TW201815403A - Application of pleurotus eryngii used for curing or preventing dementia and symptom thereof capable of achieving effectively reducing brain damage and the symptoms of memory and learning ability worsening of the individual - Google Patents
Application of pleurotus eryngii used for curing or preventing dementia and symptom thereof capable of achieving effectively reducing brain damage and the symptoms of memory and learning ability worsening of the individual Download PDFInfo
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本發明係有關於一種真菌之用途，特別係指一種杏鮑菇用於治療或預防失智症及其病徵之用途。 The invention relates to the use of a fungus, in particular to the use of Pleurotus eryngii for treating or preventing dementia and its symptoms.
按，近年來醫療科技進步及保健觀念提升，使人類平均壽命不斷延長，全球步入高齡化社會，許多退化性疾病的發生也隨之增加，其中以失智症(dementia)為大眾關注之焦點。根據國際失智症協會之報告可知，平均每3秒就會有一人罹患失智症，2015年全球失智人口超過4千萬人，並且估計於2050年時，全球會有超過1億人罹患失智症，因此，對於患者之照護成本係會成為各國健康預算之負擔。而失智症之類型中最為人所知者係為阿茲海默症，其主要成因在於腦內氧化壓力過高，造成腦部類澱粉樣胜肽(amyloid β-peptide,Aβ)斑塊堆積及神經纖維糾結(neurofibrillary tangles,NFTs)，促使腦神經細胞凋亡，最終使皮質層及海馬迴萎縮失去記憶功能。除了阿茲海默症會引起失智症外，如血管病變、外傷、感染性疾病、新陳代謝異常等皆會引起失智之症狀，包含記憶力衰退、認知障礙、學習力降低等。 According to recent advances in medical technology and health care concepts, the average life expectancy of human beings has continued to increase, and the world has entered an aging society, and the incidence of many degenerative diseases has also increased. Dementia is the focus of public attention. . According to the report of the International Dementia Association, one person suffers from dementia on average every 3 seconds. In 2015, there were more than 40 million people with dementia worldwide, and it is estimated that by 2050, there will be more than 100 million people worldwide. Dementia, so the cost of caring for patients becomes a burden on health budgets in various countries. The most known type of dementia is Alzheimer's disease, which is mainly caused by excessive oxidative stress in the brain, which causes brain amyloid β- peptide (A β ) plaques Accumulation and neurofibrillary tangles (NFTs) promote brain neuronal apoptosis, and eventually cause cortical layer and hippocampal atrophy to lose memory function. In addition to Alzheimer's disease can cause dementia, such as vascular disease, trauma, infectious diseases, metabolic abnormalities, etc. can cause symptoms of dementia, including memory loss, cognitive impairment, and decreased learning ability.
目前臨床上係未有能有效治療失智症之藥物，具體來說，對於輕度及中度失智症患者會藉由給予以醯膽鹼酶抑制劑延緩症狀之發生，或是透過運動、認知行為之衛教幫助患者改善日常生活活動，而部份失智 症患者會伴隨著精神上之疾病，故會投予精神科藥物緩和其症狀，惟，上述藥物皆無法達到治療或是有效改善失智症或其相關病徵之功效。 At present, there are no drugs that can effectively treat dementia. Specifically, for patients with mild to moderate dementia, the onset of symptoms can be delayed by the administration of cholinease inhibitors, or through exercise, Cognitive behavioral education helps patients improve their daily activities, and some patients with dementia will be accompanied by mental illness, so they will be given psychiatric drugs to alleviate their symptoms. However, none of the above drugs can achieve treatment or effectively improve Efficacy of dementia or its related symptoms.
由上可知，失智症無論是對於病患本身或是家屬皆會造成極大之負擔及痛苦，並且亦會大幅增加整體醫療成本，導致醫療資源更為缺乏，因此，尋求一種有效治療及/或預防失智症及其病徵之有效成份乃為醫藥領域研究之重要目標。 It can be seen from the above that dementia will cause great burden and pain to the patients themselves and their families, and will also greatly increase the overall medical cost, resulting in a shortage of medical resources. Therefore, an effective treatment and / or The effective ingredients for preventing dementia and its symptoms are important targets for research in the medical field.
本發明之主要目的係在於提供一種真菌之第二用途，其係指杏鮑菇具有治療或/及改善與磷酸化τ-蛋白含量增加相關疾病之用途。 The main purpose of the present invention is to provide a second use of a fungus, which refers to the use of Pleurotus eryngii to treat or / and ameliorate diseases related to increased phosphorylated τ-protein content.
本發明之另一目的係在於提供一種真菌之第二用途，其係指杏鮑菇具有治療或改善腦損傷及其相關病徵之用途。 Another object of the present invention is to provide a second use of a fungus, which refers to the use of Pleurotus eryngii to treat or improve brain damage and related symptoms.
