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Insight into Ginkgo biloba L. Extract on the Improved Spatial Learning and Memory by Chemogenomics Knowledgebase, Molecular Docking, Molecular Dynamics Simulation, and Bioassay Validations.

ABSTRACT: Epilepsy is a common cause of serious cognitive disorders and is known to have impact on patients' memory and executive functions. Therefore, the development of antiepileptic drugs for the improvement of spatial learning and memory in patients with epileptic cognitive dysfunction is important. In the present work, we systematically predicted and analyzed the potential effects of Ginkgo terpene trilactones (GTTL) on cognition and pathologic changes utilizing in silico and in vivo approaches. Based on our established chemogenomics knowledgebase, we first conducted the network systems pharmacology analysis to predict that ginkgolide A/B/C may target 5-HT 1A, 5-HT 1B, and 5-HT 2B. The detailed interactions were then further validated by molecular docking and molecular dynamics (MD) simulations. In addition, status epilepticus (SE) was induced by lithium-pilocarpine injection in adult Wistar male rats, and the results of enzyme-linked immunosorbent assay (ELISA) demonstrated that administration with GTTL can increase the expression of brain-derived neurotrophic factor (BDNF) when compared to the model group. Interestingly, recent studies suggest that the occurrence of a reciprocal involvement of 5-HT receptor activation along with the hippocampal BDNF-increased expression can significantly ameliorate neurologic changes and reverse behavioral deficits in status epilepticus rats while improving cognitive function and alleviating neuronal injury. Therefore, we evaluated the effects of GTTL (bilobalide, ginkgolide A, ginkgolide B, and ginkgolide C) on synergistic antiepileptic effect. Our experimental data showed that the spatial learning and memory abilities (e.g., electroencephalography analysis and Morris water maze test for behavioral assessment) of rats administrated with GTTL were significantly improved under the middle dose (80 mg/kg, GTTL) and high dose (160 mg/kg, GTTL). Moreover, the number of neurons in the hippocampus of the GTTL group increased when compared to the model group. Our studies showed that GTTL not only protected rat cerebral hippocampal neurons against epilepsy but also improved the learning and memory ability. Therefore, GTTL may be a potential drug candidate for the prevention and/or treatment of epilepsy.

SUBMITTER: Chen Y

PROVIDER: S-EPMC7017398 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Insight into <i>Ginkgo biloba</i> L. Extract on the Improved Spatial Learning and Memory by Chemogenomics Knowledgebase, Molecular Docking, Molecular Dynamics Simulation, and Bioassay Validations.

Chen Yan Y Feng Zhiwei Z Shen Mingzhe M Lin Weiwei W Wang Yuanqiang Y Wang Siyi S Li Caifeng C Wang Shengfeng S Chen Maozi M Shan Weiguang W Xie Xiang-Qun XQ

ACS omega 20200128 5

Epilepsy is a common cause of serious cognitive disorders and is known to have impact on patients' memory and executive functions. Therefore, the development of antiepileptic drugs for the improvement of spatial learning and memory in patients with epileptic cognitive dysfunction is important. In the present work, we systematically predicted and analyzed the potential effects of Ginkgo terpene trilactones (GTTL) on cognition and pathologic changes utilizing in silico and in vivo approaches. Base ...[more]

