TWI437998B - 大葉冬青提取物之用途 - Google Patents
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- TWI437998B TWI437998B TW100126206A TW100126206A TWI437998B TW I437998 B TWI437998 B TW I437998B TW 100126206 A TW100126206 A TW 100126206A TW 100126206 A TW100126206 A TW 100126206A TW I437998 B TWI437998 B TW I437998B
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- 235000010447 xylitol Nutrition 0.000 description 1
- 229960002675 xylitol Drugs 0.000 description 1
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 1
- 239000011787 zinc oxide Substances 0.000 description 1
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Description
本發明涉及一種大葉冬青(Ilex latifolia)提取物之用於製備預防或治療缺血性腦疾病或退行性腦疾患或改善記憶損傷之藥物或保健功能食品的用途。
缺血性腦中風(cerebral apoplexy),即,腦梗塞(cerebral infarction)的主要病因是血管動脈硬化症引起的腦動脈血栓或栓塞和心臟疾病等引發的心因性栓塞。腦血管堵住引發的腦梗塞症又分為腦血栓症和腦栓塞症。腦血栓症是高血壓、糖尿病、高血脂症等引發動脈硬化,動脈管壁變厚或變硬,由此造成血管變窄,血管內壁容易受損不光滑,血流不順暢,導致血液供應顯著降低或中斷,腦細胞得不到氧氣和營養物質,導致腦功能障礙。腦栓塞症是心瓣膜病或心房顫動等疾病導致心臟內的血流出現異常,部分血液滯留在心臟內凝固,產生血液殘渣。脫落的血液残渣堵塞腦血管引發腦梗塞。
血管性痴呆(vascular dementia)是由於腦血管疾病導致腦損傷而發生的後天性不可逆轉性認知功能的降低。腦中風和腦梗塞引發的癡呆佔全部癡呆症的三分之一左右,是繼老年癡呆症之後發病頻率高的癡呆。與一般的腦中風和腦梗塞一樣,高齡、吸煙等具有血管性危險因素的患者容易產生腦部大血管或小血管閉塞,由此大腦皮質或皮質下方的聯合神經纖維遭到破壞,發生血管性癡呆。血管性癡
呆根據構成病因的血管病理或產生癡呆的病變位置,可以分為多發性腦梗塞癡呆(multi-infarct dementia)、皮質下缺血性血管性癡呆(subcortical ischemic vascular dementia)以及閉塞導致的單一病變性癡呆(strategic infarct dementia)等。其中,閉塞導致的單一病變性癡呆是尾狀核(caudate nucleus)、內側額葉(mesial frontal lobe)、內囊膝(genu of internal capsule)等發生的單一病變導致的癡呆。小血管疾病引發的裂孔性腦梗塞或不完全硬塞引發的腦白質疏鬆(leukoaraiosis;white matter hyperintensity)主要損傷前額葉-皮質下回路(prefrontal-subcortical circuit)。可能出現的症狀不是記憶障礙等傳統的癡呆症狀,而是智力遲鈍(bradyphrenia)、失用症(apraxia)等皮質下症狀(subcorticaldysfunctio)。
