NEUROTROPHIC FACTORS AND THE DEVELOPMENT OF DRUGS TO PROMOTE MOTONEURON SURVIVAL

1. During embryonic development, neuronal populations undergo a period of naturally occurring cell death, In the vertebrate, the survival of neurons during this period is dependent upon specific neurotrophic fa ctors, Recent advances in in vitro and in vivo assays have led to the identification of a number of neurotrophic factors for spinal motoneur ons, including brain-derived neurotrophic factor, ciliary neurotrophic factor, fibroblast growth factors, insulin-like growth factors and gl ial-derived neurotrophic factor. 2. The presence of multiple trophic f actors promoting motoneuron survival suggests either that there is sig nificant functional redundancy between the factors or that they act in concert to produce their effects. 3. In addition to their physiologic al role, neurotrophic factors show tremendous clinical potential for t he treatment of human neurodegenerative diseases, such as amyotrophic lateral sclerosis, However, because they are poorly absorbed across bi ological membranes and are unstable in plasma, the recombinant neurotr ophic factors themselves are not optimally suited as drugs, One means to circumvent these problems is to use the known three-dimensional str uctures of these factors as templates to design low molecular weight c ompounds that retain neurotrophic activity but exhibit better pharmaco kinetic properties.