Multicenter, Open-Label, Prospective Study Shows Safety and Therapeutic Benefits of a Defined Ginkgo Biloba Extract for Adults with Major Neurocognitive Disorder.

INTRODUCTION: The safety and therapeutic effects of Gingko biloba extract EGb 761® to treat cognitive decline have been demonstrated in numerous clinical trials. However, trials in Indian populations have been lacking. METHODS: This open-label, multicenter, single-arm, phase IV trial enrolled 150 patients aged ≥50 years with major neurocognitive disorder due to Alzheimer's disease, major vascular neurocognitive disorder, or mixed forms of both according to the Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5) criteria and a Mini-Mental State Examination (MMSE) score of 12-24. Patients took 120 mg EGb 761® twice daily for 18 weeks. Therapeutic effects were assessed by CERAD constructional praxis and recall of constructional praxis (CERAD CP, CERAD recall of CP), Trail-Making Test (TMT), Behavioral Pathology in Alzheimer's Disease (BEHAVE-AD), Clinical Global Impressions (CGI) scale, and 11-point box scales for tinnitus and vertigo. Safety assessment was based on the occurrence of adverse events as well as changes in clinical, laboratory, and functional parameters. RESULTS: After 18 weeks, significant improvements compared to baseline were found in constructional praxis (CERAD CP, p < 0.0001), memory (CERAD recall of CP, p < 0.0001), speed and executive functioning (TMT A, p < 0.0001; TMT B, p < 0.0001), and behavioral symptoms (BEHAVE-AD, p < 0.0001). Forty-five adverse events were reported in 33 (22.0%) patients in total, including ten presumed adverse drug reactions in 9 (6.0%) patients. Headache and diarrhea of mild-to-moderate severity were the most frequent events. Two serious adverse events, both considered unrelated to the study drug, occurred in 2 (1.3%) patients. CONCLUSION: This study confirmed the favorable safety profile and suggested therapeutic benefits of EGb 761® in Indian patients with major neurocognitive disorder.

Anti-Neuroinflammatory Effects of Ginkgo biloba Extract EGb 761 in LPS-Activated BV2 Microglial Cells.

Inflammatory processes in the brain can exert important neuroprotective functions. However, in neurological and psychiatric disorders, it is often detrimental due to chronic microglial over-activation and the dysregulation of cytokines and chemokines. Growing evidence indicates the emerging yet prominent pathophysiological role of neuroinflammation in the development and progression of these disorders. Despite recent advances, there is still a pressing need for effective therapies, and targeting neuroinflammation is a promising approach. Therefore, in this study, we investigated the anti-neuroinflammatory potential of a marketed and quantified proprietary herbal extract of Ginkgo biloba leaves called EGb 761 (10-500 µg/mL) in BV2 microglial cells stimulated by LPS (10 ng/mL). Our results demonstrate significant inhibition of LPS-induced expression and release of cytokines tumor necrosis factor-α (TNF-α) and Interleukin 6 (IL-6) and chemokines C-X-C motif chemokine ligand 2 (CXCL2), CXCL10, c-c motif chemokine ligand 2 (CCL2) and CCL3 in BV2 microglial cells. The observed effects are possibly mediated by the mitogen-activated protein kinases (MAPK), p38 MAPK and ERK1/2, as well as the protein kinase C (PKC) and the nuclear factor (NF)-κB signaling cascades. The findings of this in vitro study highlight the anti-inflammatory properties of EGb 761 and its therapeutic potential, making it an emerging candidate for the treatment of neuroinflammatory diseases and warranting further research in pre-clinical and clinical settings.

Evaluating the role of Ginkgo biloba extract in the secondary prevention of acute ischemic stroke with cerebral microbleeds by quantitative susceptibility mapping (QSM).