老年痴呆症(AD;Alzheimer's disease)的特徵是神經細胞(neuron)的喪失和源於澱粉質前軀體蛋白質的39-43胺基酸肽-澱粉樣蛋白(amyloid-beta;Aβ)為主要構成成分的細胞外老年斑(senile plaque)。試管以及生物體內研究結果表明,Aβ或Aβ縮胺酸單片具有毒性效果,啟示Aβ對AD的發病起到重要的作用(Butterfield et al.,Free Radical Biology and Medicine,2002,32:1050-1060;ButterfIeld et al.,Free Radical Biology and Medicine,2007,43:658-677)。培養時,Aβ會直接誘導神經細胞的死滅,使神經細胞對興奮毒性以及氧化性損傷脆弱。NMDA(N-methyl-D-aspartate receptor)受體承擔Aβ結合的選擇性基質或Aβ-誘發的穀胺酸興奮毒
性的媒介作用。NMDA受體尤其是對Ca2+
具有高度透過性的配體-門控/伏特-敏感性陽離子通道,[Ca2+
]i的大範圍的上升會直接導致細胞功能不振、過度興奮或死滅。因此,如同Aβ的神經毒性效果被非競爭性NMDA受體拮抗劑(5R.10S)-(+)-5-甲基-10,11-脫氫-5H-吩噻惡[a,d]環庚-5,10-亞胺馬來酸酯(MK-801)[5R.10S]-(+)-5-methyl-10,11-dihydro-5H-dibenzo(a,b)cyclohepten-5,10-imine maleate]減少的報告所證明,Aβ曝光方式的通過NMDA受體的Ca2+
引入對Aβ-誘導的神經毒性中起到決定性作用。
相信活性氧(Reactive Oxygen species;ROS)的形成也干预到退行性腦疾患的發病。幾項證據證明通過妨礙神經細胞恆定性的廣泛的分子形狀,促發神經退化或使之更加容易,Aβ-媒介的神經病中作為活性因數襯托氧化反應的干預。但是,NMDA受體拮抗劑和神經細胞通道的直接阻斷劑的臨床有益性由於缺乏可確認的效能或具有嚴重的副作用。
大部分的退行性腦疾患伴隨著癡呆,尤其,認知障礙和記憶障礙(記憶力衰退)。因此,包括癡呆在內的退行性腦疾患的比較理想的治療藥物應該是延遲腦細胞的破壞和老化,保護腦細胞,恢復認知功能。目前為止開發的藥劑有,抑制活性氧對腦細胞的破壞性的維生素E和司立吉林(selegiline)等抗氧化劑、塔克林(Tacrine)、安理申(Aricept)以及艾斯能(Exelon)等乙醯膽素分解酶抑制劑
(acetylcholinesterase-inhibiting drugs)等。但是,這些藥劑都誘發相當大的副作用,且其效能並不突出。
屬於冬青科(Aquifoliaceae
)的大葉冬青(I.latifolia
)分佈在中國和越南等地,是中國南部居民喜歡飲用的苦丁茶(Ku ding cha)的主要原料。傳統醫學中苦丁茶用於頭痛、高血壓等的治療劑,尤其,大葉冬青用於缺血性心臟疾病以及心肌梗塞的治療劑。但是,實際上還沒有證實過大葉冬青對退行性腦疾患的治療效果。
因此,本發明人為了開發對腦血管疾患具有預防和療效的天然物質而努力的過程中,發現了大葉冬青提取物在誘發腦梗塞的大鼠身上抑制腦梗塞以及浮腫,注射Aβ(25-35)誘發神經毒性的老鼠身上抑制記憶的損傷,且根據注射量還可以抑制,過氧化氫(H2
O2
)誘發的氧化反應、穀胺酸以及Aβ(25-35)等毒性物質以及低氧症誘導的大腦皮質神經細胞的死亡,由此確認本發明的大葉冬青提取物可以用於腦血管疾病的預防或治療用藥物成分以及保健功能食品的有效成分,完成了本發明。
本發明的目的在於,提供將大葉冬青(Ilex latifolia
)提取物作為有效成分的缺血性疾病或退行性腦疾患的預防或治療用藥物組成物以及保健功能食品。
本發明的另一個目的在於,提供將大葉冬青提取物作為有效成分的記憶損傷改善用藥物組成物以及保健功能食品。
為了實現上述的目的,本發明提供將大葉冬青(Ilex latifolia
)提取物作為有效成分的缺血性疾病或退行性腦疾患的預防或治療用藥物組成物以及保健功能食品。
並且,本發明提供將大葉冬青提取物作為有效成分的記憶損傷改善用藥物組成物以及保健功能食品。
本發明的大葉冬青(Ilex latifolia
)提取物在誘發腦梗塞的大鼠身上抑制腦梗塞以及浮腫,注射Aβ(25-35)誘發神經毒性的老鼠身上抑制記憶損傷,有效抑制過氧化氫(H2
O2
)誘發的氧化反應、穀胺酸以及Aβ(25-35)等毒性物質以及低氧症誘導的大腦皮質神經細胞的死亡,所以能作為缺血性疾病或退行性腦疾患的預防或治療用藥物成分以及保健功能食品的有效成分使用。
下面結合附圖詳細說明本發明的具體實施方式。
本發明提供,將大葉冬青(Ilex latifolia
