Ginkgo biloba, also known as ginkgo or maidenhair tree, is a unique species of tree with no close living relatives. It is a living fossil, similar to fossils dating back 270 million years. Native to China, ginkgo is widely cultivated and was introduced early to human history.
Uses : Ginkgo biloba leaves are often used as a source of food, but they are mostly cultivated for medical purposes. The physiological dosage of ginkgo extracts ranges between 120 and 240 mg/day in humans.
Constituents: Extracts of ginkgo leaves contain flavonoid glycosides (myricetin and quercetin) and terpenoids (ginkgolides, bilobalides) .
Quercetin has got a molecular structure like or derived from flavone. It is found in fruits, vegetables, leaves and grains. Several studies has demonstrated its anti-inflammatory activity because of direct inhibition of initial processes of inflammation
Myricetin is a flavonoid found in many grapes, berries, fruits, vegetables, herbs, as well as other plants. It has antioxidant properties.
Ginkgolides are biologically active terpenic lactones present in Ginkgo biloba.
Their clinical application gained popularity in herbal medicine due to treatment of early-stage Alzheimer’s disease, cerebrovascular disorders, PAF antagonism (especially ginkgolide B) and vestibular disorders. Moreover, ginkgolides showed potent antioxidant activities via scavenging of reactive oxygen and nitrogen species.
Bilobalide is a main constituent of the terpenoids found in Ginkgo leaves.
Pharmacological properties of Ginkgo extract
- Antioxidative effects The particularity of Ginkgo biloba extract is that unlike vitamins E and C, the polyphenolic flavanoids are able to act at the mitochondrial level.
Mitochondrial abnormalities in patients with primary open-angle glaucoma
- Stabilization of the mitochondria Some studies revealed several mitochondrial abnormalities in patients with glaucoma. Oxidative damage in mitochondria is particularly relevant for the following reasons:
- The mitochondria themselves are major sources of free radicals,
- Mitochondria have a reduced DNA repair capacity
- An oxidative damage leads to reduced membrane potential and a reduced ATP-production; this makes the cell more vulnerable to other damaging factors,
- If the damage of the mitochondria exceeds a certain level, cytochrome C is released and this molecule then start a chain reaction leading to apoptosis. Ginkgo has been proven to act at the mitochondrial level, by stabilizing the inner membrane and increasing the membrane potential, restoring the respiratory chain.
The protective effect of EGb 761 in isolatedischemic/reperfused rat hearts: a link between cardiac
function and nitric oxide production
- Anti-inflammatory effects Many diseases, including neurodegenerative diseases, have a certain inflammatory component. These are normally not acute inflammations, but rather low-grade inflammations affecting certain cells. When these cells are activated, they produce inflammatory molecules such as TNFα , COX-2 , etc.
Ginkgo extract has been shown to reduce the activation of cells; under treatment with EGb761, NOS-2 is less upregulated and thereby less NO is produced. If NO production is increased in areas with oxidative stress, NO fuses with O2-, thus releasing ONOO-, a highly cell damaging molecule. It has been demonstrated the dual effect of EGb761: it decreases the production of O2- and reduces the production of NO.
It was found that PAF (platelet-activating factor) was able to reproduce (a) Ca2+ influx via N-methyl-D-aspartic acid (NMDA) receptors, (b) enhancement of Ca2+ response to NMDA via activation of protein kinase C (PKC), © the increase of extracellular concentrations of glutamate and (d) the increase in cytosolic free Ca2+ ([Ca2+]i). Moreover, each of these events could be blocked by Ginkgo biloba extract EGb761, a free radical scavenger with PAF antagonism, and by quercetin, a constituent with well-established free radical scavenging property. Also ginkgolide B, another constituent of EGb761 with well-established PAF-antagonizing activity, protected the neurons against Ca2+ dyshomeostasis induced by PAF.
Improved haemorrheological properties by Ginkgo biloba extract (Egb 761) in type 2 diabetes mellitus complicated with retinopathy
- Rheological effects These alterations affect the macrocirculation to a lesser extent, while it has a significant effect on microcirculation. Ginkgo promotes erythrocytes deformability, decreases fibrinogen levels, improves blood viscosity and viscoelasticity.
The World Health Organization reported possile medicinal uses of Ginkgo biloba shown in preliminary clinical research including treatment of the effects of mild to moderate cerebrovascular insufficiency and peripheral arterial occlusive diseases.
