Neurotrophic molecules: strategies for designing effective therapeutic molecules in neurodegeneration.
Over the past several years, neurotrophic factors-a description generally applied to naturally occurring polypeptides that support the development and survival of neurons-have made considerable progress from the laboratory into the clinic. Evidence from preclinical and clinical studies indicates that it may be possible to use neurotrophic factors to prevent, slow the progression of, or even reverse the effects of a number of neurodegenerative diseases and other types of insults in both the central nervous system (CNS) and the peripheral nervous system. Initially, 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 to treating nervous system disorders, especially those of the CNS, increasing attention has now turned to the development of alternative strategies and, in particular, small molecule mimetics. Regulation of the transcription of neurotrophic factors may provide a means of manipulating endogenous factor production; gene therapy may also allow for the circumvention of exogenous neurotrophic factor administration. The problem of transport across the blood-brain barrier may be overcome by developing small-molecule mimetics that maintain the neurotrophic activity of the protein while having improved pharmacokinetic and disposition characteristics. Components of neurotrophic factor signal transduction pathways may provide additional targets for novel drugs that can induce or modulate the responses normally activated by the binding of the 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.
Skaper
S D
SD
Neuroscience Research Department, SmithKline Beecham Pharmaceuticals, New Frontiers Science Park, Third Avenue, Harlow, Essex, CM19 5AW, United Kingdom.
Walsh
F S
FS
D000818:Animals; D002493:Central Nervous System Diseases / Q000188:drug therapy / Q000503:physiopathology; D015195:Drug Design; D006801:Humans; D009410:Nerve Degeneration / Q000188:drug therapy* / Q000503:physiopathology; D009414:Nerve Growth Factors / Q000737:chemistry / Q000502:physiology* / Q000627:therapeutic use; D019636:Neurodegenerative Diseases / Q000188:drug therapy* / Q000503:physiopathology; D018696:Neuroprotective Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000627:therapeutic use*; D010523:Peripheral Nervous System Diseases / Q000188:drug therapy / Q000503:physiopathology; D017475:Receptors, Nerve Growth Factor / Q000502:physiology; D015398:Signal Transduction
D009414:Nerve Growth Factors; D018696:Neuroprotective Agents; D017475:Receptors, Nerve Growth Factor