)提取物作為有效成分的缺血性疾病或退行性腦疾患的預防或治療用藥物組成物。
並且,本發明提供,將大葉冬青提取物作為有效成分的記憶損傷改善用藥物組成物。
大葉冬青可以自由採用人工栽培或市場上銷售的。
上述大葉冬青提取物是包括下列步驟的製造方法來製作比較理想,但並不限於此。
依次執行:1)在大葉冬青添加提取溶劑進行提取的步驟;2)晾乾步驟1)的提取物進行過濾的步驟;以及3)將步驟2)中過濾的提取物進行迴流冷凝後烘乾的步驟可以製作。
上述提取溶劑最好選用水、酒精或其混合物。上述酒精最好採用C1至C2的低級酒精,當採用乙醇時,比其他溶劑的提取效果更好,所以低級酒精選用乙醇更理想。提取方法上採用振盪提取、索格裏特(Soxhlet)提取或迴流提取法比較好,但並不限於此。將乾燥大葉冬青份量5至15倍的提取溶劑添加進去進行提取比較好,最好的比例是添加大葉冬青份量的十倍。提取溫度控制在40-100℃比較好,最好是控制在60-80℃,但並不限於此。並且,提取時間控制在4-24小時比較好,最好是控制在8-15小時,但並不限於此。與此同時,提取次數控制在1-5次比較好,最好是反復提取三次,但並不限於此。
上述方法上,步驟3)的乾燥選用減壓乾燥、真空乾燥、沸騰乾燥、噴霧乾燥或凍結乾燥等比較好,但並不限於此。
上述缺血性疾病或退行性腦疾患最好是腦梗塞、腦缺血、腦中風、癡呆、老年癡呆症、杭廷頓氏舞蹈病、匹克病(pick病)以及克羅伊茨費爾特-雅各氏病(Creutzfeld-Jakob)病組成的疾病組之一,但並不限於此。
本發明的具體實施方式中,發明人在誘發腦梗塞的大鼠身上確認了大葉冬青提取物對腦梗塞以及浮腫的抑制效果(見圖1以及圖2、表1)。並且,注射β-澱粉樣蛋白(amyloid β protein;Aβ(25-35))誘發神經毒性的老鼠身上,通過大小鼠避暗測試(passive avoidance test;Step through)以及水迷宮(Morris water maze)測試,確認了大葉冬青提取物對記憶損傷的抑制效果(見圖3以及圖4)。
並且,本發明的具體實施方式中,還確認了大葉冬青提取物根據其注射量,對過氧化氫(H2
O2
)誘發的氧化反應、穀胺酸以及Aβ蛋白質等毒性物質造成的大腦皮質神經細胞的死亡具有抑制效果(見5至圖7)。並且,確認了通過低氧症誘導的大腦皮質神經細胞的死亡,根據大葉冬青提取物的注射量受到抑制(見圖8)。
因此,本發明的大葉冬青提取物可以作為腦血管疾患的預防或治療用,或記憶損傷改善用藥物組成物的有效成分使用。
含有本發明大葉冬青提取物的成分佔總重量的0.1至50重量比比較合適,但並不限於此。
本發明的成分在臨床上被使用時,可以採用口服或非口服的方式,可以作為一般的醫藥品製劑的形態使用。本
發明的成分在實際臨床上使用時,可以採用口服以及非口服的各種制形。製作成製劑時,採用通常使用的填充劑、增量劑、濕潤劑、崩解劑以及表面活動劑等的稀釋劑或賦形劑調製。用於口服的固形製劑包括,片劑、丸劑、散劑、顆粒劑、膠囊劑等,這些固形製劑是本發明的藥物成分中至少添加一種以上的賦形劑,比如,澱粉、碳酸鈣、蔗糖、乳糖以及凝膠等調製。並且,除了純賦形劑之外,還使用鎂、硬脂酸酯(stearate)、滑石等潤滑劑。口服的液狀製劑有,懸浮液、內容液狀以及糖漿等。除了通常使用的純稀釋劑水、液體蠟之外,可以包括各種賦形劑,比如,濕潤劑、甘味劑、芳香劑、保存劑等。非口服的製劑有,滅菌水溶液、非水性溶劑、懸浮劑、乳劑、凍結乾燥劑、佐劑等。非水性溶劑以及懸浮溶劑有,丙二醇、聚乙二醇、橄欖油等植物性油、油酸乙酯(ethyl oleate)等可注射的酯類。作為佐劑的基劑可以採用外特索(witepsol)、聚乙二醇、特溫61(Tween 61)、可哥豆脂、羥基香茅醛、甘油以及凝膠等。本發明藥物組成物的非口服使用方法有,皮下注射、靜脈注射或肌肉注射等。
用藥單位而言,比如,含有個別用藥量的1、2、3或4倍,或可以含有1/2、1/3或1/4倍。個別用藥量最好含有有效藥物每次口服或注射的量,這相當於通常每日用藥量的全部、1/2、1/3或1/4倍。本發明組成物的有效容量為0.0001~10g/kg,最好的用藥量為0.0001g~5g/kg,一天可以口服或注射1~6次。
本發明的組成物在腦血管疾病的預防或治療過程中,可以單獨使用,也可以配合手術、激素治療、化療以及生物學反應調節劑的其他方法使用。
