Mechanism of Action
General
The applicable parts of ginkgo are the leaf and the seed. Ginkgo leaf is the most commonly used form of ginkgo, usually as an extract.
Ginkgo leaf and its extracts contain several active constituents including flavonoids, terpenoids, and organic acids. Many ginkgo leaf extracts are standardized to contain about 24% to 25% flavonoid glycosides and 6% terpenoids. The major flavonoids are primarily derived from the flavonol rutin and include isorhamnetin, quercetin, kaempferol, and proanthocyanidins. The primary terpenoids are ginkgolides A, B, C, M, and J, and bilobalide. Other constituents of ginkgo leaf extracts include biflavones, proanthocyanidins, alkylphenols, phenolic acids, and polyprenols.
Although many of ginkgo’s constituents have intrinsic pharmacological effects individually, there is evidence that the constituents work synergistically to produce more potent pharmacological effects than any individual constituent.
Anticancer effects
Some clinical or epidemiological evidence suggests that ginkgo may be helpful in the prevention or treatment of colorectal cancer, gastric cancer, ovarian cancer, and pancreatic cancer. The exact anticarcinogenic mechanism of action of ginkgo extract is not clear. In humans, ginkgo extract appears to prevent the iodine-131-induced increase in lymphocyte micronuclei and clastogenic factors, which suggests that ginkgo extract may prevent genotoxic damage. In vitro evidence suggests that ginkgo extract and the constituents quercetin and ginkgolides A and B inhibit ovarian cancer cell proliferation by blocking the G0/G1 to S phase of the cell cycle. Additional in vitro research shows that ginkgolide B, a constituent of ginkgo extract, can up- and down-regulate various proteins involved in proliferation, tumor suppression, and DNA damage repair in breast cancer gene 1 (BRCA1)-mutant ovarian epithelial cells. Other in vitro evidence suggests that exocarp polysaccharides from ginkgo extract can induce apoptosis and differentiation of gastric cancer cells, possibly by altering the expression of c-myc, bcl-2, and c-fos genes.
Anticoagulant/antiplatelet effects
Ginkgolides in the leaf competitively inhibit platelet activating factor (PAF) binding at the membrane receptors of numerous cells. PAF inhibition decreases platelet aggregation. Also, preliminary research suggests that ginkgo leaf extract can inhibit formation of platelet thromboxane A2 and thromboxane B2, which reduces platelet aggregation.
However, in humans, there is evidence that ginkgo leaf may not reduce platelet aggregation and blood clotting with short-term use. In one study, healthy men who took the specific ginkgo leaf extract (EGb 761) 160 mg twice daily for 7 days did not have reduced prothrombin times. It has been suggested that ginkgo has to be taken for at least 2-3 weeks to have a significant effect on platelet aggregation. However, a meta-analysis of 18 studies (1985 patients) using standardized ginkgo extracts, 80-480 mg daily for up to 32 weeks, did not find a significant effect on platelet aggregation, fibrinogen concentration, or PT/aPTT.
Antidiabetic effects
Ginkgo might affect insulin secretion. In healthy volunteers, ginkgo leaf extract (EGb 761) seems to increase pancreatic beta-cell function in response to glucose loading and modestly reduce blood pressure. Some researchers speculate that ginkgo might decrease development of hyperinsulinemia associated with hypertension, which often precedes development of type 2 diabetes and atherosclerotic cardiovascular disease .
In patients with type 2 diabetes, the effect of ginkgo on insulin appears to be dependent on the insulin-producing status of the patient. In diet-controlled diabetes patients with hyperinsulinemia, taking ginkgo does not seem to significantly affect insulin or blood glucose levels following an oral glucose tolerance test. In those patients with hyperinsulinemia who are treated with oral hypoglycemic agents, taking ginkgo seems to result in decreased insulin levels and increased blood glucose following an oral glucose tolerance test. Researchers speculate that this could be due to ginkgo-enhanced hepatic metabolism of insulin or of diabetes drugs; however, ginkgo does not seem to significantly affect the pharmacokinetics of metformin. In patients with pancreatic exhaustion, taking ginkgo seems to stimulate pancreatic beta-cells resulting in increased insulin levels and increase C-peptide levels in response to an oral glucose tolerance test. Ginkgo does not appear to affect insulin resistance or glucose disposal in patients with or without type 2 diabetes.
