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Natural Product Research: Formerly Natural Product Letters Publication details, including instructions for authors and subscription information: http://www.tandfonline.com/loi/gnpl20
Phytochemical and medicinal importance of Ginkgo biloba L. a
b
b
Tapan Kumar Mohanta , Yasinalli Tamboli & P.K. Zubaidha a
National Institute of Plant Genome Research (Lab. No. 102), Aruna Asaf Ali Marg, New Delhi 110067, India b
School of Chemical Sciences, Swami Ramanand Teerth Marathwada University, Nanded, Maharashtra 431606, India Published online: 05 Feb 2014.
To cite this article: Tapan Kumar Mohanta, Yasinalli Tamboli & P.K. Zubaidha (2014) Phytochemical and medicinal importance of Ginkgo biloba L., Natural Product Research: Formerly Natural Product Letters, 28:10, 746-752, DOI: 10.1080/14786419.2013.879303 To link to this article: http://dx.doi.org/10.1080/14786419.2013.879303
PLEASE SCROLL DOWN FOR ARTICLE Taylor & Francis makes every effort to ensure the accuracy of all the information (the “Content”) contained in the publications on our platform. However, Taylor & Francis, our agents, and our licensors make no representations or warranties whatsoever as to the accuracy, completeness, or suitability for any purpose of the Content. Any opinions and views expressed in this publication are the opinions and views of the authors, and are not the views of or endorsed by Taylor & Francis. The accuracy of the Content should not be relied upon and should be independently verified with primary sources of information. Taylor and Francis shall not be liable for any losses, actions, claims, proceedings, demands, costs, expenses, damages, and other liabilities whatsoever or howsoever caused arising directly or indirectly in connection with, in relation to or arising out of the use of the Content. This article may be used for research, teaching, and private study purposes. Any substantial or systematic reproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or distribution in any form to anyone is expressly forbidden. Terms & Conditions of access and use can be found at http://www.tandfonline.com/page/termsand-conditions
Natural Product Research, 2014 Vol. 28, No. 10, 746–752, http://dx.doi.org/10.1080/14786419.2013.879303
REVIEW Phytochemical and medicinal importance of Ginkgo biloba L. Tapan Kumar Mohantaa, Yasinalli Tambolib and P.K. Zubaidhab*
Downloaded by [KU Leuven University Library] at 04:54 07 May 2014
a National Institute of Plant Genome Research (Lab. No. 102), Aruna Asaf Ali Marg, New Delhi 110067, India; bSchool of Chemical Sciences, Swami Ramanand Teerth Marathwada University, Nanded, Maharashtra 431606, India
Ginkgo biloba L., also popularly known as living fossil, possesses a variety of biological and pharmacological activities. The leaf extract of G. biloba L. (EGb 761) has been used for years to treat age-related memory-deficit problems, including Alzheimer’s and dementia. Experimental and clinical studies have revealed its beneficial effects on a wide range of pathological conditions including hepatoprotective, photoprotective effects, DNA repair mechanism, antioxidant and anti-inflammatory activities. Recent studies have also suggested that leaf extract of G. biloba L. may exert beneficial effects on cancer. This review focuses on recent scientific evidence of the reported medicinal effects of G. biloba L. Keywords: Ginkgo biloba L; Alzheimer’s; ginkgolide; bilobalide; EGb 761
1. Introduction The maidenhair tree Ginkgo biloba L., popularly known as living fossil, has undergone very little evolutionary changes over 200 million years and is considered to be native to China, Japan and Korea. Its place of origin is believed to be remote mountainous valleys of Zhejiang province of eastern China (Singh et al. 2008). Nowadays, it is widely cultivated for its nuts as well as for its leaves. Medicinal extracts of the dry leaves have been used for 5000 years in traditional Chinese medicine for various purposes. Studies on the biological activity of different components of the Ginkgo leaf began with the advent of modern scientific methods about 20 years ago and its true pharmaceutical value has been realised only recently. The amazing vitality exhibited by fresh or dried leaves of Ginkgo has led to its therapeutic applications in health, food and supplements. The predominant pharmacologically active constituents were identified to be flavonols (kaempferol, quercetin, myricetin, apigenin, isorhamnetin, luteolin and tamarixetin) and terpene trilactones (ginkgolide A, ginkgolide B, ginkgolide C, ginkgolide J, ginkgolide M, ginkgolide K, ginkgolide L and bilobalide) (Figure 1) (Van Beek & Montoro 2009). Recently, two new ginkgolides (ginkgolide P and Q) were isolated from the leaves of G. biloba L. (Liao et al. 2011). 2. Earlier studies For hundreds of years, traditional Chinese medicine has used the leaf extracts of G. biloba L. termed as ‘EGb 761’, as an essential therapy for age-related memory deficit and it is more popular in Europe as compared with China. The leaf extract of G. biloba L. EGb 761 is composed of flavonol glycosides (24%), terpene trilactones (ginkgolides and bilobalide 6%), proanthocyanidins, organic acids and other constituents. The observed therapeutic and
*Corresponding author. Email: [email protected] q 2014 Taylor & Francis
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Figure 1. Chemical structures of the main compounds identified in Ginkgo biloba.