BACKGROUND: EGb 761, a standardized dry extract of Ginkgo biloba leaves, has certain anti-inflammatory and thrombotic effects and can be used to treat cerebrovascular diseases. METHODS: A total of 49 patients were randomly assigned to the Aspirin group (24 cases in Controlled group) and the Aspirin + Ginkgo biloba group (25 cases in Treatment group). The quantitative magnetic sensitivity and venous oxygen saturation of cerebral microbleeds were analyzed at admission, discharge, and after follow-up for 3 and 6 months. RESULTS: The demographic details age, gender, and admission to NIHSS were not significantly different between the two groups (p < 0.05). Quantitative susceptibility mapping (QSM) showed that the magnetic sensitivity of patients in both groups remained stable after 3 and 6 months of follow-up, while the venous oxygen saturation of the Treatment group increased. The venous oxygen saturation at 3 and 6 months of follow-up was negatively correlated with the modified mRS grade score. CONCLUSIONS: QSM can be used as a quantitative follow-up tool in monitoring both oxygen saturation and Magnetic susceptibility of microbleeds noninvasively in ischemic stroke patients with cerebral microbleeds. EGB combined with Aspirin can improve blood oxygen saturation in those patients and this effect is particularly significant in the long-term efficacy of secondary prevention.

Ginkgo biloba extract 761 reduces vascular permeability of the ovary and improves the symptom of ovarian hyperstimulation syndrome in a rat model.

AIMS: Ginkgo biloba extract (EGb) has been widely applied in the treatment of cerebrovascular and neurological diseases. However, the effect of EGb761 on ovarian hyperstimulation syndrome (OHSS), a vascular disorder and life-threatening complication of In Vitro Fertilization and Intracytoplasmic Sperm Injection therapy (IVF/ICSI), has not been evaluated. MATERIALS AND METHODS: Forty female Wistar rats aged 22-days old (D22) were divided into eight groups: Control rats received intraperitoneal injection of saline for 5 consecutive days (D22-D26); OHSS model group received 10 IU equine chorionic gonadotropin (eCG) for 4 consecutive days (D22-D25) and 30 IU of human chorionic gonadotropin (hCG) on the 5th day (D26); Prophylactic treatment group received three doses of EGb761 (50, 100, and 200 mg/kg/d) one hour before injection of eCG (hCG) for 7 consecutive days; Therapeutic treatment group received three doses of EGb761 (50, 100, and 200 mg/kg/d) 48 h after injection of eCG (hCG) for 7 consecutive days. RESULTS: All three doses of EGb761 therapeutic medication significantly reduced ovarian mass index in the OHSS model (p ≤ .01). Further, the therapeutic treatment group exhibited improved vascular permeability, decreased estradiol and progesterone levels, lower corpus luteum, and higher follicle numbers compared with the OHSS model. Elevated protein expression of vascular endothelial growth factor (VEGF) and VEGF receptor (VEGFR) in both ovary and kidney of the OHSS model was restrained by EGb761 therapeutic treatment. CONCLUSIONS: EGb761 therapeutic medication decreases vascular permeability in OHSS rat model by inhibiting VEGF and VEGFR expression, which may contribute to the treatment of OHSS.

Ginkgo biloba extract 761 reduces vascular permeability of the ovary and improves the symptom of ovarian hyperstimulation syndrome in a rat model.

AIMS: Ginkgo biloba extract (EGb) has been widely applied in the treatment of cerebrovascular and neurological diseases. However, the effect of EGb761 on ovarian hyperstimulation syndrome (OHSS), a vascular disorder and life-threatening complication of in vitro fertilization and intracytoplasmic sperm injection therapy (IVF/ICSI), has not been evaluated. MATERIALS AND METHODS: Forty female Wistar rats aged 22-days old (D22) were divided into eight groups: Control rats received intraperitoneal injection of saline for five consecutive days (D22-D26); OHSS model group received 10 IU equine chorionic gonadotropin (eCG) for four consecutive days (D22-D25) and 30 IU of human chorionic gonadotropin (hCG) on the 5th day (D26); Prophylactic treatment group received three doses of EGb761 (50, 100, and 200 mg/kg/day) 1 h before injection of eCG (hCG) for seven consecutive days; Therapeutic treatment group received three doses of EGb761 (50, 100, and 200 mg/kg/day) 48 h after injection of eCG (hCG) for seven consecutive days. RESULTS: All three doses of EGb761 therapeutic medication significantly reduced ovarian mass index of OHSS model rats (p ≤ .01). Furthermore, therapeutic treatment group exhibited improved vascular permeability, decreased estradiol and progesterone levels, lower corpus luteum, and higher follicle numbers compared with the OHSS model. Elevated protein expression of vascular endothelial growth factor (VEGF) and VEGF receptor (VEGFR) in both ovary and kidney of the OHSS model was restrained by EGb761 therapeutic treatment. CONCLUSIONS: EGb761 therapeutic medication decreases vascular permeability in OHSS rat model by inhibiting VEGF and VEGFR expression, which may contribute to the treatment of OHSS.

