1 . Chinese medicine offers new  treatments

 2. Ancient Chinese herb may cure hangovers, alcoholism

 3. Chinese tree extract stops rats getting drunk

 4. 枳椇子：抗帕金森抗衰老

 5. 返老还童，抗帕金森药抗衰老

 6. Advances in neuroprotective ingredients of medicinal herbs by using cellular and anamal models of parkinson's d disease

     

     Turnjujube（Hovenia） is an ancient Chinese herbal medicine.

     It is the fleshy stalk of fruits and seeds of Smoothleaf Turnjujube plants. It mainly produced in China's Shanxi, Guangdong, Hubei, Zhejiang, Jiangsu, Anhui, Fujian and other places. It is in both of wild or cultivated. It harvests in October to November. Take off from the stalk of the fruit, dried or crushed husk, sieve out the seeds, remove impurities, dried, in raw use.

     Turnjujube modern research.

     1. Chemical composition: Hovenia contains alkali, EHD glycosides, glucose and potassium malate, and so on.

     2. Pharmacological effect: A significant diuretic effect, Hovenia saponins has antihypertensive effect, Hovenia homogenates has anti-lipid peroxidation and enhanced cold-resistant and heat-resistant.

    Chinese medicine offers new  treatments

                           DAILY NEWS

  

17 June 2011

                    

    A hooked herb, root extract and a dash of bark – it may sound like a witches’ brew, but these compounds could provide treatments for diseases that have so far foiled western doctors, such as Parkinson’s and irritable bowel syndrome.

    For over 2000 years Chinese doctors have treated “the shakes” – now known as Parkinson’s disease – with gou teng, a herb with hook-like branches.

    Early this year, 115 people with Parkinson’s were given a combination of traditional Chinese medical herbs, including gou teng, or a placebo for 13 weeks. At the end of the study, volunteers who had taken the herbs slept better and had more fluent speech than those taking the placebo.

    Gou teng appears to stabilise symptoms, says Li Min, a traditional Chinese doctor at Hong Kong Baptist University. Now, Li and her colleagues have figured out how it might work.

    Preserving dopamine

    Parkinson’s symptoms, such as muscle tremors, slowness of movement and rigidity, are caused by the progressive destruction of brain cells that produce dopamine. Previous work has suggested that an abundance of a protein called alpha-synuclein may be to blame. Current treatments aim to boost levels of dopamine, which only partly alleviates symptoms and does not affect the protein clusters.

    It is thought that clumps of alpha-synuclein accumulate because brain cells cannot remove them through autophagy – a type of programmed cell death. Mice without the genes needed for autophagy quickly develop Parkinson’s-like symptoms.

    According to Li, autophagy is the only known process that gets rid of abnormal proteins within cells. “Enhancing this pathway may be key to treating Parkinson’s,” she says.

    Li’s team screened gou teng for its active compounds and tested which of these compounds increase the rate of autophagy and remove alpha-synuclein. To do this, the team added the compounds to human nerve cells and fruit flies that had been genetically modified to develop alpha-synuclein clusters.

    Rapamycin connection

    One of the compounds, an alkaloid called isorhy, induced autophagy for alpha-synuclein at a similar rate to a drug called rapamycin. Rapamycin is normally used to suppress the immune system in transplant patients, but has recently been touted as a promising candidate for Parkinson’s treatment because it prevents nerve cell death in flies with a Parkinson’s-like disease. However, because rapamycin depresses the immune system, it would have serious side effects for people with Parkinson’s. Gou teng, meanwhile, has been taken for centuries with no apparent side effects.

    Further testing found that isorhy activates autophagy through a different pathway to rapamycin, which may explain why it does not affect the immune system in the same way. Li, who recently presented her results at the Keystone Symposia on Molecular and Cellular Biology in Whistler, British Columbia, Canada, will begin trials of Isorhy in rodents later this year.

    Herbs for the gut

    Meanwhile, Zhaoxiang Bian, also at Hong Kong Baptist University, is developing a drug called JCM-16021 for irritable bowel syndrome (IBS) using seven herbal plants and based on a Chinese formulation called tong xie yao fang, used to treat IBS since the 1300s.

    IBS affects up to 20 per cent of people, causing abdominal pain, constipation and diarrhoea. “They feel really rotten, and it’s sufficiently severe for people to take time off work,” says John Furness at the University of Melbourne, Australia. Stress management can help symptoms, but there is no effective medicine to treat it.

    In 2007, Bian gave 80 people with IBS either JCM-16021 with Holopon – a drug that interrupts nerve impulses in the parasympathetic nervous system responsible for digestion – or Holopon alone. After eight weeks, 52 per cent of those given JCM-16021 with Holopon reported reduced IBS symptoms, compared with 32 per cent of those given Holopon alone.

   IBS is partly caused by high levels of serotonin in the gut. Last year, Bian found that giving JCM-16021 to rats with IBS-like symptoms broke down serotonin in their bowel faster than normal, reducing their discomfort.

    His team has since isolated several active compounds in JCM-16021 that block serotonin’s activity in the rat gut, including magnolol, a herb taken from the bark of Magnoliae officinalis.

    Root of relief

    This month, Keiko Lee at Juntendo University in Tokyo, Japan, found that paeoniflorin, a root extract used in JCM-16021, acts as an analgesic in rats, inhibiting adrenaline receptors in the spine.

    Bian is now combining the active extracts of JCM-16021 to develop a new drug that attacks IBS from different angles. Unlike conventional approaches, which target only one aspect of the disease, he believes the combination drug will be more effective.

    “I think it is a very rational way to go,” says Furness, but warns that combination drugs usually take longer to gain approval because of the greater-than-usual possibility of unexpected side effects. But because these compounds have a long history of being safe for human consumption, it is hoped they will be approved faster, says Li.

    “In the past the pharmaceutical industry didn’t put much effort into traditional Chinese medicine,” says Jing Kang, a biochemist at Harvard Medical School in Boston. “In the past few years this has been changing. More people are paying attention.”

    Journal references: gou teng and Parkinson’s: Parkinson’s Disease, DOI: 10.4061/2011/789506; rapamycin and Parkinson’s: Nature Neuroscience, DOI: 10.1038/nn.2372; JCM-16021 and serotonin:World Journal of Gastroenterology, DOI: 10.3748/wjg.v16.i7.837; paeoniflorin and pain relief: European Journal of Pain DOI: 10.1016/j.ejpain.2011.04.011

 Ancient Chinese herb may cure 

                    hangovers, alcoholism

Experiment shows that a Hovenia Dulcis extract mitigates many of the negative effects of alcohol.

By Tuan Nguyen | January 13, 2012 -- 06:00 GMT (22:00 PST) | Topic: Innovation

Whether it's drunk texting or drunk dialing, technology and booze usually don't mix. And now a recent finding may make it so that people are a lot less likely to find themselves in these embarassing situations. That's because scientists believe they have discovered a compound that mitigates many of the impairing effects of alcohol.

We're talking about an antidote that can ease the feeling of a nasty hangover, help you sober up and possibly even eliminate the need for 12-step programs. Actually, perhaps "discovered" isn't quite the right word. The sobering properties of the Hovenia Dulcis tree have been touted by Chinese herbalists for centuries. But it's only recently that a group of researchers from UCLA began lab-testing such claims by running a series of experiments using a chemical extract from the seed known as Dihydromyricetin (DHM).

Instead of human subjects, the researchers used intoxicated rats since alcohol consumption impacts both in similar ways. After having the rodents down about the human equivalent of 15 to 20 bottles of beer over a period of two hours, they found that the ones that were given booze spiked with DHM had a higher tolerance and were able to sober up quicker, in about 15 minutes. They also found that, within two days, the extract helped to clear up hangover symptoms, such as anxiety and susceptibility to seizures.

• Related: New car technology can stop drunks from driving

But the really significant finding was that while some rats tended to consume even higher quantities of alcohol after the initial drinking session, the ones that took it with DHM didn't have the same craving. "When you drink alcohol with DHM, you never become addicted," lead researcher Jing Liang wrote in the Journal of Neuroscience.