Inhibition of platelet activating factor (PAF)-induced aggregation of human thrombocytes by ginkgolides
Effects of Ginkgo biloba extract (EGb 761) on cerebral thrombosis and blood pressure in stroke prone spontaneously hypertensive rats
- Antithrombotic properties Ginkgo extract has an antithrombotic effect. However, the actual data do not corroborate the hypothesis Ginkgo extract may significantly increase the risk of clinically relevant and dangerous hemorrhages.
PAF is an alkyl phosphoglyceride (1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine) that is synthesized by numerous cells and tissues upon appropriate stimulation.
It derives from the acetilation on the second carbon of lyso PAF, that derives from the hydrolisis of a alkylacylglycerophosphocoline by phospholipase A2. PAF is released by neutrophils, basophils, platelets, and some other cells, to induce platelets aggregation, inflammation and anaphylaxis. PAF is considered to be a mediator of cell-to-cell communication and functions as either an inter- or intracellular messenger. In vitro, it promotes various biological responses such as platelet secretion and activation, neutrophil stimulation, increase of vascular permeability, and contraction of smooth muscle cells.
PAF was subsequently used at standard concentrations of 200 and 1 ng/ml to evaluate PAF-antagonistic effects of gingkolides and the Ginkgo extract EGb 761® with human and rabbit PRP, respectively. In both species ginkgolides and EGb 761® concentration-dependently inhibited the PAF-induced platelet aggregation. Considering the PAF-antagonistic potential of the individual ginkgolides as well as their proportion in EGb 761®, ginkgolide B contributes to about two-thirds to the PAF-inhibitory activity of the total extract.
Under normal physiological conditions, PAF is only minimally expressed and is mainly produced by a de novo pathway which it mostly operative in the kidneys and the central nervous system. Thus, PAF is obviously not of particular significance for primary hemostasis. Furthermore, PAF is classified as a ‘weak’ platelet activator that depends on autocrine stimulation (e.g., by fibrinogen, prostaglandins/thromboxanes and endogenous ADP) to promote the full sequence of platelet responses such as shape change, aggregation, secretion and liberation of arachidonates. During acute inflammation, hypersensitivity reactions or conditions of oxidative stress, synthesis of PAF is markedly upregulated and production occurs by a remodeling route from membrane phospholipides in stimulated inflammatory cells (e.g. monocytes/macrophages, neutrophiles, eosinophiles, basophiles) as well as platelets, endothelial cells and cardiomyocytes. Under these circumstances, PAF is involved in many pathophysiological processes and may trigger coagulation and thrombus formation.
Ginkgo biloba extract improves coronary blood flow in healthy elderly adults: role of endothelium-dependent vasodilation
- Vasorelaxative properties Ginkgo biloba increases microcirculation by improving the endothelium dependent vasodilation.
The effect of EGb-761 on morphologic vasospasm in canine basilar artery after subarachnoid hemorrhage
- Antivasospastic properties Also in glaucoma, vasospasms play a crucial role . The antivasospastic property of Ginkgo biloba has clearly been demonstrated. Moreover, the results show that endothelin is increased in glaucoma patients, particularly in patients with normal tension glaucoma.
Ginkgo Biloba and Glaucoma
- Pathophysiology of glaucoma Ginkgo biloba positively influences oxidative stress and disturbed vascular circulation. Both reduced microcirculation and oxidative stress are involved in the pathogenesis of glaucoma. Therefore, already from a theoretical point of view, the pharmacological properties of Ginkgo can be expected to be beneficial for eye as well.
Oxidative stress is involved in the pathogenesis of IOP, whereas for GON, factors associated with disturbed vascular regulation play a major role.
Glaucomatous outflow pathway and oxidative stress
- Intraocular pressure (IOP) Oxidative stress has been implicated to be a cause of increased intraocular pressure by triggering trabecular meshwork ™ degeneration and thus contributing to alterations in the aqueous outflow pathway.
The TM is in constant contact with the aqueous humor from which ROS may be generated through light catalyzed reactions, metabolic pathways or inflammation .Disturbance of the TM cell status by an insult such as oxidative stress, may lead to cellular loss and an overexpression or alteration in the structures of various glycoproteins in the extracellular matrix , which interfere with the TM function, and lead to impaired aqueous humor outflow and thereby an increase in IOP.
The pathogenic role of oxidative stress in increasing IOP by reducing aqueous outflow facility, is supported by various experimental studies performed in vitro and in vivo.