Therapeutic Versus Preventative Use of Ginkgo biloba Extract (EGb 761) against Indomethacin-Induced Gastric Ulcer in Mice.

The main bioactive constituents in the standardized Ginkgo biloba leaf extract (EGb 761) are the terpene lactones and flavonoid glycosides. EGb 761's antioxidant and anti-inflammatory properties have previously been demonstrated. Indomethacin-induced gastric ulcers have a multifactorial etiology and represent a major restriction to its therapeutic utility. The underlying ulcerogenic process involves oxidative and inflammatory biomolecular insults. This study was performed to explore the curative and preventative benefits of EGb 761 in experimentally-induced ulcers. To develop gastric ulcers in mice, indomethacin (40 mg/kg) was administered orally. EGb 761 (200 mg/kg) was given by gavage for 7 days before (preventative) and after (therapeutic) indomethacin administration. The histological alterations and macroscopic mucosal lesions were assessed. In gastric tissue homogenates, malondialdehyde (MDA), reduced glutathione (GSH), nitric oxide (NO), and inflammatory cytokines were measured. The expressions of cyclooxygenase-2 (COX-2), cytokines, and proliferating cell nuclear antigen (PCNA) in the stomach mucosa were also investigated. The ulcer index, histological alterations, gastric oxidants, and inflammatory biomarkers were all significantly increased by indomethacin. In stomach specimens, it increased COX-2 and PCNA expression. EGb 761 treatments, both prophylactic and therapeutic, resulted in significant reductions in ulcer lesions, nitrosative and oxidative damage, and inflammatory markers, along with the lowering of COX-2 and PCNA expressions. Furthermore, in the fight against stomach ulcers, EGb 761 treatment was found to be more efficient than prevention.

EGb761 Protects Brain Microvascular Endothelial Cells Against Oxygen-Glucose Deprivation-Induced Injury Through lncRNA Rmst/miR-150 Axis.

In the present study, we aimed to illustrate the roles and working mechanisms of long non-coding RNA (lncRNA) rhabdomyosarcoma 2-associated transcript (Rmst) and EGb761 in oxygen-glucose deprivation (OGD)-induced brain microvascular endothelial cells (BMECs). OGD exposure augmented the level of Rmst while reduced the expression of miR-150 in bEnd.3 cells. MiR-150 could directly bind to Rmst in bEnd.3 cells. Rmst silencing abrogated the inhibitory influences on the proliferation and migration and the promoting impact on the apoptosis of bEnd.3 cells caused by OGD exposure. Rmst overexpression intensified OGD-induced injury in bEnd.3 cells. OGD induced the injury of bEnd.3 cells through Rmst/miR-150 axis. EGb761 attenuated the damage in bEnd.3 cells induced by OGD through targeting Rmst/miR-150 axis. EGb761 might be an effective therapeutic agent to protect brain microvascular endothelial cells from hypoxia-ischemia induced injury.

Gingko biloba extract EGB761 alleviates heat-stress damage in chicken heart tissue by stimulating Hsp70 expression in vivo in vascular endothelial cells.