於本發明之一實施例中係揭露將杏鮑菇用於製備治療及/或預防與磷酸化τ-蛋白含量增加相關疾病之組合物之用途。而藉由投予含有一有效量之杏鮑菇之組合物至一個體，尤其是腦中磷酸化τ-蛋白含量過高之個體，其係能有效改善該個體腦部損傷、記憶力及學習能力衰退之病徵，以達到改善或治療與磷酸化τ-蛋白含量過高相關疾病之功效。 In one embodiment of the present invention, the use of Pleurotus eryngii for preparing a composition for treating and / or preventing diseases related to increased phosphorylated τ-protein content is disclosed. And by administering a composition containing an effective amount of Pleurotus eryngii to an individual, especially an individual with an excessively high content of phosphorylated τ-protein in the brain, it can effectively improve the individual's brain damage, memory and learning ability. Symptoms of decline in order to achieve the improvement or treatment of diseases associated with excessive phosphorylation τ-protein content.
較佳地，該疾病係為失智症，如阿茲海默症。 Preferably, the disease is dementia, such as Alzheimer's disease.
較佳地，對於60公斤人體來說，每日杏鮑菇之有效劑量至少為3.8g，其中，又以7.75g以上為佳。 Preferably, for a 60 kg human body, the effective daily dose of Pleurotus eryngii is at least 3.8 g, and more preferably 7.75 g or more.
於本發明之另一實施例係揭露將杏鮑菇用於製備改善腦損傷及其相關病徵之組合物之用途，其中，相關病徵係為學習能力降低或記憶力降低。 In another embodiment of the present invention, the use of Pleurotus eryngii for preparing a composition for improving brain injury and related symptoms is disclosed, wherein the related symptoms are decreased learning ability or reduced memory.
更進一步來說，該腦損傷係由Aβ斑塊沈積或腦部氧化壓力過大所造成者。 Furthermore, the brain injury was caused by A β plaque deposition or excessive oxidative stress in the brain.
而對於60公斤人體來說，每日杏鮑菇之有效劑量至少為3.8g，其中，又以7.75g以上為佳。 For a 60 kg human body, the effective daily dose of Pleurotus eryngii is at least 3.8 g, and more preferably 7.75 g or more.
第一圖係為分析各組小鼠進行空間探索試驗之游泳路徑之結果。 The first figure is the result of analyzing the swimming path of the space exploration test of the mice in each group.
第二圖係為各組小鼠到達目標象限所需時間之統計結果。 The second graph is the statistical results of the time required for each group of mice to reach the target quadrant.
第三圖係為分析各組小鼠進行空間探索試驗之游泳距離百分比之結果。 The third graph is the result of analyzing the percentage of swimming distance of the mice in each group in the space exploration test.
第四圖係為分析各組小鼠於目標象限穿梭次數之結果。 The fourth graph is the result of analyzing the number of times the mice of each group shuttled in the target quadrant.
第五圖係為分析各組小鼠游泳速率之結果。 The fifth graph is the result of analyzing the swimming speed of the mice in each group.
第六圖係為分析各組小鼠進行T字迷宮試驗反應之結果。 The sixth graph is the result of analyzing the T-maze test of the mice in each group.
第七圖係為分析各組小鼠腦中磷酸化τ-蛋白表現之結果。 The seventh graph is the result of analyzing the expression of phosphorylated τ-protein in the brains of mice in each group.
第八圖係為分析各組小鼠腦中脂質過氧化產物濃度之結果。 The eighth graph is the result of analyzing the concentration of lipid peroxidation products in the brains of mice in each group.
第九圖係為分析各組小鼠腦中蛋白質羰基氧化物濃度之結果。 The ninth graph is the result of analyzing the protein carbonyl oxide concentration in the brains of mice in each group.
第十圖係為各組小鼠之腦中Aβ斑塊沉積情形。 The tenth figure is the deposition of Aβ plaques in the brain of mice in each group.
第十一圖係為分析各組小鼠Aβ斑塊面積百分比之結果。 The eleventh figure is the result of analyzing the percentage of Aβ plaque area of mice in each group.
為能說明本發明之功效，以下將以若干實例並搭配數據作更進一步說明如后。 In order to illustrate the efficacy of the present invention, a few examples and data will be used for further explanation below.
實例一：動物飼養條件 Example 1: Animal feeding conditions
自國家實驗動物中心(National Laboratory Center,Taiwan, R.O.C)購買72隻5週齡之C57BL/6J雄性小鼠，體重約27公克。該等小鼠先以一般實驗動物飼料(Laboratory Rodent Diet 5001)預養至16週齡，飼養環境溫度控制於25±2℃、相對溼度60±10%及各12小時光暗循環。 Seventy-two 5-week-old C57BL / 6J male mice were purchased from the National Laboratory Center (Taiwan, R.O.C.) and weighed approximately 27 grams. The mice were pre-raised with general laboratory animal feed (Laboratory Rodent Diet 5001) to 16 weeks of age. The temperature of the breeding environment was controlled at 25 ± 2 ° C, the relative humidity was 60 ± 10%, and the light and dark cycles were 12 hours each.
