Mechanism of Action:
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.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. 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.
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 might work by protecting tissues from oxidative damage. Ginkgo leaf flavonoids have antioxidant and free radical scavenging properties. 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. Protecting neurons and other tissues from oxidative damage might prevent progression of tissue degeneration in patients with dementia and other conditions.
- 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.
- 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. Preliminary research also suggests that ginkgo leaf extract can inhibit formation of platelet thromboxane A2 and thromboxane B2, further reducing platelet aggregation. 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.
- 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.
- 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.
- 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.
- 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 leaf might have some antimicrobial activity, including activity against Pneumocystis carinii and possibly some gram-positive bacteria and yeast.
- 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.
- some crude extracts from ginkgo leaves contain the constituent ginkgolic acid. This constituent can have strong allergenic properties and might have possible mutagenic and carcinogenic properties. Standardized ginkgo leaf extracts such as EGb 761 contain no greater than 5 ppm in concentration of ginkgolic acids.
- ginkgo seeds seem to have antibacterial and antifungal effects.
- ginkgo seeds contain the neurotoxin ginkgotoxin (4'-O-methylpyridoxine). Ginkgotoxin 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. GABA is synthesized from glutamate by glutamate decarboxylase. By inhibiting glutamate decarboxylase, ginkgotoxin indirectly inhibits GABA. Boiling ginkgo seeds seems to reduce 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.
- 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. 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.
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 suggest that taking ginkgo 90mg/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 gingko might not cause clinical significant interactions through this mechanism. In healthy volunteers, ginkgo does not seem to significantly alter the pharmacokinetics of the OATP substrate ticlopidine.
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