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Review Article

Ginkgo Biloba Extract in Ophthalmic and Systemic Disease, With a Focus on Normal-Tension Glaucoma

Labkovich, Margarita BA; Jacobs, Erica B. BS; Bhargava, Siddharth BS; Pasquale, Louis R. MD; Ritch, Robert MD

Author Information
Asia-Pacific Journal of Ophthalmology: May-June 2020 - Volume 9 - Issue 3 - p 215-225
doi: 10.1097/APO.0000000000000279
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Glaucoma is a highly prevalent neurodegenerative condition of the optic nerve (and thus is actually a brain disease) and is the leading cause of irreversible blindness worldwide. Vascular insufficiency, expressed as reduced mean ocular perfusion pressure, is a prominent feature of normal-tension glaucoma (NTG) and leads to progressive death of retinal ganglion cells (RGCs), resulting in progressive thinning of the nerve fiber layer and irreversible vision loss.1,2 Despite the diverse etiology of glaucoma, the only proven approach to treatment centers around lowering IOP with medical, laser, and surgical interventions, which decreases vascular resistance, increasing mean vascular flow. These treatments, however, are not effective in cases of nonelevated IOP etiology.

In addition to elevated IOP, other risk factors, including systemic diseases, low intracranial pressure, genetic factors, and factors associated with neurodegenerative diseases such as mitochondrial dysfunction, oxidative damage, excitotoxicity, and microglial activation can predispose individuals to glaucomatous optic nerve damage. The only Food and Drug Administration (FDA)-approved treatment addressing the vascular risk factors are calcium channel blockers, but their efficacy has been questioned.3 Given this, new pharmaceutical approaches that alter causative genetic, biochemical, cell biological, and pathophysiologic mechanisms, many of which remain to be discovered, and agents, which provide neuroprotection, must be explored to target non-IOP-dependent risk factors.

Nonpharmaceutical medicines (herbal extracts, alternative medicine) have been used by every society since before recorded history and are also used by animals other than humans. Formerly derided after the growth of pharmaceutical medicine, these are now being widely sought after by pharmaceutical companies worldwide. The earliest of these recorded in the first textbook of Chinese medicine approximately 5000 years ago is Ginkgo biloba extract (GBE).4,5 In this review, we will discuss physiological and molecular mechanisms of GBE and its effectiveness in light of our enhanced understanding of glaucoma.


The etiology of NTG is associated with systemic conditions such as ischemic migraine, atrial fibrillation, intermittent claudication, Raynaud, Flammer syndrome, and obstructive sleep apnea syndrome (OSAS).4,6–9 These conditions have been characterized by remodeling and degeneration of the ONH,10 and metabolic dysregulation that is especially damaging in locations of the body with deep layer microvasculature, such as in the eye.11–13

Increased risk for NTG has been identified in patients with low blood pressure, autonomic dysfunction, and cardiovascular disease.14–16 Some patients with NTG have abnormal hemorheological parameters that result in lower oxygen transport efficiency, leading to decreased microperfusion and decreased perfusion to the ONH.17


The use of medicinal plants precedes human societies. Chimpanzees in the wild eat bitter-tasting Vernonia species that contain steroid-related compounds, which are known for their antiparasitic activity and stimulation of uterine contractions and eaten by pregnant females.18,19 Orangutans self-medicate themselves with a paste derived from Dracaena cantleyi, which inhibits tumor necrosis factor (TNF)-α induced inflammatory cytokines, by rubbing it in locations of pain.20 As chronic medical conditions have many common underlying pathological features that can be targeted, a large number of nonpharmaceutical agents have been studied for their neuroprotective, anti-inflammatory, anti-oxidative, and other properties.21


Historic Significance

Ginkgo biloba belongs to the first order of true trees, originating during the Permian Era about 250 million years ago. In Asian cultures, specifically those of China and Japan, these trees are widely cultivated and the seeds are used for both food and medicinal purposes. GBE was originally used in Chinese traditional medicine as treatment in a multitude of medical conditions and symptoms.4

GBE was first introduced to the European market by Dr. Willmar Schwabe's preparation in 1965, known as EGb 761, which is a current criterion standard.22,23 Research trials followed thereafter to evaluate the therapeutic effects of GBE through both basic and clinical science research. EGb 761 was modified to maximize the percentage of active ingredients, by increasing percent fraction of flavonoid and terpene compounds and minimizing ginkgolic acid to concentrations <0.0005% to avoid the allergenic and genotoxic effects associated with this substance.24,25


GBE is a leaf extract and its composition is not held responsible to FDA's standards; therefore, its chemical composition can vary. Commercially available GBE consists of 60 bioactive compounds and is a sole source of about 30 of them.26,27 In the most widely used EGb 761 extract, the 2 major component groups are flavonoids and terpenoids. Flavonoids constitute 24% to 27% of the extract, examples of which are biflavones, catechin derivatives, flavonol glycosides, and 7% proanthocyanidins. Terpenoids make up 5% to 7% of the extract with examples of bilobalide; ginkgolide A; ginkgolide B, ginkgolide C; ginkgolide J. The extract also contains alkylphenols (ginkgolic acids) and organic acids.26,27

Vasoactive Effects

Nitric oxide (NO) has several functions depending on the cellular environment surrounding its release. Under normal physiologic conditions, GBE increases NO levels, leading to vasodilation and an increase in blood flow. Additionally, it upregulates gene expression, activating enzymes for NO synthesis (eNOS) and modulating molecular pathways that culminate in NO production.28,29 NO regulates blood flow through vasodilatory molecules such as bradykinin, histamine, acetylcholine, substance P, and insulin. Upon activation, eNOS has an increased affinity for calcium, which results in increased muscle contractility, and further vasodilation.28,29

During an oxygen-deprived, ischemic state, where NO mediates neurotoxicity through neurodegeneration and apoptosis, EGb 761 inhibits the synthesis of NO through inducible NO synthase (iNOS) enzyme inhibition and downregulation of its nuclear factor (NF)-κB transcription factor.30–32

GBE also decreases endothelin-1, another molecule with vasoconstrictive properties.33 Systemically, GBE's regulation of vasoactive substances increased both systolic and diastolic peak velocity measures.33 Flavones inhibit phosphodiesterase-5, which is a property leveraged in antihypertensive drugs, as it has a vasorelaxant effect.28,34,35 Another major impact on vasculature occurs through the renin–angiotensin pathway, which induces vasoconstriction. GBE decreases renin release by inhibiting prostaglandin PGI2, which positively induces renin.35 Meanwhile, clinical studies, using dynamic susceptibility contrast magneic resonance imaging, showed that GBE increased global cerebral blood flow.36

Hemorrheological Regulation

Abnormal hemorheological properties contribute to the development of microvascular diseases such as microangiopathies seen in diabetes mellitus (DM). GBE impacts the hemorheological properties of blood by promoting erythrocyte deformability, and improving blood viscosity.37 GBE has a strong fibrinolytic effect equivalent to that of streptokinase, decreasing fibrinogen levels important for clotting.37,38 These changes improve blood perfusion, as shown by increased blood flow rates in the retinal capillaries of patients with diabetic retinopathy by altering hemorheological blood parameters.37

Anti-inflammatory Effects

On a molecular level, the inflammatory response is attributed to TNF-α activating an inflammatory cascade by enhancing the activity of leukocytes, neutrophils, monocytes, and increasing endothelial adhesion. GBE suppresses TNF-α by regulating the protein-1 signaling pathway.39

Prostaglandin E2 (PGE2) contributes significantly to inflammatory-based diseases.40 GBE suppresses PGE2 levels by downregulating cyclooxygenase-2 (COX-2) expression, which is responsible for producing prostaglandins from arachidonic acid. One transcription factor that regulates COX-2 expression is NF-kB. NF-kB is a transcription factor that regulates many genes that are involved in the inflammatory process, including COX-2, NO synthase, and TNF-α.40 By downregulating NF-kB, GBE is thus able to downregulate PGE2.31,41

Cytokines are the main mediators of signaling during the inflammatory cascade. GBE decreased MIP-2 and MCP-1 cytokine levels, resulting in an anti-inflammatory effect.40 Zhang et al in 2018 showed that GBE suppresses cytokine signaling 2, which further suppressed the inflammatory response.42