實例二：製備杏鮑菇子實體粉末 Example 2: Preparation of Pleurotus eryngii fruit body powder
取杏鮑菇子實體，以本發明所屬技術領域之通常技術將之製備為粉末，並且，分析出杏鮑菇子實體粉末之麥角硫因含量為1.3486mg/g。 Take the Pleurotus eryngii fruit body and prepare it into powder according to the ordinary technology in the technical field to which the present invention belongs, and analyze that the ergothione content of the powder of Pleurotus eryngii body is 1.3486mg / g.
根據美國食品藥物管理局公告內容可知：麥角硫因成人每日容許攝取量(acceptable daily intake,ADI)為10.5mg，並且以成人60公斤為基準，小鼠平均體重為27公克，根據小鼠與人體之換算係數12.3(Ranter,2005)，可得知小鼠每日麥角硫因攝食量，再將根據杏鮑菇子實體粉末之麥角硫因含量推算出杏鮑菇子實體粉末餵食劑量為43mg/mouse/day，將之作為中劑量，而高劑量係為中劑量之2.5倍、低劑量係為中劑量之0.5倍。 According to the US Food and Drug Administration announcement, ergothioneine's acceptable daily intake (ADI) for adults is 10.5 mg, and based on an adult's 60 kg, the average mouse weight is 27 grams. The conversion coefficient with human body is 12.3 (Ranter, 2005), we can know the daily ergotine intake of mice, and then calculate the Pleurotus eryngii body powder feeding based on the ergothione content of Pleurotus eryngii body powder The dose was 43 mg / mouse / day, which was taken as the middle dose, while the high dose was 2.5 times the middle dose and the low dose was 0.5 times the middle dose.
實例三：建立阿茲海默動物模式 Example 3: Establishing Alzheimer's Animal Model
參考先前文獻所揭阿茲海默症誘發手術(Jhoo等人，2004)，將預養16週齡之小鼠製備為阿茲海默之小鼠模式。 Referring to the Alzheimer's disease-induced surgery disclosed in the previous literature (Jhoo et al., 2004), pre-raised 16-week-old mice were prepared as Alzheimer's mouse models.
詳言之，將Aβ1-40溶於35%乙腈及0.1%三氟乙酸(pH=2.0)溶液中，製備為濃度0.16mM之Aβ1-40溶液。將小鼠先用異氟醚(3L/min)麻醉，根據Franklin及Paxions(2005)之小鼠腦部解剖圖，以立體定位儀進行海馬迴兩側CA1定位。以頭蓋骨bregma為原點，左右橫軸1.8mm(X軸±1.8mm)，縱軸2.3mm(Y軸-2.3mm)進行鑽孔，待鑽孔後，將Aβ1-40溶液以注射方式注入腦部深度1.5mm處，每邊之流速為2.5μL/5min。完成後以生物黏合劑修補頭蓋骨，並用縫合針及縫合器進行縫合。 In detail, the Aβ 1-40 was dissolved in 35% acetonitrile and 0.1% trifluoroacetic acid (pH = 2.0) solution, prepared in 0.16mM concentration of Aβ 1-40 solution. The mice were anesthetized with isoflurane (3L / min), and CA1 localization on both sides of the hippocampal gyrus was performed using a stereotactic instrument according to the brain anatomy of Franklin and Paxions (2005). Using the cranium bregma as the origin, drill the left and right horizontal axis 1.8mm (X axis ± 1.8mm) and the vertical axis 2.3mm (Y axis -2.3mm). After the hole is drilled, inject the Aβ 1-40 solution by injection. At a brain depth of 1.5 mm, the flow rate on each side was 2.5 μL / 5min. After completion, the cranium was repaired with bioadhesive and sutured with suture needles and staplers.
實例四：動物試驗 Example 4: Animal tests
將實例一中預養至16週齡之小鼠分為6組，每組12隻，其中，第一組係為正常小鼠，第二至六組係為阿茲海默模式小鼠，各該組小鼠係以下表一所示處理條件連續飼養六週。於飼養期間進行記憶學習能力試驗，而後將各該組小鼠予以犧牲，分別採集血液及臟器，以供後續實例進行分析。 The mice pre-raised to 16 weeks of age in Example 1 were divided into 6 groups of 12 mice, of which the first group was normal mice and the second to sixth groups were Alzheimer's mice. The mice in this group were reared for six weeks under the treatment conditions shown in Table 1 below. During the feeding period, a memory and learning ability test was performed, and then the mice in each group were sacrificed, and blood and organs were collected for analysis in subsequent examples.
