RESUMEN
Alzheimer's disease (AD) is a neurodegenerative disorder characterized by gradual deterioration of cognitive function, memory, and inability to perform daily, social, or occupational activities. Its etiology is associated with the accumulation of ß-amyloid peptides, phosphorylated tau protein, and neuroinflammatory and oxidative processes in the brain. Currently, there is no successful pharmacological treatment for AD. The few approved drugs are mainly aimed at treating the symptoms; however, due to the increasing discovery of etiopathological factors, there are great efforts to find new multifunctional molecules to slow down the course of this neurodegenerative disease. The commercial Ginkgo biloba formulation EGb 761® and Huperzine A, an alkaloid present in the plant Huperzia serrata, have shown in clinical trials to possess cholinergic and neuroprotective activities, including improvement in cognition, activities of daily living, and neuropsychiatric symptoms in AD patients. The purpose of this review is to expose the positive results of intervention with EGb 761® and Huperzine in patients with mild to moderate AD in the last 10 years, highlighting the pharmacological functions that justify their use in AD therapy.
Asunto(s)
Enfermedad de Alzheimer , Ginkgólidos/uso terapéutico , Actividades Cotidianas , Alcaloides/farmacología , Alcaloides/uso terapéutico , Enfermedad de Alzheimer/tratamiento farmacológico , Ginkgólidos/farmacología , Humanos , Enfermedades Neurodegenerativas/tratamiento farmacológico , Extractos Vegetales/farmacología , Extractos Vegetales/uso terapéutico , Sesquiterpenos/farmacología , Sesquiterpenos/uso terapéuticoRESUMEN
This clinical value-oriented comprehensive evaluation of drugs was carried out in accordance with Guidelines for Management of Comprehensive Clinical Evaluation of Drugs(trial version 2021), with the qualitative and quantitative evaluation methods adopted. Based on the evidence-based medicine, epidemiology, clinical medicine, pharmacoeconomics, mathematical statistics, and health technology evaluation(HTA), the clinical value of Ginkgolide Injection was evaluated from the "6+1" dimension by giving weight to the criterion level and index level and calculating with multi-criteria decision analysis(MCDA) model and CSC v2.0. After entering the market, Ginkgolide Injection has been subjected to phase â £ clinical trial, spontaneous reporting system(SRS)-based data monitoring, systematic review and Meta-analysis, acute toxicity and long-term toxicity assays, active monitoring, and RCTs, and the evidence of safety was sufficient. The results of active monitoring showed that the incidence of adverse reactions was 0.09%(rare), mainly manifested as flushing, dizziness, rash, nausea, and vomiting. According to the nested case-control study, the adverse reactions of this drug had nothing to do with the product batch, implying that the drug quality was controllable. The adverse reactions mainly resulted from the pharmacodynamic reactions. Because the drug was effective in resisting platelet aggregation, the resulting adverse reactions such as flushing, dizziness, headache, and phlebitis were caused by vasodilation. Skin rash and gastrointestinal symptoms were mainly attributed to the patients' sensitivity to drugs and their own allergic constitution. According to the sufficiency of evidence and the incidence of adverse reactions in the safety research, the safety of Ginkgolide Injection was grade A. The results of Meta-analysis showed that Ginkgolide Injection combined with conventional western medicine was superior to conventional western medicine in improving the clinical effective rate, neurological function score, and activity of daily living score of patients with cerebral infarction. The validity evidence was evaluated according to the PICO principle to be high. According to the GREAD evaluation principle, the quality of such evidence as clinical effective rate, National Institute of Health stroke scale(NIHSS), and Barthel Index(BI) was evaluated, and the results demonstrated that the evidence quality of clinical effective rate and activity of daily living score was medium. The effectiveness of Ginkgolide Injection was grade A. According to the economic report of Ginkgolide Injection, it had short-term and long-term pharmacoeconomic advantages in the treatment of ischemic stroke, and the economic evidence value was good. According to the CASP economic evaluation checklist, the overall quality evaluation results of the economic report are basically clear. To be specific, the