Although promising, the study's results are still preliminary and A. Leslie Morro, a neuroscientist at UNC warns of jumping to conclusions. According to a report in Science News:

Though the results are exciting, they don’t mean that a hit of Hovenia extract can enable a night of consequence-free binge drinking, Morrow says. Alcohol has many effects in the brain, and DHM may not block them all.

Alcohol works in part by changing the behavior of proteins known as GABA receptors, which are involved in curbing brain excitation. DHM blocks alcohol’s effects by latching onto these receptors in the brain. Another compound called RO15-4513, discovered by Paul and collaborators, also blocked alcohol by interfering with GABA receptors, but it caused seizures.

So far, Liang and her team have found no side effects from DHM. The researchers now plan to test DHM’s effect on people.

Chinese tree extract stops rats getting drunk

For hardened drinkers, it sounds too good to be true: a natural substance that keeps them sober no matter how much they drink, neutralises hangovers and eventually breaks the cycle of alcohol addiction.

Alcoholism is a huge problem globally, killing 2.5 million people a year according to the World Health Organization. There has been serious research recently looking for drugs that stop people drinking, or at least encourage them to drink less.

Extracts of a Chinese variety of the oriental raisin tree (Hovenia dulcis) could be the answer. The extracts have been used for 500 years to treat hangovers in China. Now dihydromyricetin (DHM), a component of the extract, has proved its worth as an intoxication blocker in a series of experiments on boozing rats. It works by preventing alcohol from having its usual intoxicating effects on the brain, however much is in blood.

Soon, a preparation containing DHM will be tested for the first time in people. “I would give it to problem drinkers who can’t resist going to the pub and drinking,” says pharmacologist Jing Liang of the University of California, Los Angeles, who led the research team.

“DHM will reduce the degree of drunkenness for the amount of alcohol drunk and will definitely reduce the hangover symptoms,” says Liang. “In time, it will reduce their desire for alcohol.”

Too drunk to stand

Liang first tested whether DHM blocks the clumsiness and loss of coordination caused by drinking too much. To do this, she measured how long it took for treated rats to right themselves after being laid on their backs in a V-shaped cradle.

After she injected rats’ abdomens with a dose of alcohol proportionate to the amount a human would get from downing 15 to 20 beers in 2 hours by a human, they took about 70 minutes, on average, to right themselves. However, when an injection of the same amount of booze included a milligram of DHM per kilogram of rat body weight, the animals recovered their composure within just 5 minutes.

DHM also stopped rats in a maze from behaving in ways resembling anxiety and hangovers. Rats given heavy doses of alcohol cowered away in corners of the maze, whereas those given the extract with their alcohol behaved normally and were as inquisitive as rats given no alcohol at all, exploring the more open corridors of the maze.

Finally, DHM appeared to discourage rats from boozing when they had a free choice between drinking a sweetened solution of alcohol or sweetened water. Over a period of three months, rats will normally get addicted to increasing volumes of the hard stuff. Rats given DHM, though, drank no more than about a quarter of the amount that the “boozers” eventually built up to. Moreover, boozy rats that had worked up to the higher levels suddenly dropped down to a moderate intake when given DHM after seven weeks.

All the benefits of DHM were lost instantly when Liang also gave the rats a drug called flumazenil, which is known to block receptors in the brain for a neurotransmitter called gamma aminobutyric acid (GABA). According to Liang, this proved that DHM works by stopping alcohol from accessing the same receptors. This, she says, explains why DHM kept the rats sober even when they had huge amounts of alcohol in their blood.

Good idea?

“This supports other data that GABA receptors are key in the actions of alcohol and that targeting this interaction is a viable approach to reducing alcohol intake,” says David Nutt of Imperial College London, former head of the British government’s advisory committee on drugs. “Let’s hope it’s safe to use in humans.”

Other alcohol experts fear that the availability of a “sobriety pill” could encourage more, not less drinking. Markus Heilig, clinical director of the US National Institute on Alcohol Abuse and Alcoholism in Bethesda, Maryland, says that Roche abandoned development of a similar compound called Ro15-4513. “There was a lot of philosophical worry that an ‘alcohol antidote’ would entice people to consume alcohol and then count on being able to terminate the intoxicating effects on demand,” says Heilig.

Ro15-4513 caused serious side effects, including anxiety and convulsions. Liang says there is no sign that DHM carries similar side effects.

Journal reference: The Journal of Neuroscience, DOI: 10.1523/jneurosci.4639-11.2012

枳椇子：又一个中药传奇？_华人新闻_新闻中心_ - 侨报网

          http://news.sina.com   2015年10月23日 21:05   僑報

【僑報記者蕭東】枳椇，是一種落葉闊葉高大喬木，別名拐棗、鷄爪果、萬壽果等。庭院宅旁常有栽培。在中國大部份省區均有零星分佈。枳椇子，就是枳椇的果實（Hovenia）

　　中國人很早就發現枳椇子的藥用功能。最早見於《唐本草》，刊行於1590年的李時珍《本草綱目》说它“味甘、性平、無毒”， “其枝、葉，止嘔逆，解酒毒，辟蟲毒”。

　　洛杉磯加州大學（UCLA）的首席研究員梁京所領導的團隊發現，枳椇子這一味古老的中藥，有着遠超古人理解的神奇功能。

　　一、化酒為水，這回老鼠沒有沉醉

　　梁京在實驗室裏。（僑報記者蕭東攝 ）

　　“今宵酒醒何處，楊柳岸，曉風殘月。” 古詩詞中的醉酒充滿浪漫，但在現實生活中，醉酒是有害的，致命的。 美國每年有超過萬人死於因醉駕而引發的車禍。因此，尋找解酒藥，成為輓救生命的另一場戰爭。梁京團隊也加入了這場戰爭。她把目光聚焦到了枳椇子。梁京说，她之所以注意到枳椇子，因為她發現，做菜時放一些枳椇子，就不容易醉酒。

　　枳椇子最先被人發現的特殊功能就是解酒。陸璣《疏義》記載了一個有趣的故事：“昔有南人修舍用此木，誤落一片入酒瓮中，酒化為水也”。《蘇東坡集》中還記載了這樣一則故事:蘇東坡的一個同鄉揭穎臣因長期喝酒得了一種飲食倍增、小便頻頻的病。后來蘇東坡向他推薦了一個名叫張肱的醫生，用醒酒藥治愈。張肱所用的一味主藥就是枳椇子。

　　作為科學家，就不能停留在古人“知其然而不知所以然”的境地，而必須找出導致枳椇子産生解酒功能的化學成分。在研究中，梁京團隊找出了他們稱之為枳椇子素的成分，其藥理作用原理是，酒精通過改變大腦抑制系統的神經GABA受體的可塑性，來改變或降低大腦抑制調節系統的功能，也稱酒精的毒性效應。而枳椇子素使這些大腦中的受體少受酒精的毒性效應影響。

　　他們做了兩組實驗，用鼠來模擬人類酒精中毒及酒后綜合症。 在第一組，讓鼠“喝入”一定量酒精，相當於人在兩小時內喝10至15罐啤酒，鼠馬上就“沉醉不知歸路”，失去了知覺及生理反射，不能自行翻轉。一個小時后才逐漸恢復常態。但當這些鼠接受枳椇子素后，知覺及生理反射約15分鐘后恢復。他們還做了第二組實驗，測試枳椇子素對酒精成癮性的療效。他們驚喜地發現，一直不斷“喝酒”的鼠，在服用枳椇子素后，就沒有再産生酒精依賴性。

　　梁京團隊的這一研究成果，發表在2012年的《神經科學 》（ Neuroscience）雜誌上，並引發了主流媒體的廣泛報導。2012年1月份的《新科學家》 （New Scientists）雜誌以“中國草藥提取物使老鼠停止醉酒”為題，報導他們的成果。可以想象，酒醉后如果嚼一片含有枳椇子素的口香糖，人馬上清醒如初，將是一件美妙的事情。

　　二、再寫傳奇？ 枳椇子向“老人殺手” 開戰

　　枳椇子。（網絡照片）

　　假如停留在解酒，那麼枳椇子還不足以成為一個傳奇。在研究解酒藥的過程中，梁京發現了枳椇子素的更強大的功能 。

　　實驗中，梁京團隊用的是兩歲的鼠。在通常只有3年壽命的鼠中， 這些是名副其實的“老鼠”。在研究過程中，梁京發現，服用枳椇子素后的“老鼠”們，居然活到了4歲多。而且還神氣活現，“不知老之將至”。