1. This study aimed to investigate the protective effects of Gingko biloba extract EGB761 on heat-stressed chicken heart in vivo and its underlying relevance to Hsp70.2. A total of 50 one-day-old female chicks were randomly divided into five groups: control (Con), heat-stress (HS), 0.1% EGB761 plus heat-stress (0.1%EGB+HS), 0.3%EGB761 plus heat-stress (0.3%EGB+HS) and 0.6%EGB761 plus heat-stress (0.6%EGB+HS) groups. After administration of EGB761 for 45 days, the chickens in each group were exposed to a single heat-stress event at 38 ± 1°C for 3 h.3. EGB761 attenuated the abnormal symptoms and pathological scores of myocardium of heat-stressed chickens. Despite a reduction in the transcription and translation of the Hsp70 gene in heat-stressed myocardium, EGB761 induced the expression of Hsp70 in endothelial cells of the microarteries and venules into the blood, and reduced heat-stress damage in vascular endothelial cells.4. Supplementation with EGB761 before heat-stress exposure protected chicken myocardium from damage by increasing serum Hsp70 protein from myocardial cells and cardiac microvascular endothelial cells and protected the microvascular system from adverse injury.

Ginkgo biloba extract protects human melanocytes from H2 O2 -induced oxidative stress by activating Nrf2.

Vitiligo is a common skin depigmenting disorder characterized by the loss of functional melanocytes. Its pathogenesis is complicated and oxidative stress plays a critical role in the development of vitiligo. Thus, antioxidant therapy is a promising therapeutic strategy to prevent or even reverse the progression of depigmentation. Ginkgo biloba extract EGb761 has been confirmed to have protective effects on neurons against oxidative stress. Notably, several clinical trials have shown that patients with stable vitiligo achieved repigmentation after taking EGb761. However, the exact mechanism underlying the protective effects of EGb761 on melanocytes against oxidative stress has not been fully elucidated. In the present study, we found that EGb761 effectively protected melanocytes against oxidative stress-induced apoptosis and alleviated the excessive accumulation of reactive oxygen species (ROS) and lipid peroxidation by enhancing the activity of antioxidative enzymes. Furthermore, the antioxidative effect of EGb761 was achieved by activating Nrf2 and its downstream antioxidative genes. In addition, interfering Nrf2 with siRNA abolished the protective effects of EGb761 on melanocytes against oxidative damage. In conclusion, our study proves that EGb761 could protect melanocytes from H2 O2 -induced oxidative stress by activating Nrf2. Therefore, EGb761 is supposed to be a potential therapeutic agent for vitiligo.

Alleviation of Simvastatin-Induced Myopathy in Rats by the Standardized Extract of Ginkgo Biloba (EGb761): Insights into the Mechanisms of Action.

Statins are the most widely prescribed cholesterol-lowering drugs to reduce the risk of cardiovascular diseases. Statin-induced myopathy is the major side effect of this class of drugs. Here, we studied whether standardized leaf extracts of ginkgo biloba (EGb761) would improve simvastatin (SIM)-induced muscle changes. Sixty Wistar rats were allotted into six groups: control group, vehicle group receiving 0.5% carboxymethyl cellulose (CMC) for 30 days, SIM group receiving 80 mg/kg/day SIM in 0.5% CMC orally for 30 days, SIM withdrawal group treated with SIM for 16 days and sacrificed 14 days later, and EGb761-100 and EGb761-200 groups posttreated with either 100 or 200 mg/kg/day EGb761 orally. Muscle performance on the rotarod, serum creatine kinase (CK), coenzyme Q10 (CoQ10), serum and muscle nitrite, muscle malondialdehyde (MDA), superoxide dismutase (SOD), and catalase (CAT) activities were estimated. Additionally, muscle samples were processed for histopathological evaluation. We found that SIM decreased muscle performance on the rotarod, serum CoQ10, as well as muscle SOD and CAT activities while it increased serum CK, serum and muscle nitrite, as well as muscle MDA levels. SIM also induced sarcoplasmic vacuolation, splitting of myofibers, disorganization of sarcomeres, and disintegration of myofilaments. In contrast, posttreatment with EGb761 increased muscle performance, serum CoQ10, as well as muscle SOD and CAT activities while it reduced serum CK as well as serum and muscle nitrite levels in a dose-dependent manner. Additionally, EGb761 reversed SIM-induced histopathological changes with better results obtained by its higher dose. Interestingly, SIM withdrawal increased muscle performance on the rotarod, reduce serum CK and CoQ10, and reduced serum and muscle nitrite while it reversed SIM-induced histopathological changes. However, SIM withdrawal was not effective enough to restore their normal values. Additionally, SIM withdrawal did not improve SIM-induce muscle MDA, SOD, or CAT activities during the period studied. Our results suggest that EGb761 posttreatment reversed SIM-induces muscle changes possibly through its antioxidant effects, elevation of CoQ10 levels, and antagonizing mitochondrial damage.

