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GINGKO + VITAMIN E RESEARCH

This scientific research is for informational use only.

The results reported may not necessarily occur in all individuals.

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INTRODUCTION

Ginkgo biloba extract (GBE) consists of flavonoid glycosides, terpene lactone (ginkgolides), and other organic acids [1]. GBE is widely used in treating vascular diseases such as peripheral circulation diseases and cerebral insufficiency [2], because of its favorable effect on blood circulation. Flavonoids can dilate blood vessels by increasing the release of endothelium-derived relaxing factor and prostacyclin (PGI2) from vascular endothelial cells and decrease blood viscosity by antagonizing platelet-activating factor [3]. Moreover, flavonoid glycosides act as antioxidants by scavenging free radicals [4].

It readily scavenges reactive oxygen and nitrogen radicals and inhibits oxidative modifications that occur to proteins in vitro. It enters intact cells and protects them from alloxanmediated and light-mediated stress, and the nuclear DNA from single-strand breaks. It also effectively inhibits chemically induced apoptosis. It does not modulate the activities of endogenous antioxidant enzymes, nor does it have any significant antimicrobial activity. Unlike some other plant extracts, it is not phototoxic. Ginkgo Biloba's inherent antioxidant, anti-apoptotic and cytoprotective action and potential anticataract ability appear to be some of the factors responsible for its beneficial effects.

Areas Of Scientific Research

EYES

Ginkgo biloba extract is freely available and has several biological actions which combine to make it a potentially important agent in the treatment of glaucoma [5]: improvement of central and peripheral blood flow, reduction of vasospasm, reduction of serum viscosity, antioxidant activity, platelet-activating factor inhibitory activity, inhibition of apoptosis, and inhibition of excitotoxicity.

EYES - NORMAL TENSION GLAUCOMA (NTG)

Normal-tension glaucoma (NTG) is a form of glaucoma in which optic nerve damage and glaucomatous visual field loss occur without the intraocular pressure (IOP) exceeding the normal range [6]. Treatment of glaucoma has almost always focused on lowering the IOP, but some patients with NTG continue to suffer a visual field defect despite sufficient control of IOP.

GBE is used for numerous retinal disorders and glaucoma [7]. They are considered beneficial for various vascular diseases. GBE is also used by patients with peripheral vascular disease and to treat cerebral insufficiency [2]. Mechanisms of action of GBE have been described:

  • (1) effects on blood circulation, such as vast regulatory activity and rheological effects (decreased viscosity and antagonism of platelet-activating factor receptors);
  • (2) metabolic changes, for example, effects on neuron metabolism such as increased tolerance to anoxia;
  • (3) beneficial effects on neurotransmitter disturbances; and
  • (4) prevention of damage to cell membranes caused by free radicals.

A study was performed [8] to evaluate the effect of GBE and anthocyanins on visual function in patients with normal-tension glaucoma (NTG) based on the vascular theory of mechanisms of glaucomatous optic nerve damage. The results suggest that anthocyanins and GBE may be helpful in improving visual function in some individuals with NTG.

Other results suggest [9] that systemic administration of anthocyanins and GBE improves visual function in some individuals with NTG. From these results, our study suggested that anthocyanins and GBE might be effective for improving visual function in patients with NTG. We think that the mechanisms of anthocyanins and GBE action are effects on blood circulation and antioxidant properties.

  • Another possible explanation of the beneficial effects of anthocyanins and GBE in NTG patients is the effects of anthocyanins and GBE on improvements in the cognitive function [10]. This effect has been demonstrated in patients with cerebral vascular insufficiency [2]. Cerebral small-vessel ischemia is more common in NTG patients than in normal subjects [11,12], so a reasonable assumption is that anthocyanin or GBE administration improves BCVA and the mean deviation in VF indices via increased cerebral blood flow, thus improving the ocular blood flow, and improving retinal sensitivity, concentration, and alertness [13].

Quaranta et al. reported an effect of GBE on pre-existing visual field damage in patients with NTG [9]. After 40 mg of orally administered GBE, three times daily for 4 weeks, a significant improvement in visual field indices (the mean deviation and the corrected pattern standard deviation) was recorded without changes in the arterial blood pressure, heart rate, or IOP [14]. These properties support the therapeutic value of anthocyanins and GBE in treating NTG.

GBE was also found [15] to increase blood flow in the ophthalmic artery, in healthy human volunteers, when administered orally at a dose of 40 mg three times a day for 2 days [16].

After GBE treatment, the mean blood flow, volume, and velocity increased at almost all points, and there was a statistically significant increase in blood flow at almost all points, in comparison to the placebo [17]. Blood volume significantly increased only in the superior nasal and superior temporal neuroretinal rim areas. GBE also significantly increased blood velocity in areas of the inferior temporal neuroretinal rim and superior temporal peripapillary area.

