紅麴山藥與中草藥對老年疾病預防之效果

The effect of red mold dioscorea and Chinese herb for elderly people geriatric disease prevention

陳建利(Chien-Li Chen)

指導教授 ： 潘子明

國立臺灣大學/生命科學院/生化科技學系/博士(2014年)

https://doi.org/10.6342/NTU.2014.00713

摘要

隨著生活水準提高與醫療科技的進步，人類的平均壽命延長，伴隨著年齡增長而引發的慢性疾病與老化現象的研究議題逐漸受到國人的重視及探討。本研究以不同模式之代謝症候群老鼠同時給予紅麴山藥及控制血脂、血糖及血壓之藥物，探討是否會引起非預期性效應。在高血脂部份，以敘利亞倉鼠 (Syrian Hamster) 誘導高血脂模式老鼠，實驗結果得知，高膽固醇飲食倉鼠每百克體重餵食紅麴山藥一倍以上劑量可顯著降低血液中膽固醇濃度達 23.3% 以上 (p < 0.05)。以 streptozotocin 誘導並施打 nicotinamide 保護劑，誘導為第二型糖尿病之模式動物。在糖尿病大鼠每公斤體重餵食紅麴山藥 176.0 mg 之一倍以上劑量血液中胰島素含量與糖尿病組相比，可顯著增加 3.0 IU/mL 以上 (p < 0.05)。在糖化血色素方面與糖尿病組相比，則可顯著降低 3.4% 以上 (p < 0.05)。在高血壓部份，以自發性高血壓大鼠為模式老鼠，將紅麴山藥與 amlodipine 併用，以單次餵食紅麴山藥 (176 mg/kg) 顯著降低收縮壓與舒張壓 6.1% 和 7.0% (p<0.05)。在肝、腎功能方面，無論是正常組或是高血脂、糖尿病與高血壓組，在服用紅麴山藥或是紅麴山藥與藥物併用下，對於肝、腎代謝或是生理功能並未造成其負擔且未引發橫紋肌溶解症。
在第二部分，本研究經衛生福利部認可之可供食品使用且文獻曾記載具延緩老化之中藥作為素材，篩選出萃取物具高抗氧化力之中草藥，後續探討開發預防阿茲海默症之保健食品。以 IMR 32 神經細胞為模擬細胞，分析其細胞毒性與抗 Aβ 引起之細胞傷害。由 IMR 32 細胞試驗得知，雷公根與酸棗仁酒精萃取物對細胞不會產生毒性造成細胞凋亡的現象，再以聚集的Aβ1-40 所產生的神經毒素與細胞共培養也具有保護 IMR32 細胞免於受到 Aβ1-40 神經毒性傷害。
針對篩選出抗 Aβ 毒性之雷公根與酸棗仁兩種中草藥萃取物，以 8 週大之Sprague-Daw1ey 系雄性大鼠為模式動物，應用腦部手術以 ALZET 腦部輸注幫浦在大鼠腦部海馬迴處連續輸注類澱粉樣蛋白 (amyloid β-peptide, Aβ)，造成其在腦部沉積並破壞海馬迴組織，誘導大鼠產生阿茲海默症 (Alzheimer’s disease, AD)。除此之外，由本研究室先前利用傳統變異法篩選得到 Monascus purpureus NTU 568 之紅麴菌株，其以紅麴米發酵之產物經研究證實對阿茲海默症危險因子具改善作用，且已發表多篇期刊論文證實以山藥當基質之紅麴發酵物具改善數種氧化壓力及發炎反應相關代謝症候群疾病的能力，推測此菌株發酵生產之紅麴山藥對Aβ 腦部輸注之阿茲海默症大鼠記憶學習能力應具改善潛力，因此與篩選出之中藥一併進行各項試驗。經過連續餵飼 28 天酸棗仁、雷公根萃取物或紅麴山藥在記憶學習和行為能力皆有改善現象，達到延緩衰老之功效。實驗動物犧牲後分析血液中脂質含量、肝、腎功能和電解質均無顯著差異。再分析腦部海馬迴組織中連續輸注類澱粉樣蛋白會增加乙醯膽鹼酯酶活性和氧化壓力傷害，降低總抗氧化能力。由動物記憶、行為試驗和血液安全性與功效性指標實驗與分析結果得知，酸棗仁、雷公根萃取物與紅麴山藥，在科學性的多方試驗下，對於以 Aβ 誘導之阿茲海默症大鼠確實能減緩阿茲海默症產生的失憶，提供更充分的證據證實其功效，在治療上或許能達到輔助效果。未來將以此優勢開發多效性之延緩老化保健食品。