　　憑藉著職業敏感和對神經系統的內在聯繫的理解，梁京考慮到，枳椇子素應該對老化的腦功能甚至老年腦疾患有作用。於是，梁京把目光投放人類的一個頑症：阿爾茨海默症（Alzheimer），俗稱老年痴呆症（老年痴呆症因涉嫌歧視，在香港已經改名為”認知障礙症”）。其典型癥狀是記憶減退，認知和學習能力下降，及大腦功能性的實質體的漸進性萎縮。由於目前臨床上沒有對阿爾茲海默症的治療有很肯定效果的藥物，阿爾茲海默症被視為是一種不可預防、不能治療，甚至不能減緩的病症。一旦家中老人患上阿爾茲海默症，只能“等死”。2015年，美國阿爾茨海默病患者高達估計有530萬人，其中510萬是65歲以上老人。 而全球的數據估計在4千4百萬人以上。

　　目前，美國和其他國家，正在發起一場攻克阿爾茲海默症的戰爭。至2012年，超過一千個機構已經完成或正在進行治療阿爾茨海默症藥品的臨床試驗。然而，所有試驗都拿不出明確證據來證明這些藥物會産生延遲阿爾茨海默症作用，更不用说逆轉了。可以说，目前能有效治療阿爾茲海默症的藥物是零。

　　大腦中有一種支持和建立神經元之間聯繫的蛋白質，稱為支撐蛋白（Gephyrin，蓋佛瑞）。支撐蛋白的功用如同一個信息網絡。梁京團隊首次發現了阿爾茨海默症的一個關鍵病理改變，即支撐蛋白降低至正常量的百分之五十以下。在示意圖上，正常人腦如同一棵枝葉繁茂的大樹，但阿爾茨海默患者的大腦，就如同枯枝。原來的綠葉狀的神經連接，變成斷續的斑點狀，看起來像一鍋粥。他們的研究成果，發表在2014年6月份的《神經化學》（Neurochemical）雜誌上。

　　梁京團隊在實驗過程中使用了患有阿爾茨海默症的試驗鼠，枳具子再一次顯示了神奇。阿爾茨海默症鼠腦中的支撐蛋白隨着給藥時間的延長，逐漸恢復至正常水平，和神經連接的恢復，伴隨着記憶、認知能力及學習能力的顯著恢復。從鼠腦切片照片對比可以清楚地看到，大腦中的澱粉樣蛋白沉澱也明顯減少。病鼠的切片呈灰蒙蒙的一片，服用了枳具子素后，切片如同健康鼠一樣清爽。梁京说，”枳椇子功能相當於清道夫“，清除了大腦中的污垢，修復了其神經系統。

　　梁京團隊開發出來了作為飲食補充品的新産品SmartoOne，獲得了FDA的許可。初步效果令人鼓舞，一些患者病情出現了逆轉現象，痴呆患者服用后智力測驗評分有提高。不能進食進水者能緩慢自主進食進水。認知能力改善，如不能完成完整句子的敘述的可以完成了，焦慮及精神發作癥狀也減少。嶺南画派著名画家楊之光就是其中一員。其夫人鷗洋在近日發給梁京的短信中说，“我認定您的藥粉有功勞。”

　　當然，對阿爾茲海默症戰爭不是能夠輕言勝利的。 他們完成了病理研究，目前還處在臨床前(pre-Clinic)階段。但至少，他們在藥物開發已經佔據了一個有利地形，看到了天際露出的曙光。洛杉磯加大的奧爾森（Dr. Richard Olsen）教授是麻醉學、分子與醫學藥理學權威。他曾獲得丹麥女皇頒發的榮譽教授（Distinguished Professor）稱號。他寫道，“來自亞洲的枳椇子素被發現在動物體內和體外試驗中，改善了阿爾茲海默病的癥狀，它具有成為藥品的廣闊潛力（remarkable potential drug activity）。而梁京是在這項發現的創造性人物。”

　　三、 孤獨鬥士， 梁京“一生為此而活”

　　梁京的履歷很“學霸”。她1984年畢業於北京大學(原北京醫學院)醫學專業，1994年在日本東京大學醫學院獲得醫學博士，之后在日本旭化成醫藥開發部做研究員。2000年來到洛杉磯加大分子醫學藥學部，從博士后、助理研究員、副研究員一路走來。如今是副教授及首席研究員，團隊主持人。同時還是南加大（ＵＳＣ）的教授。

　　梁京還擁有一連串“高大上”的頭銜，如美國神經學會、美國酒精研究學會、國際酒精研究學會的會員、美國生物化學及藥學專刊主編、瑞士國家科學基金委基金申請海外評審員、中國自然科學基金委基金申請海外評審員等。她在2012年入選《神經科學》評選的2012年國際最熱話題，2012年入選英國評選的 “新科學家“， 2012年入選美國的“千人教師”（Faculty of 1000）。

　　梁京一次在中國國內講學時，一名聽衆说，你真幸運，作出了重大發現。但她今天的成果，豈能是用“幸運”二字就可以輕鬆概況的？梁京從2000年開始，這麼多年聖誕，感恩節，几乎都是在實驗室渡過的。與她一起過節的是試驗鼠們。有兩次，路上汽車爆胎，她只能打電話讓朋友來幫忙。

　　為了省錢，他們在廣州做枳椇子的提純，羊城的夏天溽暑逼人，他們揮汗如雨。

　　實驗經費不足，一度到了彈盡糧絶的境地，梁京把父母留下的相當於十幾萬美元的房産都投了進去，也如杯水車薪。在最困難的時候，梁京甚至想到過死，只是信仰的力量讓她堅強起來。她说，”我的一生就為此而活。” 她指的是攻克阿爾茲海默這一世紀頑症。她说，“在世界上有比無端的名牌欲更有價值的享受，是用科學知識去發明和創造更多的為人類健康有益的事業，使更多的人遠離病痛。”

　　（編輯：楊櫟）

枳椇子

　　枳椇子，别名：木蜜、树蜜、木饧、白石木子、蜜屈律、鸡距子、癞汉指头、背洪子、兼穹拐枣、天藤、还阳藤、木珊瑚、鸡爪子、鸡橘子、结留子、曹公爪、棘枸、白石枣、万寿果、鸡爪梨、甜半夜、龙爪、碧久子、金钩钩、酸枣、鸡爪果、枳枣、转钮子、鸡脚爪、万字果、橘扭子、九扭、金约子。为鼠李科植物北枳椇、枳椇和毛枳椇的成熟种子。亦有用带花序轴的果实。北枳椇种子扁平圆形，背面稍隆起，旗面较平坦，直径-5mm，厚1-1.5mm。表面红棕色、棕黑色或绿棕色，有光泽，于扩大镜下观察可见散在凹点，基部凹陷处有点状淡色种脐，顶端有微凹的合点，腹面有纵行隆起的种脊。种皮坚硬，胚乳白色，子叶淡黄色，肥厚，均富油质。气微，味微涩。

目录

• ? 枳椇子的功效与作用
• ? 现代研究
• ? 枳椇子的食用方法
• ? 枳椇子的禁忌
• ? 枳椇子图片

枳椇子的功效与作用编辑本段回目录

枳椇子的功效

　　【性味】 甘酸，平。

　　1.《唐本草》:"味甘，平，无毒。"

　　2.《本草再新》:"味甘酸，性平，无毒。"

　　【归经】 1.《本草再新》:"入心、脾二经。"

　　2.《本草撮要》:"入手太阴经。"

　　【功能主治】 治酒醉，烦热，口渴，呕吐，二便不利。

　　1.《荆楚岁时记》:"辟虫毒。"

　　2.《唐本草》:"主头风，小腹拘急。"

　　3.《本草拾遗》:"止渴除烦，润五脏，利大小便，去膈上热，功用如蜜。"

　　4.《滇南本草》:"治一切左瘫右痪，风湿麻木，能解酒毒；或泡酒服之，亦能舒筋络。小儿服之，化虫，养脾。"

