investigations focused on recombinant neurotrophic proteins that are identical or highly homologous to the natural human sequence. Given the difficulties inherent with a protein therapeutic approach t o treating nervous system disorders, especially those of the CNS, incr easing attention has now turned to the development of alternative stra tegies and, in particular, small molecule mimetics. Regulation of the transcription of neurotrophic factors may provide a means of manipulat ing endogenous factor production; gene therapy may also allow for the circumvention of exogenous neurotrophic factor administration. The pro blem of transport across the blood-brain barrier may be overcome by de veloping small-molecule mimetics that maintain the neurotrophic activi ty of the protein while having improved pharmacokinetic and dispositio n characteristics. Components of neurotrophic factor signal transducti on pathways may provide additional targets for novel drugs that can in duce or modulate the responses normally activated by the binding of th e neurotrophic factor to its receptor. This review focusses on some of the major themes and lines of mechanistic and therapeutic advances in this fast-moving field of neuroscience.