Anti-inflammatory effects
Central nervous system (CNS) disorders, such as dementia, and other conditions including peripheral arterial disease, hypersensitivity disorders, allergies, asthma, and bronchitis might benefit from ginkgo’s anti-inflammatory effects. Preliminary clinical evidence shows that ginkgo extract 1 gram three times daily for 3 months reduces levels of interleukin (IL)-6, IL-8, and tumor necrosis factor-alpha (TNF-alpha) in patients with pulmonary interstitial fibrosis, leading to improvements in symptoms and lung function. In animals, the standardized ginkgo extract called EGb 761 has been showed to inhibit carrageenan-induced inflammation.
Antimicrobial effects
Ginkgo leaf might have some antimicrobial activity, including activity against Pneumocystis carinii and possibly some gram-positive bacteria and yeast. Ginkgo seeds seem to have antibacterial and antifungal effects.
Antioxidant effects
Although the mechanism of action of ginkgo leaf is only partially understood, there are several theories about how it might work for various disease states. Ginkgo leaf flavonoids have antioxidant and free radical scavenging properties. In elderly patients, intake of ginkgo extract has been shown to increase levels of the radical scavenger glutathione in the liver of elderly patients and reduce platelet malondialdehyde levels in patients with type 2 diabetes. The flavonoids seem to prevent or reduce cell membrane lipid peroxidation , and decrease oxidative damage to erythrocytes. Ginkgo’s flavonoids also protect neurons and retinal tissue from oxidative stress , and injury following ischemic episodes. Ginkgo terpene lactones, such as ginkgolide B, Protecting neurons and other tissues from oxidative damage might prevent progression of tissue degeneration in patients with dementia and other conditions.
Cardiovascular effects
Ginkgolides in the leaf competitively inhibit platelet activating factor (PAF) binding at the membrane receptors of numerous cells. PAF inhibition decreases platelet aggregation, decreases phagocyte chemotaxis and smooth muscle contraction, prevents degranulation of neutrophils, decreases free radical production, decreases damaging glycine production after brain injury, and reduces excitatory amino acid receptor function. Inhibition of PAF might increase cardiac contractility and coronary blood flow.
Ginkgo leaf products might benefit CNS and vascular conditions by improving circulation. Ginkgo leaf seems to improve blood flow to capillaries throughout the body including in the CNS, eyes, ears, extremities, and other tissues. Ginkgo leaf likely improves circulation by both decreasing blood viscosity and affecting vascular smooth muscle. Ginkgo leaf seems to restore the balance between prostacyclin and thromboxane A2, resulting in improved vasoregulation. Therefore, ginkgo leaf relaxes spasmodic contracting vasculature and contracts abnormally dilated vessels. It is not clear exactly how ginkgo causes vascular contraction and improves venous tone, but these effects might be due to phosphodiesterase inhibition, resulting in increased cAMP levels and release of catecholamines. Some ginkgo constituents may also have a potent relaxing effect on vascular smooth muscle and improve blood flow to the corpus cavernosum; which is thought to be helpful for erectile dysfunction. Overall, ginkgo leaf seems to increase cerebral and peripheral blood flow microcirculation, and reduce vascular permeability.
In addition to decreasing platelet aggregation and improving circulation, some evidence shows that ginkgo extract may also have cardioprotective effects. When administered to patients as part of the cardioplegia perfusion during cardiac surgery, ginkgo extract appears to induce the production of plasma vascular endothelial growth factor (VEGF). Also, evidence from animal research shows that ginkgo extract or its constituent ginkgolide B may attenuate ischemia- and reperfusion-induced arrhythmia and other injury.
Drug metabolizing effects
Ginkgo appears to affect several cytochrome P450 enzymes in vitro and in animal models; however, in humans, ginkgo does not seem to significantly affect most of these enzymes. There is preliminary evidence that ginkgo leaf extract is a weak inhibitor of cytochrome P450 1A2 (CYP1A2), decreasing activity by approximately 13%; however, contradictory clinical research suggests that ginkgo leaf extract does not significantly affect the activity of CYP1A2. The effects of ginkgo leaf extract on CYP3A4 are unclear. There is some in vitro evidence that ginkgo leaf extract might inhibit CYP3A4; however, in vivo, ginkgo leaf extract does not seem to inhibit CYP3A4. In addition, there is anecdotal evidence that suggests ginkgo leaf extract might actually induce CYP3A4, but this effect has not yet been verified.
