Evidence suggests that parallel biochemical and regulatory processes occur during normal development and following various forms of central nervous system (CNS) injury. Among these areas of particular interest are: (1) identification of CNS neurotrophic factors; and (2) the analysis of the regulation of neurotrophic factor and neuropeptide gene expression during development and in response to injury. Studies are underway to identify trophic factors produced in specific model systems, since recent evidence suggests that a family of nerve growth factors (NGF) exists, each specific for certain populations of neurons. 6-OHDA lesioned rats represent a Parkinsonian-like model in which changes in NGF and the related neurotrophic factors BDNF (brain-derived neurotrophic factor) and NT-3 are being examined at the level of mRNA, protein, and biologic activity. Since astrocytes can synthesis a number of neurotrophic factors, primary cultures of astrocytes are used to determine factors which regulate production of these potential trophic factors. Reactive astrocytes are prepared from regions affected by the various injuries and their production of trophic factors compared to that of control astrocytes. Potential neurotrophic functions for the neuropeptides, enkephalin and somatostatin, in early CNS development have been demonstrated in culture and in transgenic mice: enkephalin acts as a negative modulator of CNS development while somatostatin is a positive trophic factor. Cytokines can induce expression of trophic factors as well as of nitric oxide synthase: since microglia activated by brain injury are being examined. Analysis of a neurologic syndrome found in 60% of transgenic mice expressing an antisense interleukin-3 construct has demonstrated a cellular lesion in the cerebellar peduncle. A retinal pigment epithelium-derived factor (PEDF) functions as a survival factor for cerebellar granule cells.
