Neurotrophic Factors and Intracellular Signal Transduction Pathways

A clear limitation of treating diseases of the central nervous system arises from the loss of regenerative potential of the brain at a very early age. Improper development of neural circuits or injury of neurons appears to be permanently fixed in the adult, with seemingly little hope of restorative therapy. This is most clearly true of the spectrum of neurologic diseases, such as neurodegenerative diseases (e.g., Alzheimer’s or Parkinson’s disease and stroke) and inflammatory disease (e.g., multiple sclerosis). In addition, breakthrough disorders such as epilepsy or myoclonus reflect inappropriate ‘‘wiring’’ or lack of appropriate feedback control of neuronal activity. It has also become apparent that some psychiatric diseases represent similar fixed deficits or lack of appropriate functional adaptation. Neurochemical and neuroanatomic deficits have been documented in affective diseases, schizophrenia, and anxiety disorders. Methods to recreate the early restorative potential of the brain would have great potential for significantly, and possibly permanently, reversing the often debilitating features of these neurologic and psychiatric diseases. Over the last several years, of body of literature has delineated the important roles of neurotrophic factors in guiding the development of the nervous system. The first identified neurotrophic factor, nerve growth factor (NGF), was identified and characterized in the pivotal studies of Levi-Montalcini (1). The general properties of NGF now essentially define what neuroscientists consider a neurotrophic factor. A neurotrophic factor is capable of supporting the survival of at least one population of neurons in culture. It is secreted by a target tissue (either neuronal or nonneuronal) and acts on the neurons that innervate that tissue to support their survival or differentiation. Finally, a neurotrophic factor is expressed in the appropriate region and at the appropriate