　　5.《滇南本草图说》:"补中益气。痰火闭结于胸中，用此可解。’

　　6.《纲目》:"止呕逆。"

　　【用法用量】 内服:煎汤，3～5钱；浸酒或入丸剂。

 

枳椇子的作用:

　　1.治饮酒多发积，为酷热蒸熏，五脏津液枯燥，血泣小便并多，肌肉消烁，专嗜冷物寒浆:枳椇子二两，麝香一钱。为末，面糊丸，如梧子大。每服三十丸，空心盐汤吞下。（《世医得效方，枳棋子丸）

　　2.治酒色过度，成劳吐血:拐枣四两，红甘蔗一根。炖猪心肺服。（《重庆草药》）

　　3.治小儿惊风:枳椇果实一两。水煎服。（《湖南药物志》）

　　4.治手足抽搐:枳椇果五钱，四匹瓦五钱，蛇莓五钱。水煎服。（《湖南药物志》）

　　5.治小儿黄瘦:枳椇果实一两。水煎服。（《湖南药物志》）

现代研究编辑本段回目录

化学成份

　　北枳椇种子含黑麦草碱（perlolyrine），β-咔啉（β-carboline），枳椇甙（hovenoside）C、D、G、G’和H，其中枳椇甙D和G相应的甙元为酸枣甙元（jujubogenin）；果实含多量葡萄糖（glucose），硝酸钾（nitre）和苹果酸钾（potassiummalate）；果柄和花序轴均含葡萄糖，果糖（fructose）和蔗糖（sucrose），在花序轴中这三者的含量分别为111.14％、4.74％和12.59％；根皮含欧鼠李碱（frangulanine）和枳积椇碱（hovenine）A、B，枳椇碱A即去-N-甲基欧鼠李碱（des-N-methylfrangulanine）；木质部含枳椇酸（hovenic acid）。

药理作用

　　果实对家兔有显着的利尿作用，而无任何副作用。

　　拐枣子是一种中药，拐枣子为鼠李科乔木植物拐枣带有肉质果柄的果实。甘、酸，归心、脾、胃经。

　　清热生津：用于热病心烦，口渴，呕吐，二便不利等，取本品10—25g，水煎服。

　　解酒毒：用于饮酒过度，有止渴除烦的功能，取本品20g，浓煎后代茶饮。

　　醒酒安神：枳椇子中含有大量的葡萄糖、有机酸，既能扩充人体的血容量，又能解酒毒，故有醒酒安神的作用。

　　通利二便：枳椇子含有大量水分、葡萄糖、有机盐、脂类物质，具有促进尿液排泄，加速肠道蠕动等作用，故能通利二便。

　　祛风通络止痉：枳椇子中含有大量的钙和枳椇子皂甙，具有中枢抑制作用，能够抗惊厥，防止手足抽搐痉挛，可用来治疗风湿痹痛麻木之症。

　　止渴除烦，补充营养：枳椇子中含有大量的葡萄糖、蔗糖、果糖、有机酸、无机盐、维生素等，能生津止渴，清热除烦，并能给人体补充养分，增强机体的抗病能力。

　　降血压：近年来研究发现，枳椇子中含有麦草碱、B-咔啉、枳椇甙C、D、G、H、鼠李碱等，具有抗脂质过氧化和降低血压等作用。

　　对金黄色葡萄球菌、卡他球菌、绿脓杆菌、肠炎杆菌等有抑制作用。

枳椇子的食用方法编辑本段回目录

　　枳椇猪肺汤

　　鲜枳椇子120克，猪心、肺各1具，红蔗糖30克。枳子洗净，猪心、肺洗净并切成小块；将枳椇子、猪心肺、红蔗糖共同放入瓦罐中，加清水1000毫升，文火慢炖60分钟后，调入少许精盐、味精即可食用。本肴具有解渴除烦之功效，可作为酒痨吐血患者的饮食治疗

　　枳椇子酒

　　枳椇子干2枚，低度烧酒500毫升。先将枳椇子洗净，用刀切开，浸人烧酒中，密封，1周后启封饮用，每日2次，每次20毫升。本酒具有祛风胜湿的功效，适宜于风湿性关节炎患者饮用。

　　枳椇子鸡肝

　　干枳椇子2枚，黄鸡肝1具。先将枳椇子杵成细末备用；鸡肝洗净，用刀切十字刀花，盛于盘中，撒上枳椇子末，适量精盐，入笼中蒸20分钟取出食用。本肴具有健脾消疳的效果，可用来治疗小儿疳积。

　　枳椇子四莓汤

　　鲜枳椇子4枚，四匹瓦、蛇莓各10克。以上三味用清水洗净后，共入瓦罐中，加水适量，先以旺火烧沸，改用小火炖20分钟，滤出汤汁顿服。本汤具有祛风通络的功效，可用于治疗肝风内动，手足抽搐，小腹疼痛狗急，头风等病症。

　　枳椇粥

　　【组成】枳椇子30克，粳米100克。
　　【制法】先煎枳椇子，去渣取汁，后入米煮粥。
　　【用法】空腹食之。
　　【功用】清热除烦，解酒毒。适用于损伤后烦热口渴、二便不利，以及酒醉呕逆等症。

　　枳椇炖香鸭

　　【组成】枳椇子250克，白香鸭肉1千克，植物油1匙，黄酒3匙。
　　【制法】上料共炖，鸭至酥烂时即可。
　　【用法】佐餐食用。
　　【功用】祛风湿，补虚损。适用于类风湿性关节炎。

　　枳椇汤

　　【组成】枳椇子500克。
　　【制法】将枳椇子放入沙锅内，加水适量，先以武火煮沸，再以文火慢煎，取浓汁饮用。
　　【用法】口渴即少饮之，不分次数。
　　【功用】益胃生津，止消渴，解酒毒。适用于胃阴不足，口渴欲饮，饮不解渴，消谷善肌的渴病，以及醉酒伤胃。

　　枳椇解酒饮

　　【组成】枳椇子9克，葛花9克，柠檬汁适量。
　　【制法】先将枳椇子和葛花分别洗净，煎熬数滚过滤加柠檬汁煎沸后，再过滤即成。
　　【用法】酒醉时即服。
　　【功用】止渴，除烦，解酒，醒脾。适用于伤酒发热烦渴、不思饮食、呕逆吐酸。

枳椇子的禁忌编辑本段回目录

　　 《得配本草》:"脾胃虚寒者禁用。"

November 12, 2015

Experimental drug targeting Alzheimer's disease shows anti-aging effects

Salk team finds molecule that slows the clock on key aspects of aging in animals

LA JOLLA–Salk Institute researchers have found that an experimental drug candidate aimed at combatingAlzheimer’s disease has a host of unexpected anti-aging effects in animals.

The Salk team expanded upon their previous development of a drug candidate, called J147, which takes a different tack by targeting Alzheimer’s major risk factor–old age. In the new work, the team showed that the drug candidate worked well in a mouse model of aging not typically used in Alzheimer’s research. When these mice were treated with J147, they had better memory and cognition, healthier blood vessels in the brain and other improved physiological features, as detailed November 12, 2015 in the journal Aging.

“Initially, the impetus was to test this drug in a novel animal model that was more similar to 99 percent of Alzheimer’s cases,” says Antonio Currais, the lead author and a member of Professor David Schubert’s Cellular Neurobiology Laboratory at Salk. “We did not predict we’d see this sort of anti-aging effect, but J147 made old mice look like they were young, based upon a number of physiological parameters.”

Abstract

Parkinson’s disease (PD) is a multifactorial disorder, which is neuropathologically identified by age-dependent neurodegeneration of dopaminergic neurons in the substantia nigra. Development of symptomatic treatments has been partly successful for PD research, but there remain a number of inadequacies in therapeutic strategies for the disease. The pathogenesis of PD remains intricate, and the present anti-PD treatments appears to be clinically insufficient. Comprehensive research on discovery of novel drug candidates has demonstrated that natural products, such as medicinal herbs, plant extracts, and their secondary metabolites, have great potential as therapeutics with neuroprotective activity in PD. Recent preclinical studies suggest that a number of herbal medicines and their bioactive ingredients can be developed into optimum pharmaceuticals for treating PD. In many countries, traditional herbal medicines are used to prevent or treat neurodegenerative disorders, and some have been developed as nutraceuticals or functional foods. Here we focus on recent advances of the evidence-linked neuroprotective activity of bioactive ingredients of herbal origin in cellular and animal models of PD research.