pharmacological effects are attributed to multiple components present in the extract and no individual component has been assigned to exert the effect (DeFeudis 1991). Recent studies confirmed that G. biloba L. leaf extract (EGb 761) has been very useful in the treatment of Alzheimer’s disease (AD), neurodegenerative disease, cerebral insufficiency, neurosensory problems (e.g. tinnitus, vertigo), eye ailments, vascular insufficiencies, age-related memory deficit and oxidative stress (Kleinjnen & Knipschield 1992; Oyama et al. 1996; Yucheng et al. 1996; Barry et al. 1998; Robert et al. 2003). In addition, it has been demonstrated to be effective in preventing apoptosis and radical scavenging (Marcocci et al. 1994; Maitra et al. 1995). It is a very useful antioxidant and can be used for enhancing sexual pleasure in individuals suffering from sexual dysfunction (Cohen & Bartlik 1997). G. biloba L. extracts (GBEs) were also tested in cancer research, but very little is known so far (Cohen & Bartlik 1997; DeFeudis et al. 2003; Marie-Noelle et al. 2011). The whole extract provides maximum benefit for the indications as compared with individual compounds isolated from the plant. One of the isolated compound ginkgolide B has been shown to have potential therapeutic effects such as anti-angiogenesis (Kuribara et al. 2003), anti-inflammatory (Ou-Yang et al. 2005) and anti-asthmatic (Chu et al. 2011).
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3. Recent advances 3.1. Alzheimer’s and dementia G. biloba L. has a long history as an effective herbal medicine against AD, and the extract EGb 761 has been used to reduce cognitive dysfunction in a model of vascular dementia in gerbils (Ralf et al. 2011). The studies reveal significant recovery of spatial memory on regular postischaemic treatment with the extract. At cellular level, the extract has been demonstrated to reduce plasma superoxide dismutase activity and protected the hippocampal CA1 neuron, and this study supports the beneficial role of EGb 761 in vascular dementia. To test the efficacy and safety of consumption of the EGb 761 formulation once a day in the treatment of patients experiencing dementia with neuropsychiatric feature, Ralf et al. (2011) carried out randomised controlled trials in 410 outpatients with moderate dementia (AD, vascular dementia or mixed form), and patients were randomly allocated to double-blind treatment with 240 mg of EGb 761 or placebo once daily for 24 weeks (Kaschel 2011). The study revealed that EGb 761, 240 mg once daily, was significantly superior to placebo in the treatment of patients experiencing dementia with neuropsychiatric symptoms. Another study with 188 middle-aged volunteers revealed that EGb 761 enhances cognitive performance and is very useful for the treatment of patients with cognitive impairment (Yang et al. 2011). Further, to ascertain the role of EGb 761 on distinct memory-related functions, a meta-analysis comprising five random trials with 819 patients suffering from AD was undertaken by Silberstein et al. (2011).They found that EGb 761 expresses good therapeutic effect for mild and moderate Alzheimer’s condition. However, they suggested that high-quality, randomised, double-blind and controlled trials are needed to further confirm its therapeutic effects. Experimental study carried out to investigate the role and effect of GBEs on enteric nervous system of diabetic rats revealed a significant decrease in the neuronal population in both plexus of jejunum, and with regard to the ileum there was significant decrease only in the myenteric plexus. In addition, the cell body area increased profoundly in the myenteric plexus of both the segments and in the ileum submucosal plexus, as compared with control group while the treatment reduced the cell body area of submucosal neurons of both the segments and jejunum myenteric neurons. Electrophysiological studies revealed that GBE activated left temporal and prefrontal cortex leading to improved performance. Randomised controlled trials carried out using 240 mg daily dosage on patients with mild to moderate dementia showed effective reduction in behavioural and neuropsychiatric symptoms (Bachinskaya et al. 2011). 3.2. Vascular functions and haemorrhage The effects of GBE on vascular functions have been well investigated, and studies were carried out to observe pressure wave reflection and blood pressure (Gillian et al. 2011). The digital volume pulse was monitored to measure reflection index (DVP-RI) and stiffness index (DVP-SI) while peripheral augmentation index (pAIx) was assessed using radial pulse wave analysis at baseline after 2, 4 and 6 h treatment. The results indicate DVP-SI to be slightly higher and pAIx to be reduced after 2 h of treatment (Hall et al. 2008) and the same was observed after consumption of high-carbohydrate meal. In addition, GBE has been shown to increase cerebral blood flow but individual lobar regions did not show any significant change in post-consumption of the GBE analysis (Ameneh et al. 2011). Besides the vascular functions, hepatoprotective effects of polyprenols from G. biloba L. have been well analysed against carbon tetrachlorideinduced hepatic damage in Sprague-Dawley rats. The elevated levels of serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase, albumin, total protein, hyaluronic acid, laminin, triglyceride and total cholesterol were restored towards normal values in a significant way by GBE in a dose-dependent manner. GBE also reversed the CCl4diminished activity of the antioxidant enzymes and reduced the CCl4-elevated levels of
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malondialdehyde (MDA). In general, the effects of GBE were not significantly different from those of the standard drug essentials (Lan et al. 2011). The pharmacokinetics and pharmacodynamics of GBE on warfarin have been investigated in a randomised, doubleblinded, placebo-controlled two-way cross-over trial, and the results indicate that GBE has minimum effects on the pharmacokinetics and no effect on the pharmacodynamics of singledose warfarin (Yulu & Rong 2011). GBE also has no effect on the clotting process as such; however, individuals associated with haemorrhage and bleeding problems should give special attention to the prescription of GBE with co-prescription of anticoagulants or antiplatelet drugs (Agnes et al. 2011), as it may lead to increased risk of bleeding in elderly persons and in view of the fact that intracranial cerebral haemorrhage without any structural abnormalities in young women has been reported (Pedroso et al. 2011). On the basis of vascular theory of glaucoma, evaluation has been done to study the effects of GBE on peripapillary blood flow in patients with normal-tension glaucoma and they were treated with 80 mg of GBE twice a day for four weeks. Ocular examination performed after the GBE treatment revealed increased mean blood flow, volume and velocity at almost all the points compared with placebo and significant increase in blood volume was observed in superior basal and superior temporal neuroretinal rim areas while significant increase in blood velocity was observed in areas of the inferior temporal neuroretinal rim and superior temporal peripapillary area (Woon et al. 2011). Prolonged administration (40 mg/kg/day) of EGb 761 for 10 weeks brings about changes in retinal constituents especially in the underlying amide region of the secondary protein structure and the NH – OH region (Gamal et al. 2011). 