Medical Attributes of Ginkgo biloba - The Maidenhair Tree

by Neil Kocher, Justin Crawford, and Licia Witt
Wilkes University
Wilkes-Barre, PA

May, 2009
Ginkgo biloba, commonly known as the maindenhair tree, is considered a living fossil and the oldest extant tree species in the world (Shen, et al. 2005).  As the sole member of the Ginkgoaceae, G. biloba is approximately 270 million years old.  G. biloba is a gymnosperm with fan-shaped deciduous leaves, however it is distinguished from the conifers by possessing multiflagellated sperm cells (Beek, 2000).  While it was once a global species, Ginkgo biloba is currently native to China, but has since been cultivated worldwide for both its beauty and medicinal properties (Kwant, 2009).

The Chinese have utilized Ginkgo biloba seeds for thousands of years as part of Traditional Chinese Medicine (TCM) (Beek, 2000).  G. biloba seeds were primarily used for their presumed anticancerous and anthelmintic properties, as well as to promote digestion and circulation (Anon., 2009; Kwant, 2009).  However, beginning in the 1950s, Western culture has focused specifically on Ginkgo leaves for its therapeutic benefits including memory enhancement and improved circulation.

The leaves of Ginkgo biloba contain a wide variety of chemical constituents.  In general, G. biloba possesses flavonoids (flavones and biflavones), terpenes (trilactones, triterpenes, carotenoids, polyprenols), organic acids (bilabol and ginkgolic acid), carbohydrates, as well as miscellaneous organic and inorganic compounds (Feng, Zhang, & Zhu, 2009; Nakanishi, et al. 2003).

One of the issues concerning herbal remedies such as Ginkgo biloba is that of standardization.  Various factors, including the composition of active ingredients within the extract, can cause ambiguous results in clinical studies.  However, concerning Ginkgo biloba, a standardized extract known as EGb-761 has been produced and studied extensively (Clostre, 1999).  EGb-761 contains approximately 24% flavonoids (Feng, Zhang, & Zhu, 2009) as well as about 6% terpene lactones (2.8-3.4% ginkgolides A, B, and C, and 2.6-3.2% bilobalide).  Ginkgolide B and bilobalide therefore account for roughly 0.8% and 3% of the total extract, respectively (Anon., 2003).

A recent study by Lotito and Frei (2007) determined that flavonoids do not act as antioxidants.  The body reacts to flavonoids by activating Phase-II enzymes, which also respond to mutagens and carcinogens.  However, through increased activation of nitric oxide synthase, flavonoids have also been shown to lower blood pressure and prevent inflammation (Lotito & Frei, 2007).  Though not antioxidants, flavonoids are still considered important in preventing heart disease and cancer through different mechanisms (Stauth, 2007).

The terpene trilactones, including ginkgolides and bilobalide, are unique compounds found solely in Ginkgo biloba (Lichtblau, 2002).  Ginkgolides are particularly important in inhibiting platelet-activating factor (PAF), which permits both an anti-inflammatory and reduced blood clotting effect (Chang 2003).  There are several classes of ginkgolides, including A, B, C, M, and J, which are characterized by the presence of one to several hydroxyl groups (Chang, 2003; Noe, 1997).  Bilobalide, a compound structurally similar to the ginkgolides, antagonistically blocks GABAA receptors and has proposed neuroprotective properties.  In animal models with acute neurodegeneration, such as cerebral hypoxia and ischemia, bilobalide has shown beneficial effects (Kiewert, et al. 2007).

EGb-761 has been shown to improve circulation by increasing endothelial vasodilation.  Schneider et al. (2009) investigated the effects of EGb-761 against diabetes-induced myocardial interstitium and microvasculature damage along with additional ischemia/reperfusion injury.  This study showed that diabetic myocardium was more vulnerable to ischemia and that the inflammation response increases compared to controls.  It was shown, however, that pre-treatment with EGb-761 resulted in an overall improvement in endothelial vasodilation and reduced ischemia.  These effects lead to a more improved myocardial ultrastructure by diminishing mast cell and substance P accumulation (Schneider, et al., 2009).

Atherosclerosis results from a chronic inflammatory response in arterial walls and is signaled by a pro-atherosclerotic stressor called oxLDL, (oxidized low density lipoprotein) (Ou, et al. 2009). A recent study was able to demonstrate that in vitro treatment with EGb-761 was able to ameliorate the detrimental effects on endothelial cells caused by the accumulation of LDLs (Ou, et al. 2009).  In addition, a previous study concluded that EGb-761 was able to reduce atherosclerotic nanoplaque formation in cardiovascular high-risk patients.  This medicinal effect is hypothesized to be due to an up-regulation in the body's own free radical scavenging enzymes (Rodríguez, et al., 2007).