Anti-oxidative Effects

Flavonoids have free radical scavenging activity targeting reactive oxygen species (ROS), hydroxyl, superoxide peroxyl, hydroxyl radicals, and reactive nitrogen species such as NO and ferryl ion species.43,44 Terpenoids, however, inhibit free radical release. Bilobalide and ginkgolide constituents of terpenoids increase reducing enzymes such as superoxide dismutase, glutathione peroxidase, catalase, heme-oxygenase-1 activity that process free radical molecules. Decreasing circulating free radicals reduce lipid peroxidation, erythrocyte malonaldehyde levels, decrease endothelial adhesive properties, reducing membrane peroxidation, while preserving its fluidity and integrity.45


Ischemia-reperfusion Injury

GBE is a multifunctional neuroprotective agent, and the protection is associated with activation of the Heme oxygenase 1 (HO1)/Nrf2 pathway, which has antioxidant effects; it promotes neurite growth and angiogenesis by upregulating vascular endothelial growth factor (VEGF).24,46–48 In addition, animals used that received EGb 761 in this study before ischemic induction had an increased number of activated astrocytes and microglia, further indicating its neuroprotective effect.24,46,49–51

Other studies determined ginkgolide B (GKB) to be neuroprotective post-ischemic induction by increasing nestin, an intermediate filamentous protein lining the ventricles, and inducing neuron specific-enolase, which partakes in glycolysis.52 Wu et al demonstrated that GKB inhibits expression of stress-related protein RTP801, thereby decreasing post-ischemia-reperfusion injury stress.53

One neuroprotective hypothesis that has been suggested is the idea of preconditioning post-hypoxic-ischemic injury. In vitro studies showed that GBE pre-treatment before ischemic onset had the same effect as hypoxic preconditioning, both resulting in upregulation of p-glycogen synthase kinase (p-GSK), p-extracellular receptor kinase (p-ERK)/t-ERK, hypoxia-inducible factor-1α, and erythropoietin expression.23,54

Neuronal Differentiation and Protection

GBE provides neuroprotection against ROS, calcium overload, negative effects of NO signaling in apoptosis, and beta-amyloid-induced toxicity.55 GKB administration was associated with an increase in neuronal and astrocytic markers such as brain-derived epidermal factor and epidermal growth factor.52 Cai et al cotransplanted neural stem cells with astrocytes and brain microvascular endothelial cells in rodents, leading to memory improvement post-stroke.51

Suppression of cytokine signaling (SOCS2) pertaining to neurite growth was positively impacted by GKB administration and has been attributed to JAK/STAT signaling pathway.56,57 SOCS2 also has been shown to bind Epidermal Growth Factor receptor, which stimulated neuronal differentiation and neurite growth. Behaviorally, these molecular changes were paralleled by improvements in neurological function.42

RGC death has been the underlying cause of neurodegenerative diseases tied to hypoxia, glutamate toxicity, and oxidative stress. Flavonoids such as nicotiflorin, rutin, and quercetin increased RGC survival rate. Immunoreactivity assays showed that rutin inhibited caspase-3 under hypoxia and glutamate stress conditions, thereby decreasing cell death.55,58 It has been suggested that there is a time window between the decrease in function before RGC death when GBE intervention is effective.55

GBE produces a 3-fold increase in expression of the transthyretin gene, which sequesters amyloid-β (Aβ) protein in vitro, resisting Aβ aggregation, and prevents amyloid formation directly and through adaptor proteins that interact with Alzheimer β-amyloid precursor protein.59 Patients taking GBE improved in cognitive abilities, global functional, and behavioral outcomes.60,61 GBE was most beneficial for patients with neuropsychiatric comorbidities in addition to cognitive decline, which are frequently seen in dementia.62 Immunohistochemistry revealed that EGb 761 positively influenced molecular mechanisms underlying memory formation by modulating the expression of GAP-43, CREB-1, and GFAP.63

Metal Homeostasis

GBE maintains homeostasis of manganese (Mn) and copper (Cu) metals in the brain. Mn and Cu are prominent cofactors of antioxidant enzymes.43,64 Homeostasis is important for proper function, and GBE regulates metal concentration to stay within a physiologically optimal range.43,64

Neurotransmitter Regulation

The bilobalide and ginkgolide components of GBE antagonize gamma-amino butyric acid and glycine inhibitory receptors, inducing an overall excitatory effect. Global excitation ultimately strengthens synapse formation. GBE upregulates excitatory receptors, such as voltage-gated calcium CACNG2 and chloride channels ClCN3 that are expressed in brain regions responsible for sensory, motor, and cognitive functions.59

Specifically, GBE upregulates gene expression of AMPA-2 or GluRB receptors, which is an ionotropic glutamate receptor responsible for synaptogenesis, memory formation, and learning.59 GBE also demonstrated antagonistic activity on N-methyl-d-aspartate receptors from the same receptor class as AMPA-2. N-methyl-d-aspartate allows calcium ions (Ca2+) inside the cells, thereby inducing a toxic environment for the cell. Glutamate neurotransmitter, although essential in interneuronal communication of inner retinal cells, is also toxic to neuronal ganglion cells in high concentrations by increasing intracellular calcium levels.59

Hormonal Alteration

GBE increases the expression of several hormones, such as thyroid hormone, growth hormone, and prolactin, which are essential for neuronal proliferation and differentiation, cognitive capacity related to memory, mental alertness, motivation, and working capacity. Thyroid hormone levels are increased through transthyretin, responsible in the transport of thyroid precursor, thyroxine.59 Growth hormone deficiency is a hallmark of declined growth and decreased cognitive performance. GBE increased the expression of growth hormone in the cortex region. GBE reduced serum prolactin levels in rat models, suggesting that prolactin secretion is regulated through the dopaminergic system.65 Increases in dopamine in the medial preoptic area and the arcuate nucleus have been related to enhancements of copulatory behavior accompanied by decreases in prolactin.65


Molecular Tumor Suppression and DNA Repair

GBE impacts expression of proteins involved in DNA damage signaling, repair, and gene expression through histone remodeling.66,67 Certain flavonoids and terpenoids within GBE have antimutagenic properties, reducing substances such as ofloxacin and acridine orange by 99%.68 EGb 761 can regulate the cell-cycle via ERK1/2 signaling that is implicated in gastric cancer.69 GBE also interacts with steroidogenesis pathways and has aromatase activity that is prominent in breast cancer cells and sensitizing cells to antineoplastic drugs.70–72 Additional cancer pathways impacted by GBE include apoptosis induction via p53 transcription factor, Akt, and NF-kB in melanoma.73,74


Aging has been associated with many biomarkers, one of which is cell cycle halting and reduction in differentiation. GBE produced neurogenic effects in elderly mice via a decrease in apoptotic cells that had activated caspase-3 markers, increased neural stem cells and production of new neurons.75 GBE was also shown to regulate cell cycle progression through MAPK14 and CDK7 kinase enzymes.76

A key molecule associated with aging mechanisms is mammalian target of rapamycin. The inhibition of this pathway was noted to slow aging process in model organisms, and GBE was found to downregulate it.77

Proteins Regulation

Heat shock proteins are important for preserving the structural integrity of proteins by acting as chaperones that preserve protein conformation in stressful environments such as cold, heat, and ultraviolet (UV) exposure. It has been found that GBE downregulated a shock protein associated with metastasis in non-small lung cancer cell lines.78

Aglycon components of GBE exhibit proteasome inhibitory functions. Proteasomes are responsible for the degradation of proteins that are tagged with a ubiquitin molecular tag. In vitro studies in HL-60 cells, which are leukemia preprogrammed cells, revealed that aglycons inhibited chymotrypsin-like enzyme activity, contributing to the anticarcinogenic, antioxidative, anti-inflammatory, and neuroprotective activities.79

Mitochondrial-level Regulation

Electron Transport Chain

Flavonoids, with their hydrophobic acid chemical characteristics, increase proton permeability across the inner mitochondrial membrane, which results in uncoupling, decreasing free radical species.80 Studies with EGb 761 showed beneficial effects on mitochondrial complexes I, IV, and V, and protected against nitrosative stress.81 Given its vital function and prominent presence across the mitochondrial membrane, it is essential to maintain the viability of Na/K ATPase. The membrane density of Na/K ATPase is reduced in oxidative stress, and GBE has been shown to counteract this decrease.82,83


Studies have demonstrated anti-apoptotic effects of GBE by preventing cathepsin-mediated cell death, inhibiting stress-activated protein kinase/c-Jun N-terminal kinase activation.84,85 GBE led to blocking the mitochondrial apoptotic pathway, which is reflected in the directed downregulation of proapoptotic genes such as Fas, Bax, Bcl-xS, and AT2 receptor genes.86