3.3. Anti-inflammatory activities Ginkgolide B was found to be a potent anti-inflammatory agent and it is known to inhibit the platelet-activating factor, which is an important factor in the pathogenesis of asthma. Treatment with ginkgolide B effectively inhibits the increase of T-helper 2 cytokines, such as interleukin (IL)-5 and IL-13, in branchoalveolar lavage fluid with substantial decrease in oeosinophil count. Also, ginkgolide B substantially inhibited ovalbumin-induced oeosinophils in lung tissue and mucus hyper-secretion by goblet cells in the airways. This suggests that ginkgolide B may be useful for the treatment of asthma (Chu et al. 2011). 3.4. Cancer As far as cancer research is concerned, medical science has evolved to its full potential to tackle different kinds of cancer, but the role of phytomedicine cannot be undermined in the development of novel therapeutically useful anticancer agents. Women carrying BRCA1 mutation are at high risk of developing ovarian cancer and the best option available for treatment is prophylactic surgery, which is often accompanied by poor quality of life and permanent damage to fertility. There is an obvious and urgent need to identify a noninvasive approach to prevent ovarian cancer risk especially in women of reproductive age. Microarray analysis of BRCA1 mutant treated with ginkgolide B shows multiple mechanisms and signalling pathways to be involved in anticancer activities (Wei et al. 2011) such as cell proliferation, tumour suppression and DNA damage repair. In another study, involvement in DNA repair mechanism due to oxidative stress in Saccharomyces cerevisiae has been well documented by the application of GBE In addition, the extract also improved the rate of DNA repair after oxidative shock and the extract appears to have profound effect on DNA repair mechanism in addition to protective action against oxidative damage to DNA. Further studies show that the observed DNA repair depends on the DNA repair machinery since no DNA repair was observed under restrictive conditions in a conditional mutant of the CDC9 gene (Marques et al. 2011).
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Mutagenic and morphogenic effects induced by 1.8 GHz global system for mobile communication-modulated radio frequency radiation on human peripheral blood lymphocytes are known to produce morphological changes, destruction of organelles and nucleus structure on long exposure with chromatin changes, loss of mitochondrial cristae and significant increase in sister chromatid exchange frequency and this study was compared with lymphocytes pre-treated with EGb 761. EGb 761 pre-treatment significantly decreased sister chromatid exchange, increased cell viability and inhibited cell proliferation caused by radio frequency radiation (Esmekaya et al. 2011).
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3.5. Jaundice The hepatoprotective effect of GBEs on rats suffering from obstructive jaundice has been well studied (Weng et al. 2011). They reported that GBE could significantly lower serum transaminase levels and ameliorate liver histological damage leading to liver protection. Feeding 4 mg/kg of GBEs to male rats for 5 days significantly decreased the serum activities of ALT and AST. GBE partially prevented the increase of liver MDA (55% ^ 14%) with decrease of albumin concentration to 12% ^ 0.2%. The pre-treatment prevented the down-regulation of tumour necrosis factor-alpha and up-regulated interleukin 6 (IL-6) mRNA steady-state level. Moreover, the GBE treatment reduced the amount of necrotic area in the central lobe (Cha´vezMorales et al. 2011). 3.6. Photoprotective and oxidative effects GBEs and their derivatives have been used in cosmetics to protect the skin against ravages caused by UV radiation and to prevent signs of ageing (Fischer et al. 1995). In one study, hairless mice treated with topical application of G. biloba L. and green tea, were subjected to UV radiation to evaluate different parameters such as skin barrier damage, erythema, histological alteration and sunburn cell formation. The results compared after 20 h of UV exposure revealed that formulations containing GBE provided total protection against UV radiation damage such as skin barrier damage and erythema (Nishizawa et al. 1996; Dal et al. 2011). Also, GBE treatment partially uncoupled mitochondrial oxidation by phosphorylation that reduces the generation of free radicals in the mitochondria and diminishes ischaemia-induced myocardial damage and stimulates degree of respiration by exogenous cytochrome c. (Jurga et al. 2011). 4. Conclusion and future perspective Recent advances in neuroscience have revealed a greater, in-depth understanding of the complexities associated with memory. Contemporary theories hold that an integral relationship between memory formation, stabilisation and consolidation revolves around the plasticity of neuronal networks. The associated requisite receptors alpha-amino-3-hydroxy-5-methyl-4isoxazole propionic acid and N-methyl-D -aspartate and cellular mechanisms surrounding plasticity also display strong correlations in the pathogenesis of dementias. When the brain is in a diseased state as a result of malignant neurotransmission (i.e. in AD), the homoeostatic balance required for normal neuronal processes is disrupted, which leads to degeneration of neural circuitry. Present efforts to find new treatments aimed at reversing or halting neurodegeneration are immense, with increased attention being placed on investigations based on herbal medicines such as G. biloba L. GBEs and compounds present in them have already proved their therapeutic efficacy when tested against known pathogenic markers for AD-associated dementia. GBE has now became a familiar medicine for the treatment of Alzheimer’s, and memoryand vascular-related problems. However, the potential of G. biloba L. is in its infantile stage as
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far as cancer and jaundice research is concerned. Although a very little work has been done so far in this field, undoubtedly, further investigations will give a dramatic breakthrough in the treatment of cancer and jaundice-related diseases.