並且,本發明提供將大葉冬青提取物作為有效成分的缺血性疾病或退行性腦疾患的預防或改善用保健功能食品。
與此同時,本發明提供,將大葉冬青提取物作為有效成分的極易損傷改善用保健功能食品。
本發明的具體實施方式中,發明人在誘發腦梗塞的大鼠身上確認了大葉冬青提取物對腦梗塞以及浮腫的抑制效果(見圖1、圖2、表1),還在誘發神經毒性的老鼠身上,確認了大葉冬青提取物對記憶損傷的抑制效果(見圖3以及圖4)。並且,確認了根據大葉冬青提取物的注射量,對氧化反應、毒性物質以及低氧症引發的大腦皮質神經細胞的死亡具有抑制效果(見圖5至圖8)。
因此,將大葉冬青提取物作為有效成分的本發明藥物組成物,可以用於物質缺血性疾病或退行性腦疾患的預防或改善用,或記憶損傷改善用保健功能食品。
本發明的保健功能食品可以直接添加大葉冬青提取物,或與其他食品或食品成分配合使用,按照通常的方法可以合理使用。有效成分的混合量可以根據使用目的(預防、保健或治療性處置)來決定。一般來講,製造食品或飲料時,本發明成分對原料的添加比為15重量份以下,最好是10重量份以下的量。但是,以保健以及衛生作為目的或
調節身體為目的的長期服用時,攝入量可能比上述範圍少,但是由於安全性方面沒有任何問題,有效性份可以超過上述範圍以上的量。
上述食品的種類沒有特別的限制。可以添加上述物質的食品有,肉類、香腸、麵包、巧克力、糖果類、點心類、餅乾類、匹薩、速食麵、其他麵食類、口香糖、霜淇淋在內的乳品、各種湯類、飲料、茶、飲品、酒精飲料以及複合維生素等,包括通常意義上的所有保健食品。
本發明的保健飲料成分可以與普通的飲料一樣,含有各種香味劑或天然碳水化合物等。上述的天然碳水化合物有,葡萄糖、果糖等單醣、麥芽糖、蔗糖等二糖類以及葡聚糖、環糊精等多醣、木糖醇、山梨糖醇、赤蘚醇等糖乙醇。甘味劑可以選用非洲竹芋甜索、甜菊提取物等天然甘味劑或糖精、阿斯巴甜等合成甘味劑。上述天然碳水化合物的比率而言,本發明成分每100ml含有約0.01~0.04g,最好是含有約0.02~0.03g。
除了上述之外,本發明的大葉冬青提取物可以含有,各種營養劑、維生素、電解質、風味劑、著色劑、果膠酸及其鹽、海藻酸及其鹽、有機酸、保護性膠體增粘劑、pH調節劑、穩定劑、防腐劑、甘油、酒精、碳酸飲料中使用的碳酸化劑等。除此之外,本發明的大葉冬青提取物可以含有,製造天然果汁、果汁飲料、蔬菜飲料為目的的果肉。可以獨立或组合使用這些成分。雖說這些添加劑的比率不
太重要,但是通常在本發明的成分每100重量份0.02~1重量份的範圍內選擇。
本發明的大葉冬青提取物幾乎沒有毒性和副作用,作為預防目的可以長期服用。
下面,結合實施例和製造例詳細說明本發明。
但,下面的實施例和製造例只是本發明的例示,並非本發明內容限定在下面的實施例和製造例。
<1-1>乙醇提取物的製造
大葉冬青是在首爾慶東的中藥材市場購買後切碎使用。準備100克大葉冬青後,在室溫環境下利用3L的100%乙醇,三個小時內用迴流冷凝器中提取了三次。通過沃特曼1號紙過濾上述溶液後烘乾,最終收穫了乙醇提取物18.7g。最終收穫的大葉冬青提取物是放入二甲基亞碸(dimethylsulfoxide;DMSO)內溶解成50mg/ml
的濃度,保管在-20℃的環境中。實驗時,對實驗緩衝液進行稀釋,使DMSO的最終濃度達到0.1%一下後使用。
<1-2>水提取物的製造
除了作為提取溶劑用水取代100%乙醇之外,按上述實施例<1-1>的提取方法獲得了粉末(收率21.5%)。
<1-3>80%乙醇提取物的製造
除了作為提取溶劑用80%的乙醇取代100%乙醇之外,按上述實施例<1-1>的提取方法獲得了粉末(收率20.4%)。
<1-4>100甲醇提取物的製造
除了作為提取溶劑用100%的甲醇取代100%乙醇之外,按上述實施例<1-1>的提取方法獲得了粉末(收率19.1%)。
本發明人為了在誘發腦梗塞的大鼠身上確認大葉冬青提取物的效能,實施了如下的實驗。首先,使300±5g的SD大鼠(SAMTAKO,京畿道)吸入1-2%異氟醚(isoflurane)(N2
:O2