Systemic Diseases

GBE ameliorates conditions related to inflammation and immune hypersensitivity seen in asthma, ulcerative colitis, and inflammatory bowel disease. Patients with asthma given GBE had a significant decrease in interleukin-5, protein kinase C-α-positive inflammatory cells, eosinophils, and increased forced expiratory volume in 1 second.87 GBE attenuated colon damage in ulcerative colitis and inflammatory bowel disease by decreasing myeloperoxidase activity, TNF-α, and interleukin-1β levels and increased glutathione concentration, which ameliorates oxidative and inflammatory responses that contribute to tissue fibrosis.88

GBE improved auditory function in cases of Meniere disease, exceeding anti-vertiginous drugs such as betahistine in its clinical effectiveness for patients with vertigo and Meniere disease.89,90

GBE was effective in controlling vitiligo spread by cessation of progression of pigment loss.91,92 Patients with DM taking GBE had a decrease in HbA1c, fasting serum glucose, insulin, insulin resistance, visceral adiposity index, lipid profile, and inflammatory markers.93,94 GBE contains endophytes, which after a 3-fold dilution of a CDW7 bioactive strain inhibited the mycelial growth and conidia germination of Fusarium graminearum pathogen.95

Effects on Vasculature

GBE has a well-documented influence on blood flow due to its vasodilatory properties. Given these identified effects, GBE exhibited protective effects against edema,96 which is one of the major causes of cerebral ischemia. Cerebral ischemia can lead to headaches such as ischemic migraines, and clinical studies with GKB reduced migraines with typical aura or migraine aura without headache.97

GBE's vasoactive properties have been studied in coronary artery disease and peripheral vascular disease (PVD) diseases such as intermittent claudication, Raynaud phenomenon, obstructive OSAS, and erectile dysfunction. GBE improved outcomes in myocardial functional recovery, reduced the number of ventricular extrasystoles, reperfusion-induced ventricular tachycardia, and slowed myocardial stunning.54,98,99 In cases of PVD, GBE increased claudication distance, measured as distance subjects walked without pain.100 Muir et al6 showed that GBE was effective in decreasing the number of Raynaud attacks that occur due to episodic vasospasms. It had a positive impact on OSAS by reducing corticotrophin-releasing hormone activity and thus the sympathetic activity, thereby reversibly increasing non-rapid eye movement sleep density.7,13,101 GBE has also been tested in patients with erectile dysfunction, which is a frequent side-effect of antidepressant medication, showing significant improvements upon long-term administration.102,103

GBE attenuated diabetic atherosclerosis by counteracting endoplasmic reticulum stress with autophagy, which is significant in atherosclerosis. GBE ultimately resulted in lower cholesterol deposits by downregulating lectin-like oxidized low-density lipoproteins-receptor-1, NADPH oxidase 4, intercellular adhesion molecule-1, and vascular cell adhesion molecule-1.40,104,105 GBE flavonoids were beneficial in counteracting venous insufficiency in patients with varicosities,106 which occur from hypoxia, inflammation, ROS generation, and oxidative stress.


Retinal Diseases

The most prevalent diseases of the eye are neurodegenerative in nature. They include age-related macular degeneration (MD), retinal diseases, and glaucoma, and occur in the context of ischemia and oxidation. GBE offers potential in addressing these pathologies, given its properties of inducing lysosomal autophagy, thereby promoting clearance of neurodegenerative aggregates. 32,107 RGCs coalesce to form the ONH, projecting their axons to the brain, so that the degeneration of RGCs leads to optic nerve head abnormalities. The length of the axons makes them more susceptible to oxidative damage, radical damage, mechanical compression, and photo-oxidative damage.

The retina is highly susceptible to oxidative and free radical damage due to light exposure of photoreceptors, which are the main source of ROS production. Animal studies showed less apoptotic cells in the photoreceptor and outer nuclear layer, and increased survival of RGCs with GBE administration post either light-induced damage or ONH crushing.108,109 Studies also suggested the potential use of GBE in retinitis pigmentosa that occurs from oxidative dysregulation.110 EGb 761 treatment also decreased the frequency of retinal detachment, prevented inflammation related to retinal disease, and reduced inflammation in cases of uveitis.40,111,112

DM can manifest as microvascular damage to the eye and result in diabetic retinopathy, which is diagnosed in one-third of the population with DM.113 In diabetic animal models, GBE decreased pathological molecular mechanisms that manifest as the breakdown of blood–retina barrier, exudates, hemorrhages, ischemia, and neovascularization.31,114–119 The retina is very metabolically active and is, therefore, very sensitive to the ischemic conditions such as retinal vascular occlusion or diabetic retinopathy, vascular dysregulation, and atherosclerotic changes.105,120 By increasing blood flow to the retina, EGb 761 can prevent retinal degenerative processes.121

MD and Cataracts

MD occurs due to mechanisms related to ischemia, oxidation, and free radical formation that lead to death of retinal pigment epithelium in the macula. GBE's neuroprotective functions showed improvement in dry and senile MD with its positive effects on retinal pigment epithelium and thus visual acuity.122–127

Oxidative stress plays an important role in cataractogenesis or lens opacification. Animal studies showed that 75% of rats on GBE did not develop cataracts and 25% showed minimal opacification compared with the control group.128 This finding was attributed to increased levels of lenticular antioxidant enzyme activity, glutathione in its reduced form, and higher levels of malonaldehyde, indicative of an overall reduced molecular state.128 Studies with streptozotocin-induced cataractogenesis in rat models showed that GBE, rutin, and quercetin delayed the progression of lens opacification with quercetin being most effective.31,128


RGC apoptosis in glaucoma has been linked to the NO-related oxidative stress due to endogenous and exogenous ROS. Studies on animal models revealed GBEs neuroprotective, anti-oxidant, and anti-inflammatory properties on RGCs.31,129–132 Most recent clinical studies have shown that GBE increases ocular blood flow, however, the visual field (VF) impact continues to be inconclusive.133 Given a wide potential of the active substances found in GBE in addressing glaucomatous damage on a molecular level, studies were performed to assess its effect on cases of NTG to see whether we can leverage its neuroprotective properties.


Ocular Blood Flow

Glaucoma patients who were prescribed GBE for a short period of time of two days had enhanced ophthalmic artery end-diastolic velocity as measured by color Doppler imaging.134 A different study showed that GBE also increases blood flow velocity in the retrobulbular vasculature, superior, and inferior capillaries compared with placebo, and reduced vascular resistance in central retinal and nasal short posterior ciliary arteries.135 A study with NTG patients, specifically, who were prescribed GBE for 4 weeks, demonstrated increased peripapillary blood flow, and increased blood volume and velocity.136

Choroidal Blood Flow

Choroidal blood supply to the retina is essential in maintaining nerve fiber layer nourishment, which is impacted in NTG. Juárez et al examined GBE's effect on the choroid in rodents and discovered enlarged vessel caliber and high flow rate, which provided cells with the necessary metabolic demands.137 More studies need to be done on humans to address both short and long-term effects of a therapeutic dose of GBE on choroidal blood flow.138

Trabecular Meshwork

Changes in the trabecular meshwork (TM) are involved in glaucoma as degeneration of the sclerocorneal TM layer alters porosity and reduces drainage of aqueous humor. A DNA analysis of patients with primary open angle glaucoma showed high expression of endothelial-leukocyte adhesion molecules, which results in imbalance of redox reactions.139 Experimental models with steroid-induced changes to the TM revealed that GBE prevents dexamethasone-induced changes to the TM.140 GBE administration suppressed steroid-induced increased IOP, reduced accumulation of extracellular materials in the cribriform layers, resulted in better cellularity of TM cells, and lowered steroid-induced myocilin expression. On a molecular level, GBE attenuated apoptosis promoted by anti-Fas ligand, modulated the expression of αβ -crystallin and heat-shock protein 70 and 90.140 These findings indicate that GBE exhibits properties that can be extrapolated to counteract the changes that occur within the TM.


RGCs located in the inner layer of the retina receive information from photoreceptors and transmit this information to several brain regions. Studies investigated the effect of GBE against neurotoxicity of the environment formed by the artificially induced high IOP. Hirooka et al produced elevated IOP by cauterizing three episcleral vessels, and then measuring secondary degeneration in a group receiving GBE for 5 months and a control group without anything.141 The group receiving GBE had significantly lower levels of RGC loss in the superior colliculi brainstem region that is involved in vision processing.