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References Agnes CF, Henry LC, Wen WJ. 2011. Risk of hemorrhage associated with co-prescription for Ginkgo biloba and antiplatelet or anticoagulant drugs. J Altern Complement Med. 17:513–517. Ameneh M, Dzung PL, David YM. 2011. Effects of Ginkgo biloba on cerebral blood flow assessed by quantitative MR perfusion imaging: a pilot study. Neuroradiology. 53:185–191. Bachinskaya N, Hoerr R, Ihl R. 2011. Alleviating neuropsychiatric symptoms in dementia: the effects of Ginkgo biloba. Neuropsychiatr Dis Treat. 7:209–215. Barry SK, Daniel MS, Jeffrey AK. 1998. The efficacy of Ginkgo biloba on cognitive function in Alzheimer’s disease. Arch Neurol. 55:1409– 1415. Cha´vez-Morales RM, Jaramillo-Jua´rez F, Posadas del Rı´o FA, Reyes-Romero MA, Rodrı´guez-Va´zquez ML, Martı´nezSaldan˜a MC. 2011. Protective effect of Ginkgo biloba extract on liver damage by a single dose of CCl4 in male rates. Hum Exp Toxicol. 30:209–216. Chu X, Ci X, He J. 2011. A novel anti-inflammatory role for ginkgolide B in asthma via inhibition of ERK/MAPK signaling pathway. Molecules. 16:7634– 7648. Cohen A, Bartlik B. Treatment of sexual dysfunction with Ginkgo biloba extract scientific reports-paper session. The Proceedings of the APA Annual Meeting 1997; San Diego, CA, USA. Dal BE, Rigo GL, Campos PM, Berardo GM. 2011. Photoprotective effects of tropical formulations containing a combination of Ginkgo biloba and green tea extracts. Phytother Res. 25:1854 –1860. DeFeudis FV. 1991. Ginkgo biloba extract (EGb 761): pharmacological activities and clinical applications. Paris: Elsevier. DeFeudis FV, Vassilios P, Katy D. 2003. Ginkgo biloba extract and cancer: a research area in its infancy. Fundam Clin Pharmacol. 17:405–417. Esmekaya MA, Aytekin E, Ozgur E, Gu¨ler G, Ergun MA, Omerog˘lu S, Seyhan N. 2011. Mutagenic and morphologic impacts of 1.8 GHz radio frequency radiation on human peripheral blood lymphocytes (hPBLs) and possible protective role of pre-treatment with Ginkgo biloba (EGb 761). Sci Total Environ. 410:59 – 64. Fischer M, Goering S, Theis H. Topical composition containing Ginkgo extracts and glycine to prevent skin aging. Patent. Ger. DE. 4,429,928C1 1995. Gamal EM, Aly EM, Mahmoud SS, Talaat SS, Sallam AS. 2011. FTIR assessment of the effect of Ginkgo biloba leaf extract (EGb 761) on mammalian retina. Cell Biochem Biophys. 61:169–177. Gillian K, Lauren DA, Louise HW. 2011. Acute effects of Ginkgo biloba extract on vascular function and blood pressure. Plant Foods Hum Nutr. 66:209–211. Hall WL, Formanuik NL, Harnpanich D, Cheung M, Talbot D, Chowienczyk PJ, Sanders TA. 2008. A meal enriched with soy isoflavones increases nitric oxide-mediated vasodilation in healthy postmenopausal women. J Nutr. 138:1288–1292. Jurga B, Daiva M, Rimantas P. 2011. The effect of Ginkgo biloba extract on mitochondrial oxidative phosphorylation in the normal and ischemic rat heart. Phytother Res. 25:1054–1060. Kaschel R. 2011. Specific memory effects of Ginkgo biloba extract EGb 761 in middle-aged healthy volunteers. Phytomed. 18:1202– 1207. Kleinjnen J, Knipschield P. 1992. Ginkgo biloba (drug profiles). Lancet. 340:1136. Kuribara H, Weintraub ST, Yoshihama T, Maruyama Y. 2003. An anxiolytic-like effect of Ginkgo biloba extract and its constituent, ginkgolide-A, in mice. J Nat Prod. 66(10):1333–1337. Lan Y, Cheng-zhang W, Jian-zhong Y. 2011. Hepatoprotective effects of polyprenols from Ginkgo biloba leaves on CCl (4)-induced hepatotoxicity in rats. Fitoterapia. 82:834–840. Liao HJ, Zheng YF, Li HY, Peng GP. 2011. Two new ginkgolides from leaves of Ginkgo biloba. Planta Med. 77:1818–1821. Maitra I, Marcocci L, Droy-Lefaix MT, Packer L. 1995. Peroxyl radical scavenging activity of Ginkgo biloba extract EGb 761. Biochem Pharmacol. 49:1649 –1655. Marcocci PL, Sckaki A, Albert GM. 1994. Antioxidant action of Ginkgo biloba extracts EGP761. Methods Enzymol. 234:462–475. Marie-Noelle R, Denis C, Brigitte S. 2011. Long-term treatment with standardized Ginkgo biloba Extract (EGb 761) attenuates cognitive deficits and hippocampal neuron loss in a gerbil model of vascular dementia. Fitoterapia. 82:1075–1080.