=4:1)進行麻醉後,通過外科手術小心地曝光出了右側頸動脈。對大鼠的外徑動脈分支到中央部的舌動脈(linguinal artery)和從外頸動脈向內頸動脈分支的甲狀腺動脈(thyroid artery),通過電灼進行了結紮。此時,在動脈結紮前30分鐘、結紮後一個小時、去除結紮後一個小時後,餵食了大葉冬青提取物(分別50,100或200mg/kg)或作為陽性對照組的MK-801(1mg/kg)。作為陰性對照組使用了未添加任何物質的實驗緩衝液(生理食鹽水注射液)的注射大鼠。之後,發現內頸動脈上方的Y字形分支為止,清理好周圍後,將外頸動脈的頭部用線結紮切斷血流,並為了防止總頸動脈和內頸動脈之間的血流,用夾子夾住了上下。之後,在總頸動脈打一個小孔***探針後,用線輕輕結紮探針和外頸動脈的下方部位止血,然後去除了防止血流的夾子。切開***探針的孔和結紮外頸動脈的部位之間,將***到外頸動脈的探針小心地挪到內頸動脈***
後,在內頸動脈上方分支為Y字形的血管中,向內側血管***了探針。此時,探针從總頸動脈分支只***了20mm。手術後馬上測量直腸溫度開始,在6小時內維持了37±0.5℃。結紮(occlusion)2小時後去除探針進行再灌注(reperfusion),然後24小時後使脫骨致死並分離了腦。利用腦基質(Brain matrix)將上述步驟中分離的腦切割成2mm厚度後,利用2%TTC溶液在37℃溫度條件下染色30分鐘,然後用數位相機拍攝,利用影像分析系統(Image analysis system,Optimas 6.1,Media Cybernetics,Silver Springs,美國)測量了梗塞容積和浮腫容積。此時,將賦形液(vehicle)的處理組作為對照組,表1中顯示了各提取物的梗塞容積,並將效果最好的乙醇提取物的腦梗塞容積和浮腫容積顯示在圖1的曲線圖中。
如圖1所示,大葉冬青顯著降低了,通過缺血/再迴流(ischemia/reperfusion)法引發梗塞的大鼠腦組織的梗塞容積和浮腫容積。第一行的腦組織為正常狀態下大鼠的腦,沒有出現缺血,所以整個腦部都是通紅的。第二行圖片是未經任何處理的狀態下,誘導腦缺血時的照片,腦梗塞在左半球已經生成。與此相比,第三行的腦部圖片為分別在動脈結紮前三十分鐘、一個小時、以及去除動脈結紮後一個小時內,口服大葉冬青200mg/kg的動物腦部,圖中可見,顯著抑制了頸動脈結紮誘發的腦缺血引發的腦梗塞。第四行為作為陽性對照組使用的注射MK-801的大鼠腦部照片。
並且,如圖2所示,陰性對照組表現出354.3mm3
的梗塞容積相比,大葉冬青50mg/kg注射組為166.0mm3
、100mg/kg注射組為136.3mm3
、200mg/kg注射組為108.3mm3
,可見梗塞抑制效果依賴於注射量。並且,賦形液注射組的腦浮腫容積為62.5mm3
相比,大葉冬青50mg/kg注射組為40.6mm3
、100mg/kg注射組為28.3mm3
、200mg/kg注射組為21.8mm3
,顯著降低了腦浮腫。之後的實驗中,只採用腦梗塞抑制效果最好的乙醇水溶液提取物進行了實驗。
實驗動物采用了ICR老鼠(BioLink Co.韓國),購買後經過一段時间的適應期後,在實驗第一天(0day)喂食了大葉冬青(25 50或100mg/kg),30分鐘後使用安装27號針頭(gauge nuddle)的微细注射器,將15μl(15nmol)的1mM Aβ(25-35)(Bachem,瑞士)慢慢注入到了腦室中(Maurice T et al.,Brain Reserch,1996,706:181-193)。之後的一個星期之內,每天一次分别喂食25、50以及100mg/kg的大葉冬青提取物,並將動物放置在逐步通過装置(Step through
apparatus)(Gemini II avoidance system,Sandiego Instrument)的敞亮的箱子中,進行了三次敞亮區域適用測試。第七天喂食大葉冬青提取物(25,50或100mg/kg),30分鐘後將動物放置在敞亮的箱子內,10秒後打開箱門,當動物進入暗箱時門被關閉同時施加電擊(0.2mA,2sec),讓上述的老鼠熟悉了單一-跟蹤逐步通過被動回避實驗(One trail step through passive-task)。上述的被動回避箱為斷頭臺型門,分為格子地板和衝擊生成器兩個區域(各25(W)×21(D)×19(H)cm)。在昏暗的條件下將老鼠放在起始點,50秒後開燈並開門,當老鼠進入暗箱時門被關閉並施加電擊(0.2mA,2秒),讓動物記住了暗箱內的電擊體驗。24小時後,將動物置於敞亮箱內進行相同的實驗時,記住前一天電擊的動物沒有移動到暗箱。測量動物在亮箱中的逗留時間,作為記憶形成的指標,逗留時間達到5分鐘以上的視為5分鐘。
