王丹丹,耿　越

(山東省動(dòng)物抗性生物學(xué)重點(diǎn)實(shí)驗(yàn)室,山東師范大學(xué)生命科學(xué)學(xué)院,山東濟(jì)南 250014)

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食源性植物化學(xué)物在防治神經(jīng)退行性疾病中的研究進(jìn)展

王丹丹,耿越*

(山東省動(dòng)物抗性生物學(xué)重點(diǎn)實(shí)驗(yàn)室,山東師范大學(xué)生命科學(xué)學(xué)院,山東濟(jì)南 250014)

神經(jīng)退行性疾病是一種由于大腦和脊髓細(xì)胞神經(jīng)元及其髓鞘喪失而導(dǎo)致的神經(jīng)元功能障礙的狀態(tài)。研究表明,一些食源性植物化學(xué)物如白藜蘆醇、原花青素、人參皂苷具有抗氧化、抗脂質(zhì)過氧化、神經(jīng)保護(hù)等作用,對神經(jīng)退行性疾病的防治有一定作用。本文就一些常見的、易于獲得的食源性植物化學(xué)物對神經(jīng)退行性疾病的保護(hù)作用的研究進(jìn)展作一綜述。

食源性植物化學(xué)物,天然,神經(jīng)退行性疾病,氧化應(yīng)激

神經(jīng)退行性疾病(neurodegenerative diseases,NDs),是一種由于大腦和脊髓細(xì)胞神經(jīng)元及其髓鞘喪失而導(dǎo)致神經(jīng)元功能障礙的疾病狀態(tài)。該病按表型主要分為兩大類,一類是與影響記憶有關(guān)的病癥,如阿爾茨海默病(alzheimer disease,AD)等,主要表現(xiàn)為記憶減退和認(rèn)知失調(diào)[1];另一類則會(huì)影響運(yùn)動(dòng)功能,如帕金森氏病(parkinson’s disease,PD)、肌萎縮性脊髓側(cè)索硬化癥(amyotrophic lateral sclerosis,ALS)、亨廷頓氏舞蹈病(huntington’s disease,HD)、中風(fēng)(stroke)等,主要表現(xiàn)為運(yùn)動(dòng)遲緩、靜止性震顫等[2],這嚴(yán)重影響人們的健康和生活。本文對一些天然的食源性植物化學(xué)物對神經(jīng)退行性疾病的防治作用的研究進(jìn)展進(jìn)行論述。

1　食源性植物化學(xué)物

植物化學(xué)物是植物的次級代謝物,是一類經(jīng)過合成或降解后產(chǎn)生不再對代謝過程起作用的化合物的總稱。按照不同化學(xué)結(jié)構(gòu)和功能特點(diǎn),植物化學(xué)物可分為多酚、皂苷、萜類、類胡蘿卜素、有機(jī)硫化物、植物固醇、植物雌激素、芥子油苷及蛋白酶抑制劑等。植物化學(xué)物具有促進(jìn)機(jī)體健康的特性,如抗氧化、抗炎、神經(jīng)保護(hù)作用等[3]。食源性植物化學(xué)物可從常見的食物中獲取,具有天然、無毒副作用或毒副作用很小的特點(diǎn)。因此,作為一種很有前景的防治神經(jīng)退行性疾病的天然物質(zhì),食源性植物化學(xué)物受到越來越多的關(guān)注。

2　防治神經(jīng)退行性疾病的食源性植物化學(xué)物

2.1多酚類化合物

2.1.1白藜蘆醇(Resveratrol)白藜蘆醇(3,4′,5-三羥基-反-二苯乙烯),屬于非黃酮類多酚化合物,主要存在于葡萄、桑葚中,具有良好的神經(jīng)保護(hù)作用[4]。Masayuki等選用HT22細(xì)胞作為體外模型,接觸高濃度谷氨酸后HT22細(xì)胞產(chǎn)生氧化損傷。10 μmol/L白藜蘆醇處理后,激活了PI3K/Akt和GSK-3β/β-連環(huán)蛋白信號通路,有選擇地誘導(dǎo)超氧化物歧化酶(SOD)的表達(dá),降低細(xì)胞線粒體的氧化損傷,從而達(dá)到保護(hù)細(xì)胞的作用[5]。