Studies utilizing an optic nerve crush model showed that GBE application increased the survival rate of RGCs on a side with a crushed ONH in a dose-dependent manner.108 As RGC loss is one of the underlying markers of glaucomatous damage, including conditions of NTG, it can be used to halt glaucoma progression.


GBE's neuroprotective properties on RGCs have been demonstrated in hypoxic conditions. Oxidative injury produces hydrogen peroxide and hypoxic injury was induced by clamping the ONH with a “microserrefine clip” with an applicator. The density of RGCs measured was higher in animals treated with EGb 761 in both vivo and vitro cases, exhibiting neuroprotective effects.142 Additionally, Wang et al looked at the effect of GBE on glutamate-induced toxicity and found a decrease in percentage of RGC loss.143 GBE's components, terpenoid and flavonoids, showed neuroprotective properties in cases of necrosis and apoptosis induced by ROS, NO, and β-amyloid-induced toxicity, and further elucidated protective effects on calcium cytotoxicity.23

VF Changes

A study done by Lee et al with NTG patients, testing a long-term effect of GBE on VFs, showed a significant improvement in VFs that were evaluated using Humphrey Vision Field Analyzer for a period of 4 years.144 Both the regression coefficient and mean total deviation improved when measured before and after GBE treatment, whereas the IOPs did not show a significant change across all participants.

A case report of a patient with progressive deterioration of VF and acuity despite a stable IOP controlled by medications showed marked improvement in vision acuity with long-term GBE administration.5 The patient's vision improved from counting fingers at 1 foot occulus dexter (OD) and 20/50 occulus sinister (OS) to 20/40 OD and 20/30 OS after 30 months of 120 mg GBE and pentoxifylline addition to a daily regimen of IOP-lowering glaucoma medications.

Quaranta et al looked at GBEs effects on 27 patients with NTG that demonstrated preexisting, progressive VF deficits.145,146 These patients received 40 mg of GBE 3 times per week. Patients showed improvements in their VF performance compared with controls. There were no changes to IOP or blood pressure; hence, these VF improvements are due to secondary effects such as increased ocular blood flow or cognitive function, which were not measured. Guo et al studied 26 NTG Chinese participants and reported that GBE had no changes in VFs.147 However, they did not show proof of VF deterioration before the study began. Quaranta et al reported that there was no distinction made between NTG and isolated ischemic event in their sample.145,146

Adverse Effects

Multiple studies have reported minimal adverse effects (AEs) of GBE within a specific prescribed dosage range.126,148,149 Overall, GBE continues to be a well-tolerated supplement with a low side effect profile. Systematic reviews of Cochrane database,150,151 PubMed/MEDLINE, EMBASE,151,152 and Google Scholar,151 report no statistically significant difference in AEs between 80 and 600 mg of GBE and placebo. Several self-reported AEs included upset stomach, headache, dizziness, constipation, palpitations, and allergic skin reactions.153

Findings show spontaneous hyphema in patients taking GBE154; however, assessment of 29 coagulation parameters showed no evidence of altered blood coagulation or platelet aggregation.155 GBE was detected to bind cytochrome P450-CYP2C9, which is responsible for the metabolism of warfarin and nonsteroidal anti-inflammatory drug flurbiprofen.156,157 Studies reported no increase in bleeding risk nor any interaction between EGb 761 and phenprocoumon, acetyl salicylic acid, or anticoagulative, antiplatelet medication.158


Flavoprotein Fluorescence Imaging

Flavoprotein fluorescence (FPF) is a sensitive biomarker for monitoring functional retinal metabolic health at a subclinical level, providing insight to mitochondrial damage that resulted from oxidative stress.159 Previous studies have shown that increasing oxidative stress led to gradual increases in FPF levels.160,161 Increased FPF levels were positively correlated with both decreased mitochondrial membrane potential and increased risk of apoptosis via caspase-3.160,161 FPF signal intensity is consistent with the proportion of flavin adenine dinucleotide molecules in oxidized electronic states.162 Lower-energy electrons, as seen in oxidized states, are more susceptible to blue light excitation and a green autoflorescent light is emitted. It is important to note that FPF signal is only detectable in living cells and intensity correlates with the level of mitochondrial damage.162 Given aforementioned molecular pathology of mitochondrial damage, this technology can be used as a screening tool for studying the effects of GBE by bringing scientific technologies to the patients.

Further Suggestions

Studies looking at GBE's effect on ocular blood flow parameters have relied on technology such as Color Doppler imaging (CDI) and confocal scanning laser Doppler flowmetry (CSLDF)163. CDI software allows looking at larger retroocular blood vessels’ oxygen delivery, pH, pCO2, potassium levels etc, but it cannot be used to visualize retinal vasculature. CSLDF, in contrast to CDI, is able to provide information on retinal vasculature, but is hard to reproduce due to high sensitivity to illumination changes and eye movement.164 An alternative solution is to use technology such as ocular coherence tomography angiography, which is becoming greatly utilized in the field for assessing ocular blood flow. In addition, long-term prospective clinical studies with randomized controls should be performed to elucidate the effect of GBE on NTG patients. Molecular research should apply focus on emerging evidence of mitochondrial involvement in people with NTG compared with the healthy controls.