其結果,如圖3所示,將Aβ(25-35)(15nmol)注射到腦室,一個星期後進行被動回避實驗時,未注射的試驗組在259秒後移動到暗處相比,Aβ(25-35)注射組在30秒後移動到了暗處。這意味著沒有形成記憶。與此相比,一個星期內每天餵食大葉冬青提取物25、50以及100mg/kg的試驗組,隨著餵食量的增加,移動到暗箱的時間延長,25mg/kg餵食組為70秒、50mg/kg餵食組為197秒、100mg/kg餵食組為238秒,所有試驗組的逗留時間均呈現有意義的增加,確認了Aβ(25-35)導致的記憶損傷抑制功能。
將直徑90cm、深度40cm的圓形水槽進行四等分,在其中的一個區內設置了高20cm的平臺。水溫控制在20℃,水位高出平臺1.5cm後,用全脂奶粉使水渾濁,這樣在水面上就看不到平臺。將老鼠分為任意的試驗組後,每隔一個小時在四個區域實施使老鼠在每個區域都游泳一次後找到平臺的實驗(pretest),測定了其時間(prevalue)。最長的游泳時間控制在2分鐘,當找不到平臺時人為地將老鼠放在平臺一分鐘。第二天,與被動回避實驗中一樣,在老鼠的腦室內注射15nmol的Aβ(25-35)(0 day),對照組注射了滅菌生理食鹽水。大葉冬青提取物是注射Aβ(25-35)之日起每天口服一次,直到水迷宮測試結束。注射Aβ(25-35)後,第四天至第八天(4 day-8 day)內每天與pretest相同的方法,測量各老鼠每隔一個小時四次找到平臺的時間,取得平均值(latency time)後測量了記憶形成程度。
其結果,如圖4所示,比較所有組的注射Aβ(25-35)(15nmol)前的值(第0天)和注射後實驗第五天的值時,對照組為116.2->27.9秒形成了記憶,但是只注射Aβ(25-35)的組為114.8->116.1秒沒有形成記憶。與此相比,五天餵食大葉冬青提取物的組而言,25mg/kg餵食組為114.5->76.5秒、50mg/kg餵食組為113.2->35秒、100mg/kg餵食組為105.0->62.5秒,所有餵食組都形成記憶,確認了對Aβ(25-35)所導
致記憶損傷的抑制效果。50mg/kg餵食組的抑制效果最為突出。
<5-1>大腦皮質神經細胞的培養
初始(Primary)的大腦皮質神經细胞是15-16天齡的SD白化大鼠(Sprague-Dawley)胚胎中,通過已知的方法準備的(Ban JY et al.,Life science,2006,79:2251-2259)。對懷孕15天的大鼠進行***麻醉後去除胚胎,在顯微鏡下只分離了大腦皮質。將大腦皮質放入含有胰蛋白酶(0.25mg/ml)的JMEM(Joklik-modified Eagle's medium)中,利用5ml滴管進行機械分散後,在37℃條件下培養10分鐘,實施了酶分離。對上述的細胞懸浮液以1,500rpm的轉速進行五分鐘的離心分離後,在所獲得的含細胞的沉澱層內添加,含有碳酸氫鈉(sodium bicarbonate;44mM)、盤尼西林(40U/ml)、慶大黴素(gentamicin;50g/ml)、KCl(5mM)以及10%胎牛血清(fetal bovine serum)的DMEM,將細胞濃度調整為2×106cells/ml,流經尼龍篩網(nylon mesh;35μm)後植入到事先用多聚賴胺酸(poly-L-lysine)塗層的培養容器中。在維持37℃、5% CO2
/95%氮條件的CO2
培養基中進行了培養。
<5-2>大葉冬青提取物抑制神經細胞死亡的效果測定
本發明人為了確認實施例1中獲取的大葉冬青的混合提取物對神經細胞死亡產生的影響,實施了下列實驗。此時,將實施例5-2中準備的大腦皮質神經細胞在培養第3-4
天時用於實驗。對上述的神經細胞未經任何處理,或分別用10、50以及100μg/ml的上述實施例1中獲取的大葉冬青提取物進行了處理。處理15分鐘後,為了誘導神經細胞毒性,使用在無血清DME培養基(Serum free Dulbecco's modified Eagle's medium;DMEM)中溶解的10μM Aβ(25-35)(Bachem,瑞士)處理上述的神經細胞後,在37℃條件下培養了36小時(Aβ單獨處理組以及Aβ+大葉冬青提取物處理組)。之後,用已知的方法進行了3-(4,5-二甲基賽唑-2-基-2,5-二苯基四唑溴(3-(4,5-dimethylthiazol-2-yl-2,5-diplenyltetrazolium bromide;MTT)分析。(Ban JY et al.,2006)