In Europe, EGb-761 is currently utilized for treating degenerative dementias, specifically Alzheimer’s (Maurer, 1997).  The cornerstone of neurodegenerative disorders is neuronal cell loss; a treatment that targets the mechanism responsible for cell death could therefore delay or even stop progressive neurodegeneration (Luo, 2001).  EGb-761 has thus received increasing attention for its ability to stimulate the growth factor-mediated cell survival pathway.  One study determined that EGb-761 is effective in stabilizing and improving cognitive performance of demented patients (Berman, 1997).  Moreover, the additional benefits of Ginkgo biloba such as increased blood flow, inhibition of PAF and nitric oxide, and neuroprotective activity suggest that EGb-761 could be of major therapeutic value in the treatment of Alzheimer’s disease (Luo, 2001).  However, the benefits of Ginkgo biloba leaves have recently been disputed in the United States.  An innovative study suggests “inconsistent and unconvincing” evidence that G. biloba had clinically significant benefits for individuals with dementia or cognitive impairment (Schneider, 2008).  In an attempt to gain marketing approval for EGb-761 by the Food and Drug Administration, Schwabe Pharmaceuticals conducted a 6-month regulatory trial of 513 patients with mild to moderate Alzheimer’s disease, which ultimately failed to establish its effectiveness (Schneider, 2008).

Contrary to its supposed ability to reduce dementia, recent literature concerning Ginkgo biloba reveal its alleged ability to induce seizures.  It is interesting to note that Ginkgo is popular as a treatment for Alzheimer’s disease, and it is these patients that are 6-10 times more likely to have seizures than are matched controls (Hauser, 1986).  However, a recent study suggests that one major concern with Ginkgo use among elderly patients with epileptic disorder is the lack of standardization associated with various Ginkgo products.  It is therefore likely that patient consumption of impure products, which may contain the G. biloba plant parts associated with seizure induction, could result from such a lack of standardization (Harms, 2006).

Despite the recent dispute concerning its medicinal effects, Ginkgo biloba has been used for centuries in different cultures for myriad purposes, most notably for its ability to improve circulation and memory.  Moreover, with the standardization of its extract EGb-761, more extensive research into the therapeutic benefits of G. biloba can now be performed.  While recent studies performed by Schneider, et al (2008, 2009) suggest that Ginkgo permits both a beneficial and harmful effect, additional work by Harms (2006), Luo (2001), and many others have yielded results indicating benefits for ischemia, atherosclerosis, and dementia.  With several inconsistencies still unexplained, primarily its neurological effects on Alzheimer’s disease and epilepsy, the medicinal properties of Ginkgo biloba must be studied further in order to elucidate its exact contribution to the medical community

 

LITERATURE CITED

Anonymous.  2009.  Herbs at a glance: Ginkgo.  http://nccam.nih.gov/health/ginkgo/

Anonymous.  2003.  EGb-761: Ginkgo biloba extract, Ginkor. Drugs R D.  4(3): 188-93
   
Beek, T.  2000.  Ginkgo biloba: Medicinal and Aromatic Plants -- Industrial Series #12.   CRC Press, 2000: 7-9.

Berman N., A.M. Freedma, P.L. LeBars, K.M. Martin, & M. Turan.  1997.  A placebo-controlled, double-blind, randomized trial of an extract of Ginkgo Biloba for dementia. Journal of the American Medical Association. 278 (16): 1327-1332.

Chang, P.  2003.  Ginkgo biloba: Disease Mechanism IV: Free Radical Damage.” http://www.stanford.edu/group/hopes/treatmts/antiox/k2.html.

Clostre, F. 1999.  Ginkgo biloba extract (EGb 761).  State of knowledge in the dawn of the year 2000.  Ann Pharm Fr. 57 Suppl 1: 158-188.

Feng, X., L. Zhang, & H. Zhu.  2009. Comparative anticancer and antioxidant activities of different ingredients of Ginkgo biloba extract (EGb 761). Planta Med. Mar 13.

Harms, S.L., J. Garrard, P. Shwinghammer, L.E. Eberly, C. Yanping, & I.E. Leppik.  2006. Ginkgo biloba use in nursing home elderly with epilepsy or seizure disorder.  Epilepsia 47(2): 323-329.

