Evidence suggests that parallel biochemical and regulatory processes occur during normal development and following various forms of CNS injury. Among these areas of particular interest are: (1) identification of CNS neurotrophic factors; and (2) the analysis of the regulation of 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. An NGF-like factor increases in the cerebellum of the pcd mutant mouse as the Purkinje cells die out and astrocytes proliferate. MPTP-lesioned animals (both mice and monkeys) represent a Parkinson-like model in which changes in NGF and the related neurotrophic factors BDNF (brain-derived neurotrophic factor) and NT-3 (neurotropin-3) are being examined at the level of mRNA, protein and biological activity. Since astrocytes can synthesize NGF, primary cultures of astrocytes are being used to determine factors which regulate NGF gene transcription as well as to assess production of these other 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 are being explored in several model culture systems. At the same time, these injury models can be evaluated for changes in neuropeptide and/or neurotransmitter synthesis occurring in response to the lesions. One can derive an estimate of peptide turnover by combining measurements of the precursor mRNA, the precursor, and the peptide. Our studies have demonstrated that peptides are differentially regulated by such chronic drug treatments as reserpine, haloperidol, 6-hydroxydopamine or 5,7-dihydroxytryptamine. Work is in progress to determine the effects of CNS injury and recovery, including MPTP treatment, on various neuropeptides as well as such neurotransmitter synthetic enzymes as tyrosine hydroxylase and GAD, and the dopamine D2 receptor.
