呂國棟博士Kwok-Tung Lu蘇雅雯Ya-Wen Su2019-09-052005-2-252019-09-052005http://etds.lib.ntnu.edu.tw/cgi-bin/gs32/gsweb.cgi?o=dstdcdr&s=id=%22N2005000149%22.&%22.id.&http://rportal.lib.ntnu.edu.tw:80/handle/20.500.12235/104461人類利用植物治療疾病的歷史相當久遠。遠在五千年前，銀杏的功 效即被記載於「神農本草經」；另外中國著名的藥物著作「本草綱目」 亦有相關記載。近年來銀杏葉萃取物EGb761 更是引起西方國家的高度 關注，目前許多相關研究指出，銀杏萃取物EGb761 可用以改善年老人 的疾病，例如：暈眩、注意力喪失和失智等，具有影響神經內分泌機制 進而改善認知功能等功效。另外，EGb761 其中ginkgolides 和bilobalide 的 成分則為血小板活化因子(platelet-activating factor, PAF)之拮抗劑可改善血 小板凝集，用於治療哮喘、腦栓塞及心肌梗塞等心腦血管疾病。近來更 有研究報導指出，銀杏萃取物EGb761 具有促進認知(cognitive enhancer)和 緩衝壓力(anti-stress buffer)的功能。 本實驗利用恐懼所促進之動物驚跳反應(fear-potentiated startle)模式， 來研究銀杏萃取物EGb761 對於條件化恐懼學習四個不同階段之生理生 化影響。根據前人所提出之條件化恐懼實驗操作，在四種不同時間點給 予藥物或破壞腦區，分別代表動物在學習條件化恐懼之不同階段表現， 包括對新恐懼記憶的獲取(acquisition)、固化(consolidation)、表現(expression) 及消減(extinction)等。因此本實驗於特定的學習時間點，施以不同濃度的 藥物處理，從實驗結果顯示，銀杏萃取物EGb761 在條件化恐懼模式中， 於不同階段有不同的影響，EGb761 之投予能促進恐懼記憶之獲取和消減 作用；然則對於固化和表現作用則無顯著影響。 另外，前人的研究亦指出，杏仁核中的麩胺酸NMDA 型接受器和條 件化恐懼的消減作用有關，並且麩胺酸NMDA 型接受器拮抗劑對於消減 作用之拮抗需經過蛋白激MAP kinase 之活化。由本實驗的結果亦發 現，無論是周邊的腹腔給予麩胺酸NMDA 型接受器拮抗劑MK-801 或是 於中樞的杏仁核給予MAPK 磷酸化抑制劑U0126 都能有效拮抗EGb761 所促進之消減作用，而且杏仁核區之MAPK 磷酸化表現增加。因此，由 本研究一系列實驗結果推知，EGb761 會透過活化NMDA 接受器及增加 MAPK 的磷酸化，進而調控動物於條件化恐懼之消減作用。 最後，本實驗藉由銀杏萃取物EGb761 此認知功能促進劑來進行研 究，盼能使我們對於其在恐懼記憶形成的相關機轉有所瞭解，進而在消 除恐懼記憶的實驗中有所突破，使銀杏萃取物在開發及臨床上對於恐懼 失調的治療有更多的貢獻及應用。The leaves of the Ginkgo biloba have been cultivated for their medicinal properties for several thousands years. It has been used in the treatment of various common geriatric complaints including vertigo, short-term memory loss, hearing loss, lack of attention or vigilance. It is also applied for the treatment of cerebral vascular disorder. Recent results suggest that it can serve as a cognitive enhancer and anti-stress buffer. It raises a possibility that the extract of ginkgo biloba may have effects on the fear conditioning. In this study, we used fear potentiated startle to evaluate the possible effect of Ginkgo biloba extracts on the different stages of fear conditioning. Briefly, EGb761, a standard extract of Ginkgo biloba was administrated to the male Sprague- Dawley rats during acquisition、consolidation、expression or extinction stages of fear conditioning. Results shown that administration of EGb761 30 min prior to the conditioning facilitated acquisition and extinction of conditioned fear. No significant differences between control group and EGb761 treated group had been observed in either consolidation or expression of conditioned fear. The above findings indicate that NMDA receptors within the amygdala play an important role in conditioned fear extinction. NMDA antagonists block extinction via activation MAP kinase. Our data show that the effect of EGb761 was blocked by the MAPK/ERK inhibitors either systemic administration or intra-amygdala infusion. Therefore, these results indicate that the effect on extinction of EGb761 is mediated by actions at the MAPK pathway. Finally, these results point to the potential utility of using EGb761, Ginkgo biloba extract as adjunct pharmacological tools in the treatment of fear disorders.