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Marques F, Azevedo F, Johansson B, Oliveira R. 2011. Stimulation of DNA repair in Saccharomyces cerevisiae by Ginkgo biloba leaf extract. Food Chem Toxicol. 49:1361–1366. Nishizawa Y, Kanazawa S, Hotsuta M, Kidena H, Kobayashi H. Hair growth stimulants containing plant extracts and other agents for synergistic effects. Patent. Jpn. Kokai Tokkyo Koho. JP 08 73,324 [96 73,324] 1996. Ou-Yang XY, Wang WJ, Liao WH, Chen XH. 2005. Inhibitory effect of ginkgolide B on angiogenesis in chronic inflammation. Acta Pharmaceutica Sinica. 40(4):311. Oyama Y, Chikahisa L, Ueha T, Kanemaru K, Noda K. 1996. Ginkgo biloba extract protects brain neurons against oxidative stress induced by hydrogen peroxide. Brain Res. 712:349–352. Pedroso JL, Henriques Aquino CC, Esco´rcio Bezerra ML, Baiense RF, Suarez MM, Dutra LA, Braga-Neto P, Povoas Barsottini OG. 2011. Ginkgo biloba and cerebral bleeding: a case report and critical review. Neurologist. 17:89–90. Ralf I, Natalia B, Amos KD. 2011. Efficacy and safety of a once-daily formulation of Ginkgo biloba extract EGb 761 in dementia with neuropsychiatric features: a randomized controlled trial. Int J Geriatr Psychiatry. 26:1186–1194. Robert WS, Felix E, Balz F, Doris K, Jessica N, Joseph FQ. 2003. Prevention of age related spatial memory deficits in a transgenic mouse model of Alzheimer’s disease by chronic Ginkgo biloba treatment. Exp Neurol. 184:510 –520. Silberstein RB, Pipingas A, Song J. 2011. Examining brain-cognition effects of Ginkgo biloba extract: brain activation in the left temporal and left prefrontal cortex in an object working memory task. Evid Based Complement Alternat Med; article number: 164239. Singh B, Kaur P, Gopichand, Singh RD, Ahuja PS. 2008. Biology and chemistry of Ginkgo biloba. Fitoterapia. 79:401–418. Van Beek TA, Montoro P. 2009. Chemical analysis and quality control of Ginkgo biloba leaves, extracts, and phytopharmaceuticals. J Chromatogr A. 12:2002–2032. Wei J, Weiliang Q, Yisheng W. 2011. Ginkgo may prevent genetic-associated ovarian cancer risk: multiple biomarkers and anticancer pathways induced by ginkgolide B in BRCA1-mutant ovarian epithelial cells. Eur J Cancer Prev. 20:508–517. Weng MZ, Zhou XP, Jia JG, Ding J, Fang CF, Qin YY, Tao SF, Rao LH, Li JY, Quan ZW. 2011. The hepatic protective mechanism of Ginkgo biloba extract in rats with obstructive jaundice. Bosn J Basic Med Sci. 11:209–213. Woon PJ, Jung KH, Seok CW. 2011. Short-term effects of Ginkgo biloba extract on peripapillary retinal blood flow in normal tension glaucoma. Korean J Ophthalmol. 25:323–328. Yang Z, Li W, Huang T, Chen J, Zhang X. 2011. Meta-analysis of Ginkgo biloba extract for treatment of Alzheimer’s disease. Neural Regen Res. 6:1125– 1129. Yucheng N, Baolu Z, Jingwu H, Wenjuan X. 1996. Preventive effect of Ginkgo biloba extract on apoptosis in rats cerebellar neuronal cells induced by hydroxyl radicals. Neurosci Lett. 214:115–118. Yulu Z, Rong Z. 2011. Effects of Ginkgo biloba extract on anticoagulation and blood drug level of warfarin in healthy volunteers. China J Mater Med. 36:2290–2293.
Natural Product Research: Formerly Natural Product Letters Publication details, including instructions for authors and subscription information: http://www.tandfonline.com/loi/gnpl20
Phytochemical and medicinal importance of Ginkgo biloba L. a
b
b
Tapan Kumar Mohanta , Yasinalli Tamboli & P.K. Zubaidha a
National Institute of Plant Genome Research (Lab. No. 102), Aruna Asaf Ali Marg, New Delhi 110067, India b
School of Chemical Sciences, Swami Ramanand Teerth Marathwada University, Nanded, Maharashtra 431606, India Published online: 05 Feb 2014.