economic evidence quality was high. Based on the comprehensive economic evidence quality and economic value, the economy of this drug was grade A. The innovation of this product was evaluated from three aspects: clinical innovation, enterprise service system innovation, and industrial innovation. Ginkgolide Injection could be used 24 h after intravenous thrombolysis for improving patients' neurological function without increasing bleeding, indicating its important clinical innovation. There were many innovations in ensuring drug supply, especially at the grass roots, drug safety, effectiveness, and reasonable price, which has provided reference for establishing enterprise philosophy, managing drug resources, developing process and technology, and determining enterprise management and marketing. Therefore, its innovation was grade A. The drug had no special medication plan in use, exhibiting good suitability for doctors, nurses, and patients. The suitability was grade B. Compared with similar drugs, its price was at a medium level, meaning good affordability, sufficient production capacity, and easy accessibility. Its accessibility was therefore grade B. This drug belonged to Chinese medicinal injection. The large-sample real-world research revealed rich human use experience, so it was grade C for the traditional Chinese medicine characteristic. According to the comprehensive evaluation, the clinical value of Ginkgolide Injection in the treatment of cerebral infarction fell into class A. It is suggested that it can be transformed into the relevant policy results of basic clinical medication management according to the procedure.
Asunto(s)
Medicamentos Herbarios Chinos , Ginkgólidos , Estudios de Casos y Controles , Infarto Cerebral/tratamiento farmacológico , Medicamentos Herbarios Chinos/uso terapéutico , Ginkgólidos/uso terapéutico , Humanos , Medicina Tradicional ChinaRESUMEN
The application of ginkgolides as a herbal remedy reaches ancient China. Over time many studies confirmed the neuroprotective effect of standard Ginkgo biloba tree extract-the only available ginkgolide source. Ginkgolides present a wide variety of neuroregulatory properties, commonly used in the therapy process of common diseases, such as Alzheimer's, Parkinson's, and many other CNS-related diseases and disorders. The neuroregulative properties of ginkgolides include the conditioning of neurotransmitters action, e.g., glutamate or dopamine. Besides, natural compounds induce the inhibition of platelet-activating factors (PAF). Furthermore, ginkgolides influence the inflammatory process. This review focuses on the role of ginkgolides as neurotransmitters or neuromodulators and overviews their impact on the organism at the molecular, cellular, and physiological levels. The clinical application of ginkgolides is discussed as well.
Asunto(s)
Ginkgólidos/farmacología , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Fármacos Neuroprotectores/farmacología , Animales , Biomarcadores , Estudios Clínicos como Asunto , Manejo de la Enfermedad , Evaluación Preclínica de Medicamentos , Medicamentos Herbarios Chinos/química , Medicamentos Herbarios Chinos/farmacología , Medicamentos Herbarios Chinos/uso terapéutico , Ginkgo biloba/química , Ginkgólidos/química , Ginkgólidos/uso terapéutico , Humanos , Inmunomodulación/efectos de los fármacos , Fármacos Neuroprotectores/química , Fármacos Neuroprotectores/uso terapéutico , Neurotransmisores/química , Neurotransmisores/farmacología , Extractos Vegetales/química , Extractos Vegetales/farmacología , Resultado del TratamientoRESUMEN
Inflammatory demyelination in the central nervous system (CNS) is a hallmark of multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE). Besides MS disease-modifying therapy, targeting myelin sheath protection/regeneration is currently a hot spot in the treatment of MS. Here, we attempt to explore the therapeutic potential of Bilobalide (BB) for the myelin protection/regeneration in EAE model. The results showed that BB treatment effectively prevented worsening and demyelination of EAE, accompanied by the inhibition of neuroinflammation that should be closely related to T cell tolerance and M2 macrophages/microglia polarization. BB treatment substantially inhibited the infiltration of T cells and macrophages, thereby alleviating the enlargement of neuroinflammation and the apoptosis of oligodendrocytes in CNS. The accurate mechanism of BB action and the feasibility of clinical application in the prevention and treatment of demyelination remain to be further explored.