Treatment effects of Ginkgo biloba extract EGb 761® on the spectrum of behavioral and psychological symptoms of dementia: meta-analysis of randomized controlled trials.

ABSTRACTBackground:In randomized controlled trials, Ginkgo biloba extract EGb 761® has been found to be effective in the treatment of behavioral and psychological symptoms of dementia (BPSD). METHODS: To assess the effects of EGb 761® on specific BPSD, we analyzed data from all randomized, placebo-controlled, at least 20-week, trials of EGb 761® enrolling patients with dementia (probable Alzheimer's disease (AD), probable vascular dementia or probable AD with cerebrovascular disease) who had clinically significant BPSD (Neuropsychiatric Inventory (NPI) total score at least 6). Data were pooled and joint analyses of NPI single item composite and caregiver distress scores were performed by meta-analysis with a fixed effects model. RESULTS: Four trials involving 1628 patients (EGb 761®, 814; placebo, 814) were identified; treatment duration was 22 or 24 weeks; the daily dose of EGb 761® was 240 mg in all trials. Pooled analyses including data from the full analysis sets of all trials (EGb 761®, 796 patients; placebo, 802 patients) revealed significant superiority of EGb 761® over placebo in total scores and 10 single symptom scores. Regarding caregiver distress scores, EGb 761®-treated patients improved significantly more than those receiving placebo in all symptoms except delusions, hallucinations, and elation/euphoria. The benefit of EGb 761® mainly consists of improvement in symptoms present at baseline, but the incidence of some symptoms was also decreased. CONCLUSIONS: Twenty two- to twenty four-week treatment with Ginkgo biloba extract EGb 761® improved BPSD (except psychotic-like features) and caregiver distress caused by such symptoms.

EGb761 improves the cognitive function of elderly db/db-/- diabetic mice by regulating the beclin-1 and NF-κB signaling pathways.

To assess whether EGb761 could protect elderly diabetic mice with cognitive disorders and explore the role of beclin-1-mediated autophagy in these protective effects. Two-month-old male db/db-/- mice and wild-type C57/BL6 mice were randomly divided into six groups: db/db-/- control, db/db-/- 50 mg, db/db-/- 100 mg, wild-type (WT) control, WT 50 mg, and WT 100 mg. EGb761 (50 mg/kg or 100 mg/kg of bodyweight) was given by gavage once a day for 1 month from the age of 6 months. Y-maze and social choice tests were performed at 8th months. The blood pressure was measured. The imaging changes in the brain were measured using magnetic resonance imaging (MRI). The expression and distribution of beclin-1, LC3, and NF-κB were detected using immunohistochemistry staining and western blotting. Ultrastructure alterations in the hippocampus were observed using transmission electron microscopy. Compared with WT mice, the learning ability, memory and overall cognitive function of db/db-/- mice decreased (P < 0.05), and EGb761 could significantly improve the learning and memory function of db/db-/- mice (P < 0.05). EGb761 significantly improved systolic blood pressure in db/db-/- mice (P < 0.01). In addition, fMRI-bold showed a decline in the hippocampus of mice in the db/db-/- group compared with WT. EGb761 could improve these above changes. Immunohistochemistry staining and western blotting confirmed that EGb761 significantly increased beclin-1 and reduced LC3-II/I levels in the brains of db/db-/- mice (P < 0.05). NF-κB levels were obviously higher in the db/db-/- group than that in the WT group, and EGb761 significantly reduced NF-κB levels in db/db-/- mice (P < 0.05). There was a trend of increased autophagosomes in db/db-/- mice, but EGb761 did not change obviously the number of autophagosomes. Compared with normal aged WT mice, aging db/db-/- mice had more common complications of cerebral small vessel disease and cognitive dysfunction. EGb761 could significantly improve the cognitive function of aging db/db-/- mice via a mechanism that may involve the regulation of beclin-1, LC3, and NF-κB.