1. Mao LK, Stewart WC, Shields MB. Correlation between intraocular pressure control and progressive glaucomatous damage in primary open-angle glaucoma. Am J Ophthalmol 1991; 111:51–55.
2. Mavrommatis MA, De Cuir N, Reynaud J, et al. An examination of the frequency of paravascular defects and epiretinal membranes in eyes with early glaucoma using en-face slab OCT images. J Glaucoma 2019; 28:265–269.
3. Siegner SW, Netland PA, Schroeder A, Erickson KA. Effect of calcium channel blockers alone and in combination with antiglaucoma medications on intraocular pressure in the primate eye. J Glaucoma 2000; 9:334–339.
4. Ritch R. Potential role for Ginkgo biloba extract in the treatment of glaucoma. Med Hypotheses 2000; 54:221–235.
5. Dorairaj S, Ritch R, Liebmann JM. Visual improvement in a patient taking ginkgo biloba extract: a case study. Explore (NY) 2007; 3:391–395.
6. Muir AH, Robb R, McLaren M, Daly F, Belch JJ. The use of Ginkgo biloba in Raynaud's disease: a double-blind placebo-controlled trial. Vasc Med 2002; 7:265–267.
7. Faridi O, Park SC, Liebmann JM, Ritch R. Glaucoma and obstructive sleep apnoea syndrome. Clin Exp Ophthalmol 2012; 40:408–419.
8. Konieczka K, Ritch R, Traverso CE, et al. Flammer syndrome. EPMA J 2014; 5:11.
9. Gasser P, Flammer J. Blood-cell velocity in the nailfold capillaries of patients with normal-tension and high-tension glaucoma. Am J Ophthalmol 1991; 111:585–588.
10. Yan X, Tezel G, Wax MB, Edward DP. Matrix metalloproteinases and tumor necrosis factor alpha in glaucomatous optic nerve head. Arch Ophthalmol 2000; 118:666–673.
11. Sein J, Galor A, Sheth A, Kruh J, Pasquale LR, Karp CL. Exfoliation syndrome: new genetic and pathophysiologic insights. Curr Opin Ophthalmol 2013; 24:167–174.
12. Chan KKW, Tang F, Tham CCY, Young AL, Cheung CY. Retinal vasculature in glaucoma: a review. BMJ Open Ophthalmol 2017; 1:e000032.
13. Balbay EG, Balbay O, Annakkaya AN, et al. Obstructive sleep apnoea syndrome in patients with primary open-angle glaucoma. Hong Kong Med J 2014; 20:379–385.
14. Flammer J, Konieczka K. The discovery of the Flammer syndrome: a historical and personal perspective. EPMA J 2017; 8:75–97.
15. Barthelmes J, Nagele MP, Ludovici V, Ruschitzka F, Sudano I, Flammer AJ. Endothelial dysfunction in cardiovascular disease and Flammer syndrome-similarities and differences. EPMA J 2017; 8:99–109.
16. Konieczka K, Flammer J, Sternbuch J, Binggeli T, Fraenkl S. Leber's hereditary optic neuropathy, normal tension glaucoma, and flammer syndrome: long term follow-up of a patient. Klin Monbl Augenheilkd 2017; 234:584–587.
17. Tan HB, Zhong YS, Cheng Y, Shen X. Rho/ROCK pathway and neural regeneration: a potential therapeutic target for central nervous system and optic nerve damage. Int J Ophthalmol 2011; 4:652–657.
18. Jisaka M, Ohigashi H, Takegawa K, Huffman MA, Koshimizu K. Antitumoral and antimicrobial activities of bitter sesquiterpene lactones of Vernonia amygdalina, a possible medicinal plant used by wild chimpanzees. Biosci Biotechnol Biochem 1993; 57:833–834.
19. Jisaka M, Kawanaka M, Sugiyama H, et al. Antischistosomal activities of sesquiterpene lactones and steroid glucosides from Vernonia amygdalina, possibly used by wild chimpanzees against parasite-related diseases. Biosci Biotechnol Biochem 1992; 56:845–846.
20. Morrogh-Bernard HC, Foitová I, Yeen Z, et al. Self-medication by orang-utans (Pongo pygmaeus) using bioactive properties of Dracaena cantleyi. Sci Rep 2017; 7:16653.
21. Aggarwal BB, Prasad S, Reuter S, et al. Identification of novel anti-inflammatory agents from Ayurvedic medicine for prevention of chronic diseases: “reverse pharmacology” and “bedside to bench” approach. Curr Drug Targets 2011; 12:1595–1653.
22. DeFeudis FV. A brief history of EGb 761 and its therapeutic uses. Pharmacopsychiatry 2003; 36: (suppl 1): S2–7.
23. Yin B, Xu Y, Wei R, Luo B. Ginkgo biloba on focal cerebral ischemia: a systematic review and meta-analysis. Am J Chin Med 2014; 42:769–783.
24. Ahlemeyer B, Krieglstein J. Neuroprotective effects of Ginkgo biloba extract. Cell Mol Life Sci 2003; 60:1779–1792.
25. Ahlemeyer B, Krieglstein J. Pharmacological studies supporting the therapeutic use of Ginkgo biloba extract for Alzheimer's disease. Pharmacopsychiatry 2003; 36: (suppl 1): S8–14.
26. Unger M. Pharmacokinetic drug interactions involving Ginkgo biloba. Drug Metab Rev 2013; 45:353–385.
27. Pan X, Tan N, Zeng G, Zhang Y, Jia R. Amentoflavone and its derivatives as novel natural inhibitors of human Cathepsin B. Bioorg Med Chem 2005; 13:5819–5825.
28. Koltermann A, Hartkorn A, Koch E, Furst R, Vollmar AM, Zahler S. Ginkgo biloba extract EGb 761 increases endothelial nitric oxide production in vitro and in vivo. Cell Mol Life Sci 2007; 64:1715–1722.
29. Kubota Y, Tanaka N, Kagota S, et al. Effects of Ginkgo biloba extract on blood pressure and vascular endothelial response by acetylcholine in spontaneously hypertensive rats. J Pharm Pharmacol 2006; 58:243–249.
30. Park YM, Won JH, Yun KJ, et al. Preventive effect of Ginkgo biloba extract (GBB) on the lipopolysaccharide-induced expressions of inducible nitric oxide synthase and cyclooxygenase-2 via suppression of nuclear factor-kappaB in RAW 264.7 cells. Biol Pharm Bull 2006; 29:985–990.
31. Martinez-Solis I, Acero N, Bosch-Morell F, et al. Neuroprotective potential of Ginkgo biloba in retinal diseases. Planta Med 2019; 85:1292–1303.
32. Tian J, Popal MS, Liu Y, et al. Ginkgo biloba leaf extract attenuates atherosclerosis in streptozotocin-induced diabetic ApoE-/- mice by inhibiting endoplasmic reticulum stress via restoration of autophagy through the mTOR signaling pathway. Oxid Med Cell Longev 2019; 2019:8134678.
33. Wu YZ, Li SQ, Zu XG, Du J, Wang FF. Ginkgo biloba extract improves coronary artery circulation in patients with coronary artery disease: contribution of plasma nitric oxide and endothelin-1. Phytother Res 2008; 22:734–739.
34. Wu Y, Li S, Cui W, Zu X, Du J, Wang F. Ginkgo biloba extract improves coronary blood flow in healthy elderly adults: role of endothelium-dependent vasodilation. Phytomedicine 2008; 15:164–169.
35. Nishida S, Satoh H. Mechanisms for the vasodilations induced by Ginkgo biloba extract and its main constituent, bilobalide, in rat aorta. Life Sci 2003; 72:2659–2667.
36. Mashayekh A, Pham DL, Yousem DM, Dizon M, Barker PB, Lin DD. Effects of Ginkgo biloba on cerebral blood flow assessed by quantitative MR perfusion imaging: a pilot study. Neuroradiology 2011; 53:185–191.
37. Huang SY, Jeng C, Kao SC, Yu JJ, Liu DZ. Improved haemorrheological properties by Ginkgo biloba extract (Egb 761) in type 2 diabetes mellitus complicated with retinopathy. Clin Nutr 2004; 23:615–621.
38. Naderi GA, Asgary S, Jafarian A, Askari N, Behagh A, Aghdam RH. Fibrinolytic effects of Ginkgo biloba extract. Exp Clin Cardiol 2005; 10:85–87.
39. Cheng SM, Yang SP, Ho LJ, et al. Down-regulation of c-jun N-terminal kinase-activator protein-1 signaling pathway by Ginkgo biloba extract in human peripheral blood T cells. Biochem Pharmacol 2003; 66:679–689.
40. Ilieva I, Ohgami K, Shiratori K, et al. The effects of Ginkgo biloba extract on lipopolysaccharide-induced inflammation in vitro and in vivo. Exp Eye Res 2004; 79:181–187.
41. Kwak WJ, Han CK, Son KH, et al. Effects of Ginkgetin from Ginkgo biloba Leaves on cyclooxygenases and in vivo skin inflammation. Planta Med 2002; 68:316–321.
42. Zhang Y, Liu J, Yang B, et al. Ginkgo biloba extract inhibits astrocytic lipocalin-2 expression and alleviates neuroinflammatory injury via the JAK2/STAT3 pathway after ischemic brain stroke. Front Pharmacol 2018; 9:518.