To cite this article: Tapan Kumar Mohanta, Yasinalli Tamboli & P.K. Zubaidha (2014) Phytochemical and medicinal importance of Ginkgo biloba L., Natural Product Research: Formerly Natural Product Letters, 28:10, 746-752, DOI: 10.1080/14786419.2013.879303 To link to this article: http://dx.doi.org/10.1080/14786419.2013.879303
PLEASE SCROLL DOWN FOR ARTICLE Taylor & Francis makes every effort to ensure the accuracy of all the information (the “Content”) contained in the publications on our platform. However, Taylor & Francis, our agents, and our licensors make no representations or warranties whatsoever as to the accuracy, completeness, or suitability for any purpose of the Content. Any opinions and views expressed in this publication are the opinions and views of the authors, and are not the views of or endorsed by Taylor & Francis. The accuracy of the Content should not be relied upon and should be independently verified with primary sources of information. Taylor and Francis shall not be liable for any losses, actions, claims, proceedings, demands, costs, expenses, damages, and other liabilities whatsoever or howsoever caused arising directly or indirectly in connection with, in relation to or arising out of the use of the Content. This article may be used for research, teaching, and private study purposes. Any substantial or systematic reproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or distribution in any form to anyone is expressly forbidden. Terms & Conditions of access and use can be found at http://www.tandfonline.com/page/termsand-conditions
Natural Product Research, 2014 Vol. 28, No. 10, 746–752, http://dx.doi.org/10.1080/14786419.2013.879303
REVIEW Phytochemical and medicinal importance of Ginkgo biloba L. Tapan Kumar Mohantaa, Yasinalli Tambolib and P.K. Zubaidhab*
Downloaded by [KU Leuven University Library] at 04:54 07 May 2014
a National Institute of Plant Genome Research (Lab. No. 102), Aruna Asaf Ali Marg, New Delhi 110067, India; bSchool of Chemical Sciences, Swami Ramanand Teerth Marathwada University, Nanded, Maharashtra 431606, India
Ginkgo biloba L., also popularly known as living fossil, possesses a variety of biological and pharmacological activities. The leaf extract of G. biloba L. (EGb 761) has been used for years to treat age-related memory-deficit problems, including Alzheimer’s and dementia. Experimental and clinical studies have revealed its beneficial effects on a wide range of pathological conditions including hepatoprotective, photoprotective effects, DNA repair mechanism, antioxidant and anti-inflammatory activities. Recent studies have also suggested that leaf extract of G. biloba L. may exert beneficial effects on cancer. This review focuses on recent scientific evidence of the reported medicinal effects of G. biloba L. Keywords: Ginkgo biloba L; Alzheimer’s; ginkgolide; bilobalide; EGb 761
1. Introduction The maidenhair tree Ginkgo biloba L., popularly known as living fossil, has undergone very little evolutionary changes over 200 million years and is considered to be native to China, Japan and Korea. Its place of origin is believed to be remote mountainous valleys of Zhejiang province of eastern China (Singh et al. 2008). Nowadays, it is widely cultivated for its nuts as well as for its leaves. Medicinal extracts of the dry leaves have been used for 5000 years in traditional Chinese medicine for various purposes. Studies on the biological activity of different components of the Ginkgo leaf began with the advent of modern scientific methods about 20 years ago and its true pharmaceutical value has been realised only recently. The amazing vitality exhibited by fresh or dried leaves of Ginkgo has led to its therapeutic applications in health, food and supplements. The predominant pharmacologically active constituents were identified to be flavonols (kaempferol, quercetin, myricetin, apigenin, isorhamnetin, luteolin and tamarixetin) and terpene trilactones (ginkgolide A, ginkgolide B, ginkgolide C, ginkgolide J, ginkgolide M, ginkgolide K, ginkgolide L and bilobalide) (Figure 1) (Van Beek & Montoro 2009). Recently, two new ginkgolides (ginkgolide P and Q) were isolated from the leaves of G. biloba L. (Liao et al. 2011). 2. Earlier studies For hundreds of years, traditional Chinese medicine has used the leaf extracts of G. biloba L. termed as ‘EGb 761’, as an essential therapy for age-related memory deficit and it is more popular in Europe as compared with China. The leaf extract of G. biloba L. EGb 761 is composed of flavonol glycosides (24%), terpene trilactones (ginkgolides and bilobalide 6%), proanthocyanidins, organic acids and other constituents. The observed therapeutic and
*Corresponding author. Email: [email protected] q 2014 Taylor & Francis
Downloaded by [KU Leuven University Library] at 04:54 07 May 2014
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Figure 1. Chemical structures of the main compounds identified in Ginkgo biloba.
pharmacological effects are attributed to multiple components present in the extract and no individual component has been assigned to exert the effect (DeFeudis 1991). Recent studies confirmed that G. biloba L. leaf extract (EGb 761) has been very useful in the treatment of Alzheimer’s disease (AD), neurodegenerative disease, cerebral insufficiency, neurosensory problems (e.g. tinnitus, vertigo), eye ailments, vascular insufficiencies, age-related memory deficit and oxidative stress (Kleinjnen & Knipschield 1992; Oyama et al. 1996; Yucheng et al. 1996; Barry et al. 1998; Robert et al. 2003). In addition, it has been demonstrated to be effective in preventing apoptosis and radical scavenging (Marcocci et al. 1994; Maitra et al. 1995). It is a very useful antioxidant and can be used for enhancing sexual pleasure in individuals suffering from sexual dysfunction (Cohen & Bartlik 1997). G. biloba L. extracts (GBEs) were also tested in cancer research, but very little is known so far (Cohen & Bartlik 1997; DeFeudis et al. 2003; Marie-Noelle et al. 2011). The whole extract provides maximum benefit for the indications as compared with individual compounds isolated from the plant. One of the isolated compound ginkgolide B has been shown to have potential therapeutic effects such as anti-angiogenesis (Kuribara et al. 2003), anti-inflammatory (Ou-Yang et al. 2005) and anti-asthmatic (Chu et al. 2011).
