開發中草藥純物質AG/RT作為預防或治療阿茲海默症中拮抗麩胺酸受體及相關分子之新穎藥物

Extracellular β amyloid peptide (Aβ)-containing neuritic plaques and intracellular phospho-tau-positive neurofibrillary tangle are two hallmark lesions in Alzheimer’s disease (AD). Recently, some clinical trials agents which are γ-secretase inhibitors, β secretase inhibitors, and monoclonal antibodies all targeting amyloid production and/or plaques are failed in phase III. It is reasonable to re-think the amyloid hypothesis. However, a number of evidences have showed Aβ oligomers indeed induced neuronal death. The mechanism mediates an increase of glutamate concentration by which it binds receptors such as NMDA receptors and AMPA receptors at the synaptic cleft and subsequently trigger excitotoxicity. Moreover, memantine, the synthetic NMDA receptor antagonist, had been the only one developed to clinical use for treat mild to severe AD patients. Accordingly, the strategies which search for the substance ameliorating Aβ oligomer-induced pathophysiology shall still sustain. We aim to develop new drugs which could have the effect on alleviating the Aβ-induced pathophysiology in the plan. This final report contains four chapters. First of all, ginkgolide A (GA), a pure compound extracted from Ginkgo biloba, was found to attenuate Aβ-induced abnormal depolarization in mouse primary cortical neurons. GA inhibits both NMDA receptors and AMPA receptors. The Aβ-induced increase in c-Jun N-terminal kinase phosphorylation in neurons was prevented by GA. Furthermore, when the pure compound was tested on wildtype/J20 animal model mice, GA improves the memory of wild-type mice, but not the J20 mice. The discrepancy remains to be further investigated. Secondly, AD has been linked to the dysregulation of nutrients. We have been studying AD by searching for the medicine and/or diet therapy. Interestingly, we found that three-weeks old mice injected with ceramides or mineral oil for a month, followed by fed with normal chow or high fat diet show no significant differences on mice's body weight and blood glucose between ceramides treatment and control. However, the groups injected with ceramides could promote the memory in ether diet these mice were given. The molecular mechanism is under investigation. Third, rutin (RT), a pure compound also extracted from Ginkgo biloba, is able to ameliorate Aβ-induced depolarization in which this effect mediates NMDA receptors, but not AMPA receptors. The study of signaling mechanism is underway. Forth, we are trying to establish a novel drug screening platform by using mouse embryonic stem cells-differentiated glutamatergic neurons. Currently, we found that these neurons can response to KCl treatment. The result of these neurons response to memantine with or without Aβ is testing. Taken together, GA is a candidate for further drug development to treat for AD. Moreover, this compound might be with great potential to target the NMDA receptors in AD patients in addition to memantine. Ceramides given at childhood might enhance the memory behavior during the adulthood. In addition to GA, RT could be used as NMDA receptor antagonist. After our study, both GA and RT greatly become hopeful therapeutic drugs for treatment of AD patients.