實例五：水迷宮試驗 Example 5: Water Maze Test
實例四之各該組小鼠分別以其處理條件飼養至第28天後進行水迷宮試驗，並以攝影機觀察各該組小鼠之動態，再以影像分析軟體(Etho Visoin XT))分析數據，其中，所採用之泳池尺寸約為直徑125公分、高45公分；一直徑12公分及高25公分之平台，設於該泳池內，用以供小鼠休息；池內水位高度係高於該平台2公分，並且加入奶粉，形成混濁之水體，以隱藏該平台。 Each group of mice in Example 4 was reared under the treatment conditions until the 28th day, and a water maze test was performed. The dynamics of each group of mice were observed with a camera, and the data was analyzed by image analysis software (Etho Visoin XT). Among them, the size of the pool used is about 125 cm in diameter and 45 cm in height; a platform with a diameter of 12 cm and a height of 25 cm is set in the pool for the rest of the mice; the water level in the pool is higher than the platform 2 cm, and milk powder is added to form a turbid body of water to hide the platform.
於第28~30天時，該平台係固定於泳池第四象限之中心點，小鼠係頭向外進入泳池第二象限，每次游90秒，若於90秒內找到該平台，該小鼠則可於該平台上休息30秒，再於籠中休息30秒後，進行下次試驗，而若於90秒內未找到該平台，則引導該小鼠置該平台上休息30秒，再於籠中休息30秒後進行下次試驗。每天各該組之每隻小鼠進行4次試驗，統計各該小鼠每天之搜尋時間及搜尋距離。於第31天時，將該平台移至該泳池外，小鼠係頭向外進入泳池第二象限，使之游泳90秒，並以影像分析軟體紀錄小鼠於參考記隱試驗中，搜尋平台所放置之象限停留時間、游泳距離及穿越次數與全程游泳之路徑，結果如第一圖至第四圖所示。 On the 28th to 30th days, the platform was fixed at the center of the fourth quadrant of the swimming pool. The mouse head entered the second quadrant of the swimming pool and swam for 90 seconds each time. If the platform was found within 90 seconds, the platform The mouse can rest on the platform for 30 seconds, and then rest in the cage for 30 seconds, and then perform the next test. If the platform is not found within 90 seconds, guide the mouse to rest on the platform for 30 seconds, and then Rest in the cage for 30 seconds before proceeding to the next test. Each mouse of the group was tested 4 times a day, and the searching time and searching distance of each mouse were counted. On the 31st day, the platform was moved out of the pool, and the mouse head was moved out into the second quadrant of the pool and allowed to swim for 90 seconds. The image analysis software was used to record the mice in the reference cryptography test and search for the platform. The placed quadrant dwell time, swimming distance and number of crossings and the path of the whole swim, the results are shown in the first to fourth pictures.
由搜尋時間之統計結果可知，於試驗第一天(第28天)時，第一組至第六組找到該平台所花費之時間分別為：87.17±4.57、85.67±6.76、84.92±7.64、85.21±5.51、84.67±6.87及75.15±13.73秒，顯示第六組小鼠所花費之時間係明顯低於其他組小鼠。於試驗第二天，第一組小鼠係明顯縮短找到平台之時間(18.64±4.84秒)，第二組小鼠係花費83.38±10.28秒找到平台，第四組至第六組小鼠找到平台之時間分別為61.29±17.28、40.67±7.73及40.10±8.28。相較於第二組小鼠，第四組至第六組小鼠係分別縮短26%、51%及52%之搜尋時間。於試驗第三天，相較於第二組小鼠，其他各組小鼠之搜尋時間係分別縮短32~85%之時間。 From the statistical results of the search time, it can be known that on the first day (day 28) of the test, the time taken by the first to sixth groups to find the platform was 87.17 ± 4.57, 85.67 ± 6.76, 84.92 ± 7.64, 85.21 ± 5.51, 84.67 ± 6.87, and 75.15 ± 13.73 seconds, showing that the time taken by the sixth group of mice was significantly lower than that of the other groups of mice. On the second day of the experiment, the first group of mice significantly shortened the time to find the platform (18.64 ± 4.84 seconds), the second group of mice took 83.38 ± 10.28 seconds to find the platform, and the fourth to sixth groups of mice found the platform The time was 61.29 ± 17.28, 40.67 ± 7.73 and 40.10 ± 8.28. Compared with the second group of mice, the search time of the fourth to sixth groups of mice was reduced by 26%, 51%, and 52%, respectively. On the third day of the experiment, compared with the second group of mice, the searching time of the other groups of mice was shortened by 32 to 85%.
