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研究生(外文):Sheng-Yun Wang
論文名稱(外文):Study on The Anti-amnesic Effects of Baicalein
指導教授(外文):Jyh-Fei Liao
外文關鍵詞:BaicaleinAlzheimer''''s diseaseLearning and memoryBeta amyloidStep-through passive avoidance test
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Baicalein 被報導在體外試驗中可有效保護培養之大鼠初級大腦皮質神經細胞受 b-amyloid peptide-(25-35) 之神經毒性傷害。為了研究 baicalein在體內是否有類似之作用,本研究以被動逃避行為試驗來探討baicalein 對於側腦室注射3 nmol b-amyloid peptide-(25-35) 引致 ICR 小鼠學習與記憶障礙之影響。因為先前研究發現,baicalein 可能作用在 GABAA 受器上的 benzodiazepine 結合處而在小鼠具有抗焦慮的作用,又benzodiazepine 藥物會產生失憶的副作用,所以本研究首先檢驗 baicalein 對於學習與記憶之影響。結果顯示與腹腔注射 benzodiazepine 藥物chlordiazepoxide (10 mg/kg) 不同,baicalein在訓練前 30 分鐘給予10-100 mg/kg 並不會產生失憶現象,並且 baicalein (10 mg/kg, i.p.) 在訓練前 30分鐘、訓練後立即、或測試前 30 分鐘給予,對於 scopolamine 或 b-amyloid peptide-(25-35) 所引致的失憶作用亦無改善的情形,顯示baicalein 對學習與記憶亦無促進作用。然而,如在 b-amyloid peptide-(25-35) 注射前 30 分鐘預處理單劑量baicalein (5 或 10 mg/kg, i.p.) 則可減弱 b-amyloid peptide-(25-35) 引致之失憶現象,但如在 b-amyloid peptide-(25-35) 注射後第 3 天或第 8 天給予baicalein則無此效果。如在 b-amyloid peptide-(25-35) 注射後第2天起連續每天給予baicalein (10 或 15 mg/kg, i.p.) 共7天或13天則可減弱 b-amyloid peptide-(25-35) 引致之失憶現象。同樣地連續多劑量給予而不是單劑量給予抗氧化劑 melatonin (10 mg/kg, i.p.) 亦有相似效果。此外,如以高鉀溶液刺激海馬迴切片乙醯膽鹼 (ACh) 釋放之程度當作海馬迴cholinergic 神經活性之指標,本研究發現在側腦室注射 b-amyloid peptide-(25-35) 後第十六天,海馬迴組織之cholinergic 神經活性會降低而脂質過氧化會增加。經連續後處理 baicalein 七天而明顯改善學習與記憶之小鼠,其海馬迴組織之 cholinergic 神經活性及脂質過氧化均被改善,但是預處理 baicalein者雖可改善學習與記憶障礙及海馬迴組織之 cholinergic 神經活性,卻無法改善脂質過氧化。造成此差異性之原因未明。綜合上述結果,本研究首度闡示 baicalein 在小鼠無促進學習與記憶之作用,但可預防或減緩b-amyloid peptide-(25-35) 對神經細胞所造成的傷害及產生學習與記憶的障礙,其作用機轉可能部份與 baicalein 之抗氧化作用有關。
Baicalein has been reported to protect cultured rat cortical neurons from b-amyloid peptide-(25-35)-induced toxicity in vitro. To study whether it has similar effect in vivo, the present study examined the effects of baicalein on b-amyloid peptide-(25-35) (3 nmol/mouse, i.c.v.)-induced impairment of learning and memory in ICR mice using the step-through passive avoidance test. Since baicalein may act on the benzodiazepine binding site of GABAA receptor to exert anxiolytic-like effect in mice as demonstrated in our previous study and benzodiazepine drugs have amnesic side-effect, this study first examined the effect of baicalein on learning and memory. Unlike the benzodiazepine drug chlordiazepoxide (10 mg/kg, i.p.), the results showed that baicalein (10-100 mg/kg, i.p.) had no significant amnesic effect when administered 30 min before the training trial. Furthermore, baicalein (10 mg/kg, i.p.) also had no significant effects on scopolamine (1 mg/kg, i.p.)- and b-amyloid peptide-(25-35)-induced amnesia, when administered 30 min before or immediately after the training trial, or 30 min before the retention test, indicating no facilitating effect on learning and memory. However, one dosage of baicalein (5 or 10 mg/kg, i.p.) attenuated b-amyloid peptide-(25-35)-induced amnesia when administered 30 min before but not on day 3 or day 8 after i.c.v b-amyloid peptide-(25-35) administration (as day 1). Baicalein (10 or 15 mg/kg, i.p.) also attenuated b-amyloid peptide-(25-35)-induced amnesia when administered once per day for 7 days or 13 days from day 2 after i.c.v. administration of b-amyloid peptide-(25-35). Similar results were obtained for an antioxidant melatonin (10 mg/kg, i.p.) when it was post-treated with multiple dosages but not single dosage. In addition, the present study also found a decrease in the cholinergic activity (using the extent of high K+-stimulated release of acetylcholine from hippocampal slices as an index) and an increase in the lipid peroxidation in the hippocampal tissues on day 16 after i.c.v. administration of b-amyloid peptide-(25-35). Post-treatment with baicalein for 7 days improved the learning and memory, cholinergic activity, and lipid peroxidation. In contrast, pretreatment with baicalein improved the learning and memory, cholinergic activity, but not lipid peroxidation. The reason for this discrepancy is unclear. In summary, the present study demonstrated for the first time that baicalein has no facilitating effect on the learning and memory, but has preventive or protective effect on b-amyloid peptide-(25-35)-induced neurotoxicity and impairment of learning and memory in mice. The action mechanism of baicalein may partially attribute to its antioxidant effect.
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