EGb-761 Attenuates the Anti-proliferative Activity of Fluoride via DDK1 in PC-12 Cells.

EGb-761 is commonly used as a treatment for ischemic brain injury, neurodegenerative diseases and some types of tumors (Christen and Maixent, in Cell Mol Biol 48(6):601-611, 2002). However, it is unclear whether EGb-761 affects the proliferation of cells exposed to fluoride. In this study, the proliferation and apoptosis of PC-12 cells exposed to fluoride were investigated and EGb-761 was used to protect PC-12 cells against the effects of fluoride. We found that the canonical Wnt signaling pathway was involved in the anti-proliferation of PC-12 cells exposed to fluoride. Furthermore, the results also showed that EGb-761 could attenuate the anti-proliferative activity of fluoride via DDK1 in PC-12 cells. This study may provide a new method for protecting against the inhibition of cell proliferation induced by fluoride.

Lead-induced morphometric changes in the kidneys of albino rats ameliorated by ginkgo biloba extract (EGb 761).

OBJECTIVE: To observe the effects of ginkgo biloba extract on lead-induced morphometric changes in the kidneys of albino rats. METHODS: This randomised controlled study was conducted at the Institute of Basic Medical Sciences, Dow University of Health Sciences, Karachi, from April 2009 to March 2010, and comprised male Wistar albino rats weighing between 150-180 gm who were randomly divided into three equal groups, A, B and C. These were further split into subgroups 1, 2, 3 and 4 according to the duration of the experiment (one, two, four and six weeks). Group A rats were given 1 ml normal saline intraperitoneally daily, group B rats were given lead acetate 8mg/kg intraperitoneally daily, while group C animals received 100mg/kg ginkgo biloba extract orally along with 8mg/kg lead acetate injection. The animals were sacrifised at the end of the prescribed period, and kidneys were retrieved, fixed, stained and examined under light microscope. SPSS 16 was used for data analysis. RESULTS: Of the 120 rats, there were 40(33.3%) in each group. Time-dependent deterioration was observed in the histological architecture of kidneys in group B animals compared to the group A animals, whereas less marked changes were observed in the protected group C animals. In group B animals, the diameter of proximal convoluted tubules increased, the number of proximal convoluted tubules and their nuclei decreased, whereas diameter of the nuclei decreased after an initial increase during the first and second weeks. These parameters remained largely undisturbed in group A animals, whereas changes in group C animals were comparable with those in the controlled group A animals. CONCLUSIONS: Ginkgo biloba extract had a protective effect on lead-induced morphometric changes in the kidneys of albino rats.

A retrospective classification of diagnoses in terms of DSM-5 for patients included in randomized controlled trials of Ginkgo biloba extract EGb 761(®).

When the early trials of Ginkgo biloba extract EGb 761(®) were conducted, different terms were used to denote ageing-associated neurocognitive disorders. With the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5), a taxonomy covering dementia and pre-dementia stages of such disorders became available. DSM-5 diagnostic criteria for neurocognitive disorders (NCDs) were applied to patients with any type of ageing-associated cognitive impairment, including dementia, enrolled in randomized controlled clinical trials of EGb 761(®), taking into account the reported inclusion and exclusion criteria and patient characteristics at baseline. For 23 of 31 trials (74 %), the inclusion diagnoses could be classified as NCD in accordance with DSM-5. Thirteen trials enrolled patients with major NCD, four trials enrolled patients with mild NCD and six trials enrolled patients with NCD, who could not be classified unambiguously as having mild or major NCD. Although various terms were formerly used for neurocognitive disorders, the patients enrolled in the majority of clinical trials with EGb 761(®) could be classified retrospectively using modern DSM-5 diagnostic criteria.

Effects of Ginkgo biloba extract EGb 761® on cognitive control functions, mental activity of the prefrontal cortex and stress reactivity in elderly adults with subjective memory impairment - a randomized double-blind placebo-controlled trial.