43. Montes P, Ruiz-Sanchez E, Rojas C, Rojas P. Ginkgo biloba extract 761: a review of basic studies and potential clinical use in psychiatric disorders. CNS Neurol Disord Drug Targets 2015; 14:132–149.
44. Wang J, Zheng M, Chen L, et al. Rapid screening, separation, and detection of hydroxyl radical scavengers from total flavonoids of Ginkgo biloba leaves by chromatography combined with molecular devices. J Sep Sci 2016; 39:4158–4165.
45. Mahadevan S, Park Y. Multifaceted therapeutic benefits of Ginkgo biloba L.: chemistry, efficacy, safety, and uses. J Food Sci 2008; 73:R14–19.
46. Tulsulkar J, Shah ZA. Ginkgo biloba prevents transient global ischemia-induced delayed hippocampal neuronal death through antioxidant and anti-inflammatory mechanism. Neurochem Int 2013; 62:189–197.
47. Shah ZA, Nada SE, Dore S. Heme oxygenase 1, beneficial role in permanent ischemic stroke and in Gingko biloba (EGb 761) neuroprotection. Neuroscience 2011; 180:248–255.
48. Nada SE, Shah ZA. Preconditioning with Ginkgo biloba (EGb 761(R)) provides neuroprotection through HO1 and CRMP2. Neurobiol Dis 2012; 46:180–189.
49. Han D, Cao C, Su Y, et al. Ginkgo biloba exocarp extracts inhibits angiogenesis and its effects on Wnt/beta-catenin-VEGF signaling pathway in Lewis lung cancer. J Ethnopharmacol 2016; 192:406–412.
50. Wu X, Zhou C, Du F, et al. Ginkgolide B preconditioning on astrocytes promotes neuronal survival in ischemic injury via up-regulating erythropoietin secretion. Neurochem Int 2013; 62:157–164.
51. Cai Q, Chen Z, Song P, et al. Co-transplantation of hippocampal neural stem cells and astrocytes and microvascular endothelial cells improve the memory in ischemic stroke rat. Int J Clin Exp Med 2015; 8:13109–13117.
52. Yang X, Zheng T, Hong H, et al. Neuroprotective effects of Ginkgo biloba extract and Ginkgolide B against oxygen-glucose deprivation/reoxygenation and glucose injury in a new in vitro multicellular network model. Front Med 2018; 12:307–318.
53. Wu C, Zhao X, Zhang X, Liu S, Zhao H, Chen Y. Effect of Ginkgo biloba extract on apoptosis of brain tissues in rats with acute cerebral infarction and related gene expression. Genet Mol Res 2015; 14:6387–6394.
54. He W, Qian Zhong M, Zhu L, et al. Ginkgolides mimic the effects of hypoxic preconditioning to protect C6 cells against ischemic injury by up-regulation of hypoxia-inducible factor-1 alpha and erythropoietin. Int J Biochem Cell Biol 2008; 40:651–662.
55. Song E, Tang S, Xu J, Yin B, Bao E, Hartung J. Lenti-siRNA Hsp60 promote bax in mitochondria and induces apoptosis during heat stress. Biochem Biophys Res Commun 2016; 481:125–131.
56. Yang HL, Sun C, Sun C, Qi RL. Effect of suppressor of cytokine signaling 2 (SOCS2) on fat metabolism induced by growth hormone (GH) in porcine primary adipocyte. Mol Biol Rep 2012; 39:9113–9122.
57. Letellier E, Haan S. SOCS2: physiological and pathological functions. Front Biosci (Elite Ed) 2016; 8:189–204.
58. Nakayama M, Aihara M, Chen YN, Araie M, Tomita-Yokotani K, Iwashina T. Neuroprotective effects of flavonoids on hypoxia-, glutamate-, and oxidative stress-induced retinal ganglion cell death. Mol Vis 2011; 17:1784–1793.
59. Watanabe CM, Wolffram S, Ader P, et al. The in vivo neuromodulatory effects of the herbal medicine ginkgo biloba. Proc Natl Acad Sci U S A 2001; 98:6577–6580.
60. Weinmann S, Roll S, Schwarzbach C, Vauth C, Willich SN. Effects of Ginkgo biloba in dementia: systematic review and meta-analysis. BMC Geriatr 2010; 10:14.
61. Muller WE, Eckert A, Eckert GP, et al. Therapeutic efficacy of the Ginkgo special extract EGb761((R)) within the framework of the mitochondrial cascade hypothesis of Alzheimer's disease. World J Biol Psychiatry 2019; 20:173–189.
62. DeKosky ST, Williamson JD, Fitzpatrick AL, et al. Ginkgo biloba for prevention of dementia: a randomized controlled trial. JAMA 2008; 300:2253–2262.
63. Oliveira DR, Sanada PF, Saragossa Filho AC, et al. Neuromodulatory property of standardized extract Ginkgo biloba L. (EGb 761) on memory: behavioral and molecular evidence. Brain Res 2009; 1269:68–89.
64. Rojas P, Montes S, Serrano-Garcia N, Rojas-Castaneda J. Effect of EGb761 supplementation on the content of copper in mouse brain in an animal model of Parkinson's disease. Nutrition 2009; 25:482–485.
65. Yeh KY, Pu HF, Kaphle K, et al. Ginkgo biloba extract enhances male copulatory behavior and reduces serum prolactin levels in rats. Horm Behav 2008; 53:225–231.
66. Martelli-Palomino G, Paoliello-Paschoalato AB, Crispim JC, et al. DNA damage increase in peripheral neutrophils from patients with rheumatoid arthritis is associated with the disease activity and the presence of shared epitope. Clin Exp Rheumatol 2017; 35:247–254.
67. Marques F, Azevedo F, Johansson B, Oliveira R. Stimulation of DNA repair in Saccharomyces cerevisiae by Ginkgo biloba leaf extract. Food Chem Toxicol 2011; 49:1361–1366.
68. Krizková L, Chovanová Z, Duracková Z, Krajcovic J. Antimutagenic in vitro activity of plant polyphenols: pycnogenol and Ginkgo biloba extract (EGb 761). Phytother Res 2008; 22:384–388.
69. Liu SQ, Xu CY, Qin MB, et al. Ginkgo biloba extract enhances chemotherapy sensitivity and reverses chemoresistance through suppression of the KSR1-mediated ERK1/2 pathway in gastric cancer cells. Oncol Rep 2015; 33:2871–2882.
70. Sakurada Y, Shirota M, Inoue K, Uchida N, Shirota K. New approach to in situ quantification of ovarian gene expression in rat using a laser microdissection technique: relationship between follicle types and regulation of inhibin-alpha and cytochrome P450aromatase genes in the rat ovary. Histochem Cell Biol 2006; 126:735–741.
71. Jiang W, Cong Q, Wang Y, Ye B, Xu C. Ginkgo may sensitize ovarian cancer cells to cisplatin: antiproliferative and apoptosis-inducing effects of Ginkgolide B on ovarian cancer cells. Integr Cancer Ther 2014; 13:N10–17.
72. Chang Z, Wang HL, Du H. Protective effect of Ginkgo flavonoids, amifostine, and leuprorelin against platinum-induced ovarian impairment in rats. Genet Mol Res 2014; 13:5276–5284.
73. Park HJ, Kim MM. Flavonoids in Ginkgo biloba fallen leaves induce apoptosis through modulation of p53 activation in melanoma cells. Oncol Rep 2015; 33:433–438.
74. Cao C, Su Y, Gao Y, et al. Ginkgo biloba exocarp extract inhibits the metastasis of B16-F10 melanoma involving PI3K/Akt/NF-kappaB/MMP-9 signaling pathway. Evid Based Complement Alternat Med 2018; 2018:4969028.
75. Osman AM, Neumann S, Kuhn HG, Blomgren K. Caspase inhibition impaired the neural stem/progenitor cell response after cortical ischemia in mice. Oncotarget 2016; 7:2239–2248.
76. Adefegha SA, Leal DBR, de Oliveira JS, Manzoni AG, Bremm JM. Modulation of reactive oxygen species production, apoptosis and cell cycle in pleural exudate cells of carrageenan-induced acute inflammation in rats by rutin. Food Funct 2017; 8:4459–4468.
77. Johnson SC, Rabinovitch PS, Kaeberlein M. mTOR is a key modulator of ageing and age-related disease. Nature 2013; 493:338–345.
78. Tsai JR, Liu PL, Chen YH, et al. Ginkgo biloba extract decreases non-small cell lung cancer cell migration by downregulating metastasis-associated factor heat-shock protein 27. PLoS One 2014; 9:e91331.
79. Dreiseitel A, Schreier P, Oehme A, et al. Inhibition of proteasome activity by anthocyanins and anthocyanidins. Biochem Biophys Res Commun 2008; 372:57–61.
80. van Dijk C, Driessen AJ, Recourt K. The uncoupling efficiency and affinity of flavonoids for vesicles. Biochem Pharmacol 2000; 60:1593–1600.