2.1.2肉桂多酚(Cinnamon polyphenols)肉桂多酚是肉桂的水提物,最主要的活性組分為原花青素-A二聚體。Kiran等研究發(fā)現(xiàn)肉桂多酚可以改善線粒體功能障礙,減輕缺氧缺糖引起的神經(jīng)膠質(zhì)細(xì)胞腫脹,降低線粒體跨膜電位(ΔΨm),減輕腦水腫病變及其并發(fā)癥[6]。此外,肉桂多酚可增加巨噬細(xì)胞RAW264.7鋅指蛋白36(一種抗炎蛋白質(zhì))mRNA的水平,該蛋白可作為一種胰島素增敏劑,而胰島素可以減輕大鼠和沙鼠局部缺血的腦損傷[7]。

2.1.3姜黃素(Curcumin)姜黃素是從姜科姜黃塊莖中提取的一種多酚類物質(zhì)。Wu等研究發(fā)現(xiàn),在缺血性損傷的大鼠大腦皮層神經(jīng)元中,姜黃素能夠提高NAD(P)H、醌氧化還原酶(NQO1)的表達(dá),降低Akt磷酸化水平,減少細(xì)胞損傷。同時(shí),姜黃素能夠提高核因子E2相關(guān)因子2(nuclear factor-erythroid 2-related factor 2,Nrf2)與抗氧化反應(yīng)元件(antioxidant response element,ARE)的結(jié)合活性。在該實(shí)驗(yàn)中,動(dòng)脈閉塞60 min的大鼠經(jīng)5 μmol/L姜黃素處理后,明顯減少梗塞面積,降低動(dòng)脈閉塞大鼠體內(nèi)的氧化應(yīng)激水平[8]。

2.1.4原兒茶酸(Protocatechuic acid)原兒茶酸(3,4-二羥基苯甲酸),是一種單分子酚類,廣泛分布在蔬菜、水果中,其結(jié)構(gòu)中酚羥基、羧基可與活性氧反應(yīng),具有抗自由基作用[9]。Guan等研究發(fā)現(xiàn),0.06 mmol/L的原兒茶酸與胎牛血清(FBS)結(jié)合能夠促進(jìn)神經(jīng)分化、有效地促進(jìn)神經(jīng)突生長。同時(shí),原兒茶酸可以提高培養(yǎng)的神經(jīng)干細(xì)胞和祖細(xì)胞的存活率,激活細(xì)胞內(nèi)抗氧化酶的活性,進(jìn)一步保護(hù)神經(jīng)細(xì)胞。結(jié)果表明,原兒茶酸具有促進(jìn)大腦修復(fù)和保護(hù)神經(jīng)的作用,對于神經(jīng)退行性疾病的防治有重要意義[10]。

2.1.5白皮杉醇(Piceatannol)白皮杉醇(反式-3,3′,4,5′-四羥基二苯乙烯),是一種存在于葡萄、藍(lán)莓和甘蔗中的多酚物質(zhì)。Kim等人發(fā)現(xiàn),20 μmol/L白皮杉醇能降低H2O2及過氧亞硝酸鹽發(fā)生劑3-嗎啉代斯德酮亞胺[3-(4-morpholinyl)sydnonimine hydrochloride,SIN-1]誘導(dǎo)的PC12細(xì)胞死亡。白皮杉醇處理后,能夠減輕H2O2及SIN-1對PC12細(xì)胞的毒性作用,清除細(xì)胞內(nèi)的ROS和RNS,上調(diào)Bcl-XL表達(dá)水平,抑制caspase-3和caspase-8活性。同時(shí),白皮杉醇抑制c-Jun-N-激酶(JNK)磷酸化,JNK的失活也是白皮杉醇保護(hù)PC12細(xì)胞的一種分子機(jī)制[11]。

