Neurotrophic actions of novel compounds designed from cyclopentenone prostaglandins

Previously we found that some cyclopentenone prostaglandin derivatives prom oted neurite outgrowth from PC12 cells and dorsal root ganglia explants in the presence of nerve growth factor; and so we, referred to them as neurite outgrowth-promoting prostaglandins (NEPPs). In this study, NEPPs protected HT22 cells against oxidative glutamate toxicity. NEPPG, one of the most ef fective promoters of neurite outgrowth in PC12 cells, protected the cells m ost potently among NEPPs 1-10. Several derivatives, NEPPs 11-19, were newly synthesized based on the chemical structure of NEPPG. NEPP11 had a more po tent neuroprotective effect than NEPPG. NEPP11 also prevented the death of cortical neurons induced by various stimuli and reduced ischemic brain dama ge in mice. Biotinylated compounds of NEPPs were synthesized to investigate their cellular accumulation. NEPPG-biotin protected the cells and emitted potent signals from the cells. In contrast, biotinylated non-neuroprotectiv e derivatives emitted much weaker signals. These results suggest that NEPPs are novel types of neurotrophic compounds characterized by their dual biol ogical activities of promoting neurite outgrowth and preventing neuronal de ath and that their accumulation in the cells is closely associated with the ir neuroprotective actions.