In multiple neuronal populations, growth factors attenuate cell death induced by a variety of insults. Because of the wide range of protective effects of growth factors they are currently being considered as potential therapeutic agents for stroke, amyotrophic lateral sclerosis, Parkinson's disease, and other neurodegenerative conditions. However, to date, and for a variety of reasons, the results of clinical trials using neurotrophic factors have been disappointing. Furthermore, while most in vitro and animal studies have shown protective effects of growth factors against neuronal cell death, there have also been a number of studies showing injury enhancing effects of growth factors. The hypothesis to be tested in this proposal is that, under specific definable conditions, many growth factors will have injury potentiating effects. Preliminary data indicates that while growth factors are consistently protective against insults, which induce apoptotic cell death, they potentiate some forms of necrotic cell death. It follows that to maximize the therapeutic usefulness of growth factors it is necessary to determine the mechanism(s) by which the injury enhancing effects occur. Study of the mechanism(s) of growth factor potentiation of cell death will focus on expanding preliminary results which suggest a role for increased mitochondrial free radical formation, increased calcium influx, and altered neurotransmitter release. Preliminary studies have focused on the effects of brain derived neurotrophic factor on oxygen-glucose deprivation in cortical cultures. Proposed experiments will use neuronal cultures prepared from selected brain regions, and with specific growth factors, each chosen because of known mechanisms of cell death and relevance to disease conditions. It is believed that these studies will aid in determining under what conditions growth factor induced potentiation of cell death may be of concern regarding their therapeutic use, and how those concerns may be addressed.