PMID: 32064403

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Project description:The transient receptor potential vanilloid type 1 (TRPV1) is a heat-activated cation channel protein, which contributes to inflammation, acute and persistent pain. Antagonists of human TRPV1 (hTRPV1) represent a novel therapeutic approach for the treatment of pain. Developing various antagonists of hTRPV1, however, has been hindered by the unavailability of a 3D structure of hTRPV1. Recently, the 3D structures of rat TRPV1 (rTRPV1) in the presence and absence of ligand have been reported as determined by cryo-EM. rTRPV1 shares 85.7% sequence identity with hTRPV1. In the present work, we constructed and reported the 3D homology tetramer model of hTRPV1 based on the cryo-EM structures of rTRPV1. Molecular dynamics (MD) simulations, energy minimizations, and prescreen were applied to select and validate the best model of hTRPV1. The predicted binding pocket of hTRPV1 consists of two adjacent monomers subunits, which were congruent with the experimental rTRPV1 data and the cyro-EM structures of rTRPV1. The detailed interactions between hTRPV1 and its antagonists or agonists were characterized by molecular docking, which helped us to identify the important residues. Conformational changes of hTRPV1 upon antagonist/agonist binding were also explored by MD simulation. The different movements of compounds led to the different conformational changes of monomers in hTRPV1, indicating that TRPV1 works in a concerted way, resembling some other channel proteins such as aquaporins. We observed that the selective filter was open when hTRPV1 bound with an agonist during MD simulation. For the lower gate of hTRPV1, we observed large similarities between hTRPV1 bound with antagonist and with agonist. A five-point pharmacophore model based on several antagonists was established, and the structural model was used to screen in silico for new antagonists for hTRPV1. By using the 3D TRPV1 structural model above, the pilot in silico screening has begun to yield promising hits with activity as hTRPV1 antagonists, several of which showed substantial potency.

Project description:BackgroundTo investigate the ameliorated effects of an extract of Ginkgo biloba extract (GBE) on experimental cardiac remodeling in rats induced by acute cardiac infarction, and further explore the mechanism concentrated on myocardial type I collagen, transforming growth factor beta 1 (TGF-β1), matrix metalloproteinase 2 (MMP-2) and matrix metalloproteinase 9 (MMP-9), and provide the experimental data for clinical application of GBE.MethodsRats were divided into five groups (n = 20) as following: sham operation group (group A), acute myocardial infarction model group (group B), acute myocardial infarction model + aspirin (10 mg/kg) treatment group (group C), acute myocardial infarction model + captopril (20 mg/kg) treatment group (group D) and acute myocardial infarction model + Ginkgo biloba extract (100 mg/kg) treatment group (group E). The rat acute myocardial infarction model was reproduced by ligaturing the left anterior descending artery excluding the sham operation group which did not ligation only completed the operational process. Each group was further subdivided into treatment regimens lasting 4 weeks and 8 weeks. Immunohistochemistry and real-time polymerase chain reaction (PCR) methods were used to detect the protein expression and mRNA transcriptional levels of rat myocardial TGF-β1, type I collagen, MMP-2 and MMP-9.ResultsCompared with group B, regardless of the length of treatment (4 or 8 weeks), the TGF-β1, MMP-2 and MMP-9 mRNA transcriptional levels, and the protein expression levels of type I collagen, MMP-2 and MMP-9 in groups D, C and E were significantly decreased (P < 0.01). Furthermore, the mRNA expression levels of TGF-β1 in groups D, C and E were significantly lower after 8 weeks compared to after 4 weeks (P < 0.01), as were the expression levels of type I collagen in groups D, C and E (P < 0.05). There was no statistically significant difference in the protein expression levels of MMP-2 and MMP-9 between groups E and C.ConclusionsGBE could inhibit experimental rat myocardial remodeling after acute myocardial infarction via reduced transcription of TGF-β1, MMP-2 and MMP-9 genes and by the decreased expression of type I collagen, MMP-2 and MMP-9 proteins in myocardial cells.

