Pharmaceutical Studies Aiming at Nerve Cell Degeneration Repairing and Protecting Agent

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This research project has been performed toward development of nerve cell degeneration repairing and/or protecting agent from novel neurotrophic natural products. The following results have been obtained.(1) Two types of serum-free primary neuronal cultures have been established. Screening natural products by using these cultured neurons nine new neurite outgrowth promoting active substances and six new neuroprotective substances have been found. One of them, in particular, could protect β-amyloid-induced death of neurons.(2) Neurotrophic substance, honokiol, mastigophorenes A and B, and americanol A and isoamericanol A were synthesized by palladium-catalyzed reactions and/or HRP-catalyzed oxidative coupling. On the other hand, synthesis of plagiochin A was succeeded by intramolecular Stille-Kelly reaction. Now, our effort has directed to the synthesis of merrilactone A based on palladium-catalyzed sequential Stille-Heck reaction.(3) Pharmacological studies on honokiol-induced neurite outgrowth promoting activity were carried out by using several inhibitors. As results, RTK and MAPK signal pathway was indicated to be involved in neurite outgrowth mediated by honokiol. Additionally, Fluo 3 imaging analysis of honokiol showed that it can increase cytoplasmic free Ca^<2+> through a PLC-mediated pathway. It is worthy of note that magnolol, a analog of honokiol, could dose-dependently prevent the decrease of density of the CA1 in the hippocampus of senescence-accelerated mice (SAM).