1. Introduction

Parkinson’s disease (PD) is a chronic neurological disorder, characterized by a selective loss of dopaminergic neurons in the substantia nigra (SN) of ventral midbrain area, causing a subsequent reduction of dopamine (DA) levels in the striatum. Loss of dopaminergic supply to striatum causes imbalance with neurotransmitters like acetylcholine and DA, resulting in PD symptoms. Some typical characteristic symptoms observed in PD patients are tremor, myotonia, and dyskinesia [1]. The three main strategic developments in drug discovery that have advanced the progress in therapeutic management of PD patients have focused on the alleviation of motor symptoms by the use of dopaminergic mimetics, the development of novel nondopaminergic drugs for symptomatic improvement, and lastly, the discovery of neuroprotective compounds that have disease modifying effects in PD [2]. The pathogenesis and etiology of PD are not completely understood. Extensive study of various models mimicking key features of PD has outlined important cellular factors of dopaminergic cell death, including neuroinflammation, oxidative stress, mitochondrial dysfunction, and excitotoxicity [3, 4]. Although no model has thus far been able to reiterate all the pathological features of PD [5], the neurotoxic models have proved themselves to be a worthy tool for developing novel therapeutic strategies and assessing the efficacy and adverse effects of symptomatic treatments of PD [6].

Since ancient times, PD has been documented in various parts of the world. Based on their experience-based theories as well as practices from elsewhere, Asian countries, such as India, China, Japan, and Korea, have been using different combinations of herbal materials to treat PD within the context of ancient herbal medical systems [7]. Ayurveda, an ancient form of alternative traditional medicine followed in the Indian subcontinent describes PD as “Kampavata” [8] wherein seed preparations of mucuna are used as contemporary medicine for the treatment of PD [7]. Upon scientific investigations, it was found that Mucuna pruriens contains levodopa, which provides long-term amelioration of Parkinsonism [9, 10]. Formulation of powdered seed of Mucuna pruriens also showed positive effects on PD patients in clinical trials, with quick onset of action and without concomitant increase in dyskinesia [11]. Zandopa (HP-200), a commercial preparation ofMucuna pruriens, is also available for the treatment of PD [12]. In Chinese traditional medicine, 22,500 medicinal herbs are in use throughout China, of which only a few have been successfully investigated in animal experiments or clinical trials for potential development into herbal formulations for treating PD [13].

The past decade has substantiated considerable interest in phytochemical bioactive constituents from herbal medicines, which can have long-term medicinal or health-promoting qualities in PD [14]. In comparison, many medicinal plants exhibit specific medicinal actions without serving a nutritional role in the human diet and may be used in response to specific health problems over short- or long-term intervals [15, 16]. Therefore, a scientific re-examination of these therapies in preclinical models is valuable for the development of novel neuroprotective drugs for PD [17]. According to estimates from the World Health Organization, by 2040, neurodegenerative diseases will exceed cancer as the principal cause of death in industrialized countries. Irrespective of our advances in understanding the pathogenesis of PD, pharmacological treatments by conventional medicine have not transpired into satisfactory results. Therefore, it is plausible that the use of bioactive compounds from natural sources may yield more appropriate potential candidates for the preventive treatment of PD [18].

Comprehensive research on the discovery of novel neuroprotective drug candidates has proven that natural products, such as plant extracts and their bioactive compounds, can have tremendous potential as lead neuroprotective candidates in PD treatment. To list a few compounds from herbal origin, apomorphine, rivastigmine, and PYM-50028 are under clinical investigation to be used as potential neuroprotective agents in PD [19]. Here, we have focused on recent advances in the research of herbal medicines and their bioactive ingredients used in animal and cellular neurotoxic models of PD, so as to facilitate future basic and clinical investigations.

2. Neuroprotective Activity of Bioactive Compounds from Herbal Medicines

2.1. Ginsenoside Rg1

Ginseng is the dried root and rhizome of Panax ginseng and Panax notoginseng(Araliaceae) [13]. Ginseng is a valuable herb in traditional medicine, which has been utilized for over many centuries, based on the theory that it is a general tonic for the promotion of vitality, health, and longevity. The aqueous extract of ginseng has been used to treat many kinds of disease including ischemia, anemia, diabetes mellitus, gastritis, and insomnia [20]. There are over 30 ginsenosides among which the main active ingredients responsible for its vivid pharmaceutical actions are ginsenoside Rb1, Rd, Re, and Rg1 [21].

Recently, the aqueous extract of Panax ginseng was investigated for its protective effects against cellular model of parkinsonism like 1-methyl-4-phenylpyridine (MPP+)-induced cytotoxicity in SH-SY5Y human neuroblastoma cells. In this study, the aqueous extract of Panax ginseng decreased the overproduction of reactive oxygen species (ROS), release of cytochrome c and activation of caspase-3, elevated Bax/Bcl-2 ratio, and thus, increased cell survival in MPP+-treated SH-SY5Y cells [20]. Apart from Panax ginseng, saponins, obtained from Panax notoginseng by the induction of thioredoxin-1, elicit a very potent neuroprotective effect on MPP+ induced toxicity to PC12 cells and Kunming mice [22, 23]. In a very recent report, ginsenoside Rg1 (Figure 1(a)) was studied for the mechanistic activity behind its antioxidant effect on hydrogen peroxide (H2O2)-induced oxidative stress to PC12 cells. Pretreatment with Rg1 at concentrations of 0.1–10?μM significantly decreases the cytotoxicity induced by 400?μM of H2O2 in PC12 cells. Ginsenoside Rg1 abates the phosphorylation and nuclear translocation of nuclear factor-kappa B (NF-κB)/p65, phosphorylation, and degradation of inhibitor protein of κB (IκB), as well as the phosphorylation of IκB-kinase complex (IKK). Furthermore, Rg1 also inhibited the activation of Akt and the extracellular signal-regulated kinase 1/2 (ERK1/2). These results indicate that ginsenoside Rg1 protects the cell injury induced by H2O2 via downregulating ERK1/2 and by decreasing the activation of the NF-κB signaling pathway [24].

Figure 1: Chemical structure of ginsenoside Rg1 (a), baicalein (b), curcumin (c), and gastrodin (d).

In a report by Xu et al., it was observed that pretreatment with ginsenoside Rg1 to MES23.5 cells renews an iron-induced reduction in mitochondrial transmembrane potential. Pretreatment with ginsenoside Rg1 also decreases the increase of iron influx by inhibiting 6-hydroxydopamine (6-OHDA)-induced upregulation of an iron importer protein divalent metal transporter 1 with iron responsive element (DMT1-IRE). Further findings demonstrated that, due to the antioxidant effect of ginsenoside Rg1, it inhibits iron regulatory proteins, and thereby downregulating DMT1 and IRE expression [25]. In a parallel study, pretreatment with ginsenoside Rg1 was seen to inhibit the MPP+-induced upregulation of DMT1-IRE, which was associated with the production of ROS and translocation of NF-κB to nuclei in MES23.5 cells [26]. Similar results were reported in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of PD in C57BL/6 mice, wherein pretreatment with ginsenoside Rg1 significantly attenuated MPTP-induced elevated iron levels decreased the expression of DMT1 and increased ferroportin-1 expression in the SN [27]. Antiinflammatory effects of ginsenoside Rg1 were also evident in lipopolysaccharide (LPS)-induced microglial activation in male C57BL/6 mice. In this study, ginsenoside Rg1 is found to inhibit proinflammatory markers, including inducible nitric oxide synthase (iNOS), nitric oxide (NO), tumor necrosis factor alpha (TNF-α), and expression of ionized calcium binding adaptor molecule 1 (Iba-1) in both the cerebral cortex and hippocampus of C57BL/6 mice. Treatment with ginsenoside Rg1 suppresses downstream inflammatory markers by inhibiting the phosphorylation levels of IκB, nuclear translocation of p65 subunit of NF-κB, and phosphorylation level of ERK1/2 kinase induced by LPS [28]. Ginsenoside Rg1 is also reported to have protective effects on dopaminergic neurons in ovariectomized female SD rat injected intracerebroventricularly with 6-OHDA [29]. In a similar 6-OHDA-induced nigrostriatal injury model of PD, ginsenoside Rg1 was observed to have a neuroprotective effects on dopaminergic neurons through the insulin-like growth factor-I receptor signaling pathway [30].