這種方法是對細胞的生存、增殖進行量化測定的非常精細和穩定的方法,在活細胞內將黃色的水溶性基質MTT轉換為深藍色有色甲(formazan)的線粒體活性作為其依據。因此,所生成的有色甲的量與活細胞的數量成比例。吸光度越高,活細胞越多。去除藥物處理後經過24小時培養的細胞培基後,添加MTT(0.5mg/ml)溶液在37℃條件下培養了4個小時。以後,去除MTT溶液,將200μl的酸-異丙醇(0.04N HCl in isopropanol)添加到所有well中,溶解所形成的深藍色有色甲結晶後,通過微定量讀取機(microelisa reader)測量波長570nm(參照波長630nm)測定了吸光度。此時,將未經藥物處理的細胞作為對照組(control),該對照組作為100%時,利用各毒性物質過氧化氫(H2
O2
)、興奮性胺基酸-穀胺酸以及澱粉樣β蛋白(amyloid β protein)單獨處理的細胞組以及利用毒性物質和大葉冬青一起處理的細胞組
的吸光度顯示為%。此時,過氧化氫是為了說明缺血性腦損傷,施加氧化反應為目的使用的。
其結果,如圖5所示,與對照組(100%)相比,添加過氧化氫的神經細胞誘發了呈現58.4%生存率的細胞死亡,10μg/ml大葉冬青呈現67.4%、50μg/m呈現83.5%、100μg/m呈現105.9%的細胞生存率。由此可見,大葉冬青對氧化反應性腦神經細胞的死亡具有抑制效果。
並且,如圖6所示,向大腦皮質腦細胞添加穀胺酸(500μM)後呈現的神經細胞死亡中,對大葉冬青的抑制效果進行分析的結果,與對照組(100%)相比,穀胺酸處理組呈現出了67.7%的生存率。與此相比,大葉冬青1μg/ml呈現72.0%、10μg/ml呈現79.1%、50μg/ml呈現了80.54%的細胞生存率。我們知道腦梗塞的退行性腦疾患中,大量游離興奮性胺基酸-穀胺酸引發神經細胞死亡。即,大葉冬青可以有效抑制穀胺酸引發的細胞死亡。
與此同時,如圖7所示,將Aβ(25-35)注射到老鼠的腦室引發記憶損傷時,口服大葉冬青慢行用藥可以抑制記憶損傷。因此,作為探明生化學原理的實驗,培養大腦皮質神經細胞,誘發10μM Aβ(25-35)造成的細胞死亡,並分析大葉冬青對此的抑制效果,發現用10μM Aβ(25-35)處置時,與對照組(100%)相比呈現出69.3%的細胞生存率。用大葉冬青處理培養神經細胞時,1、10以及50μg/ml中分別恢復了84.3、88.0以及93.4%的生存率。
所培养的大腦皮質神經细胞在培养第三天,將培基更换成glucose-free HEPES缓冲液之後,放入维持2% O2
、5% CO2
的低氧性chamber well plate內,在chamber內培養了24小時。之後,將培基更換為serum-free DMEM,在5% CO2
培養基中再培養6小時,並通過MTT分析測定了細胞生存率。作為對照組,將利用不含血清DMEM(Serum-free DMEM)以及不含葡萄糖HEPES(glucose-free HEPES)緩衝液置換的細胞,放在5% CO2
培基內曝光了相同時間。並且,為了滿足貧血(ischemia)的條件,將培養的大腦皮質神經細胞放入製造低氧症(hypoxia)條件的反應室(chamber)內誘發細胞死亡,並分析了大葉冬青對此的抑制效果。
其結果,如圖8所示,在低氧症條件下呈現了58.2%的細胞生存率。分別投入10、50以及100μg/ml的大葉冬青提取物時,分別呈現出82.3、90.8以及91.3%的腦細胞生存率,確認了根據大葉冬青提取物的投入量,對低氧症引發的細胞死亡具有抑制效果。
<製造例1>:藥物製劑的製造
<1-1>散劑的製造
本發明的大葉冬青提取物300mg
乳糖100mg
滑石10mg
混合上述成分後填充到氣密佈製造散劑。
<1-2>片劑的製造
本發明的大葉冬青提取物50mg
玉米澱粉100mg
乳糖100mg
硬脂酸鎂2mg
混合上述的成分後,按照通常的片劑製造方法打錠製造片劑。