Asunto(s)
Ciclopentanos/uso terapéutico , Encefalomielitis Autoinmune Experimental/tratamiento farmacológico , Furanos/uso terapéutico , Ginkgólidos/uso terapéutico , Animales , Apoptosis/efectos de los fármacos , Polaridad Celular/efectos de los fármacos , Células Cultivadas , Citocinas/metabolismo , Femenino , Activación de Macrófagos/efectos de los fármacos , Macrófagos/inmunología , Ratones , Ratones Endogámicos C57BL , Microglía/inmunología , Regeneración Nerviosa/efectos de los fármacos , Oligodendroglía/efectos de los fármacos , Remielinización/efectos de los fármacos , Linfocitos T/inmunologíaRESUMEN
Bilobalide (BB), a constituent of the Ginkgo biloba extract, is a neuroprotective agent with multiple mechanisms of action. To further explore the potential therapeutic effects of BB in stroke, we investigated its effects on primary astrocytes using the oxygen and glucose deprivation-reoxygenation (OGD-R) model. Cell viability was measured by lactate dehydrogenase release assay and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Cell death was measured by annexin 5 conjgated with fluorescein isothiocyanate (V-FITC) assay, and reactive oxygen species (ROS) production was measured by 2',7'-Dichlorodihydrofluorescein Diacetate (DCFH-DA) probe. Manganese superoxide dismutase (MnSOD) expression was measured by western blot and immunofluorescence. Mitochondrial membrane potential was monitored using JC-1 staining. Our results show that OGD-R downregulated MnSOD and impaired mitochondrial function, which further enhanced ROS production in primary astrocytes. As a result, cell viability was compromised, and cell death increased. BB treatment protected astrocytes from those injuries mainly by restoring MnSOD level as MnSOD inhibitor abolished the effects of BB. In conclusion, we demonstrated that OGD-R induced astrocytic injury, but BB increased the expression of MnSOD, the ROS scavenger, to reverse the exacerbated astrocytic injury.
Asunto(s)
Astrocitos/efectos de los fármacos , Ciclopentanos/uso terapéutico , Furanos/uso terapéutico , Ginkgólidos/uso terapéutico , Glucosa/metabolismo , Fármacos Neuroprotectores/uso terapéutico , Oxígeno/metabolismo , Extractos Vegetales/uso terapéutico , Especies Reactivas de Oxígeno/metabolismo , Superóxido Dismutasa/metabolismo , Ciclopentanos/farmacología , Furanos/farmacología , Ginkgo biloba , Ginkgólidos/farmacología , Humanos , Fármacos Neuroprotectores/farmacología , Extractos Vegetales/farmacologíaRESUMEN
BACKGROUND/AIMS: Ischemic stroke is a leading cause of long-term disability. To date, there is no effective treatment for stroke. Previous studies have shown that Ginkgo biloba extract has protective effects against neurodegenerative disorders. In this present study, we sought to test the potential protective role of an active component of Ginkgo biloba extract, bilobalide, in a rat model of middle cerebral artery occlusion (MCAO). METHODS: A rat model of MCAO was used to test the potential protective effects of Bilobalide B on stroke protection. TTC staining was performed to evaluate infarct size of the brains. Neurological deficit score was measured to reveal the effects of the treatments on animal behavior and cognition. Immunohistochemical staining and transmission electronic microscope analysis were performed to measure the cellular responses to drug treatment. Western blotting and ELISA were performed. The expression of Cleaved- Casepase 3, Beclin-1, p62 and LC3I/II were quantified, and the Phosphorylation of eNOS and Akt were evaluated. The ratio of Bcl-2/ Bax was determined to reveal the molecular pathways that are involved in the drug treatment. RESULTS: We found that intraperitoneal delivery of various Bilobalide doses during ischemia can protect against brain injury, as evidenced by reduced infarct size and improved neurological scores after surgery. Histochemical analysis revealed that treatment with bilobalide can significantly reduce apoptosis, autophagy, and promote angiogeneis following ischemia/reperfusion injury to the brain. The performence of increased phosphorylation of eNOS and Akt suggested that bilobalide can activate Akt prosurvival and eNOS pathways to promote cell survival and angiogenesis, respectively. CONCLUSIONS: Our results suggested that bilobalide benefits stroke symptoms by reducing cell death pathways and promoting angiogenesis. As such, bilobalide may be a potential agent for improving self-repair after ischemic stroke.