2.1.6原花青素(Proanthocyanidins)原花青素,由不同數(shù)量的兒茶素或表兒茶素結(jié)合而成的黃酮類化合物,廣泛存在于葡萄籽、蘋果、山楂中。Liu等研究發(fā)現(xiàn)200 mg/kg·bw原花青素處理能降低鉛誘導(dǎo)的大鼠大腦ROS的產(chǎn)生,增強(qiáng)大腦的總抗氧化能力;降低大腦內(nèi)腫瘤壞死因子-α(tumor necrosis factor-α,TNF-α)、白介素-1β(interleukin-1β,IL-1β)和環(huán)氧合酶-2(cyclooxygenase-2,COX-2)水平;降低β淀粉樣蛋白(β-amyloid,Aβ)和磷酸化微管蛋白(tau)水平。此外,原花青素還降低了JNK、p38磷酸化水平,抑制核轉(zhuǎn)錄因子-κB(nuclear factor-κB,NF-κB)的核轉(zhuǎn)運(yùn),表明原花青素可抑制氧化應(yīng)激和炎癥反應(yīng)來改善大腦功能和認(rèn)知障礙[12]。

2.1.7蘆丁(Rutin)蘆丁,由槲皮素和蕓香二糖組成的黃酮類化合物,存在于多種植物中,如蕎麥、柑橘、蘋果和茶等。Wang等發(fā)現(xiàn),蘆丁能夠劑量依賴性減輕Aβ42誘導(dǎo)的SH-SY5Y細(xì)胞的毒性。而且,蘆丁能夠降低損傷細(xì)胞內(nèi)ROS、NO、氧化型谷胱甘肽和丙二醛(MDA)的含量;降低誘導(dǎo)型一氧化氮合酶(iNOS)活性;減少線粒體損傷;提高超SOD、CAT及GPX的活性;通過降低TNF-α和IL-1β水平來調(diào)節(jié)前炎性細(xì)胞因子(proinflammatory cytokines)水平[13]。

2.1.8槲皮素(Quercetin)槲皮素(3,3′,4′,5,7-五羥基黃酮),廣泛的存在于蔬菜、水果中,如槐米、山楂等。Pavlica等發(fā)現(xiàn)PC12細(xì)胞暴露在H2O2、叔丁基過氧化氫(tert-Butyl hydroperoxide,t-BHP)及FeSO4中時(shí),會(huì)受到不同程度的氧化損傷。而經(jīng)25 μmol/L槲皮素處理后,細(xì)胞存活率和細(xì)胞內(nèi)GSH水平以及清除ROS的能力明顯提高、,丙二醛的含量則降低[14]。Zhang等研究發(fā)現(xiàn)50 mg/kg(bw槲皮素處理能明顯減少腦出血大鼠腦損傷量和積水量,降低4種炎癥因子IL-1β、IL-4、IL-6 和 TNF-α的表達(dá)水平,減少神經(jīng)細(xì)胞凋亡的數(shù)量,表明了槲皮素對大腦損傷有修復(fù)作用[15]。

2.2皂苷

2.2.1三七皂苷(Panaxnotoginsengsaponins)三七皂苷為中藥三七(Panaxnotoginseng)中主要的活性成分。Zhou等選用H2O2氧化損傷模型來研究三七葉中總皂苷對大鼠星形膠質(zhì)細(xì)胞對抗氧化應(yīng)激的保護(hù)作用,結(jié)果表明5 μg/mL三七皂苷可以清除細(xì)胞內(nèi)ROS、上調(diào)Nrf2的表達(dá),激活下游抗氧化系統(tǒng)如血紅素氧化酶1(heme oxygenase-1,HO-1)和谷胱甘肽-S-轉(zhuǎn)移酶pi 1(glutathione S-transferase pi 1,GSTP1)活性,減少H2O2誘導(dǎo)的細(xì)胞死亡率,表現(xiàn)出三七皂苷的抗氧化性及其對神經(jīng)系統(tǒng)疾病的治療作用[16]。

