NEUROTROPHIC FACTORS AND THE DEVELOPMENT OF DRUGS TO PROMOTE MOTONEURON SURVIVAL

Authors


Dr Tony Hughes, Department of Pharmacology, University of Melbourne, Grattan Street, Parkville, Victoria 3052, Australia.

SUMMARY

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 factors. Recent advvances in in vitro and in vivo assays have led to the identification of a number of neurotrophic factors for spinal motoneurons, including brain-derived neurotrophic factor, ciliary neurotrophic factor, fibroblast growth factors, insulin-like growth factors and glial-derived neurotrophic factor.

2. The presence of multiple trophic factors promoting motoneuron survival suggests either that there is significant functional redunancy between the factors or that they act in concert to produce their effects.

3. In addition to their physiological role, neurotrophic factors show tremendous clinical potential for the treatment of human neurodegenerative diseases, such as amyotrophic lateral sclerosis. However, because they are poorly absorbed across biological membranes and are unstable in plasma, the recombinant neurotrophic factors themselves are not optimally suited as drugs. One means to circumvent these problems is to use the known three-dimensional structures of theses factors as templates to design low molecular weight compounds that retain neurotrophic activity but exhibit better pharmacokinetic properties.

Ancillary