<1-3>膠囊劑的製造
本發明的大葉冬青提取物50mg
玉米澱粉100mg
乳糖100mg
硬脂酸鎂2mg
按照通常的膠囊劑的製造方法混合上述成分後,填充到凝膠膠囊製造膠囊劑。
<1-4>注射劑的製造
本發明的大葉冬青提取物50mg
適量注射用滅菌蒸餾水
適量pH調節劑
按照通常的注射劑製造方法,按上述成分含量每ample(2ml
)的方法製造。
<1-5>糖漿的製造
本發明的大葉冬青提取物1,000mg
白糖20g
異構化糖20g
適量檸檬香
添加純淨水勾兌出1000ml
。按照通常的糖漿製造方法混合上述成分後,填充到褐色瓶,滅菌製造糖漿。
<製造業2>:保健食品的製造
本發明的大葉冬青提取物1,000mg
適量維生素混合物
維生素A醋酸鹽70μ
g
維生素E 1.0mg
維生素B1 0.13mg
維生素B2 0.15mg
維生素B6 0.5mg
維生素B12 0.2μ
g
維生素C 10mg
生物素10μ
g
煙醯胺1.7mg
葉酸50μ
g
泛酸鈣0.5mg
適量無機質混合物
硫酸亞鐵1.75mg
氧化鋅0.82mg
碳酸鎂25.3mg
磷酸二氫鉀15mg
磷酸氫鈣55mg
檸檬酸鉀90mg
碳酸鉀100mg
氯化鎂24.8mg
上述的維生素以及礦物質混合物的配比採用了比較適合保健食品的成分,作為實施例子進行了混合。但是,其配比可以任意變更,按照通常的保健食品製造方法,混合上述的成分後製造顆粒,並按照通常的方法用於保健食品組成物的製造。
<製造業3>:保健飲料的製造
本發明的大葉冬青提取物1000mg
檸檬酸1000mg
低聚糖100g
梅子濃縮液2g
牛磺酸1g
添加純淨水勾兌出900ml
按照通常的保健飲料製造方法,混合上述的成分後,在85℃的條件下攪拌加熱1個小時,將製造的溶液進行過濾,用滅菌的2l
容器取該溶液後,進行密封滅菌和冷藏保管,然後用於本發明保健飲料的組成物製造。
上述實施例僅係為了方便說明而舉例而已,本發明所主張之權利範圍自應以申請專利範圍該為準,而非僅限於上述實施例。
圖1為大葉冬青(Ilex latifolia
)對結紮/再灌注(occlusion/reperfusion)引發的腦梗塞的抑制效果(組織學病變)的確認圖。
圖2為誘發腦梗塞的大鼠身上,確認大葉冬青的腦梗塞以及腦浮腫抑制效果的結果圖。
圖3為通過Aβ(25-35)誘發神經損傷的老鼠身上,通過大小鼠避暗測試確認記憶損傷抑制效果的結果圖。
圖4為通過Aβ(25-35)誘發神經損傷的老鼠身上,通過水迷宮測試(Water maze test)確認記憶損傷抑制效果的結果圖。
圖5為大腦神經細胞上,通過MTT分析表示的過氧化氫誘導的氧化反應對細胞死亡抑制效果的分析圖。
圖6為通過MTT分析確認,大葉冬青對穀胺酸誘導的大腦神經細胞死亡抑制效果的確認圖。
圖7為通過MTT分析確認,大葉冬青對Aβ(25-35)誘導的大腦神經細胞死亡抑制效果的確認圖。
圖8為通過MTT分析確認,大葉冬青對低氧症(Hypoxia)誘導的大腦神經細胞死亡抑制效果的確認圖。
Claims (6)
- 一種大葉冬青(Ilex latifolia)100%乙醇提取物之用於製備預防或治療缺血性腦疾病或退行性腦疾患之藥物的用途。
- 一種大葉冬青(Ilex latifolia)100%乙醇提取物之用於製備改善記憶損傷之藥物的用途。
- 如申請專利範圍第1項所述之用途,其中,該缺血性腦疾病為腦梗塞、腦缺血、腦中風組成的疾病組之一,該退行性腦疾患為癡呆、老年癡呆、杭廷頓氏舞蹈病、匹克病(pick病)以及克羅伊茨費爾特-雅各氏病(Creutzfeld-Jakob)組成的疾病組之一。
- 一種大葉冬青(Ilex latifolia)100%乙醇提取物之用於製備預防或改善缺血性腦疾病或退行性腦疾患之保健功能食品的用途。
- 一種大葉冬青(Ilex latifolia)100%乙醇提取物之用於製備改善記憶損傷之保健功能食品的用途。
- 如申請專利範圍第4項所述之用途,其中,該缺血性腦疾病為腦梗塞、腦缺血、腦中風構成的疾病組之一,該退行性腦疾患為癡呆、老年癡呆、杭廷頓氏舞蹈病、匹克病(pick病)以及克羅伊茨費爾特-雅各氏病(Creutzfeld-Jakob)構成的疾病組之一。
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