- Glaucomatous optic neuropathy (GON) Beside increased IOP, vascular damage and hypoxia are often associated with glaucoma.Several studies indicate that beside IOP, disturbed regulation of microcirculation and oxidative stress are major risk factors leading to GON. Both aspects can be influenced by Ginkgo.
- Normal-pressure glaucoma
Diagnosis of normal-tension glaucoma (NTG), defined as glaucoma without a clearly abnormal IOP, depends on recognizing symptoms and signs associated with optic nerve vulnerability, in addition to absence of other explanations for disc abnormality and visual field loss.
Modern strategies for Glaucoma treatment While classic glaucoma treatment focuses on IOP reduction, open question remains, as cases exist for which a reduction of IOP does not stop the progression of the disease.
The non-IOP lowering drugs described in the review are targeted at different levels of the athophysiology involved in glaucomatous optic neuropathy, such as: inhibition of the activation of astrocytes, inhibition of nitric-oxide synthase 2, improvement of vascular regulation, counteract oxidative stress, inhibition of matrix metalloproteinase, upregulation of heat shock protein, neuroprotection.
Effect of Ginkgo biloba on glaucomatous optic neuropathy Normal-tension glaucoma, is characterized by progressive optic nerve damage and visual field loss with a statistically normal intraocular pressure. Normal-tension glaucoma is thought to be related to dysregulated blood flow of the optic nerve.
Ginkgo is used by glaucoma specialists for treatment of patients with normal tension glaucoma and for patients with a glaucoma that progresses despite IOP lowering treatment.
No other therapeutic options for these cases and on the other hand, the pharmacological profile of Ginkgo exactly fits to the pathophysiology of these special conditions. Pre-clinical data in a traditional sense are not directly available to assess the beneficial effect of Ginkgo for a) normal tension glaucoma and b) glaucoma that progresses despite a normalized IOP.
Overall conclusion from the experimental data for Ginkgo biloba and glaucoma Based on the present knowledge of the pathogenesis of glaucomatous damage, Ginkgo interferes positively on different steps involved in the pathogenesis of glaucomatous damage (oxidative stress, microcirculation, mitochondrial function etc). However experimental models for normal tension glaucoma or forglaucomatous progression despite normal IOP do not exist. Therefore, the conclusions are based on extrapolation of other studies. And these extrapolations reveal a clear positive effect of Ginkgo.
But even in high tension glaucoma, where IOP plays a major role (whereas factors such as impaired microcirculation and oxidative stress are less relevant) and where an accepted therapy (namely the IOP lowering therapy) is available, the effect of ginkgo was highly significantly positive. While all publications are indirectly in favor for Ginkgo, no single publication contradicts the positive effect of Ginkgo.
Effect of Ginkgo biloba extract on preexisting visual field damage in normal tension glaucoma
Adverse reactions under Ginkgo biloba treatment
According to published studies and reports, the use of Ginkgo seems safe and well tolerated.
In rare cases, mild gastrointestinal complaints, headache, and allergic skin reactions have been reported . There are several published case reports linking Ginkgo to episodes of minor to severe bleeding. It can be envisaged that inhibition of PAF action by an antagonist only normalize the distorted hemostatic system, but will not cause hemorrhage.
Interaction potential during Ginkgo biloba treatment
The risk of spontaneous bleeding may be increased when Ginkgo biloba extract is combined with nonsteroidal antiinflammatory drugs (NSAIDs) and anticoagulants such as heparin or warfarin .
Ginkgo biloba appears to be predominantly safe in the long term use with no excess side effects compared with placebo.
CONCLUSIONS
The classical treatment of glaucoma is and remains IOP reduction. However in normal tension glaucoma, the glaucomatous disease progresses despite a normal or normalized IOP. As the pharmacological properties of Ginkgo specifically target the factors involved in glaucomatous disease (disturbed ocular microcirculation, oxidative stress, impairment of mitochondrial function in the retinal ganglion cells), it can be assumed that Ginkgo could theoretically be beneficial for glaucoma.
Ginkgo would probably be beneficial for all glaucoma patients. However the use of ginkgo can be recommended as an adjuvant therapy only for normal tension glaucoma patients and for high tension glaucoma patients progressing despite a normalized IOP. Such a limitation is economically meaningful and medically possible, as for these two conditions, there are no other therapeutic alternative so far.
Michele Bini
Daniela Sigaudo