Asunto(s)
Autofagia/efectos de los fármacos , Ciclopentanos/farmacología , Furanos/farmacología , Ginkgólidos/farmacología , Neovascularización Fisiológica/efectos de los fármacos , Fármacos Neuroprotectores/farmacología , Óxido Nítrico Sintasa de Tipo III/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Daño por Reperfusión/patología , Animales , Apoptosis/efectos de los fármacos , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Encéfalo/patología , Caspasa 3/metabolismo , Ciclopentanos/uso terapéutico , Modelos Animales de Enfermedad , Furanos/uso terapéutico , Ginkgólidos/uso terapéutico , Infarto de la Arteria Cerebral Media/metabolismo , Infarto de la Arteria Cerebral Media/patología , Infarto de la Arteria Cerebral Media/prevención & control , Masculino , Proteínas Asociadas a Microtúbulos/metabolismo , Fármacos Neuroprotectores/uso terapéutico , Óxido Nítrico/metabolismo , Ratas , Ratas Sprague-Dawley , Daño por Reperfusión/metabolismo , Factor A de Crecimiento Endotelial Vascular/metabolismoRESUMEN
Diterpene ginkgolides meglumine injection (DGMI) is a therapeutic extract of Ginkgo biloba L, which has been used for the treatment of cerebral ischemic stroke in China. Ginkgolides A, B and C are the main components of DGMI. This study was designed to investigate the neuroprotective effects of DGMI components against ischemic stroke in vivo and in vitro. Acute cerebral ischemic injury was induced in rats by occlusion of the middle cerebral artery (MCA) for 1.5 h followed by 24 h reperfusion. The rats were treated with DGMI (1, 3 and 10 mg/kg, iv) at the onset of reperfusion and 12 h after reperfusion. Administration of DGMI significantly decreased rat neurological deficit scores, reduced brain infarct volume, and induced protein kinase B (Akt) phosphorylation, which prompted the nuclear translocation of nuclear factor-erythroid 2-related factor 2 (Nrf2) and phosphorylation of the survival regulatory protein cyclic AMP-responsive element binding protein (CREB). Nrf2 activation led to expression of the downstream protein heme oxygenase-1 (HO-1). In addition, PC12 cells were subjected to oxygen-glucose deprivation/reperfusion (OGD/R) in vitro, treatment with DGMI (1, 10 and 20 µg/mL) or ginkgolides A, B or C (10 µmol/L for each) significantly reduced PC12 cell death and increased phosphorylation of Akt, nuclear translocation of Nrf2 and activation of CREB. Activation of Nrf2 and CREB could be reversed by co-treatment with a phosphoinositide-3-kinase (PI3K) inhibitor LY294002. These observations suggest that ginkgolides act as novel extrinsic regulators activating both Akt/Nrf2 and Akt/CREB signaling pathways, protecting against cerebral ischemia/reperfusion (I/R) damage in vivo and in vitro.
