This proposal is focused on the mode of action of the ginkgolides and bilobalide (terpenoid trilactones) from the tree Ginkgo biloba. The crude extract of G. biloba, a complex mixture composed of many different compounds, have shown effects on the diseased as well as healthy state of the mammalian brain. Clinical studies, animal studies, and various in vitro studies of the extracts have demonstrated beneficial effects against various neurodegenerative diseases, particularly Alzheimer's disease, as well as memory enhancing effects in the normal brain. However, very little is known about effects of individual constituents, especially at the molecular structural level. In this proposal, we will focus on the most unique constituents of the Ginkgo biloba extract, the ginkgolides and bilobalide, but not on the action of the crude extract which clearly involves synergistic effects, e.g., between the flavonoids (a major component) and the terpenoid trilactones. Some ginkgolides are antagonists of the platelet-activating factor receptor (PAFR), and appear to have antioxidant and neuroprotective properties. We have also found that ginkgolide B is a glycine receptor antagonist, while bilobalide is a potent GABAA receptor antagonist. Our goal is to determine the neuromodulatory effects of terpene trilactones on the mammalian central nervous system, using bioorganic and spectroscopic methods, including those under development in our laboratory on a molecular level. The specific topics to be studied include synthesis of radiotracers for positron emission tomography (PET) and ex vivo autoradiography studies, design and preparation of novel photolabile and fluorescent terpene trilactones analogs to be used to elucidate the interactions of terpene trilactones and PAFR. During these studies we will develop and apply novel methodologies such as ultra-microscale photolabeling and sequencing using unconventional mass spectrometric and circular dichroic techniques, as well as """"""""membrane scissors"""""""". Using radioligand binding and microphysiometry, we will initiate studies on the effects of terpene trilactones on the cloned PAFR, using PAFR expressed in Chinese hamster ovary cells. The effects of terpene trilactones on long-term potentiation will be examined in vitro as well as in animal models. These studies can potentially provide new targets for terpene trilactones in the central nervous system that require the synthesis of new ginkgolide and bilobalide ligands. ? ?
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