The ginkgo leaf extract EGb 761 (Ginkgold, others), which is the most common extract used in clinical studies, seems to strongly inhibit CYP2C9 in vitro. Different constituents in ginkgo seem to have different effects on hepatic enzymes. The terpenoidic fraction (ginkgolides) seems to inhibit just CYP2C9 in vitro and possibly p-glycoprotein in vivo. The flavonoidic fraction (quercetin, kaempferol, myricetin, etc.) seems to inhibit CYP2C9, CYP1A2, CYP3A4, and CYP2E1 in vitro.
However, clinical research suggests that ginkgo leaf extract does not significantly affect the activity of CYP1A2, CYP2C9, or CYP2D6, while inhibition of CYP2C19 occurred in one study in humans.
Ginkgo extract appears to mildly inhibit CYP2D6 enzymes, by about 9%; however, this effect might be too small to be clinically significant. Some clinical research suggests that ginkgo leaf extract does not significantly affect the activity CYP2D6. Additional clinical research suggests that taking ginkgo 90 mg/day for 30 days does not affect donepezil levels. Donepezil is a substrate of both CYP2D6 and CYP3A4.
In vitro, ginkgo seems to inhibit organic anion transporting polypeptide (OATP) uptake of estrone-3-sulfate. But ginkgo might not cause clinically significant interactions through this mechanism. In healthy volunteers, ginkgo does not seem to significantly alter the pharmacokinetics of the OATP substrate ticlopidine.
Lipid-lowering effects:
In vitro evidence suggests that ginkgo extract decreases total cholesterol content, inhibits HMG-CoA reductase activity, and decreases cholesterol influx in cultured hepatocytes. However, it is unclear if ginkgo extract has lipid-lowering effects in animals or humans.
Neurologic/CNS effects:
Ginkgo leaf extract might be helpful for Alzheimer’s disease due to effects on beta-amyloid proteins. There is preliminary evidence that ginkgo leaf extract can inhibit toxicity and cell death induced by beta-amyloid peptides. However, this has not yet been demonstrated in vivo. Ginkgo might also influence certain neurotransmitter systems, such as the cholinergic system, and seems to produce EEG changes similar to the acetylcholinesterase inhibitor tacrine (Cognex). There has been some speculation that ginkgo leaf inhibits monoamine oxidase A and B, but so far studies have found conflicting results. It is suggested that ginkgo leaf inhibits catechol-O-methyl transferase (COMT, an enzyme which breaks down adrenergic transmitters) and increases the number of alpha-adrenoreceptors in the brain; which would help reverse the decline in brain alpha-adrenoceptor activity that occurs with aging. There is some evidence that ginkgo flavonoids have GABA-ergic effects and might directly affect benzodiazepine receptors. However, the clinical significance of this effect is not known.
Ginkgo leaf extract might have effects on neurotransmitters. Animal model studies have shown that ginkgo leaf extract significantly reduces uptake of dopamine and norepinephrine. However, this effect is not seen after a single 100 mg/kg dose, but was found after 14 days of therapy.
The ginkgolides A and B seem to decrease glucocorticoid biosynthesis, which might also play a role in ginkgo’s proposed anti-stress and neuroprotective effects. Some evidence shows that a specific ginkgo extract (EGb 761, Tanakan) reduces stress-induced rises in adrenocorticotrophic hormone (ACTH), cortisol, and blood pressure in animals and in healthy volunteers.
Ginkgo extract may also protect against neurotoxicity induced by other drugs. Animal research shows that ginkgo extract protects retinal cells against glutamate-induced neurotoxicity. Also, in vitro evidence suggests that standardized ginkgo extract called EGb 761 protects against neurodegeneration induced by verapamil or antimycin A1 plus 2-deoxy-D-glucose.
Seizure threshold-lowering effects:
Ginkgo seeds contain the neurotoxin ginkgotoxin (4′-O-methylpyridoxine), which can cause seizures, paralysis, and death when taken in high doses. Ginkgotoxin antagonizes the activity of pyridoxine, possibly by inhibiting enzymes such as pyridoxal kinase or glutamate decarboxylase in the brain. Therefore, since GABA is synthesized from glutamate by glutamate decarboxylase, by inhibiting glutamate decarboxylase, ginkgotoxin indirectly inhibits GABA. Boiling ginkgo seeds reduces the ginkgotoxin content to safe levels. Ginkgo leaves and ginkgo leaf extracts can also contain the ginkgotoxin; however, ginkgotoxin is present in much higher amounts in ginkgo seeds than leaves. It is unclear whether it is present in ginkgo leaf extracts in high enough concentrations to cause toxicity. However, seizures have been reported in people taking ginkgo leaf preparations.