  • Vascular theory (tissue ischemia from impaired blood flow causes glaucomatous damage) have been proposed [18]. Recently, many reports support the vascular theory, which suggests that vascular factors may be involved in the pathogenesis of glaucoma.

GBE also has many properties [17] that should be beneficial in treating non-IOP-dependent risk factors related not only to ocular hemodynamics but also to neuroprotective action. Neuroprotection refers to the post-injury protection of neurons that are initially undamaged or only marginally damaged by a particular insult [5]. The ultimate object of neuroprotection in glaucoma patients is to prevent retinal ganglion cell death, and this can be achieved by blocking secondary degeneration. Secondary degeneration refers to the spread of degeneration to apparently healthy neurons that are at risk from toxic stimuli (glutamate, calcium, nitric oxide, free radical) released by damaged cells [19,20,21]

BRAIN - NEUROLOGICAL DISEASES

The efficacy of the ginkgo biloba extract in outpatients with presenile and senile primary degenerative dementia of the Alzheimer type (DAT) and multi-infarct dementia (MID) has been investigated in prospective, randomized, double-blind, placebo-controlled, multi-center studies [22,23,24,25,26,27]. Ginkgo biloba appears as a useful and sensible supplementary medication to treat Alzheimer's disease, as it seems to be a synthesis of all the different profiles of action of the various, commonly used drugs but with fewer side effects.

BRAIN - COGNITIVE PERFORMANCE

Studies show that GBE alleviates symptoms associated with age-related cognitive impairment such as age-related amnesic condition, vascular dementia, and dementia of the Alzheimer's type [28,29,30,31,32,33]. Recent studies appear to indicate that GBE (120–600 mg) moderately enhances a number of cognitive processes in healthy young individuals as well as those suffering from age-related cognitive impairment [34,35,36,37,38,39,40,41,42,43].

  • One such cognitive domain that GBE has shown to improve across a number of studies is Working Memory (WM) [42,44,45]. A previous study from our laboratory [42] revealed that 30-day administration of 120 mg/day GBE in young volunteers resulted in significant improvements in both digit span backward and working memory speed. In a review of 29 randomized clinical trials examining the cognitive effects of GBE, Kaschel [46] concluded that as many as 20.7% of WM tests in chronic GBE trials had yielded significant results.
  • The compounds have been shown to possess potent free radical scavenging and antioxidant properties that may play an important role in the neuroprotective properties of GBE [47,48]. GBE also influences a number of neurotransmitter systems that are considered critical in cognition [48,49]
  • Our observation of GBE-mediated left temporal and left prefrontal inhibition may thus indicate increased efficiency of the inhibitory neural system and the consequential enhanced cognitive performance.

After each dose of the ginkgo extract [50], the breakpoint (at 480 ms) and dual coding (at 960 ms) were significantly shifted toward a shorter presentation time, indicating an improvement in the speed of information processing. The acute dose of ginkgo significantly improved performance on the sustained-attention task and pattern-recognition memory task [51].

The results showed that 120 mg of Ginkgo engendered a significant improvement on the 'quality of memory' factor that was most evident at 1 and 4 hr post-dose, but had a negative effect on performance on the 'speed of attention' factor that was most evident at 1 and 6 hr post-dose [52].

  • The current study confirmed the previous observation of modestly improved memory performance following 120 mg of GBE, but suggests that acute administration of this typical daily dose may have a detrimental effect on the speed of attention task performance which is opposite to that seen previously following higher doses

Compared with the placebo, administration of Ginkgo produced a number of significant changes on the performance measures [53]. The most striking of these was a dose-dependent improvement of the 'speed of attention' factor following both 240 mg and 360 mg of the extract, which was evident at 2.5 h and was still present at 6h. Additionally, there were a number of time- and dose-specific changes (both positive and negative) in performance of the other factors.

  • We conclude that acute administration of Ginkgo biloba is capable of producing a sustained improvement in attention in healthy young volunteers.

The results confirm that the effects of GBE extract on aspects of cognition in asymptomatic volunteers are more pronounced for memory, particularly working memory [54]. They also show that these effects may be dose dependent though not in a linear dose related manner, and that GBE 120 mg produces the most evident effects of the doses examined. Additionally, the results suggest that the cognitive enhancing effects of GBE are more likely to be apparent in individuals aged 50-59 years.

Statistical analysis indicated significant improvements in speed of information processing working memory and executive processing attributable to the EGb.

  • There was no significant differences between the EGb and placebo groups for negative side effects (e.g. headaches and nausea) but there was a significant number of positive subjective reported effects due to the EGb treatment than the placebo treatment. Positive subjective reported effects include subjective feelings of cognitive clarity, and self-reported improvements in memory and attention
    • EGb treatment improves memory processes, particularly working memory and memory consolidation
    • This improvement in functioning was clearly evident to participants throughout the trial indicating that the changes were not only statistically significant but of a magnitude that could be subjectively noticed by the participants despite the double blinding of the study.