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3. Recent advances 3.1. Alzheimer’s and dementia G. biloba L. has a long history as an effective herbal medicine against AD, and the extract EGb 761 has been used to reduce cognitive dysfunction in a model of vascular dementia in gerbils (Ralf et al. 2011). The studies reveal significant recovery of spatial memory on regular postischaemic treatment with the extract. At cellular level, the extract has been demonstrated to reduce plasma superoxide dismutase activity and protected the hippocampal CA1 neuron, and this study supports the beneficial role of EGb 761 in vascular dementia. To test the efficacy and safety of consumption of the EGb 761 formulation once a day in the treatment of patients experiencing dementia with neuropsychiatric feature, Ralf et al. (2011) carried out randomised controlled trials in 410 outpatients with moderate dementia (AD, vascular dementia or mixed form), and patients were randomly allocated to double-blind treatment with 240 mg of EGb 761 or placebo once daily for 24 weeks (Kaschel 2011). The study revealed that EGb 761, 240 mg once daily, was significantly superior to placebo in the treatment of patients experiencing dementia with neuropsychiatric symptoms. Another study with 188 middle-aged volunteers revealed that EGb 761 enhances cognitive performance and is very useful for the treatment of patients with cognitive impairment (Yang et al. 2011). Further, to ascertain the role of EGb 761 on distinct memory-related functions, a meta-analysis comprising five random trials with 819 patients suffering from AD was undertaken by Silberstein et al. (2011).They found that EGb 761 expresses good therapeutic effect for mild and moderate Alzheimer’s condition. However, they suggested that high-quality, randomised, double-blind and controlled trials are needed to further confirm its therapeutic effects. Experimental study carried out to investigate the role and effect of GBEs on enteric nervous system of diabetic rats revealed a significant decrease in the neuronal population in both plexus of jejunum, and with regard to the ileum there was significant decrease only in the myenteric plexus. In addition, the cell body area increased profoundly in the myenteric plexus of both the segments and in the ileum submucosal plexus, as compared with control group while the treatment reduced the cell body area of submucosal neurons of both the segments and jejunum myenteric neurons. Electrophysiological studies revealed that GBE activated left temporal and prefrontal cortex leading to improved performance. Randomised controlled trials carried out using 240 mg daily dosage on patients with mild to moderate dementia showed effective reduction in behavioural and neuropsychiatric symptoms (Bachinskaya et al. 2011). 3.2. Vascular functions and haemorrhage The effects of GBE on vascular functions have been well investigated, and studies were carried out to observe pressure wave reflection and blood pressure (Gillian et al. 2011). The digital volume pulse was monitored to measure reflection index (DVP-RI) and stiffness index (DVP-SI) while peripheral augmentation index (pAIx) was assessed using radial pulse wave analysis at baseline after 2, 4 and 6 h treatment. The results indicate DVP-SI to be slightly higher and pAIx to be reduced after 2 h of treatment (Hall et al. 2008) and the same was observed after consumption of high-carbohydrate meal. In addition, GBE has been shown to increase cerebral blood flow but individual lobar regions did not show any significant change in post-consumption of the GBE analysis (Ameneh et al. 2011). Besides the vascular functions, hepatoprotective effects of polyprenols from G. biloba L. have been well analysed against carbon tetrachlorideinduced hepatic damage in Sprague-Dawley rats. The elevated levels of serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase, albumin, total protein, hyaluronic acid, laminin, triglyceride and total cholesterol were restored towards normal values in a significant way by GBE in a dose-dependent manner. GBE also reversed the CCl4diminished activity of the antioxidant enzymes and reduced the CCl4-elevated levels of
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malondialdehyde (MDA). In general, the effects of GBE were not significantly different from those of the standard drug essentials (Lan et al. 2011). The pharmacokinetics and pharmacodynamics of GBE on warfarin have been investigated in a randomised, doubleblinded, placebo-controlled two-way cross-over trial, and the results indicate that GBE has minimum effects on the pharmacokinetics and no effect on the pharmacodynamics of singledose warfarin (Yulu & Rong 2011). GBE also has no effect on the clotting process as such; however, individuals associated with haemorrhage and bleeding problems should give special attention to the prescription of GBE with co-prescription of anticoagulants or antiplatelet drugs (Agnes et al. 2011), as it may lead to increased risk of bleeding in elderly persons and in view of the fact that intracranial cerebral haemorrhage without any structural abnormalities in young women has been reported (Pedroso et al. 2011). On the basis of vascular theory of glaucoma, evaluation has been done to study the effects of GBE on peripapillary blood flow in patients with normal-tension glaucoma and they were treated with 80 mg of GBE twice a day for four weeks. Ocular examination performed after the GBE treatment revealed increased mean blood flow, volume and velocity at almost all the points compared with placebo and significant increase in blood volume was observed in superior basal and superior temporal neuroretinal rim areas while significant increase in blood velocity was observed in areas of the inferior temporal neuroretinal rim and superior temporal peripapillary area (Woon et al. 2011). Prolonged administration (40 mg/kg/day) of EGb 761 for 10 weeks brings about changes in retinal constituents especially in the underlying amide region of the secondary protein structure and the NH – OH region (Gamal et al. 2011). 