81. Abdel-Kader R, Hauptmann S, Keil U, et al. Stabilization of mitochondrial function by Ginkgo biloba extract (EGb 761). Pharmacol Res 2007; 56:493–502.
82. Pierre S, Jamme I, Robert K, et al. Ginkgo biloba extract (EGb 761) protects Na,K-ATPase isoenzymes during cerebral ischemia. Cell Mol Biol (Noisy-le-grand) 2002; 48:671–679.
83. Pierre SV, Lesnik P, Moreau M, et al. The standardized Ginkgo biloba extract Egb-761 protects vascular endothelium exposed to oxidized low density lipoproteins. Cell Mol Biol (Noisy-le-grand) 2008; 54: (suppl): OL1032-42.
84. Qin XF, Lu XJ, Ge JB, Xu HZ, Qin HD, Xu F. Ginkgolide B prevents cathepsin-mediated cell death following cerebral ischemia/reperfusion injury. Neuroreport 2014; 25:267–273.
85. Zhao M, Wang XX, Wan WH. Effects of the ginkgo biloba extract on the superoxide dismutase activity and apoptosis of endothelial progenitor cells from diabetic peripheral blood. Genet Mol Res 2014; 13:220–227.
86. Loh KP, Low LS, Wong WH, et al. A comparison study of cerebral protection using Ginkgo biloba extract and Losartan on stroked rats. Neurosci Lett 2006; 398:28–33.
87. Tang Y, Xu Y, Xiong S, et al. The effect of Ginkgo Biloba extract on the expression of PKCalpha in the inflammatory cells and the level of IL-5 in induced sputum of asthmatic patients. J Huazhong Univ Sci Technolog Med Sci 2007; 27:375–380.
88. Mustafa A, El-Medany A, Hagar HH, El-Medany G. Ginkgo biloba attenuates mucosal damage in a rat model of ulcerative colitis. Pharmacol Res 2006; 53:324–330.
89. Sokolova L, Hoerr R, Mishchenko T. Treatment of vertigo: a randomized, double-blind trial comparing efficacy and safety of Ginkgo biloba extract EGb 761 and betahistine. Int J Otolaryngol 2014; 2014:682439.
90. Gananca MM, Caovilla HH, Munhoz MS, et al. Optimizing the pharmacological component of integrated balance therapy. Braz J Otorhinolaryngol 2007; 73:12–18.
91. Parsad D, Pandhi R, Juneja A. Effectiveness of oral Ginkgo biloba in treating limited, slowly spreading vitiligo. Clin Exp Dermatol 2003; 28:285–287.
92. Gianfaldoni S, Tchernev G, Wollina U, et al. Vitiligo in children: what's new in treatment? Open Access Maced J Med Sci 2018; 6:221–225.
93. Aziz TA, Hussain SA, Mahwi TO, Ahmed ZA, Rahman HS, Rasedee A. The efficacy and safety of Ginkgo biloba extract as an adjuvant in type 2 diabetes mellitus patients ineffectively managed with metformin: a double-blind, randomized, placebo-controlled trial. Drug Des Devel Ther 2018; 12:735–742.
94. Aziz TA, Hussain SA, Mahwi TO, Ahmed ZA. Efficacy and safety of Ginkgo biloba extract as an “add-on” treatment to metformin for patients with metabolic syndrome: a pilot clinical study. Ther Clin Risk Manag 2018; 14:1219–1226.
95. Xiao Y, Li HX, Li C, et al. Antifungal screening of endophytic fungi from Ginkgo biloba for discovery of potent anti-phytopathogenic fungicides. FEMS Microbiol Lett 2013; 339:130–136.
96. Berg JT. Ginkgo biloba extract prevents high altitude pulmonary edema in rats. High Alt Med Biol 2004; 5:429–434.
97. D’Andrea G, Bussone G, Allais G, et al. Efficacy of Ginkgolide B in the prophylaxis of migraine with aura. Neurol Sci 2009; 30: (suppl 1): S121–124.
98. Rioufol G, Pietri S, Culcasi M, et al. Ginkgo biloba extract EGb 761 attenuates myocardial stunning in the pig heart. Basic Res Cardiol 2003; 98:59–68.
99. Clostre F. [Protective effects of a Ginkgo biloba extract (EGb 761) on ischemia-reperfusion injury]. Therapie 2001; 56:595–600.
100. Nicolaï SP, Kruidenier LM, Bendermacher BL, Prins MH, Teijink JA. Ginkgo biloba for intermittent claudication. Cochrane Database Syst Rev 2009; CD006888.
101. Gherghel D, Hosking SL, Orgül S. Autonomic nervous system, circadian rhythms, and primary open-angle glaucoma. Surv Ophthalmol 2004; 49:491–508.
102. Meston CM, Rellini AH, Telch MJ. Short- and long-term effects of Ginkgo biloba extract on sexual dysfunction in women. Arch Sex Behav 2008; 37:530–547.
103. Wheatley D. Triple-blind, placebo-controlled trial of Ginkgo biloba in sexual dysfunction due to antidepressant drugs. Hum Psychopharmacol 2004; 19:545–548.
104. Feng Z, Yang X, Zhang L, et al. Ginkgolide B ameliorates oxidized low-density lipoprotein-induced endothelial dysfunction via modulating Lectin-like ox-LDL-receptor-1 and NADPH oxidase 4 expression and inflammatory cascades. Phytother Res 2018; 32:2417–2427.
105. Osborne NN, Casson RJ, Wood JP, Chidlow G, Graham M, Melena J. Retinal ischemia: mechanisms of damage and potential therapeutic strategies. Prog Retin Eye Res 2004; 23:91–147.
106. Lichota A, Gwozdzinski L, Gwozdzinski K. Therapeutic potential of natural compounds in inflammation and chronic venous insufficiency. Eur J Med Chem 2019; 176:68–91.
107. Cao C, Han D, Su Y, Ge Y, Chen H, Xu A. Ginkgo biloba exocarp extracts induces autophagy in Lewis lung cancer cells involving AMPK /mTOR /p70S6k signaling pathway. Biomed Pharmacother 2017; 93:1128–1135.
108. Ma K, Xu L, Zhan H, Zhang S, Pu M, Jonas JB. Dosage dependence of the effect of Ginkgo biloba on the rat retinal ganglion cell survival after optic nerve crush. Eye (Lond) 2009; 23:1598–1604.
109. Ma K, Xu L, Zhang H, Zhang S, Pu M, Jonas JB. The effect of ginkgo biloba on the rat retinal ganglion cell survival in the optic nerve crush model. Acta Ophthalmol 2010; 88:553–557.
110. Huynh TP, Mann SN, Mandal NA. Botanical compounds: effects on major eye diseases. Evid Based Complement Alternat Med 2013; 2013:549174.
111. Li Q, Peng B, Whitcup SM, Jang SU, Chan CC. Endotoxin induced uveitis in the mouse: susceptibility and genetic control. Exp Eye Res 1995; 61:629–632.
112. Maclennan KM, Darlington CL, Smith PF. The CNS effects of Ginkgo biloba extracts and ginkgolide B. Prog Neurobiol 2002; 67:235–257.
113. Chawla A, Chawla R, Jaggi S. Microvasular and macrovascular complications in diabetes mellitus: distinct or continuum? Indian J Endocrinol Metab 2016; 20:546–551.
114. Malaguarnera G, Gagliano C, Bucolo C, et al. Lipoprotein(a) serum levels in diabetic patients with retinopathy. Biomed Res Int 2013; 2013:943505.
115. Lupo G, Motta C, Giurdanella G, et al. Role of phospholipases A2 in diabetic retinopathy: in vitro and in vivo studies. Biochem Pharmacol 2013; 86:1603–1613.
116. Bucolo C, Marrazzo G, Platania CB, Drago F, Leggio GM, Salomone S. Fortified extract of red berry, Ginkgo biloba, and white willow bark in experimental early diabetic retinopathy. J Diabetes Res 2013; 2013:432695.
117. Zhao Y, Yu J, Liu J, An X. The role of Liuwei Dihuang pills and Ginkgo leaf tablets in treating diabetic complications. Evid Based Complement Alternat Med 2016; 2016:7931314.
118. Behl T, Kotwani A. Chinese herbal drugs for the treatment of diabetic retinopathy. J Pharm Pharmacol 2017; 69:223–235.
119. Behl T, Kotwani A. Downregulated brain-derived neurotrophic factor-induced oxidative stress in the pathophysiology of diabetic retinopathy. Can J Diabetes 2017; 41:241–246.
120. Xie Z, Wu X, Gong Y, Song Y, Qiu Q, Li C. Intraperitoneal injection of Ginkgo biloba extract enhances antioxidation ability of retina and protects photoreceptors after light-induced retinal damage in rats. Curr Eye Res 2007; 32:471–479.
121. Chung SY, Cheng FC, Lee MS, Lin JY, Lin MC, Wang MF. Ginkgo biloba leaf extract (EGb761) combined with neuroprotective agents reduces the infarct volumes of gerbil ischemic brain. Am J Chin Med 2006; 34:803–817.
122. Fies P, Dienel A. [Ginkgo extract in impaired vision—treatment with special extract EGb 761 of impaired vision due to dry senile macular degeneration]. Wien Med Wochenschr 2002; 152:423–426.