OBJECTIVE: Cognitive control as well as stress reactivity is assumed to depend on prefrontal dopamine and decline with age. Because Ginkgo biloba extract EGb761 increases prefrontal dopamine in animals, we assessed its effects on cognitive functions related to prefrontal dopamine. METHODS: Effects of 240-mg EGb761 daily on task-set-switching, response-inhibition, delayed response, prospective-memory, task-related fMRI-BOLD-signals and the Trier Social Stress-Test were explored in a randomized, placebo-controlled, double-blind pilot-trial in 61 elderly volunteers with subjective memory impairment. RESULTS: Baseline-FMRI-data showed BOLD-responses in regions commonly activated by the specific tasks. Task-switch-costs decreased with EGb761 compared to placebo (ANOVA-interaction: Group × Time × Switch-Costs p = 0.018, multiple tests uncorrected), indicating improved cognitive flexibility. Go-NoGo-task reaction-times corrected for error-rates indicated a trend for improved response inhibition. No treatment effects were found for the delayed response and prospective-memory tasks and fMRI-data. A non-significant trend indicated a potentially accelerated endocrine stress-recovery. EGb761 was safe and well tolerated. CONCLUSION: We observed indications for improved cognitive flexibility without changes in brain activation, suggesting increased processing efficiency with EGb761. Together with a trend for improved response inhibition results are compatible with mild enhancement of prefrontal dopamine. These conclusions on potential beneficial effect of EGb761 on prefrontal dopaminergic functions should be confirmed by direct measurements. © 2016 The Authors. Human Psychopharmacology: Clinical and Experimental published by John Wiley & Sons, Ltd.

Ginkgo biloba Extract (EGb 761®) Inhibits Glutamate-induced Up-regulation of Tissue Plasminogen Activator Through Inhibition of c-Fos Translocation in Rat Primary Cortical Neurons.

EGb 761(®) , a standardized extract of Ginkgo biloba leaves, has antioxidant and antiinflammatory properties in experimental models of neurodegenerative disorders such as stroke and Alzheimer's disease. Tissue plasminogen activator (tPA) acts a neuromodulator and plays a crucial role in the manifestation of neurotoxicity leading to exaggerated neuronal cell death in neurological insult conditions. In this study, we investigated the effects of EGb 761 on the basal and glutamate-induced activity and expression of tPA in rat primary cortical neurons. Under basal condition, EGb 761 inhibited both secreted and cellular tPA activities, without altering tPA mRNA level, as modulated by the activation of p38. Compared with basal condition, EGb 761 inhibited the glutamate-induced up-regulation of tPA mRNA resulting in the normalization of overt tPA activity and expression. c-Fos is a component of AP-1, which plays a critical role in the modulation of tPA expression. Interestingly, EGb 761 inhibited c-Fos nuclear translocation without affecting c-Fos expression in glutamate-induced rat primary cortical neurons. These results demonstrated that EGb 761 can modulate tPA activity under basal and glutamate-stimulated conditions by both translational and transcriptional mechanisms. Thus, EGb 761 could be a potential and effective therapeutic strategy in tPA-excessive neurotoxic conditions.

The efficacy and safety of systemic injection of Ginkgo biloba extract, EGb761, in idiopathic sudden sensorineural hearing loss: a randomized placebo-controlled clinical trial.