2.2.2人參皂苷(Ginsenosides)人參皂苷是人參(PanaxginsengC. A. Mey)最主要的活性成分,可分為人參皂苷Rg1、Rg2、Rg5等,其中人參皂苷Rg1對慢性應(yīng)激引起的學(xué)習(xí)和記憶損傷表現(xiàn)出保護(hù)作用[17]。Song等研究表明人參皂苷Rg1通過調(diào)節(jié)GSK3β/tau信號通路,減少Aβ形成來保護(hù)大鼠對抗黑海綿酸(OKA)誘導(dǎo)的神經(jīng)毒性和記憶損傷[18]。而大鼠經(jīng)飼喂20 mg/kg·bw人參皂苷Rg5,能夠降低鏈脲霉素誘導(dǎo)的大鼠大腦皮層和海馬體中乙酰膽堿酯酶(AChE)的活性,提高乙酰膽堿轉(zhuǎn)移酶(ChAT)的活性,提高胰島素生長因子(insulin-like growth factors 1,IGF-1)和腦源性神經(jīng)營養(yǎng)因子(brain derived neurophic factor,BDNF)的表達(dá)。結(jié)果表明,人參皂苷有利于改善認(rèn)知紊亂,降低炎癥反應(yīng)[19]。

2.2.3酸棗仁皂苷A(Jujuboside A)酸棗仁皂苷A,是從[ZiziphusjujubeMill varspinosa(Bunge)Hu ex H F Chou(Rhamnaceae)]中分離提取出的酸棗苷元的主要成分。酸棗仁皂苷A能夠抑制Ca2+內(nèi)流,調(diào)控Ca庫穩(wěn)態(tài),對谷氨酸鹽誘導(dǎo)的的神經(jīng)毒性有抑制作用[20]。此外,在高劑量(82 μmol/L)酸棗仁皂苷A作用24 h明顯提高了大鼠海馬體神經(jīng)元γ-氨基丁酸(γ-aminobutyric acid,GABAA)受體(α1,α5)的基因表達(dá),與傳統(tǒng)鎮(zhèn)定藥物安定有類似效果;而低劑量(41 μmol/L)的酸棗仁皂苷A作用24、72 h均能夠提高GABAA受體(α1,α5,β2)的基因表達(dá)。這些結(jié)果表明,酸棗仁皂苷A具有提高催眠鎮(zhèn)靜作用,是治療失眠癥的良好選擇[21]。

2.3香葉醇(Geraniol)

香葉醇(反-3,7-二甲基-2,6-辛二烯-1-醇),又名“牻牛兒醇”,是一種單萜類物質(zhì),存在于一些香木草料,如姜、檸檬等中[22]。研究表明,香葉醇能改善丙烯酰胺誘導(dǎo)的果蠅線粒體功能障礙和神經(jīng)毒性[23]。Rekha等研究發(fā)現(xiàn)經(jīng)慢性神經(jīng)毒素1-甲基-4-苯基-1,2,3,6-四氫吡啶(1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine,MPTP)誘導(dǎo)后,小鼠發(fā)生神經(jīng)退行性病變、運(yùn)動(dòng)行為紊亂。而經(jīng)100 mg/kg·bw香葉醇預(yù)處理后,MPTP誘導(dǎo)小鼠的運(yùn)動(dòng)功能得以提高、紋狀體氧化平衡得以改善[24]。這些結(jié)果表明香葉醇對于防治PD和其他神經(jīng)退行性疾病具有良好的應(yīng)用前景。

2.4蝦青素(Astaxanthin)

蝦青素(3,3′-二羥基-4,4′-二酮基-β,β′-胡蘿卜素),是一種具有抗氧化活性的類胡蘿卜素。蝦青素常常存在于蝦、螃蟹、海藻中等[25]。Zhang等研究發(fā)現(xiàn)了蝦青素能夠抑制谷氨酸誘導(dǎo)的PC12細(xì)胞的死亡率,減少ROS的產(chǎn)生,降低Bax/Bcl-2比率和caspase-3水平,抑制NF-κB和MAPK信號通路的水平[26]。此外,蝦青素能夠清除H2O2誘導(dǎo)的PC12細(xì)胞中ROS,抑制Ca2+的內(nèi)流[27]。同時(shí),10 μmol/L蝦青素預(yù)處理也能夠降低1-甲基-4-苯基吡啶陽離子(1-methyl-4-phenylpyridinium ion,MPP+)誘導(dǎo)的PC12細(xì)胞毒性,抑制激活轉(zhuǎn)錄因子1(activated transcription factor 1,Sp1)和NMDA 受體亞基1(NMDA receptor subunit 1,NR1)的mRNA及蛋白質(zhì)表達(dá)[28]。