Asunto(s)
Ginkgólidos/uso terapéutico , Infarto de la Arteria Cerebral Media/prevención & control , Fármacos Neuroprotectores/uso terapéutico , Daño por Reperfusión/prevención & control , Transducción de Señal/efectos de los fármacos , Animales , Edema Encefálico/prevención & control , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , Ginkgo biloba/química , Ginkgólidos/farmacología , Hemo Oxigenasa (Desciclizante)/metabolismo , Masculino , Meglumina/farmacología , Meglumina/uso terapéutico , Factor 2 Relacionado con NF-E2/metabolismo , Fármacos Neuroprotectores/farmacología , Células PC12 , Proteínas Proto-Oncogénicas c-akt/metabolismo , Ratas , Ratas Sprague-DawleyRESUMEN
The current study was undertaken to delineate the protective effect of Ginkgolide B, a phyto-constituent from Ginkgo biloba, on oxidized (ox)-LDL-induced endothelial dysfunction via targeting Lectin-like ox-LDL-receptor-1 (LOX-1), NADPH oxidase 4 (NOX-4), and other inflammatory proteins. Our results have shown that Ginkgolide B downregulated the expression of LOX-1 in ox-LDL-treated human umbilical vein endothelial cells (HUVECs) and RAW246.7 murine macrophages which ultimately resulted in decreased cholesterol deposits in HUVECs and RAW264.7. Moreover, Ginkgolide B suppressed the enhanced NOX4 expression, which was associated with attenuation of ROS generation in ox-LDL-stimulated HUVECs and RAW264.7 cells. Ginkgolide B also ameliorated the endothelial dysfunction by inhibiting the augmented expression of monocyte chemotactic protein-1 (MCP-1), intercellular adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1) in ox-LDL-activated HUVECs. Furthermore, the enhanced expression of many inflammatory cytokines in ox-LDL-induced RAW264.7 macrophages, both at transcription and protein level, was significantly down-regulated after Ginkgolide B treatment. Ginkgolide B also illustrated atheroprotective property via suppressing the augmented expression of matrix metalloproteinase-1 and cyclooxygenase-2 in ox-LDL-stimulated RAW264.7 macrophages. In summary, our study has established that Ginkgolide B ameliorates endothelial dysfunction via targeting LOX-1, NOX-4, MCP-1, ICAM-1, and VCAM-1 along with the markers associated with inflammatory cascades and thus could be promoted as a valuable therapeutic agent in prevention and management of atherosclerosis.
Asunto(s)
Ginkgólidos/farmacología , Ginkgólidos/uso terapéutico , Inflamación/inducido químicamente , Inflamación/tratamiento farmacológico , Lactonas/farmacología , Lactonas/uso terapéutico , Lipoproteínas LDL , Enfermedades Vasculares/inducido químicamente , Enfermedades Vasculares/tratamiento farmacológico , Animales , Aterosclerosis/inducido químicamente , Aterosclerosis/tratamiento farmacológico , Aterosclerosis/prevención & control , Células Cultivadas , Regulación hacia Abajo/efectos de los fármacos , Ginkgo biloba , Células Endoteliales de la Vena Umbilical Humana/efectos de los fármacos , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Humanos , Inflamación/metabolismo , Inflamación/prevención & control , Molécula 1 de Adhesión Intercelular/metabolismo , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Ratones , NADPH Oxidasa 4/metabolismo , Extractos Vegetales/farmacología , Extractos Vegetales/uso terapéutico , Células RAW 264.7 , Receptores Depuradores de Clase E/metabolismo , Transducción de Señal/efectos de los fármacos , Enfermedades Vasculares/prevención & controlRESUMEN
RTP801 (also known as REDD1), a stress-related protein, is induced by several environmental stresses such as ischemia and cigarette smoke. Although ischemia can dramatically up-regulate RTP801 expression in brain ischemia, up to now, the exact relation between RTP801 and neuronal death in ischemia is poorly understood. In the current study, using oxygen and glucose deprivation as an in vitro ischemic model in primary cultured cortical neurons, we found that the expression of RTP801 increased progressively with prolongation of ischemic duration, in which the expression of RTP801 is positively correlated with the release of lactate dehydrogenase (LDH) in neurons, and knockdown of RTP801 promoted neuronal survival in ischemia-reperfusion. It was further found that ginkgolide B (GB) could significantly increase cell viability and decrease LDH release, and at the same time reduce the levels of RTP801 mRNA and protein in neurons after ischemia and reperfusion. Moreover, GB-induced reduction in expression of RTP801 was blocked by application of LY294002, a specific inhibitor of phosphatidylinositol 3-kinase (PI3K). These results demonstrate that RTP801 could play a detrimental role on neurons in ischemia, and GB might protect neurons against ischemic injury by inhibiting RTP801 expression via PI3K pathway.