Steroids are currently the most frequently accepted agents for idiopathic sudden sensorineural hearing loss (ISSNHL). However, the therapeutic effect of steroids is not always satisfactory. In this pilot study, we evaluated whether systemic treatment with Ginkgo biloba extract (EGb761) has an additive therapeutic effect in patients receiving a systemic steroid due to ISSNHL. A multicenter, randomized, double-blind clinical trial was performed. Fifty-six patients with ISSNHL were allocated to either EGb761 or placebo. In both groups, methylprednisolone was administered for 14 days. EGb761 was infused intravenously for 5 days in the EGb761 group, while the same amount of normal saline was infused in the placebo group. For the efficacy evaluation, pure-tone audiometry, speech audiometry, tinnitus handicap inventory (THI) and short form-36 health (SF-36) survey outcomes were obtained before administration and on days 3, 5, 14 and 28 of administration. Twenty-four patients in each group completed the study protocol. There was no difference in hearing loss between the two groups before treatment. At day 28, air conduction threshold values in the placebo and EGb761 groups were 34.63 ± 28.90 and 23.84 ± 25.42 dB, respectively (p = 0.082). Speech discrimination scores in the placebo and EGb761 groups were 69.17 ± 40.89 and 87.48 ± 28.65 %, respectively (p = 0.050). THI and SF-36 scores in the placebo and EGb761 groups were similar. Although a combination of steroid and EGb761 for initial treatment did not show better pure tone threshold, compared with steroid alone, speech discrimination was significantly improved in combination therapy. Further studies will be needed to know if addition of EGb761 actually improves the outcome of ISSNHL treatment.

EGb761 attenuates depressive-like behaviours induced by long-term light deprivation in C57BL/6J mice through inhibition of NF-κB-IL-6 signalling pathway.

Our previous investigation found that Ginkgo extract EGb761 could attenuate the depressive-like behaviours induced by a single injection of lipopolysaccharide in mice. However, it has not been investigated whether EGb761 is effective on depressive-like behaviours induced by long-term light deprivation and whether its effects are associated with the inhibition of NF-κB-IL-6 signalling pathway. In this study, three groups (vehicle group, EGb761 low-dose group, and EGb761 high-dose group) of C57BL/6J male mice were exposed to constant darkness for four weeks. The control mice remained on a 12 : 12 light-dark cycle. Depressive-like behaviours were evaluated by tail suspension test (TST), forced swim test (FST), and sucrose preference test (SPT). Spontaneous locomotor activity was evaluated by open field test (OFT). Levels of IL-6, IL-6 mRNA, NF-κB p65, phospho-NF-κB p65, IκBα, and phospho-IκBα were measured using Elisa, western blotting, or PCR assays. NF-κB p65 DNA binding activity was evaluated using Chemi Transcription Factor Assay Kit. Results showed long-term light deprivation prolonged the immobile time in TST and FST, shortened the latency to immobility in FST, reduced spontaneous locomotor activity in OFT, decreased sucrose preference in SPT, and increased levels of IL-6, IL-6 mRNA, NF-κB p65, phospho-NF-κB p65, and phospho-IκBα in hippocampal tissue. EGb761 dose-dependently reversed the changes of the above parameters induced by long-term light deprivation, without affecting spontaneous locomotor activity. We conclude that EGb761 could attenuate the depressive-like behaviours and inhibit the NF-κB-IL-6 signalling pathway in a light-deprivation-induced mouse model of depression.

Effect of Ginkgo biloba extract on lipopolysaccharide-induced anhedonic depressive-like behavior in male rats.

The peripheral administration of lipopolysaccharide (LPS) induces depressive-like behavior. Anhedonia is a core symptom of depression, defined as a loss of the capacity to experience pleasure. The present study used the sucrose preference test to investigate the influence of Ginkgo biloba extract (EGb 761) on LPS-induced anhedonia in male rats. The animals were randomly divided into four groups: (I) vehicle + saline, (II) vehicle + LPS, (III) EGb 761 + saline, and (IV) EGb 761 + LPS. Saline or LPS (100 µg/kg) was administered intraperitoneally 2 h before the sucrose preference test. Sucrose consumption was recorded 2, 4, 6, 13, and 24 h after 100 µg/kg of LPS or saline injection in the dark phase of the light/dark cycle. Dopamine and serotonin levels in the nucleus accumbens were measured. Our results indicated that the vehicle + LPS group exhibited a significant decrease in sucrose intake compared with the vehicle + saline group. The EGb 761 + LPS group showed more sucrose and food consumption than the vehicle + LPS group. Additionally, compared with the EGb 761 + LPS group, the vehicle + LPS group had less dopamine levels in the nucleus accumbens. Treatment with EGb 761 had no effect on water intake. Our results suggest that EGb 761 may be useful for reducing anhedonic depressive-like behavior.