2.5大蒜烯(Ajoene)

大蒜烯[(Z,E)-4,5,9-三噻十二烷-1,6,11-三烯-9-氧化物],是大蒜中主要的有機(jī)硫化物。大蒜烯分為順式[-trans(E)]和反式[-cis(Z)]兩種類型。Yoo等研究大蒜烯對局部缺血再灌注損傷沙鼠海馬體的作用。與模型組相比,Z/E-大蒜烯可以保護(hù)局部缺血再灌注誘導(dǎo)的沙鼠海馬體CA1區(qū)神經(jīng)死亡,減少神經(jīng)膠質(zhì)細(xì)胞增生,降低海馬體勻漿脂質(zhì)過氧化水平,而且,Z-大蒜烯保護(hù)效果優(yōu)于E-大蒜烯[29]。

2.6植物雌激素

2.6.1大豆異黃酮(Soy isoflavone)大豆異黃酮是一種植物雌激素,是大豆生長過程中形成的次級代謝物,多存在于大豆及其制品中。辛天蓉等發(fā)現(xiàn),三個(gè)劑量(30、60、120 mg/kg ·bw)的大豆異黃酮處理能夠降低小鼠血液和海馬組織中膽堿酯酶的活性。膽堿酯酶能夠加速乙酰膽堿的分解,而乙酰膽堿是記憶形成的必需的神經(jīng)遞質(zhì)[30]。龍軍等研究表明,長期給予腦缺血再灌注大鼠60 mg/kg·bw的大豆異黃酮處理,能夠遏制過多過氧亞硝基陰離子的產(chǎn)生,促進(jìn)腦出血組織神經(jīng)元的再生,對神經(jīng)具有保護(hù)作用[31]。

2.6.2芝麻素(Sesamin)芝麻素是芝麻籽中的木脂素類化合物,具有抗氧化應(yīng)激[32]、神經(jīng)保護(hù)[33]等多種生物活性。Bournival等研究表明芝麻素通過降低MPP+誘導(dǎo)的促炎因子IL-6、IL-8和TNF-α的mRNA及蛋白表達(dá)水平、降低iNOS蛋白表達(dá)水平來降低MPP+誘導(dǎo)的神經(jīng)膠質(zhì)系統(tǒng)神經(jīng)炎癥[34]。Ahmad等發(fā)現(xiàn)在小鼠大腦局部缺血模型中,經(jīng)30 mg/kg ·bw芝麻素處理,能夠減輕小鼠大腦的神經(jīng)毒性,其機(jī)制與調(diào)節(jié)MAPK/ERK和P38信號通路的磷酸化與去磷酸化有關(guān)[35]。

2.7植物固醇(Phytosterols)

植物固醇,一種類似于環(huán)狀醇結(jié)構(gòu)的物質(zhì),廣泛存在于蔬菜、谷物和植物油中。植物固醇主要包括β-谷固醇、豆固醇、菜油固醇、菜子固醇以及巖藻固醇等,具有降低神經(jīng)炎癥、促進(jìn)神經(jīng)元再生、抑制神經(jīng)退行性病變等作用[36]。體外實(shí)驗(yàn)表明,β-谷固醇能夠提高高脂飲食小鼠空間學(xué)習(xí)記憶能力,促進(jìn)小鼠大腦功能,對神經(jīng)有保護(hù)作用,但其作用機(jī)制尚待研究[37]。

2.8芥子油苷(Glucosinolate)