Asunto(s)
Isquemia Encefálica/metabolismo , Isquemia Encefálica/prevención & control , Proteínas de Unión al ADN/antagonistas & inhibidores , Proteínas de Unión al ADN/biosíntesis , Ginkgólidos/uso terapéutico , Lactonas/uso terapéutico , Neuronas/metabolismo , Factores de Transcripción/antagonistas & inhibidores , Factores de Transcripción/biosíntesis , Proteínas Adaptadoras Transductoras de Señales , Animales , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/fisiología , Regulación de la Expresión Génica , Ginkgólidos/farmacología , Lactonas/farmacología , Ratones , Neuronas/efectos de los fármacos , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/uso terapéutico , Extractos Vegetales/farmacología , Extractos Vegetales/uso terapéuticoRESUMEN
Platelet-activating factor (PAF), a bioactive phospholipid, plays an important role in the integrity of the cellular membrane structure, and is involved in the pathogenesis of myocardial ischemia/reperfusion (IR) injuries. In this study, we tested the hypothesis that blockage of PAF receptor by BN 52021 (Ginkgolide B) can prevent IR-induced degradation of the myocardial membrane phospholipid, and deterioration of the cardiac function. Rat hearts in situ were subjected to 5 min ischemia and followed by 10 min reperfusion. Cardiac performances during periods of ischemia and reperfusion were monitored, and the amount of membrane phospholipids was analyzed. Myocardial total phospholipids, phosphatidylcholine, and phosphatidylethanolamine were decreased significantly in ischemia-reperfusion rat hearts compared with those of sham-operated rat hearts. Degradation of the membrane phospholipid was accompanied by the deterioration of cardiac functions and increase in serum lactate dehydrogenase (LDH) activity. BN 52021 (15 mg/kg), given by intravenous infusion 10 min prior to the left anterior descending coronary artery occlusion, reduced IR-related degradation of the myocardial phospholipids, the activity of serum LDH, and was concomitant with improvement of cardiac function. Furthermore, we demonstrated that the production of PAF was increased and BN 52021 decreased cellular damage in cultured anoxic cardiomyocytes. These results indicated that PAF antagonist BN 52021 has a protective effect against IR-induced myocardial dysfunction and degradation of the membrane phospholipids.