123. Pinazo-Durán MD, Gómez-Ulla F, Arias L, et al. Do nutritional supplements have a role in age macular degeneration prevention? J Ophthalmol 2014; 2014:901686.
124. Jager RD, Mieler WF, Miller JW. Age-related macular degeneration. N Engl J Med 2008; 358:2606–2617.
125. Hariprasad SM, Mieler WF, Grassi M, Green JL, Jager RD, Miller L. Vision-related quality of life in patients with diabetic macular oedema. Br J Ophthalmol 2008; 92:89–92.
126. Lawrenson JG, Evans JR. Advice about diet and smoking for people with or at risk of age-related macular degeneration: a cross-sectional survey of eye care professionals in the UK. BMC Public Health 2013; 13:564.
127. Cheung CM, Wong TY. Is age-related macular degeneration a manifestation of systemic disease? New prospects for early intervention and treatment. J Intern Med 2014; 276:140–153.
128. Cao S, Gao M, Wang N, Liu N, Du G, Lu J. Prevention of selenite-induced cataratogenesis by Ginkgo biloba extract (Egb761) in wistar rats. Curr Eye Res 2015; 40:1028–1033.
129. Pinazo-Duran MD, Shoaie-Nia K, Zanon-Moreno V, Sanz-Gonzalez SM, Del Castillo JB, Garcia-Medina JJ. Strategies to reduce oxidative stress in glaucoma patients. Curr Neuropharmacol 2018; 16:903–918.
130. Tatton NA, Tezel G, Insolia SA, Nandor SA, Edward PD, Wax MB. In situ detection of apoptosis in normal pressure glaucoma. A preliminary examination. Surv Ophthalmol 2001; 45: (suppl 3): S268–272. discussion S273-266.
131. Wang Y, Huang C, Zhang H, Wu R. Autophagy in glaucoma: crosstalk with apoptosis and its implications. Brain Res Bull 2015; 117:1–9.
132. Zhou X, Li F, Kong L, Tomita H, Li C, Cao W. Involvement of inflammation, degradation, and apoptosis in a mouse model of glaucoma. J Biol Chem 2005; 280:31240–31248.
133. Kang JM, Lin S. Ginkgo biloba and its potential role in glaucoma. Curr Opin Ophthalmol 2018; 29:116–120.
134. Chung HS, Harris A, Kristinsson JK, Ciulla TA, Kagemann C, Ritch R. Ginkgo biloba extract increases ocular blood flow velocity. J Ocul Pharmacol Ther 1999; 15:233–240.
135. Harris A, Gross J, Moore N, et al. The effects of antioxidants on ocular blood flow in patients with glaucoma. Acta Ophthalmol 2018; 96:e237–e241.
136. Park JW, Kwon HJ, Chung WS, Kim CY, Seong GJ. Short-term effects of Ginkgo biloba extract on peripapillary retinal blood flow in normal tension glaucoma. Korean J Ophthalmol 2011; 25:323–328.
137. Juárez CP, Muiño JC, Guglielmone H, et al. Experimental retinopathy of prematurity: angiostatic inhibition by nimodipine, ginkgo-biloba, and dipyridamole,;1; and response to different growth factors. Eur J Ophthalmol 2000; 10:51–59.
138. Wimpissinger B, Berisha F, Garhoefer G, Polak K, Schmetterer L. Influence of Ginkgo biloba on ocular blood flow. Acta Ophthalmol Scand 2007; 85:445–449.
139. Rhone M, Basu A. Phytochemicals and age-related eye diseases. Nutr Rev 2008; 66:465–472.
140. Jia LY, Sun L, Fan DS, Lam DS, Pang CP, Yam GH. Effect of topical Ginkgo biloba extract on steroid-induced changes in the trabecular meshwork and intraocular pressure. Arch Ophthalmol 2008; 126:1700–1706.
141. Hirooka K, Tokuda M, Miyamoto O, Itano T, Baba T, Shiraga F. The Ginkgo biloba extract (EGb 761) provides a neuroprotective effect on retinal ganglion cells in a rat model of chronic glaucoma. Curr Eye Res 2004; 28:153–157.
142. Cho HK, Kim S, Lee EJ, Kee C. Neuroprotective effect of Ginkgo biloba extract against hypoxic retinal ganglion cell degeneration in vitro and in vivo. J Med Food 2010; 22:771–778.
143. Wang YS, Xu L, Ma K, Wang JJ. [The protective effects of ginkgo biloba extract on cultured human retinal ganglion cells]. Zhonghua Yan Ke Za Zhi 2011; 47:824–828.
144. Lee J, Sohn SW, Kee C. Effect of Ginkgo biloba extract on visual field progression in normal tension glaucoma. J Glaucoma 2013; 22:780–784.
145. Quaranta L, Riva I, Floriani I. Ginkgo biloba extract improves visual field damage in some patients affected by normal-tension glaucoma. Invest Ophthalmol Vis Sci 2014; 55:2417.
146. Quaranta L, Bettelli S, Uva MG, Semeraro F, Turano R, Gandolfo E. Effect of Ginkgo biloba extract on preexisting visual field damage in normal tension glaucoma. Ophthalmology 2003; 110:359–362. discussion 362-354.
147. Guo X, Kong X, Huang R, et al. Effect of Ginkgo biloba on visual field and contrast sensitivity in Chinese patients with normal tension glaucoma: a randomized, crossover clinical trial. Invest Ophthalmol Vis Sci 2014; 55:110–116.
148. McKenna DJ, Jones K, Hughes K. Efficacy, safety, and use of ginkgo biloba in clinical and preclinical applications. Altern Ther Health Med 2001; 7:70–86. 88-90.
149. Diamond BJ, Shiflett SC, Feiwel N, et al. Ginkgo biloba extract: mechanisms and clinical indications. Arch Phys Med Rehabil 2000; 81:668–678.
150. Birks J, Grimley Evans J. Ginkgo biloba for cognitive impairment and dementia. Cochrane Database Syst Rev 2009; CD003120.
151. Yuan Q, Wang CW, Shi J, Lin ZX. Effects of Ginkgo biloba on dementia: an overview of systematic reviews. J Ethnopharmacol 2017; 195:1–9.
152. Tan MS, Yu JT, Tan CC, et al. Efficacy and adverse effects of ginkgo biloba for cognitive impairment and dementia: a systematic review and meta-analysis. J Alzheimers Dis 2015; 43:589–603.
153. Roland PD, Nergard CS. [Ginkgo biloba—effect, adverse events and drug interaction]. Tidsskr Nor Laegeforen 2012; 132:956–959.
154. Bent S, Goldberg H, Padula A, Avins AL. Spontaneous bleeding associated with ginkgo biloba: a case report and systematic review of the literature: a case report and systematic review of the literature. J Gen Intern Med 2005; 20:657–661.
155. Köhler S, Funk P, Kieser M. Influence of a 7-day treatment with Ginkgo biloba special extract EGb 761 on bleeding time and coagulation: a randomized, placebo-controlled, double-blind study in healthy volunteers. Blood Coagul Fibrinolysis 2004; 15:303–309.
156. Greenblatt DJ, von Moltke LL, Luo Y, et al. Ginkgo biloba does not alter clearance of flurbiprofen, a cytochrome P450-2C9 substrate. J Clin Pharmacol 2006; 46:214–221.
157. Gaudineau C, Beckerman R, Welbourn S, Auclair K. Inhibition of human P450 enzymes by multiple constituents of the Ginkgo biloba extract. Biochem Biophys Res Commun 2004; 318:1072–1078.
158. Gaus W, Westendorf J, Diebow R, Kieser M. Identification of adverse drug reactions by evaluation of a prescription database, demonstrated for “risk of bleeding”. Methods Inf Med 2005; 44:697–703.
159. Elner VM, Park S, Cornblath W, Hackel R, Petty HR. Flavoprotein autofluorescence detection of early ocular dysfunction. Arch Ophthalmol 2008; 126:259–260.
160. Elner SG, Elner VM, Field MG, Park S, Heckenlively JR, Petty HR. Retinal flavoprotein autofluorescence as a measure of retinal health. Trans Am Ophthalmol Soc 2008; 106:215–222. discussion 222-214.
161. Field MG, Yang D, Bian ZM, Petty HR, Elner VM. Retinal flavoprotein fluorescence correlates with mitochondrial stress, apoptosis, and chemokine expression. Exp Eye Res 2011; 93:548–555.
162. Andrade Romo JS, Lynch G, Liu K, et al. Flavoprotein fluorescence correlation with visual acuity response in patients receiving anti-VEGF injection for diabetic macular edema. Oxid Med Cell Longev 2018; 2018:3567306.
163. Gibson JM. Confocal scanning laser Doppler flowmetry in retinovascular disease. Eye (Lond) 2001; 15 (pt 3):259–260.
164. Mohindroo C, Ichhpujani P, Kumar S. Current imaging modalities for assessing ocular blood flow in glaucoma. J Curr Glaucoma Pract 2016; 10:104–112.

ginkgo; glaucoma; normal-tension; supplements

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