芥子油苷也稱為硫代葡萄糖苷或簡稱硫苷,可被葡糖硫苷酶水解為具有多種生物活性的異硫氰酸鹽、硫氰酸鹽、吲哚等。蘿卜硫素,僅在十字花科植物中發(fā)現(xiàn)的一種異硫酸氰鹽,能夠減少大腦梗死面積和水腫現(xiàn)象,減輕組織損傷,降低炎癥因子和氧化應(yīng)激水平,改善神經(jīng)功能[38]。曾濰賢等研究蘿卜硫素對大鼠局部腦缺血再灌注的抗氧化作用。結(jié)果表明,飼喂5 mg/kg·bw蘿卜硫素可誘導(dǎo)HO-1的表達(dá),減少缺血再灌注后腦中MDA含量,具有神經(jīng)保護(hù)作用[39]。

2.9蛋白酶抑制劑(Protease inhibitor)

蛋白酶抑制劑,如鈣蛋白酶抑制劑、鈣調(diào)神經(jīng)磷酸酶抑制劑、亮肽素等,多存在于豆類、谷類等種子中,具有抗氧化等作用。其中,鈣蛋白酶抑制劑呈現(xiàn)出良好的神經(jīng)保護(hù)作用。在大鼠丙烯酰胺毒性模型中,神經(jīng)胞體和軸突內(nèi)Ca2+升高,Ca2+內(nèi)流,激活細(xì)胞內(nèi)鈣蛋白酶活力。而鈣蛋白酶抑制劑能夠抑制鈣蛋白酶活力,抑制細(xì)胞凋亡[40]。Lee等發(fā)現(xiàn),共軛亞油酸可作為鈣蛋白酶抑制劑可以降低Aβ誘導(dǎo)的SH-SY5Y細(xì)胞的神經(jīng)毒性,降低促凋亡蛋白水平,提高tau蛋白磷酸化水平。這些表明,蛋白酶抑制劑可作為治療AD的潛在藥物[41]。

3　展望

隨著全球人口的老齡化趨勢加重,神經(jīng)退行性疾病如AD、PD、運(yùn)動(dòng)神經(jīng)元疾病等也呈現(xiàn)出加重趨勢,這些疾病嚴(yán)重影響人們的身體健康和生活質(zhì)量。而一些食源性植物化學(xué)物,能夠調(diào)控Ca2+、調(diào)節(jié)信號通路,具有抗氧化、抗Aβ、抗細(xì)胞凋亡等作用,對于神經(jīng)退行性疾病的防治有良好的效果,將成為未來的研究熱點(diǎn)。然而,由于分離提取技術(shù)的限制,許多植物化學(xué)物存在提取率低、提取純度不高以及提取溶劑殘留等問題。同時(shí),一些食源性植物的安全性尚不明確。因此,對于食源性植物化學(xué)物系統(tǒng)的研究、開發(fā)分離提取新技術(shù),對其安全性進(jìn)行合理評價(jià)以及其保護(hù)作用機(jī)理的深入探究有待于進(jìn)一步探索。

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Progress in foodborne phytochemical in preventing and curing neurodegenerative diseases

WANG Dan-dan,GENG Yue*

(Shandong Provincial Key Laboratory of Animal Resistance Biology,College of Life Science,Shandong Normal University,Ji’nan 250014,China)

Neurodegenerative diseases are caused by the loss of neurons and myelin in brain and spinal cord,and result in neuronal dysfunction. Researchs show that foodborne phytochemicals,such as resveratrol,proanthocyanidins,ginsenosides have antioxidant,anti-lipid peroxidation,neuroprotective effects and exhibit effect on prevention and treatment of neurodegenerative diseases. In this paper,the recent studies of the protective effect of foodborne phytochemicals which are common and available on neurodegenerative diseases were reviewed.

foodborne phytochemicals;natural;neurodegenerative disease;oxidative stress

2015-12-16

王丹丹(1990- )，女，碩士研究生，研究方向：食品科學(xué)，E-mail:wangdan.dan.cool@163.com。

耿越(1965- )，男，博士，教授，研究方向：食品科學(xué)， E-mail:gengy@sdnu.edu.cn。

TS201.1

A

1002-0306(2016)15-0385-05

10.13386/j.issn1002-0306.2016.15.067