就搜尋距離來說，試驗第一天，第一組小鼠之搜尋距離為9.90±0.59公尺，明顯低於第三組至第五組(11.47~11.95公尺)；於試驗第二天，除第二組小鼠(10.30±1.48公尺)外，其餘各組之搜尋距離皆有縮短之趨勢，依序分別為3.61±1.28、8.27±2.01、5.03±1.81、7.51±1.87及 4.78±1.35公尺。於試驗第三天，第一組至第六組之搜尋距離分別為3.36±0.44、11.06±1.12、7.94±1.68、5.23±2.19、3.56±1.31及3.46±1.78公尺；相較於第二組，其餘各組依序係分別縮短70%、28%、53%、68%及69%之搜尋距離。 In terms of search distance, on the first day of the test, the search distance of the first group of mice was 9.90 ± 0.59 meters, which was significantly lower than that of the third to fifth groups (11.47 to 11.95 meters). On the second day of the test, Except for the second group of mice (10.30 ± 1.48 meters), the search distance of the other groups has a tendency to shorten, in order of 3.61 ± 1.28, 8.27 ± 2.01, 5.03 ± 1.81, 7.51 ± 1.87, and 4.78 ± 1.35. meter. On the third day of the test, the search distances of the first to sixth groups were 3.36 ± 0.44, 11.06 ± 1.12, 7.94 ± 1.68, 5.23 ± 2.19, 3.56 ± 1.31, and 3.46 ± 1.78 meters, compared to the second group. , The remaining groups were shortened by 70%, 28%, 53%, 68%, and 69% respectively.
再者，由第一圖之結果可知：第二組小鼠搜尋平台之軌跡係集中於第二象限，無明顯之探索方向及目標；第三組小鼠之搜尋軌跡係集中於第三及第四象限；第四組至第六組小鼠之軌跡則集中於第四象限。由第二圖之結果可知，第一組小鼠於目標象限徘徊時間為25.70±5.7秒，係明顯高於第二組(12.20±6.9秒)，並且第三組至第六組小鼠之徘徊時間(21.43±4.53、23.65±5.97、22.25±3.62及29.33±3.79秒)皆較第二組小鼠增加。 Furthermore, from the results of the first figure, it can be seen that the trajectory of the mouse search platform of the second group is concentrated in the second quadrant, and there is no obvious exploration direction and target; the search trajectory of the third group of mice is concentrated on the third and the second. Four quadrants; the trajectories of the fourth to sixth groups of mice are concentrated in the fourth quadrant. It can be seen from the results in the second graph that the hovering time of the first group of mice in the target quadrant is 25.70 ± 5.7 seconds, which is significantly higher than that of the second group (12.20 ± 6.9 seconds), and the hovering time of the third group to the sixth group of mice Time (21.43 ± 4.53, 23.65 ± 5.97, 22.25 ± 3.62, and 29.33 ± 3.79 seconds) were all longer than those in the second group of mice.
由第三圖之結果可知第一組、第三組至第六組小鼠之目標象限游泳距離除以總距離之百分比係分別為26.34±5.88%、22.24±3.93%、27.19±5.60、24.30±4.16及28.40±4.29%，皆較第二組小鼠高(13.72±7.21%)，藉此結果顯示小鼠之徘徊時間與游泳距離具有一致性，並且排除小鼠因停滯不動導致停留時間增加之情形。而由第四圖之結果可知，第一組至第六組小鼠穿梭第四象限之平均次數分別為7.25±1.16、3.50±2.00、6.38±1.30、7.63±2.00、7.25±1.06及8.50±2.73次。 According to the results in the third figure, the percentages of the target quadrant swimming distance divided by the total distance of the first group, the third group to the sixth group of mice are 26.34 ± 5.88%, 22.24 ± 3.93%, 27.19 ± 5.60, 24.30 ± 4.16 and 28.40 ± 4.29%, both higher than the second group of mice (13.72 ± 7.21%). This result shows that the hovering time of the mice is consistent with the swimming distance, and the increase in the dwell time of the mice due to stagnation is excluded. situation. According to the results in the fourth figure, the average number of times the mice in the first to sixth groups shuttled the fourth quadrant was 7.25 ± 1.16, 3.50 ± 2.00, 6.38 ± 1.30, 7.63 ± 2.00, 7.25 ± 1.06, and 8.50 ± 2.73. Times.
由第28~31天之結果可知，未被投予杏鮑菇子實體粉末之阿茲海默症小鼠係不會隨著試驗天數增加而縮短搜尋時間及距離，並且無法記憶住平台位置。當阿茲海默症小鼠被投予杏鮑菇子實體粉末時，則會隨著試驗天數增加而縮短搜尋時間及距離，並能夠提昇其記憶能力。 From the results on days 28 to 31, it can be seen that Alzheimer's disease mouse lines not administered with Pleurotus eryngii fruit body powder will not shorten the search time and distance as the number of experimental days increases, and will not be able to remember the platform position. When Alzheimer's disease mice are administered powder of Pleurotus eryngii, the search time and distance will be shortened as the number of experimental days increases, and their memory capacity will be improved.
