熱孜亞·艾買提(綜述),祖麗菲亞·吾斯曼,努爾買買提·艾買提(審校)
(新疆醫(yī)科大學維吾爾醫(yī)學院,烏魯木齊 830011)
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分子生物醫(yī)學
天然多酚類抗氧化成分及治療阿爾茨海默病的潛力
熱孜亞·艾買提△(綜述),祖麗菲亞·吾斯曼,努爾買買提·艾買提※(審校)
(新疆醫(yī)科大學維吾爾醫(yī)學院,烏魯木齊 830011)
摘要:阿爾茨海默病(AD)是最常見的神經(jīng)退行性疾病,到目前為止,尚未有一個明確的方法可以控制其發(fā)展。氧化應激是該疾病的主要標志,并認為是AD的治療目標。飲食中所包含的天然多酚類化合物的神經(jīng)保護作用是通過消除自由基和增強抗氧化能力來實現(xiàn)的。此外,天然多酚類化合物通過刺激轉錄,能加速抗氧化系統(tǒng)。該文綜述了AD患者大腦中氧化應激反應的原因,并闡述了天然多酚類化合物對AD患者的神經(jīng)保護作用及其潛在的治療作用。
關鍵詞:阿爾茨海默病;多酚類;抗氧化劑;治療
阿爾茨海默病(Alzheimer′s disease,AD)是常見而尚未有明確治愈方法的神經(jīng)系統(tǒng)退行性疾病。AD發(fā)病機制可能涉及多種病理因素,但AD神經(jīng)變性潛在的機制現(xiàn)仍未被闡明。氧化應激是AD的主要標志,增加的氧化應激會導致包括DNA、RNA、脂質、核酸在內(nèi)的物質氧化以及有輕微的意識障礙[1]。在AD患者大腦中,線粒體功能障礙可使活性氧物種的釋放加劇[2]。在金屬離子存在的情況下,淀粉樣肽能產(chǎn)生自由基[3]。在輕度意識障礙患者大腦中,氮氧化物的活動性也是增加的[4-5]。膠質細胞活化是AD和輕度意識障礙的特點[6]。天然多酚類具有抗氧化作用,可有效減輕意識障礙和β-樣淀粉樣肽的病理損傷[7]。與藥物治療相比,天然多酚可能作為一種潛在的治療和預防AD的策略?,F(xiàn)就天然多酚類化合物對AD患者神經(jīng)保護作用的研究進展予以綜述。
1天然多酚類物質
天然多酚類化合物多存在于植物、水果、蔬菜、油、紅酒和茶類中,而黃酮類是其最大的組成部分,結構中含有羥基、甲氧基和糖基化,這些結構能有效影響天然多酚類化合物的化學、物理和生物學特性[7]。天然多酚類化合物通過消滅自由基或激活內(nèi)源性抗氧化能力而起到神經(jīng)保護作用;此外,其還能通過激活Nrf/ARE通路(氧化和化學應激的防御性轉導通路)來刺激合成的內(nèi)源性抗氧化劑分子[8]。除了抗氧化功能之外,這些化合物都有一些不同的目標分子,通過若干個信號通路,在細胞上呈現(xiàn)多種生物活性[如多酚可調節(jié)核因子κB 或sirtuin type 1(SIRT1)的活性]而發(fā)揮保護作用[9]。
2天然多酚類對AD患者的有益作用
2.1綠茶中的多酚類化合物綠茶含有多種生物活性物質,尤其富含黃酮類化合物(包括兒茶素及其衍生物);綠茶的其他化合物還包括黃酮醇(槲皮素、山奈酚和蘆丁)、咖啡因、酚酸類物質、茶氨酸等[10]。綠茶中的兒茶素和茶多酚通過螯合金屬離子發(fā)揮其抗氧化作用(如釋放鐵離子和鈣離子),并且通過芬頓反應防止羥基自由基的生成;該化合物也能轉移電子到DNA活性氧類誘導的自由基位點,防止DNA的氧化修飾[11]。應用綠茶治療能保護蛋白質和脂類被氧化,能降低年老老鼠海馬神經(jīng)內(nèi)的脂褐質沉積;綠茶治療的老鼠更具備一些特殊的學習能力[12]。茶多酚作為從綠茶中提取出的主要化合物,能修復β-淀粉樣蛋白引起的神經(jīng)損傷[13]。這種有益效應也許歸因于抑制核因子κB通道。茶多酚還能消除β-淀粉樣蛋白引起的氧化應激力,減少老鼠大腦內(nèi)的海馬脂質過氧化[14]。觀察發(fā)現(xiàn),茶多酚能恢復線粒體的功能,替代神經(jīng)保護的機制[15]。研究指出,綠茶中多酚類的神經(jīng)保護作用部分歸因于超氧化物歧化酶和過氧化氫酶等保護性酶;同時人類流行病學和動物研究也表明,綠茶飲食與出現(xiàn)癡呆的頻率呈反比[16]。