Project description:BackgroundEnergy deficiency and mitochondrial failure have been recognized as a prominent, early event in Alzheimer's disease (AD). Recently, we demonstrated that chronic exposure to amyloid-beta (Abeta) in human neuroblastoma cells over-expressing human wild-type amyloid precursor protein (APP) resulted in (i) activity changes of complexes III and IV of the oxidative phosphorylation system (OXPHOS) and in (ii) a drop of ATP levels which may finally instigate loss of synapses and neuronal cell death in AD. Therefore, the aim of the present study was to investigate whether standardized Ginkgo biloba extract LI 1370 (GBE) is able to rescue Abeta-induced defects in energy metabolism.Methodology/principal findingsWe used a high-resolution respiratory protocol to evaluate OXPHOS respiratory capacity under physiological condition in control (stably transfected with the empty vector) and APP cells after treatment with GBE. In addition, oxygen consumption of isolated mitochondria, activities of mitochondrial respiratory enzymes, ATP and reactive oxygen species (ROS) levels as well as mitochondrial membrane mass and mitochondrial DNA content were determined. We observed a general antioxidant effect of GBE leading to an increase of the coupling state of mitochondria as well as energy homeostasis and a reduction of ROS levels in control cells and in APP cells. GBE effect on OXPHOS was even preserved in mitochondria after isolation from treated cells. Moreover, these functional data were paralleled by an up-regulation of mitochondrial DNA. Improvement of the OXPHOS efficiency was stronger in APP cells than in control cells. In APP cells, the GBE-induced amelioration of oxygen consumption most likely arose from the modulation and respective normalization of the Abeta-induced disturbance in the activity of mitochondrial complexes III and IV restoring impaired ATP levels possibly through decreasing Abeta and oxidative stress level.Conclusions/significanceAlthough the underlying molecular mechanisms of the mode of action of GBE remain to be determined, our study clearly highlights the beneficial effect of GBE on the cellular OXPHOS performance and restoration of Abeta-induced mitochondrial dysfunction.

Project description:Background: Balance training with vibrotactile neurofeedback (VNF) can improve balance and subjective impairment in age-related vertigo and dizziness. Ginkgo biloba dry extract EGb 761 has been shown to improve subjective impairment in chronic vertigo and the efficacy of conventional balance training. The combination was expected to work synergistically in this difficult-to-treat population. Objectives: To demonstrate the efficacy of VNF added to EGb 761 for age-related vertigo and dizziness. Design: Multicenter, prospective, controlled, randomized, single-blind, two-arm trial (German Clinical Trials Register https://www.drks.de No. DRKS00007633). Setting: Specialist offices and tertiary care outpatient department. Participants: One hundred and twenty subjects aged 60+ years with chronic dizziness for over 3 months, a Dizziness Handicap Inventory (DHI) Sum Score >25 and fall risk in balance-related situations as measured by the geriatric Standard Balance Deficit Test Composite Score (gSBDT-CS)>40. Patients with other distinct vestibular pathology (e.g., Meniére's disease, stroke, BPPV) were excluded. Intervention: EGb 761 (80 mg twice daily for 12 weeks) plus 10 days of individually adapted balance training with VNF, randomized 1:1 to sensitive (active) or non-sensitive (sham) neurofeedback. Measurements: The change in gSBDT-CS after 6 weeks (primary), other gSBDT outcomes, DHI, cognition, hearing, and safety. Results: One hundred nine of 120 enrolled subjects received both treatments at least once. Over 12 weeks, the gSBDT-CS improved by 6.7 (active) vs. 4.5 (sham). There was a difference in favor of the active treatment of -2.4 (95% CI -5.4; 0.6) after 6 weeks. Under active treatment, more pronounced effects occurred in all secondary analyses and in nearly all secondary endpoints. The DHI sum score decreased from 44.1 to 31.1 in the total sample with a treatment group difference after 6 weeks of -3.1, 95% CI (-7.1; 0.9). No safety issues were reported. Conclusion: Over 12 weeks, the combination of balance training with VNF and Ginkgo biloba dry extract EGb 761 reached a clinically relevant improvement of age-related vertigo and dizziness with a good pharmacological safety profile.

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Insight into Ginkgo biloba L. Extract on the Improved Spatial Learning and Memory by Chemogenomics Knowledgebase, Molecular Docking, Molecular Dynamics Simulation, and Bioassay Validations.

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Insight into <i>Ginkgo biloba</i> L. Extract on the Improved Spatial Learning and Memory by Chemogenomics Knowledgebase, Molecular Docking, Molecular Dynamics Simulation, and Bioassay Validations.

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