更進一步者，利用第28~30天之試驗結果得知各該組小鼠之 游泳速率，如第五圖所示，可知第二組小鼠之游泳速率(14.95±4.09cm/s)係明顯低於第一組、第三組至六組小鼠(18.68±2.04、19.73±2.78、19.49±3.60、21.07±1.83及18.18±2.82cm/s)。基於先前研究(Sonn等人，2013)係揭露由於阿茲海默症小鼠之記憶力較差，使游泳速率會較控制組低，因此，由第五圖之結果顯示本發明所揭杏鮑菇係能提昇阿茲海默症小鼠之游泳速率，而能達到改善或治療阿茲海默症所引起之記憶力缺失之症狀。 Furthermore, using the test results from the 28th to 30th days to know the swimming speed of each group of mice, as shown in the fifth figure, it can be seen that the swimming speed of the second group of mice (14.95 ± 4.09cm / s) is obvious. It was lower than the mice in the first group, the third group to the sixth group (18.68 ± 2.04, 19.73 ± 2.78, 19.49 ± 3.60, 21.07 ± 1.83, and 18.18 ± 2.82cm / s). Based on previous research (Sonn et al., 2013), it was revealed that the memory of Alzheimer's mice is poor, and the swimming rate will be lower than that of the control group. Therefore, the result of the fifth figure shows the Pleurotus It can increase the swimming speed of Alzheimer's mice, and can improve or treat the symptoms of memory loss caused by Alzheimer's disease.
由上可知，藉由阿茲海默症誘發手術確實建立出阿茲海默模式小鼠，使其無法記憶平台位置，而透過投予本發明所揭杏鮑菇係能改善罹患阿茲海默症者之記憶及學習能力。 As can be seen from the above, Alzheimer's model mice are indeed established through Alzheimer's disease-induced surgery, making it impossible to memorize the platform position, and the administration of the Pleurotus eryngii line disclosed in the present invention can improve Alzheimer's disease. Memory and learning ability
實例六：T字迷宮試驗 Example 6: T-maze test
首先，以黑色壓克力製作一T字迷宮裝置，其三臂等長，該裝置之長、寬、高分別為70、10、20公分，而設置於距離地面50公分處。 First, a T-shaped labyrinth device was made of black acrylic with three arms of equal length. The length, width, and height of the device were 70, 10, and 20 cm, respectively, and it was set at a distance of 50 cm from the ground.
取實例四中以不同條件飼養33天之各該組小鼠，並於進行試驗前先禁食8小時。試驗第一天於T字迷宮裝置之左右側道底端放置食物，將各該組小鼠放進起始通道內自由行動及攝食5分鐘；第二天於右側通道底端放置食物，隨後左右側設置相互交換，而各該小鼠各邊訓練三次；第三天將左側通道設為正確路徑，右側通道係以隔板阻擋，當小鼠抵達左側即可安全吃到食物；隨後以隔板阻擋左側通道，當小鼠抵達右側通道時，抽走食物並以隔板侷限活動範圍10秒，重複3次；第四天將左側設置為正確路徑，右側為錯誤路徑，紀錄及分析各該小鼠抵達正確路徑之次數，結果如第六圖所示。 Take the mice in this group for 33 days under different conditions in Example 4, and fast for 8 hours before performing the test. On the first day of the experiment, food was placed on the bottom of the left and right sides of the T-shaped labyrinth device. Each group of mice was placed in the initial channel to move freely and ingest for 5 minutes. On the second day, the food was placed on the bottom of the right channel and left and right The side settings were exchanged, and each mouse was trained three times on each side. On the third day, the left channel was set to the correct path, and the right channel was blocked by a partition. When the mice reached the left, they could safely eat the food; Block the left channel. When the mouse reaches the right channel, remove the food and limit the range of movement with the partition for 10 seconds. Repeat 3 times. On the fourth day, set the left path to the correct path and the right path to the wrong path. The number of times the rat reached the correct path, the results are shown in Figure 6.
由第六圖之結果可知，第一組至第六組小鼠獲尋時食物之正 確率依序分別為75.56±8.82%、44.44±13.33%、71.11±10.54%、75.65±13.33%、82.22±12.02%及70.00±15.12%，其中，第二組小鼠之正確率係明顯低於其他組別。 From the results in Figure 6, it can be seen that the correct rates of food when the mice in groups 1 to 6 were found were 75.56 ± 8.82%, 44.44 ± 13.33%, 71.11 ± 10.54%, 75.65 ± 13.33%, 82.22 ± 12.02% and 70.00 ± 15.12%. Among them, the accuracy rate of the second group of mice was significantly lower than that of the other groups.
由此可知，由於阿茲海默症會使個體記憶力變差，即使於高強度刺激下，仍難以使個體產生深刻記憶，而藉由投予本發明所揭杏鮑菇係改善罹患阿茲海默症個體記憶力不佳之病症，增加尋獲食物之正確率。是以，本發明所揭杏鮑菇確實具有改善或治療失智症或其所引起記憶力缺失之病徵。 It can be seen that, because Alzheimer's disease can cause individuals' memory to deteriorate, even under high-intensity stimuli, it is still difficult for individuals to produce profound memories. Symptomatic individuals with poor memory can increase the accuracy of finding food. Therefore, the Pleurotus eryngii disclosed in the present invention does have symptoms of improving or treating dementia or memory loss caused by it.