2.2木蘭中所提取的多酚類化合物在中國和日本用木蘭做多種傳統(tǒng)的中藥制劑[17]。木蘭提取物雙苯酚結構中的新木脂素包括厚樸酚,而厚樸酚和4-O-甲基是木蘭類多種藥物效應的相關研究核心;木蘭提取物能防止神經(jīng)性損傷的發(fā)展,且通過抗氧化機制能防止毒物的攻擊[18-19]。厚樸酚類能防止神經(jīng)元受到過氧化氫、谷氨酸和N-甲基-D-天冬氨酸所誘導的毒性作用,而其抗氧化物成分有利于神經(jīng)保護[19]。此外,厚樸酚類還能衰減β-淀粉樣蛋白誘導PC12(大鼠腎上腺髓質嗜鉻細胞瘤分化細胞株)細胞凋亡[20]。這類化合物的神經(jīng)保護作用是通過減少ROS的生成,抑制細胞內(nèi)鈣的升高和胱天蛋白酶3的活性來完成的;口服厚樸酚可恢復小鼠總谷胱甘肽的水平,降低大腦內(nèi)的氧化應激[18];可預防與年齡有關的學習和記憶減退及衰老加速的老鼠體內(nèi)膽堿的缺乏[21]。研究表明,厚樸還有抗炎和抗氧化性能,這與避免神經(jīng)性炎癥與氧化應激等神經(jīng)保護作用有關[15]。4-O-甲基的藥物效應不僅能抗氧化和激活細胞外調節(jié)蛋白激酶(ERK)通道,還能抑制核因子κB通道,以減輕神經(jīng)性炎癥和β-淀粉樣蛋白的負擔[22]。目前,木蘭提取物作為商品能較易獲得,并且把這種化合物用在AD患者身上,觀察化合物對該類患者是否有效,是相對安全的[23]。
2.3藍莓中所提取的多酚類化合物藍莓含有多種多酚類化合物(包括類黃酮),兒茶素是其含有的主要類黃酮類,抗氧化能力很強[24]。體外實驗研究表明,藍莓提取物具有抗氧化和抗炎特性,可起神經(jīng)保護作用[25]。研究發(fā)現(xiàn),藍莓對β-淀粉樣蛋白誘導的神經(jīng)毒性起的神經(jīng)保護作用與谷胱甘肽的氧化還原緩沖作用相關;藍莓提取物還能抑制脂多糖誘導的炎癥反應[26]。藍莓提取物能恢復APP/PS1轉基因和非轉基因小鼠的認知功能[27],還可阻止β-淀粉樣蛋白的聚集[28],并可改善老年大鼠的空間工作記憶,這與ERK1/2的增加密切相關[29]。飲食藍莓類能改善老年老鼠額葉皮質、海馬和紋狀體,改善與年齡有關的核因子κB的表達[30]。由此得出結論,藍莓類的神經(jīng)保護效應與其激活相應通道、消除自由基、激活相關的保護信號、抑制應急信號等有關[31]。
2.4銀杏葉中所提取的多酚類化合物銀杏葉提取物包含24%的黃酮類和6%的萜烯類化合物,這種組成比例特點有其獨特的藥理作用[7]。體外研究表明,銀杏葉提取物能清除一氧化氮、羥基自由基、超氧陰離子和過氧自由基等[32]。銀杏葉提取物通過抑制β-淀粉樣蛋白纖維的形成而保護細胞免受毒性[33],其還可保護線粒體,抑制過氧化氫和β-淀粉樣蛋白的毒性[34],改善Tg2576鼠空間學習和記憶能力[35]。長期用銀杏葉提取物治療的Tg2576鼠皮層控制與對照組相比除了海馬之外,β-淀粉前體蛋白(β-Amyloid precursor protein,APP)的水平降低了約50%[36]。銀杏葉提取物無需通過修改APP的形式或α-分泌表達而刺激釋放APP(非淀粉樣過程),表明其可能參與認知增強過程[37]。銀杏葉提取物的生物效應可能與其有效成分調節(jié)蛋白質表達有關,例如:銀杏葉提取物類黃酮和萜類等成分會降低誘導型一氧化氮合酶的表達[38],其還能降低β-淀粉樣蛋白介導的核因子κB的活化[33]。文獻報道,銀杏內(nèi)酯是抗血小板活化因子的強有力拮抗劑,這種作用與其神經(jīng)保護作用有關[39]。
2.5葡萄中所提取的多酚類化合物葡萄的產(chǎn)物包括葡萄酒、葡萄籽、葡萄皮[40]。與葡萄皮相比,葡萄籽含有高濃度的單體、低聚物和聚合物黃烷-3-醇類;每克葡萄籽提取物中含有592.5 kg干重的總多酚含量(包含沒食子酸、兒茶素、表兒茶素和原花青素等);葡萄皮原花青素比葡萄籽提取物含有較高的聚合物[41]。葡萄多酚組成成分和含量在不同的葡萄榨汁也是不同的,紫葡萄汁含單個酚類化合物的量最高,并總酚濃度最高[40]。紫葡萄汁的主要成分是黃烷-3-醇、花青素和羥基肉桂[42]。紅葡萄酒的活性成分是白藜蘆醇,是一種天然的植物抗毒素,主要來源于葡萄皮[40]。白葡萄榨汁含有羥基苯乙烯,總酚類量含量最低[43],而總酚類含量和抗氧化活性密切相關[40]。最近有研究指出,葡萄籽提取物能防止AD疾病模型小鼠的認知功能破壞;老鼠口服葡萄籽提取物能改善AD型認知功能,并降低大腦中低聚β-淀粉樣蛋白的水平[7]。葡萄籽提取物中的多酚類可抑制β-淀粉樣蛋白的自我組裝及細胞毒性[44]。用葡萄籽多酚類提取物飼養(yǎng)的APP(SWE)/PS1dE9轉基因小鼠大腦和血清中的β-淀粉樣蛋白水平分別減少了33%和44%;多酚提取物能降低淀粉樣斑塊形成和小膠質細胞活化水平,分別為49%和70%[41]。一項藥代動力學研究表明,用14C標記的飲食葡萄多酚類能達到大腦內(nèi),說明其可能適用于治療神經(jīng)退行性疾病[45]。然而,另一項研究指出,葡萄籽多酚提取物口服之前在大腦內(nèi)的兒茶素、表兒茶素不能被檢測到[46]。