Chapter 15
Neuroprotective Effects of Ginkgo biloba Extract
Downloaded by NORTH CAROLINA STATE UNIV on September 26, 2012 | http://pubs.acs.org Publication Date: April 15, 1998 | doi: 10.1021/bk-1998-0691.ch015
Barbara Ahlemeyer and Josef Krieglstein Institut für Pharmakologie und Toxikologie, Fachbereich Pharmazie der PhilippsUniversität Marburg, Ketzerbach 63, D-35032 Marburg, Germany
Extracts of the leaves of Ginkgo biloba (such as EGb 761 and LI 1370) are widely used for the treatment of dementia and cerebral insufficiency. This review will summarize experimental results concerning the protective effects of EGb 761 and its constituents in different models of cerebral ischemia. Furthermore, we present the supposed mechanisms of action and the current status of clinical trials.
For more than 40 years, the extract of the leaves of Ginkgo biloba (EGb 761) has been widely used therapeutically to increase peripheral and cerebral blood flow, as well as for the treatment of cerebral ischemia, brain disorders caused by old age, and of dementia due to neuronal degeneration or to vascular deficiency. In these age-related disorders, EGb 761 should enhance the intellectual capacity of the patients, that is, improve the learning, memory and cognitive faculties. Although it has been shown that organ systems other than the brain, e.g. the lung (1, 2) and the heart (3, 4), could also benefit from the effects of EGb 761, this review will focus only on the effects of Ginkgo biloba extract on the brain function. First, we would like to present the neuroprotective effects of EGb 761 in different in vivo and in vitro models of cerebral ischemia and relate them to the different constituents of EGb 761. Thereafter, we would like to discuss in detail the effects of EGb 761 under normoxic as well as under ischemic conditions of the brain, including the effects of EGb 761 on cerebral blood flow, on cerebral glucose and lipid metabolism, and on the neurotransmitter systems. The last part of this review will summarize the present status of clinical trials on the commercial extracts of Ginkgo biloba (EGb 761 and L I 1370). The Constituents of Ginkgo Biloba Extract (EGb 761) This extract of Ginkgo biloba is prepared by highly extracting the leaves and removing the constituents ginkgole acid and the biflavones. The purified extract, EGb 761, is standardized to 24 % flavonoids. In addition, it contains approximately 6% terpene
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©1998 American Chemical Society
In Phytomedicines of Europe; Lawson, L., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1998.
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lactones (5). The flavonoid fraction consists of flavone glycosides and proanthocyanidines; whereas, the terpene lactones (non-flavonoid fraction) are composed of 2.9% bilobalide and 3.1% ginkgolides A , B, C and J (Figure 1). In addition, several organic acids, e.g. kynurenic acid and hydroxykynurenic acid, are also found. Most of the extracts of ginkgo biloba on the market are standardized to 24% flavone glycosides and 6% terpene lactones. There is convincing evidence that the terpene lactones are the effective constituents of EGb 761.
Ginkgolides
Figure 1: Chemical structures of the ginkgolides A , B, C and J and bilobalide.
The Neuroprotective Effects of EGb 761 and its Constituents in Different Models of Cerebral Ischemia and Hypoxia. Previous studies of Karcher et al. (6) showed that animals exposed to hypobaric hypoxia survived 3-4 min and that the survival time was prolonged up to 25 min in animals treated with EGb 761. Based on these findings, Oberpichler et aL (7) measured again the survival of rats and mice after lethal hypoxic conditions (the animals were exposed to an atmosphere of 3-4% O2) which was prolonged from 9±2 min to 21±4 min after a 30-min pretreatment with 100 mg/kg EGb 761. In this study only the non-flavonoid fraction of EGb 761 was effective. Further studies (8) were performed to evaluate which constituents of EGb 761 mediate the neuroprotective action. In mouse and rat models of permanent focal ischemia, administration of 5 mg/kg bilobalide, of 100 mg/kg ginkgolide B and of 50 mg/kg ginkgolide A (Lv.) 30
In Phytomedicines of Europe; Lawson, L., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1998.
212 min before ischemia significantly reduced the infarct volume 2 days after focal ischemia. Bilobalide (10 mg/kg), but not ginkgolides A and B, was also effective when added immediately after focal ischemia. None of the drugs showed neuroprotection when given 60 min after focal ischemia. Ginkgolides C and J, as well as EGb 761 (200 mg/kg) were not effective (Table I).
Downloaded by NORTH CAROLINA STATE UNIV on September 26, 2012 | http://pubs.acs.org Publication Date: April 15, 1998 | doi: 10.1021/bk-1998-0691.ch015
Table I. Neuroprotective effects of EGb 761, bilobalide and the ginkgolides A and B which were administered directly after focal ischemia in mice and rats.
Drug
Dosage
EGb 761 200 mg/kg Ginkgolide A 50 mg/kg Ginkgolide B 100 mg/kg Bilobalide 10 mg/kg
2
Percentage of infarcted area (mm ) after 48 h Control Drug-treated
29.1 ± 2 . 3 29.5 ± 3 . 1 25.2 ± 3 . 4 130 ± 2 8
(14) (12) (13) (15)
29.0 ± 4 . 4 (14) 24.7 ± 2.3 (13) 19.9 ± 4 . 0 (13) 105 ± 2 0 (15)
n.s. *** * **
Different from controls with * p