2.2. Baicalein

Baicalein (Figure 1(b)) is a flavonoid and one of the active constituents obtained from a dried root of Scutellaria baicalensis (Labiatae). Recently, ethanolic extract ofScutellaria baicalensis was demonstrated to decrease LPS-induced expression of iNOS, NO, cyclooxygenase-2 (COX-2), and prostaglandin E2 levels in BV-2 and RAW 264.7 cells [31]. In a latest study by Li et al., they investigated the effects of baicalein on rotenone-induced neurotoxicity in PC12 cells. The results demonstrated that baicalein, in a concentration-dependent manner, inhibits the accumulation of ROS, deficiency of ATP, dissipation of mitochondrial membrane potential, and activation of caspase-3/7. Baicalein suppresses rotenone-induced apoptosis, indicating that baicalein likely improves mitochondrial function. Moreover, isolated rat brain mitochondria were used by the author to evaluate the effect of baicalein. It was found that treatment with baicalein promotes mitochondrial active respiration and prevents the rotenone-induced production of ROS, deficiency of ATP, and swelling of isolated brain mitochondria [32]. In addition to the rotenone model, baicalein was also explored for its neuroprotective effect in 6-OHDA-induced cellular and animal models of experimental parkinsonism. Baicalein at 0.5 and 5?μg/mL promotes neurite outgrowth in PC12 cells and significantly attenuates the 6-OHDA-induced cell apoptosis in SH-SY5Y cells. In animal experiments, treatment with baicalein significantly attenuates muscle tremor in 6-OHDA-lesioned rats but does not have any effect on apomorphine induced rotations. Furthermore, baicalein treatment mitigates astroglial response and increases tyrosine-hydroxylase-(TH-) positive neurons in SN [33].

Analogous to this study, treatment with baicalein at 100, 200, and 400?mg/kg significantly attenuates muscle tremor in 6-OHDA-lesioned rats. Baicalein was demonstrated to modulate the balance between glutamate and gamma amino butyric acid. Baicalein was also demonstrated to inhibit cytochrome oxidase subunit I (CO-I) mRNA expression in the subthalamic nucleus [34]. In a similar study, baicalein was seen to improve impaired spontaneous motor activity and rotarod performance induced by MPTP in C57BL/6 mice. Besides, baicalein at 280 and 560?mg/kg displays a protective effect against the MPTP-induced fall of TH-positive neurons in the SN. Treatment with baicalein also abates an MPTP-induced decrease in DA levels in the striatum by changing dopamine catabolism and inhibiting dopamine turnover [35]. In a similar model of MPTP-induced loss of dopaminergic fibers in mice, pretreatment with baicalein was found to increase the levels of DA and 5-hydroxytryptamine in the striatum, increase the counts of dopaminergic neurons, and inhibit both the oxidative stress and the astroglial response [36].

Baicalein is also reported to decrease fibrillization of E46K and E46K α-synuclein-(α-syn-) induced aggregation and toxicity in N2A cells. It was also demonstrated that baicalein significantly attenuates both E46K-induced mitochondrial depolarization, significantly attenuates the inhibition of proteasome, and protects N2A cells against E46K-induced toxicity [37]. In a related study, baicalein was found to inhibit the oligomerisation of α-syn in cell-free and cellular systems, as well to act as an efficient inhibitor of α-syn fibrillation in cell-free systems. Furthermore, baicalein was demonstrated to inhibit the formation of α-syn oligomers in Hela and SH-SY5Y cells and protect SH-SY5Y cells from α-syn oligomer-induced toxicity [38].

2.3. Curcumin

Rhizomes of Curcuma longa (Zingiberaceae) with the common name of turmeric along with its active components have been comprehensively used in the Indian subcontinent as food additives and cosmetics, exhibiting several medicinal properties [39]. The multiple pharmacological activities of Curcuma longa are mainly attributed to its polyphenolic fraction, curcuminoids, comprised of curcumin (Figure 1(c)), demethoxy curcumin (DMC), and bis-demethoxy curcumin (BDMC). Following extensive research on curcumin, the major active component of curcuminoids has revealed its bioactivities, including antiinflammatory, antioxidant, proapoptotic, chemopreventive, chemotherapeutic, antiproliferative, wound healing, antinociceptive, antiparasitic, and antimalarial properties [40]. In a latest study by Jiang and coworkers, curcumin was found to ameliorate A53T α-syn-induced SH-SY5Y cell death by downregulating rapamycin/p70 ribosomal protein S6 kinase signaling [41]. In a similar study by Wang et al., curcumin was observed to decrease α-syn-induced intracellular ROS generation and inhibit caspase-3 activation in SH-SY5Y cells [42]. In a recent experiment by Ojha et al., they investigated curcuminoids for their neuroprotective effects on inflammation-mediated neurodegeneration of dopaminergic neurons of C57BL/6 mice in the acute MPTP-model. Authors found that oral pretreatment with curcuminoids (150?mg/kg/day) significantly prevents MPTP mediated loss of TH-positive neurons and depletion of DA. Furthermore, pretreatment with curcuminoids mitigates cytokines, generation of total nitrite, and the expression of protein inflammatory markers, such as glial fibrillary acidic protein (GFAP) and iNOS, in the striatum of MPTP-intoxicated mice. Moreover, curcuminoids also improved motor deficits produced by MPTP, as evidenced by rotarod and open field tests [43].

In a comparable study carried out by Pan et al., curcumin was observed to protect dopaminergic neurons from apoptosis in an MPTP mouse model of PD. Curcumin markedly ameliorated the loss of dopaminergic axons in the striatum as well as the demise of dopaminergic neurons, in an MPTP mouse model. Further mechanistic studies demonstrated that curcumin inhibits MPTP-induced hyperphosphorylation of c-Jun N-terminal kinase (JNK). Phosphorylation of JNKs is known to cause translocation of Bax to mitochondria as well as the release of cytochrome c, which ultimately results in mitochondria-mediated apoptosis. Authors have established that curcumin prevents the degeneration of nigrostriatal neurons by inhibiting the dysfunction of mitochondria through abolishing the hyperphosphorylation of JNKs induced by MPTP [44]. Apart from MPTP model, curcumin is also reported to be neuroprotective in a 6-OHDA-induced hemiparkinsonian mice model. Posttreatment with curcumin following a unilateral intrastriatal 6-OHDA injection to mice was found to decrease the 6-OHDA-induced loss of striatal TH fibers and nigral TH-immunoreactive neurons. The neuroprotection was accompanied with a significant weakening of astroglial and microglial reaction in the striatum and the substantia nigra pars compacta (SNpc). These results indicate that the neuroprotective effects of curcumin in 6-OHDA-lesioned mice may be mediated via its antiinflammatory properties, or direct protection on nigral DA neurons [45].

2.4. Gastrodin

Gastrodia elata (GE), belonging to the family of Orchidaceae, has been traditionally used as a folk medicine in Oriental countries for many centuries due to its vivid exhibition of therapeutic benefits [46]. The major compounds in GE are gastrodin, vanillyl alcohol, 4-hydroxybenzaldehyde, and vanillin (Figure 1(d)). These compounds are known to cross the blood brain barrier and also to display various biological activities, such as antioxidant, antiasthmatic, antimicrobial, and antimutagenic activities [47]. In a study by An et al., pretreatment with GE extract (10, 100, 200?μg/mL) for 4?h prior to the addition of MPP+ significantly rescued the MPP+-induced decrease in viability of SH-SY5Y cells. Pretreatment with GE at 10, 100, and 200?μg/mL for 4?h prior to the addition of 0.5?mM MPP+ significantly improves cell viability in Neuro-2a cells [46]. Pretreatment with GE (10, 100, and 200?μg/mL) reduces the proportion of apoptotic cells, ROS, and Bax/Bcl-2 ratio in a concentration-dependent manner in MPP+-induced toxicity to SH-SY5Y cells [46]. These findings suggest that treatment with GE shifts the balance between pro- and antiapoptotic members towards cell survival.