白藜蘆醇是一種葡萄和紅葡萄酒中的非類黃酮多酚類化合物,并具有廣泛的生物活性和藥理活性(包括抗氧化、抗炎、抗突變、抗癌等作用)[7]。其抗氧化性能對幾種不同的氧化損傷起神經(jīng)保護作用,如白藜蘆醇顯著降低β-淀粉樣蛋白誘導的活性氧中間體在細胞內(nèi)的累積和PC12細胞凋亡[47]。白藜蘆醇治療APP轉基因Tg19959型老鼠,減少了淀粉樣蛋白的形成,而上述均不會影響APP水平[48]。與研究相一致,側腦室注射白藜蘆醇可減少海馬中的神經(jīng)退行性疾病并可改善P25基因誘導的轉基因小鼠(AD模型體)的學習功能障礙[47]。于轉基因小鼠海馬體內(nèi)注射SIRT1,證實了SIRT1誘導的神經(jīng)保護作用[49]。SIRT1抑制劑似乎也能起神經(jīng)保護作用。
2.6植物中提取的姜黃素姜黃素是一種多酚類化合物,具有抗氧化、降血脂、抗腫瘤等多種生物活性。近年來,姜黃素對AD中β-淀粉樣蛋白誘導的神經(jīng)毒性保護作用已引起越來越多的重視。姜黃素通過抑制β-淀粉樣蛋白的生成、Tau蛋白的過度磷酸化和神經(jīng)細胞的凋亡,螯合腦組織中金屬離子、抑制胞內(nèi)鈣離子水平和抗炎、抗氧化等方式對AD誘導的神經(jīng)毒性起保護作用;姜黃素的作用方式具有多靶向、多途徑的特點,且自身毒性極小[50]。
3小結
天然多酚類化合物在治療AD的領域里起重要作用。多酚類化合物是否可影響到新的靶點,值得深入研究。作為一種藥物,天然化合物的生物利用度是一個關鍵的考慮因素。目前缺乏相關多酚類的藥動學數(shù)據(jù),希望通過更透徹的研究及分析,能研發(fā)出更有效、更安全的藥物。這將為AD等神經(jīng)退行性疾病的預防及臨床治療帶來新的突破。
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The Natural Phenolic Antioxidant Components and Its Potential in Treatment of Alzheimer DiseaseRaziyaAmat,ZulpiyaOsman,NurmuhammaAmat.(TraditionalUighurMedicineInstitute,XinjiangMedicalUniversity,Urumqi830011,China)
Abstract:Alzheimer disease (AD) is the most prevalent neurodegenerative disease.However,there is no known way to halt or cure the neurodegenerative disease.Oxidative stress is a main hallmark of the disease and has been considered as the therapeutic target for AD treatment.Dietary polyphenolic compounds exhibit neuroprotective effects through scavenging free radicals and increasing antioxidant capacity.Furthermore,they could facilitate the endogenous antioxidant system by stimulating transcription.Here is to make a review of the causes of oxidative stress in AD patients′ brains,and describe antioxidant neuroprotective effects and therapeutic potential of natural polyphenolic compounds for AD.
Key words:Alzheimer disease; Polyphenols; Antioxidant; Treatment
收稿日期:2014-05-28修回日期:2014-10-08編輯:鄭雪
基金項目:國家自然科學基金 (81260565);教育部新世紀優(yōu)秀人才支持計劃項目(NCET-11-1073);烏魯木齊市科技局科技計劃項目(H121323001)
doi:10.3969/j.issn.1006-2084.2015.09.001
中圖分類號:R741.05
文獻標識碼:A
文章編號:1006-2084(2015)09-1537-04