實例七：分析小鼠大腦之結果 Example 7: Results from analyzing mouse brains
將各該組小鼠犧牲後，分別取出大腦，右半邊大腦以10%福馬林溶液固定，左半邊大腦則進行均殖化、離心後，取上清液，分別以市售之τ-蛋白套組(沛鑫生物科技公司，Cat.No.E93893M，Taiwan)、TBARS套組(Cayman，Cat.No.10009055，美國)、protein carbonyl colorimetric套組(Cayman，Cat.No.10005020，美國)測定其內磷酸化τ-蛋白、丙二醛及蛋白羰基氧化物含量，而檢測樣本中磷酸化τ-蛋白、丙二醛及蛋白羰基氧化物含量之詳細步驟係為本發明所屬技術領域者之通常知識，故於此不加以贅述。各該組小鼠之大腦中磷酸化τ-蛋白、丙二醛及蛋白羰基氧化物含量係如第七圖至第九圖、表二所示。 After each of the sacrificed mice, brains were removed, the right half of the brain was fixed in 10% formalin, the left half of the brain was performed decolonization, after centrifugation, the supernatant protein were commercially available sets of τ- Group (Peixin Biotechnology, Cat. No. E93893M, Taiwan), TBARS kit (Cayman, Cat. No. 10009055, USA), protein carbonyl colorimetric kit (Cayman, Cat. No. 10005020, USA) Internal phosphorylation of τ-protein, malonaldehyde and protein carbonyl oxide content, and the detailed steps for detecting the content of phosphorylated τ-protein, malonaldehyde and protein carbonyl oxide in a sample are the general knowledge of those skilled in the art to which this invention belongs. , So I will not repeat them here. The contents of phosphorylated τ-protein, malondialdehyde, and protein carbonyl oxide in the brain of each group of mice are shown in Figures 7 to 9 and Table 2.
由先前文獻所揭內容可知，阿茲海默症會使個體大腦內之磷酸化τ-蛋白及自由基分子含量增加，使磷酸化τ-蛋白神經微管緊密接合而分離，導致神經崩解失去功能，而自由基分子則會攻擊白質側鏈，造成神經細胞受損；由於阿茲海默症會造成腦損傷，因而大腦內脂質氧化產物：丙二醛之含量會增加，而當丙二醛之含量越高時，代表大腦神經損傷越嚴重。因此，第二組小鼠大腦內之磷酸化τ-蛋白、丙二醛及蛋白羰基氧化物含量係皆明顯高於第一組小鼠。 According to the contents disclosed in the previous literature, Alzheimer's disease will increase the content of phosphorylated τ-protein and free radical molecules in the individual's brain, tightly bind and separate the phosphorylated τ-protein neural microtubules, resulting in loss of neurolysis. Function, and free radical molecules will attack the white matter side chain, causing nerve cell damage; As Alzheimer's disease will cause brain damage, the content of malondialdehyde in the brain will increase, and when malondialdehyde The higher the content, the more severe the nerve damage to the brain. Therefore, the contents of phosphorylated τ-protein, malondialdehyde and protein carbonyl oxide in the brain of the second group of mice were significantly higher than those in the first group of mice.
而藉由投予本發明所揭杏鮑菇至罹患阿茲海默症之個體時，能使大腦中磷酸化τ-蛋白、丙二醛及蛋白羰基氧化物含量係明顯較未投予杏鮑菇子實體粉末者低，顯示本發明所揭杏鮑菇係藉由降低腦中氧化壓力，達到降低腦中磷酸化τ-蛋白濃度之功效，亦能清除腦內自由基，使腦中蛋白質羰基氧化物濃度降低，減少神經細胞受損之情形。因此，本發明所揭杏鮑菇係具有治療或/及預防失智症及其引發神經損傷之功效。 By administration of Pleurotus eryngii disclosed in the present invention to individuals suffering from Alzheimer's disease, the content of phosphorylated τ-protein, malondialdehyde and protein carbonyl oxide in the brain can be significantly lower than that of Pleurotus eryngii The mushroom body powder is low, which shows that the Pleurotus eryngii disclosed by the present invention can reduce the oxidative stress in the brain and reduce the concentration of phosphorylated τ-protein in the brain. It can also remove free radicals in the brain and make protein carbonyl groups in the brain Reduced oxide levels reduce the risk of damage to nerve cells. Therefore, the Pleurotus eryngii disclosed in the present invention has the effect of treating or / and preventing dementia and causing nerve damage.