Application of vanillyl alcohol to MPP+ intoxicated MN9D dopaminergic cells effectively improves cell viability and inhibits cytotoxicity. The underlying mechanisms of vanillyl alcohol were found to be attenuation of the elevated ROS levels, as well as initiating a decrease in the Bax/Bcl-2 ratio and poly (ADP-ribose) polymerase (PARP) proteolysis. These results demonstrate that vanillyl alcohol protects dopaminergic MN9D cells against MPP+-induced apoptosis by relieving oxidative stress and modulating the apoptotic process [47]. In a recent study, treatment with gastrodin significantly and dose dependently protected dopaminergic neurons against neurotoxicity, through regulating free radicals, Bax/Bcl-2 mRNA, and caspase-3 and cleaved PARP in SH-SY5Y cells stressed with MPP+ [48]. Gastrodin also shows neuroprotective effects in the subchronic MPTP mouse PD model by ameliorating bradykinesia and motor impairment in the pole and rotarod tests, respectively [48]. Consistent with this finding, gastrodin prevents DA depletion and reduces reactive astrogliosis caused by MPTP in SN and striatum of C57BL/6 mice. Moreover, gastrodin is also effective in preventing neuronal apoptosis by attenuating oxidative stress and apoptosis in SN and striatum of C57BL/6 mice. Gastrodin is also reported to significantly inhibit levels of neurotoxic proinflammatory mediators and cytokines including iNOS, COX-2, TNF-α, and IL-1β by inhibiting the NF-κB signaling pathway and phosphorylation of MAPKs in LPS-stimulated microglial cells [49]. These results indicate that gastrodin has protective effects in experimental PD models and might be suitable for development as a clinical candidate to ameliorate PD symptoms [48].

2.5. Resveratrol

Resveratrol (Figure 2(a)) is a naturally occurring polyphenolic phytoalexin which occurs in plants such as grapes, peanuts, berries, and pines [50]. Resveratrol is reported to have several pharmacological properties, such as cardioprotection, scavenging of free radicals, and inhibition of COX and hydroperoxidase [50, 51]. In a recent study by Chang et al., resveratrol was found to markedly reduce levels of myeloperoxidase (MPO) in microglia and astrocytes, without increasing the levels of NO. Resveratrol-induced downregulation of MPO significantly attenuates rotenone-triggered inflammatory responses, including the production of ROS and phagocytic activity in primary microglia and astrocytes [52]. In addition, pretreatment with resveratrol also alleviates impaired responses to rotenone from primary mixed glia in MPO deficient mice. The authors further demonstrated that resveratrol attenuates rotenone-induced dopaminergic cell death in neuron-glia cocultures, as compared to perse neuronal culture. Similar effects were also shown by resveratrol in modulating MPO levels in microglia treated with MPP+, which supports its antiinflammatory profile in PD [52]. In an adjacent study by Wu et al., resveratrol was observed to protect SH-SY5Y cells against rotenone-induced apoptosis, and to enhance the degradation of α-syn in α-syn-expressing PC12 cell line via the induction of autophagy. After observing that suppression of silent information regulator 2 (SIRT1) and metabolic energy sensor AMP-activated protein kinase (AMPK) causes a decrease in protein levels of LC3-phosphatidylethanolamine conjugate (LC3-II), the authors concluded that AMPK and/or SIRT1 are required for the resveratrol-mediated induction of autophagy [53]. A similar study of the PC12 cell line demonstrated that pretreatment with resveratrol for 3?h before MPP+ significantly reduced apoptosis-mediated neuronal cell death [54]. The authors also established that resveratrol tunes mRNA levels and protein expression of Bax and Bcl-2. Further investigation revealed that resveratrol reduces apoptotic neuronal cell death by decreasing cytochrome c and nuclear translocation of the apoptosis-inducing factor (AIF) [54]. As compared to earlier neuroprotective mechanism reported for resveratrol, it was found that antiapoptotic effects elicited against MPP+ in rat cerebellar granule neurons by resveratrol are independent of the stimulation of mammalian SIRT-2, but dependent on its antioxidant properties [55].

Figure 2: Chemical structure of resveratrol (a), acteoside (b), echinacoside (c), and paeoniflorin (d).

In a chronic MPTP model in Balb/c mice, resveratrol was observed to show significant neuroprotection by alleviating MPTP-induced impairments in motor coordination, oxidative stress, and loss of TH neurons [56]. Furthermore, resveratrol at (10?mg/kg, daily) significantly attenuated toxicity induced by paraquat and maneb, by increasing the levels of cytochrome P450 2D6 gene, as well as the expressions of vesicular monoamine transporter type 2 (VMAT-2). Resveratrol also relieves the increased accumulation of paraquat in nigrostriatal tissues, as well as relieving oxidative stress, microglial activation, neuroinflammation, and increasing the number of TH-positive cells and DA content [57]. Daily oral doses of resveratrol (10, 20 and 40?mg/kg) to rats with 6-OHDA-induced degeneration of the nigrostriatal network revealed that resveratrol alleviates 6-OHDA-induced swelling of mitochondria, condensation of chromatin, and vacuolization of dopaminergic neurons in rat SN. Moreover, resveratrol treatment significantly decreases the m-RNA levels of COX-2 and TNF-α in the SN [58]. Other reports also support the neuroprotective effects of resveratrol on nigral cells, wherein it mitigated oxidative damage and depletion of DA in 6-OHDA-induced dopaminergic cell death in a rat model [59–61]. These findings support the role of these natural polyphenols in preventive and/or complementary therapies for several human neurodegenerative diseases caused by oxidative stress and apoptosis.

2.6. Acteoside and Echinacoside

Cistanches Herba is the dried juicy stem of Cistanche deserticola or Cistanche tubulosa (Orobanchaceae) [62]. Total glycosides obtained from Cistanches Herba have been demonstrated to have neuroprotective effects on dopaminergic neurons of SN in a chronically intoxicated MPTP mice model of PD [62]. Treatment with 400?mg/kg of total glycosides significantly improves the altered neurobehavioral pattern of MPTP-intoxicated mice and inhibits the reduction of nigral dopaminergic neurons and the expression of TH in the striatum [62]. Acteoside (Figure 2(b)) extracted from Cistanches Herba has neuroprotective effects against rotenone-induced damage to SH-SY5Y cells. Pretreatment of SH-SY5Y cells with acteoside (10, 20, or 40?mg/L) for 6?h significantly reduces the release of lactate dehydrogenase induced by rotenone (0.5?μM/L). Pretreatment of SH-SY5Y cells with acteoside at the same dose ranges for 6?h, dose dependently decreases the cleavage of parkin induced by 0.5?μM/L of rotenone, decreases α-syn-positive SH-SY5Y cells, and stops the dimerization of α-syn. These findings indicate that the neuroprotective effects elicited by pretreatment of acteoside are due to its ability to reduce the cleavage of parkin and inhibit the expression of α-syn induced by rotenone in SH-SY5Y cells [63]. It is also found that pretreatment with acteoside significantly attenuates LPS-induced release of NO in RAW 264.7 cells via inhibition of NF-κB and activator protein-1 (AP-1) [64]. Acteoside has also been studied for its neuroprotective effects in MPTP models of PD. Pretreatment with acteoside at 10 and 30?mg/kg significantly improved MPTP-induced behavioral deficits in C57BL/6 mice. Acteoside also increases the dopaminergic neurons and content of DA [65]. Echinacoside (Figure 2(c)) is an important bioactive compound obtained and purified from the stems of Cistanche tubulosa, a Chinese herbal medicine [66]. Simultaneous treatment with 3.5 and 7.0?mg/kg of echinacoside is observed to prevent the 6-OHDA-induced extracellular loss of monoamine neurotransmitters, including DA, 3,4-dihydroxyphenylacetic acid (DOPAC), and homovanillic acid (HVA), in rat striatum [67]. Further authors suggested that alleviation of MPTP-induced behavioral deficits in C57BL/6 mice by pretreatment of echinacoside might result from a decrease in the biliverdin reductase B level [68]. In this study, acteoside selectively suppressed AP-1 activation, which may be essential for iNOS induction in the LPS-treated macrophages. In another study, prior treatment with echinacoside to MPTP-intoxicated mice was found to increase levels of striatal DA and its metabolite, reduce behavioral deficits, cell death, and lead to a significant rise in TH expression as compared to mice treated with MPTP alone. In addition, pretreatment with echinacoside markedly reduces MPP+-induced activations of caspase-3 and caspase-8 in cerebellar granule neurons. These findings indicate that echinacoside uplifts neurochemical and behavioral outcomes in MPTP mice models of PD and inhibits caspase-3 and caspase-8 activation in cerebellar granule neurons [69]. In a comparable study, oral administration of echinacoside (30?mg/kg/day for 14 days) to MPTP-induced sub-acute mice model of PD significantly overcomes the reduction of striatal fibers, nigral dopaminergic neurons, dopamine transporter, and dopamine in MPTP-lesioned animals. As compared to vehicle-treated mice, echinacoside treatment increases mRNA and protein expression of glial cell-derived neurotrophic factor (GDNF) and brain-derived neurotrophic factor in MPTP-lesioned mice. In addition, echinacoside treatment decreases the increased apoptotic cells and mRNA/protein ratio of Bax/Bcl-2 in MPTP-lesioned mice. Echinacoside treatment was also found to improve motor deficits produced by MPTP. These findings demonstrate that echinacoside is an orally active inhibitor of apoptosis, as well as an inducer of neurotrophic factors, and thus providing preclinical support for its therapeutic potential in the treatment of PD [70].