This study [55] also suggest improvement in reaction time. The improvement with Tanakan at week 12 was significantly greater than with placebo. No signs of improvement were detected with placebo when the reaction time measures were combined using these techniques, whereas by week 4 the Tanakan group were significantly faster than at baseline, and were superior to placebo throughout the study.

  • These improvements in mental efficiency were accompanied by a significant increase in the interest taken in everyday activities, and suggest that the drug might be helpful in treating the early stages of primary degenerative dementia.

The most striking result was a dose-dependent improvement in performance on the "quality of memory" factor for the highest dose [56]. Further analysis revealed that this effect was differentially targeted at the secondary memory rather than the working memory component.

  • There was also a dose-dependent decrement in performance of the "speed of attention" factor for both the 320 and 640 mg doses

A 'working memory capacity' paradigm demonstrated a reliable 50 ms response time decrease between the placebo and Ginkgo biloba testing, suggesting that Ginkgo biloba speeds short-term working memory processing in normal adults [57].

There is consistent evidence that chronic administration improves selective attention, some executive processes and long-term memory for verbal and non-verbal material [58].

STRESS

Most of the positive effects done on rats, not many human studies

Stress involves a rise in the levels of glucocorticoids and subsequent memory dysfunction, increased anxiety, decreased immunity, gastrointestinal tract disturbances, myocardial infarction, or effects such as increased vigilance [59,60]. Since mood and emotion are related to stress, the alleviating effects of Ginkgo leaf extract may result in improving mood, thus resulting in antidepressant activity [61].

The authors reported a significant improvement in psychopathological symptoms for anxiety disorder [62]. From the study [63], GBE is more effective in acute stress. Hence these extracts possess significant anti-stress properties and can be used for the treatment of stress-induced disorders.

A single treatment with EGb 761 (120 mg) reduced the stress-induced rise in blood pressure without affecting the heart rate. Thus, this study [64] provides evidence that EGb 761 has an inhibitory action on blood pressure and it may influence cortisol release in response to some stress stimuli.

BLOOD PRESSURE

Cardioprotective effects of Ginkgo leaf extract are through antioxidant, antiplatelet activity, and increased blood flow through the release of nitric oxide and prostaglandins [65].

  • The Ginkgo leaf extract is also known to improve coronary blood flow through antiplatelet activity (by ginkgolide B) and by improving contractile functions which are due to increased release of catecholamines from endogenous liver tissue reserves by flavonoids (quercetin, kaempferol, and isorhamnetin).

The aim of this initial randomized multicentre study [66] was to evaluate the therapeutic efficacy of GBE on a neurological deficit and cognitive decline after acute stroke injury. The study demonstrated that patients with stroke who received GBE manifested better memory function, executive functions, neurological function, and daily life. Additionally, the safety data analysis demonstrated that GBE did not increase the incidence of adverse events.

  • It is reported that EGb761 protected against ischaemic brain injury by scavenging free radicals [67]. EGb761 can also suppress the activity of ACE, thereby inhibiting the contraction of small arteries, dilation of cerebral blood vessels and an increase in cerebral blood flow [68].
  • The possible molecular mechanism may include anti-apoptosis and increasing cerebral blood flow [69,70,71,72]. One double-blind, placebo-controlled, randomized controlled trial of 102 patients with ischaemic stroke concluded that regarding neurological function, the GBE group fared much better than a placebo group over a 4 month follow-up period.

Reports [73] on the effects of GBE on ocular circulation include a prospective study of 11 healthy volunteers treated in random order with GBE 120 mg/day for 2 days. GBE significantly increased the end-diastolic velocity in the ophthalmic artery, without changes in arterial blood pressure, heart rate, or IOP [74].

  • In another study, the same dose of GBE for four weeks increased the micro circular blood velocity, flow, and volume in healthy volunteers for four weeks.
  • In another study, GBE administration (160 mg/day for 4 weeks) increased the mean blood flow, volume, and velocity in NTG patients [75].

Moreover, daily life in the GBE group was significantly better than in the control group, including the BI score and EDI score [76]. Overall, administration of GBE in patients with acute stroke is recommended for its ability to improve cognition and the quality of daily life.

  • Additionally, a few studies have proposed that GBE may increase the risk of bleeding due to its inhibition of platelet aggregation and platelet activating factor function. From 1966 to 2004, 15 case reports described the association between GBE and bleeding events, including eight episodes of intracranial bleeding. Among them, some patients had previous bleeding risk factors, including liver cirrhosis, hypertension, and warfarin or high dose aspirin consumption. As intracranial hemorrhage is a serious complication, sometimes leading to death.
  • Clinicians should be careful when giving GBE to patients with these risk factors. Patients with antiplatelet contraindications, low platelet count or liver insufficiency, and those taking other antiplatelet drugs were excluded from the current study.

POTENTIAL SIDE EFFECTS

In rare cases, mild gastrointestinal complaints, headache, and allergic skin reactions have been reported when GBE was used.

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