GLIAL-CELL LINE-DERIVED NEUROTROPHIC FACTOR ENHANCES SURVIVAL AND GROWTH OF PRENATAL AND POSTNATAL SPINAL-CORD TRANSPLANTS

Glial cell line-derived neurotrophic factor was first described as a t rophic factor for developing dopamine neurons. However, it has been sh own that glial cell line-derived neurotrophic factor messenger RNA is also expressed in several areas of the developing brain and spinal cor d, suggesting that it may have additional roles in the nervous system. Intraocular transplantation of neural tissue provides a unique method to examine in vivo effects of trophic factors. We have therefore stud ied the effects of glial cell line-derived neurotrophic factor on spin al cord survival and development following grafting to the anterior ch amber of the eye of adult rats. We used spinal cord tissue from fetal stages (embryonic days 14 and 18) and postnatal days 1 and 14 as donor s. The spinal cord tissue was allotransplanted to the anterior eye cha mber of Sprague-Dawley host rats after incubation in buffered saline c ontaining 100 mu g glial cell line-derived neurotrophic factor/ml or 1 00 mu g cytochrome C/ml. One group of postnatal day 1 spinal cord graf ts was also treated with concentrations of 20 and 10 mu g glial cell l ine-derived neurotrophic factor/ml. In all cases, 5 mu l of the same s olution was injected into the anterior eye chamber on postgrafting day s 5, 10, 15 and 20 (total amounts 0.5, 0.1 and 0.05 mu g/eye/injection , respectively). We found that all glial cell line-derived neurotrophi c factor-treated spinal cord grafts grew more than controls. The effec t of glial cell line-derived neurotrophic factor was most prominent in grafts from newborn rats. In these grafts we found a dose-dependent e ffect of glial cell line-derived neurotrophic factor on growth. Moreov er, grafts treated with the highest dose (0.5 mu g) grew to sizes exce eding the initial size at transplantation. In these transplants we als o found greater numbers of large neurons compared to controls. Glial f ibrillary acidic protein immunoreactivity, in contrast, showed increas ed gliosis in controls. Similar results were found with syngeneic spin al cord postnatal day 1 grafts in Fisher hosts. Spinal cord tissue gra fts from two-week-old rats treated with the highest glial cell line-de rived neurotrophic factor dose every fifth day, through day 35 postgra fting, responded with increased growth and less necrotic tissue compar ed with controls; however, we could not detect neurofilament immunorea ctivity in these transplants. Taken together, these results suggest th at glial cell line-derived neurotrophic factor may be a potent trophic factor for neurons in the spinal cord and in spinal cord transplants. Of particular importance is that glial cell line-derived neurotrophic factor treatment can be used to obtain survival of postnatal spinal c ord tissue, that would otherwise show minimal or no survival. Thus, gl ial cell line-derived neurotrophic factor allows successful transplant ation of more mature spinal cord tissue, which may have important impl ications for both basic and clinical neuroscience.