2.7. Paeoniflorin

Paeoniae alba Radix is the red root of Paeonia lactiflora or Paeonia veitchii, used extensively as a component of traditional Chinese prescriptions to treat amenorrhea, traumatic injuries, epistaxis, inflammation, boils, and sores and to relieve pain in the chest and costal regions [71]. Paeoniflorin (PF) (Figure 2(d)) is a main principal bioactive component of P. alba Radix [72]. PF has been cited to exhibit many pharmacological effects, such as antiinflammatory and antiallergic effects, anti-hyperglycemic effects, analgesic effects, neuromuscular blocking effect, cognition-enhancing effects, and inhibitory effects on steroid protein binding [71]. Pretreatment of PF (2.5 and 5?mg/kg) for 11 days has been shown to protect striatal nerve fibers and TH-positive neurons in SN mitigate bradykinesia observed in an acute MPTP model of PD [71]. Posttreatment with PF for 60?min (2.5 and 5?mg/kg) once a day for the subsequent 3 days after MPTP administration significantly ameliorated the dopaminergic neurodegeneration in a dose-dependent manner [71]. MPTP-induced activation of microglia and astrocytes, accompanied with the upregulation of proinflammatory genes, is also significantly attenuated by posttreatment with PF. Further mechanistic studies revealed that the neuroprotective and antineuroinflammatory effects of PF are associated with the activation of adenosine A1 receptor [71]. The effect of PF was also studied in neurological impairments following 6-OHDA-induced unilateral striatal lesion in Sprague-Dawley (SD) rat. Subchronic treatment with PF (2.5, 5 and 10?mg/kg, subcutaneously, twice daily for 11 days dose dependently reduces apomorphine-induced rotation, indicating that PF has an alleviative effect on the 6-OHDA-induced neurological impairments). Since PF had no direct action on dopamine D1receptor or dopamine D2 receptor, these results suggest that PF might provide an opportunity to develop a nondopaminergic management of PD [73].

In a recent report, PF was observed to protect PC12 cells from MPP+ and acid-induced damage via an autophagic pathway. Treatment with 50?μM of PF protects PC12 cells against both MPP+ and acid-induced injury, as determined by MTT assay, and decreases the release of lactate dehydrogenase and apoptotic rate. PF also reduces the influx of Ca2+ and reduces its cytosolic content. Further mechanistic study found that the neuroprotective effects of PF were closely associated with the upregulation of LC3-II protein, which is specifically associated with autophagic vacuole membranes. In addition to this, PF also inhibits the MPP+-induced overexpression of LAMP2a, which is directly correlated with the activity of the chaperone-mediated autophagy pathway [74]. In a similar study by Sun et al., PF was observed to increase the autophagic degradation of α-syn by regulating the expression and activity of acid-sensing ion channels and thus eliciting protective effects against its cytotoxicity in PC12 cells [75].

2.8. Tenuigenin

Polygalae radix (PRE) is the dried root of Polygala tenuifolia (polygalaceae). PRE is composed of various xanthones, saponins, and oligosaccharide esters [76–78]. PRE is one of the most frequently prescribed herbal remedies in traditional Korean medicine and is used for the treatment of various cognitive symptoms associated with aging, senile dementia, and PD [79, 80]. In a recent finding, PRE (0.05–1?μg/mL) was demonstrated to significantly inhibit 6-OHDA induced damage to PC12 cells, with a maximal effect observed at a dose of 0.1?μg/mL. PRE at 0.1?μg/mL ameliorates the production of ROS, NO, and activity of caspase-3. At the same dose, PRE prevents the abnormal shrinking of dendrites and promotes the survival of mesencephalic dopaminergic neurons from MPP+-induced toxicity. In an acute MPTP model of PD, pretreatment with PRE (100?mg/kg/day, 3 days) guards dopaminergic neurons and fibers from MPTP-induced toxicity in striatum and SNpc in C57BL/6 mice [81]. Tenuigenin (Figure 3(a)) is a bioactive principle found in Polygala tenuifolia root extracts [82]. In one study by Liang et al., tenuigenin was evaluated for its neuroprotective activity in 6-OHDA-induced cytotoxicity in SH-SY5Y cells. This study found that a 10?μM dose of tenuigenin significantly increased cell viability and reduced cell death [82].

3. Evidence-Linked Bioactive Components Exhibiting Neuroprotective Activity in In Vivo and In Vitro Models of PD

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4. Conclusion

PD as a disease has multifactorial pathological mechanisms, and till now currently available conventional treatments are not been able to elicit disease modifying effects by targeting each of these pathomechanisms. Herbal medicines have been known to possess a combination of bioactive components which might target different pathomechanisms in neurodegenerative diseases. Recently, the identification and characterization of medicinal plants to cure PD by conventional medicine is one of the major increasing scientific interest. Although there are more than 120 traditional medicines being used for therapy of central nervous system (CNS) disorders in Asian countries, lack of their quality control data and safety in consumption across the population limits their use in modern world of medicines. A significant amount of people in the developing countries now consume CAM as they are viewed as being innately safer than synthetic chemical compounds. From the ethnobotanical and ethnopharmaceutical resources, many of the bioactive compounds from natural sources have recently been reported to exert neuroprotective effects in various experimental models of PD. Although demand for bioactive compounds from natural sources is increasing, a large-scale, double-blind, and placebo-controlled trials and there pharmacokinetic data to optimize the dosage form are still required to establish the clinical effect of CAM on PD. In addition to this, a very important property of a neuroprotective agent depends on its ability to cross the blood-brain barrier (BBB), in order to reach the target sites of the CNS. Whereas there have been a limited number of animal and cell a based studies focusing on penetration of BBB. Here, we have searched the literature for the most recent available data about bioactive constituents from natural sources that possess neuroprotective activity in various experimental models of PD. Bioactive constituents listed in this current write-up belong to different chemical classes like including, Terpenes (ginsenoside Rg1, tenuigenin, astragaloside IV), flavones (puerarin, luteolin and baicalein, morin), stilbenoids (resveratrol), phenylpropanoid (echinacoside), phenylethyl glycoside (acteoside), coumarin (umbelliferone and esculetin), and catechol (curcumin and protocatechuic acid). The bioactive ingredients discussed have traditionally been used in many countries for different ailments, and thus providing a basis for their validation in comparison with modern day supplements. Even though the range of these studies reported are not vast, all the mentioned bioactive compounds have demonstrated a significant neuroprotective effect in PD models. Hence, bioactive compounds from natural sources can be used as alternative and valuable sources for anti-Parkinsonian drugs.