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 demonstrates the existence of numerous different neurotrophic factors. 6-OHDA-lesioned rats represent a Parkinsonian-like model in which changes in nerve growth factor, 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 6-OHDA-lesioned brain: monoclonal antibodies raised against epitopes expressed only by reactive astrocytes in vivo can distinguish between normal adult and reactive astrocytes in culture. Astrocytes from newborn animals more closely resemble reactive astrocytes in terms of expression of these epitopes. Production of trophic factors by these reactive astrocytes is compared to that of control astrocytes to determine how injury may alter the regulatory pathways. Cytokines, produced at high levels in injured brain, induce expression of neurotrophic factors as well as of nitric oxide synthase, which may be responsible for some of the neuronal damage. Depletion of the cytokine interleukin-3 (IL-3) by an antisense construct results in transgenic mice expressing a neurologic syndrome. The lesion results from migration/activation of microglia in the cerebellar peduncle. Among novel enkephalin and somatostatin, both produced by astrocytes, have been demonstrated in culture as well as in transgenic mice. Enkephalin acts as a negative modulator of CNS development while somatostatin is a positive trophic factor. A retinal pigment epithelium-derived factor (PEDF) not only functions as a survival factor for cerebellar granule cell neurons but also can protect them against both glutamate toxicity and apoptotic cell death. In addition, PEDF activates microglia, which produce an as yet unidentified factor which inhibits astrocyte proliferation and may thus be useful in situations of gliosis due to astrocyte division.