關鍵字

紅麴山藥 ； 酸棗仁 ； 雷公根 ； 阿茲海默症 ； 延緩老化

並列摘要

With improvements in living conditions and advances in medical technologies, humans are living longer. Aging puts people at a greater risk for health issues, metabolic syndrome and chronic diseases related to aging have an impact on society as a whole. The aging related issues have brought great attention to the world and have been discussed extensively.
In this study, we aimed to investigate the effects of interaction of red mold dioscorea (RMD), which has long been considered a food product, with medicines in different animal models of metabolic syndrome. Results obtained from hyperlipidemia groups indicated that the blood cholesterol levels in groups that feeding RMD more than 22.96 mg/100 g hamster were significantly decreased by 23.3% (p < 0.05). Rat models of streptozotocin (STZ)-induced type II diabetes were established. These animals were divided into groups that feeding RMD more than 176 mg/kg rat the insulin concentrations were increased significantly up to 3.0 IU/mL (p < 0.05). Furthermore, in glycated hemoglobin significant decreases 3.4% (p < 0.05). Further, we used RMD with amlodipine to investigate RMD’s effect on the anti-hypertension effect of amlodipine in a rat model of spontaneous hypertension. The results indicated that a single oral dose of RMD (176 mg/kg) administered over an 8-h period significantly (p < 0.05) decreased systolic blood pressure (SBP) and diastolic blood pressure (DBP) by 6.1% and 7.0%, respectively. No change in heart rate was observed. We did not observe rhabdomyolysis, a potentially dangerous side effect of statin drugs, in any experiments with animal models of metabolic syndrome. Furthermore, no animal exhibited signs of liver or kidney dysfunction.
In the second part, we aimed to develop functional foods by using Chinese herbs to counteract the effects of Alzheimer’s disease (AD). For this purpose, extracts of the Chinese herbs Rosa rugosa, Crataegus pinnatifida, Centella asiatica, and Semen Zizyphi spinosae were selected from their high antioxidant activity. In the aggregated Aβ1-40 neurotoxin model of IMR 32 cells, we found that Centella asiatica and the Semen Zizyphi spinosae ethanol extract had lower cell toxicity and protected IMR 32 cells from aggregation of the neurotoxic Aβ1-40 peptide.
We established an animal model of AD by continuously injecting Aβ into the hippocampus of SD rats by using an ALZET brain infusion pump. Groups fed Centella asiatica, Semen Zizyphi spinosae ethanol extract, or RMD demonstrated slight improvements in learning and memory capacity. After the animals were sacrificed, serum biochemical analyses for liver function, renal function, and electrolyte balance were performed. No changes were observed in any of these parameters. Serum and hippocampus samples were collected to examine AD risk factors. Aβ40 infusion increased acetylcholinesterase activity and decreased total antioxidant status and superoxide dismutase activity in the brain; however, these damages were potently reversed upon administration of Centella asiatica, Semen Zizyphi spinosae ethanol extract, or RMD. Moreover, the protection afforded by these herbs was more significant than that afforded by cholinesterase inhibitor drugs.
In conclusion, our study provides further efficacy data in support of traditional functional foods for the treatment of diseases. We found that Centella asiatica, Semen Zizyphi spinosae, and RMD inhibit Aβ-induced neurotoxicity and may play a role in preventing the deleterious effects associated with AD. On the basis of these findings, we recommend the development of functional foods for therapy or as adjuvant agents for the prevention of AD.

並列關鍵字

red mold dioscorea ； Semen Zizyphi spinosae ； Centella asiatica ； Alzheimer’s disease ； ageing delaying

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