實例八：免疫組織化學染色之結果 Example 8: Results of immunohistochemical staining
將各該組小鼠之大腦進行免疫組織化學染色分析，其中，組 織切片、染色之步驟係為本發明所屬技術領域之通常知識，故於此不加以冗言。而經染色後之組織切片係於40倍顯微鏡視野下進行拍攝，結果如第十圖所示，並以析影像軟體(Image J,pro plus 6.3,MediaCybernetics Inc,USA)分析各該小鼠大腦Aβ斑塊沉積量之百分比，其中，計算公式：Aβ斑塊面積百分比=(Aβ斑塊面積/大腦面積)x 100%，結果如第十一圖及表三所示。 The brains of the mice in each group were analyzed by immunohistochemical staining. The steps of tissue sectioning and staining are common knowledge in the technical field to which the present invention belongs, and therefore will not be repeated here. The stained tissue sections were photographed under a microscope field of 40x. The results are shown in Figure 10, and the mouse brain A was analyzed with image analysis software (Image J, pro plus 6.3, MediaCybernetics Inc, USA). The percentage of β plaque deposition, where the calculation formula: A β plaque area percentage = (A β plaque area / brain area) x 100%, the results are shown in Figure 11 and Table 3.
由本實例之結果可知，第二組小鼠大腦內Aβ斑塊面積係高於第一組，而相較於第二組小鼠，第三組至第六組小鼠大腦內Aβ斑塊面積係明顯降低。更進一步來說，由先前研究所揭內容可知，褪黑激素係透過降低腦部壓力，使阿茲海默症小鼠內之Aβ斑塊沈積數量變少，因此可知，本發明所揭杏鮑菇係能藉由減少腦部氧化壓力，使腦部中類澱粉前身蛋白表現及β分泌酶活性降低，以減少Aβ斑塊沈積於腦部。據此，本發明所揭杏鮑菇係能有效地預防或/及治療失智症或其相關病徵。 From the results of this example, it can be seen that the area of A β plaques in the brain of the second group of mice is higher than that of the first group, and compared to the second group of mice, the A β plaques in the brain of the third to sixth groups of mice The area is significantly reduced. Furthermore, it is known from the previous research that melatonin reduces the amount of Aβ plaque deposition in Alzheimer's mice by reducing brain pressure. Therefore, it can be known that Mushrooms can reduce the expression of amyloid precursor protein and β-secretase activity in the brain by reducing oxidative stress in the brain to reduce the deposition of Aβ plaques in the brain. Accordingly, the Pleurotus eryngii line disclosed in the present invention can effectively prevent or / and treat dementia or its related symptoms.
藉由上述實施例及實例之內容可清楚得知本發明所揭杏鮑 菇子實體係確實能夠減少神經細胞受損之情形、提昇個體學習能力及記憶力，故當投予有效量之本發明所揭杏鮑菇至一個體，尤其是罹患失智症或是阿茲海末症者，係能有效改善或治療失智症或其相關病徵，如學習障礙、認知功能衰退、記憶力減弱等。 According to the contents of the above embodiments and examples, it can be clearly known that the Pleurotus eryngii seedling system disclosed in the present invention can indeed reduce the damage of nerve cells and improve the learning ability and memory of individuals. Therefore, when an effective amount of the present invention is administered, Revealing Pleurotus eryngii to a body, especially those suffering from dementia or Alzheimer's disease, can effectively improve or treat dementia or its related symptoms, such as learning disabilities, cognitive decline, and memory loss.
而更進一步來說，經上述實例之結果可知小鼠每日須攝食21.5mg之杏鮑菇(低劑量)，可達到預防或治療失智症及其相關病徵之功效，又以攝食43mg以上之杏鮑菇效果更佳。根據人與小鼠間之換算係數為12.3，以及杏鮑菇內麥角硫因量之含量(1.3486mg/g)，可知以60公斤之成人來說，每日至少須攝食3.875g以上之杏鮑菇，始能達到預防或治療失智症及其相關病徵之功效，並於杏鮑菇之攝食量達到7.75克以上時，效果最佳。而考量人體每日建議攝取麥角硫因量，建議60公斤之成人每日攝取量不要超過8克杏鮑菇。 Furthermore, according to the results of the above examples, it is known that mice need to ingest 21.5 mg of Pleurotus eryngii (low dose) daily, which can achieve the effect of preventing or treating dementia and related symptoms, and ingesting more than 43 mg Pleurotus eryngii is more effective. According to the conversion factor between human and mouse is 12.3, and the content of ergothionein in Pleurotus eryngii (1.3486mg / g), it can be known that for a 60 kg adult, at least 3.875g of apricots must be consumed daily. Pleurotus ostreatus can achieve the effect of preventing or treating dementia and its related symptoms, and the best effect is when the amount of Pleurotus eryngii eating exceeds 7.75 grams. Considering the human body's recommended daily intake of ergothioneine, it is recommended that the daily intake of a 60 kg adult should not exceed 8 grams of Pleurotus eryngii.
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