Hauser W.A., M.L. Morris, & L.L. Heston. 1986. Seizures and muoclonus in patients with Alzheimer’s disease.  Neurology, 36: 1226-1230.

Kiewert, C, V. Kumar, O. Hildmann, M. Rueda, J. Hartmann, R.S. Naik, & J. Klein.  2007.  Role of GABAergic antagonism in the neuroprotective effects of bilobalide.  Brain Res., 1128(1): 70-78.

Kwant, C.  2009.  The Ginkgo Pages.  http://www.xs4all.nl/~kwanten/history.htm.

Leng, B. and J. Cai. 2007.  Update of the Anti-oxidation Effects of Extract From Ginkgo biloba.

Lichtblau, D., J.M. Berger, & K. Nakanishi. 2002.  Efficient extraction of ginkgolides and bilobalide from Ginkgo biloba leaves.  J. Nat. Prod., 65(10): 1501-1504.

Lolito, S., & B. Frei.  2006.  Consumption of flavonoid-rich foods and increased plasma antioxidant capacity in humans: Cause, consequence, or epiphenomenon? Free Radical Biology and Medicine. 41(12): 1727-1746.

Luo, Y. 2001.  Ginkgo biloba neuroprotection: Therapeutic implications in Alzheimer’s disease. Journal of Alzheimer’s Disease 3: 401-407.

Maurer, K., R. Ihl, T. Dierks, & L. Frolich. 2007. Clinical efficacy of Ginkgo biloba special extract EGb761 in dementia of the Alzehimer type. J. Psychiatry 31: 645-655.

Mazza, M., A. Capuano, P. Bria, & S. Mazza. 2006.  Ginkgo biloba and donepezil: a comparison in the treatment of Alzheimer's dementia in a randomized placebo-controlled double-blind study.  European Journal of Neurology. 13: 981-985.

Nakanishi, K., N. Berova, S. Jaracz, S.R. Kim, S. Krane, S. Malik, K. Strømgaard, M. Suehiro, & S.B. Vogensten. 2003.  Bioorganic Studies on Ginkgolides.  http://www.columbia.edu/cu/chemistry/groups/nakanishi/ginkgo.html.

Noe, J.  1997.  Ginkgo biloba: A Monograph.  Journal of Naturopathic Medicine.  8(1): 47-59.

Ou, H.C., W.J. Lee, I.T. Lee, T.H. Chiu, K.L. Tsai, C.Y. Lin, & W.H. Sheu.  2009. Ginkgo biloba extract attenuates oxLDL-induced oxidative functional damages in endothelial cells. J Appl Physiol. Feb 19.

Rodríguez, M., L. Ringstad, P. Schafer, S. Just, H.W. Hofer, M. Malmstem, & G. Siegel.  2007. Reduction of atherosclerotic nanoplaque formation and size by Ginkgo biloba (EGb 761) in cardiovascular high-risk patients. Atherosclerosis. 192(2): 438-44.

Schneider, R., K. Welt, W. Aust, H. Loster, & G. Fitzl. 2009. Cardiac ischemia and reperfusion in spontaneously diabetic rats with and without application of EGb 761: II. Interstitium and microvasculature. Histol. Histopathol. 24(5): 587-98.

Schneider, R. & S. Lon. 2008. Gingko biloba extract and preventing Alzheimer disease. Journal of the American Medical Association. 300: 2306-2308.

Shen, L., X.Y. Chen, C.X. Fu, Y.Y. Li, & Y.X. Qiu. 2005.  Genetic variation of Ginkgo biloba L. (Ginkgoaceae) based on cpDNA PCR-RFLPs: inference of glacial refugia.  Heredity. 94: 396-401.

Stauth, D (2007).  Studies force new view on biology of flavonoids. http://www.eurekalert.org/pub_releases/2007-03/osu-sfn030507.php.

This paper was developed as part of the BIO 368 - Medical Botany course offered at Wilkes University during the summer of 2009. Course instructor was Kenneth M. Klemow, Ph.D. (kenneth.klemow@wilkes.edu). The information contained herein is based on published sources, and is made available for academic purposes only. No warrantees, expressed or implied, are made about the medical usefulness or dangers associated with the plant species in question.

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This page posted and maintained by Kenneth M. Klemow, Ph.D., Biology Department, Wilkes University, Wilkes-Barre, PA 18766. (570) 408-4758, kenneth.klemow@wilkes.edu.