3.3. Anti-inflammatory activities Ginkgolide B was found to be a potent anti-inflammatory agent and it is known to inhibit the platelet-activating factor, which is an important factor in the pathogenesis of asthma. Treatment with ginkgolide B effectively inhibits the increase of T-helper 2 cytokines, such as interleukin (IL)-5 and IL-13, in branchoalveolar lavage fluid with substantial decrease in oeosinophil count. Also, ginkgolide B substantially inhibited ovalbumin-induced oeosinophils in lung tissue and mucus hyper-secretion by goblet cells in the airways. This suggests that ginkgolide B may be useful for the treatment of asthma (Chu et al. 2011). 3.4. Cancer As far as cancer research is concerned, medical science has evolved to its full potential to tackle different kinds of cancer, but the role of phytomedicine cannot be undermined in the development of novel therapeutically useful anticancer agents. Women carrying BRCA1 mutation are at high risk of developing ovarian cancer and the best option available for treatment is prophylactic surgery, which is often accompanied by poor quality of life and permanent damage to fertility. There is an obvious and urgent need to identify a noninvasive approach to prevent ovarian cancer risk especially in women of reproductive age. Microarray analysis of BRCA1 mutant treated with ginkgolide B shows multiple mechanisms and signalling pathways to be involved in anticancer activities (Wei et al. 2011) such as cell proliferation, tumour suppression and DNA damage repair. In another study, involvement in DNA repair mechanism due to oxidative stress in Saccharomyces cerevisiae has been well documented by the application of GBE In addition, the extract also improved the rate of DNA repair after oxidative shock and the extract appears to have profound effect on DNA repair mechanism in addition to protective action against oxidative damage to DNA. Further studies show that the observed DNA repair depends on the DNA repair machinery since no DNA repair was observed under restrictive conditions in a conditional mutant of the CDC9 gene (Marques et al. 2011).
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Mutagenic and morphogenic effects induced by 1.8 GHz global system for mobile communication-modulated radio frequency radiation on human peripheral blood lymphocytes are known to produce morphological changes, destruction of organelles and nucleus structure on long exposure with chromatin changes, loss of mitochondrial cristae and significant increase in sister chromatid exchange frequency and this study was compared with lymphocytes pre-treated with EGb 761. EGb 761 pre-treatment significantly decreased sister chromatid exchange, increased cell viability and inhibited cell proliferation caused by radio frequency radiation (Esmekaya et al. 2011).
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3.5. Jaundice The hepatoprotective effect of GBEs on rats suffering from obstructive jaundice has been well studied (Weng et al. 2011). They reported that GBE could significantly lower serum transaminase levels and ameliorate liver histological damage leading to liver protection. Feeding 4 mg/kg of GBEs to male rats for 5 days significantly decreased the serum activities of ALT and AST. GBE partially prevented the increase of liver MDA (55% ^ 14%) with decrease of albumin concentration to 12% ^ 0.2%. The pre-treatment prevented the down-regulation of tumour necrosis factor-alpha and up-regulated interleukin 6 (IL-6) mRNA steady-state level. Moreover, the GBE treatment reduced the amount of necrotic area in the central lobe (Cha´vezMorales et al. 2011). 3.6. Photoprotective and oxidative effects GBEs and their derivatives have been used in cosmetics to protect the skin against ravages caused by UV radiation and to prevent signs of ageing (Fischer et al. 1995). In one study, hairless mice treated with topical application of G. biloba L. and green tea, were subjected to UV radiation to evaluate different parameters such as skin barrier damage, erythema, histological alteration and sunburn cell formation. The results compared after 20 h of UV exposure revealed that formulations containing GBE provided total protection against UV radiation damage such as skin barrier damage and erythema (Nishizawa et al. 1996; Dal et al. 2011). Also, GBE treatment partially uncoupled mitochondrial oxidation by phosphorylation that reduces the generation of free radicals in the mitochondria and diminishes ischaemia-induced myocardial damage and stimulates degree of respiration by exogenous cytochrome c. (Jurga et al. 2011). 4. Conclusion and future perspective Recent advances in neuroscience have revealed a greater, in-depth understanding of the complexities associated with memory. Contemporary theories hold that an integral relationship between memory formation, stabilisation and consolidation revolves around the plasticity of neuronal networks. The associated requisite receptors alpha-amino-3-hydroxy-5-methyl-4isoxazole propionic acid and N-methyl-D -aspartate and cellular mechanisms surrounding plasticity also display strong correlations in the pathogenesis of dementias. When the brain is in a diseased state as a result of malignant neurotransmission (i.e. in AD), the homoeostatic balance required for normal neuronal processes is disrupted, which leads to degeneration of neural circuitry. Present efforts to find new treatments aimed at reversing or halting neurodegeneration are immense, with increased attention being placed on investigations based on herbal medicines such as G. biloba L. GBEs and compounds present in them have already proved their therapeutic efficacy when tested against known pathogenic markers for AD-associated dementia. GBE has now became a familiar medicine for the treatment of Alzheimer’s, and memoryand vascular-related problems. However, the potential of G. biloba L. is in its infantile stage as
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far as cancer and jaundice research is concerned. Although a very little work has been done so far in this field, undoubtedly, further investigations will give a dramatic breakthrough in the treatment of cancer and jaundice-related diseases.
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