Asunto(s)
Membrana Celular/efectos de los fármacos , Ginkgólidos/uso terapéutico , Lactonas/uso terapéutico , Daño por Reperfusión Miocárdica/prevención & control , Miocitos Cardíacos/efectos de los fármacos , Fosfolípidos/metabolismo , Factor de Activación Plaquetaria/antagonistas & inhibidores , Animales , Hipoxia de la Célula/efectos de los fármacos , Membrana Celular/metabolismo , Células Cultivadas , Ginkgólidos/administración & dosificación , Infusiones Intravenosas , L-Lactato Deshidrogenasa/sangre , Lactonas/administración & dosificación , Masculino , Potenciales de la Membrana/efectos de los fármacos , Daño por Reperfusión Miocárdica/metabolismo , Miocitos Cardíacos/metabolismo , Ratas WistarRESUMEN
AIM: To evaluate the effect of ginkgolide B treatment on vascular endothelial function in diabetic rats. METHODS: The study included four groups with 15 male Sprague-Dawley rats: control group; control group treated with ginkgolide B; diabetic group; and diabetic treated with ginkgolide B. The activity of superoxide dismutase (SOD), malondialdehyde content, and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunits, and glutathione peroxidase 1 (GPX1) protein expression were determined in aortic tissues. Vasoconstriction to phenylephrine (PHE) and vasorelaxation to acetylcholine (Ach) and sodium nitroprusside (SNP) were assessed in aortic rings. Nitric oxide (NO) and hydrogen sulfide (H2S) were measured, as well as cystathionine γ lyase (CSE) and cystathionine ß synthetase (CBS) protein expression, and endothelial nitric oxide synthase (eNOS) activity. RESULTS: Diabetes significantly impaired PHE-induced vasoconstriction and Ach-induced vasorelaxation (P<0.001), reduced NO bioavailability and H2S production (P<0.001), SOD activity, and GPX1 protein expression (P<0.001), and increased malondialdehyde content and NADPH oxidase subunits, and CSE and CBS protein expression (P<0.001). Ginkgolide B treatment improved PHE vasoconstriction and Ach vasorelaxation (P<0.001), restored SOD (P=0.005) and eNOS (P<0.001) activities, H2S production (P=0.044) and decreased malondialdehyde content (P=0.014). Vasorelaxation to SNP was not signiï¬cantly different in control and diabetic rats with or without ginkgolide B treatment. Besides, ginkgolide B increased GPX1 protein expression and reduced NADPH oxidase subunits, CBS and CSE protein expression. CONCLUSION: Ginkgolide B alleviates endothelial dysfunction by reducing oxidative stress and elevating NO bioavailability and H2S production in diabetic rats.
Asunto(s)
Diabetes Mellitus Experimental/tratamiento farmacológico , Endotelio Vascular/efectos de los fármacos , Fibrinolíticos/uso terapéutico , Ginkgólidos/uso terapéutico , Sulfuro de Hidrógeno/metabolismo , Lactonas/uso terapéutico , Acetilcolina/farmacología , Animales , Cistationina gamma-Liasa/metabolismo , Diabetes Mellitus Experimental/metabolismo , Endotelio Vascular/metabolismo , Glutatión Peroxidasa/metabolismo , Masculino , Malondialdehído/metabolismo , NADPH Oxidasas/metabolismo , Óxido Nítrico/metabolismo , Óxido Nítrico Sintasa de Tipo III/metabolismo , Nitroprusiato/farmacología , Estrés Oxidativo/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Superóxido Dismutasa/metabolismo , Glutatión Peroxidasa GPX1RESUMEN
PURPOSE: Platelet-activating factor (PAF) has been found in various ocular tissues; the activity of PAF depends on the binding to its specific receptor, PAF-receptor. We investigated the therapeutic effects of PAF-receptor antagonists (CV-3988 and Ginkgolide B) on alkali burn-induced corneal neovascularization (CNV). METHODS: CNV was induced by applying a 0.2 N sodium hydroxide (3 µl, NaOH) solution directly on mice corneas. CV-3988 (1 mM/10 µl) and Ginkgolide B (1 mM/10 µl) were administered topically on the corneas three times daily for three consecutive days. CNV was evaluated under a slit-lamp microscope. Corneas were processed for histological, immunohistochemical and reverse transcription polymerase chain reaction analysis. Human umbilical vein endothelial cells were used for the migration and tube formation assay. RESULTS: Application of CV-3988 and Ginkgolide B inhibited CNV caused by alkali burn. CV-3988 and Ginkgolide B attenuated the expression of PAF-receptor mRNA. Alkali injury induced a massively increased intraocular mRNA expression of an angiogenic factor in cornea tissues, whereas these increments were attenuated by the application of CV-3988 and Ginkgolide B. CONCLUSIONS: CV-3988 and Ginkgolide B reversed opacity and neovascularization in alkali burn-induced corneas. Our findings suggest that CV-3988 and Ginkgolide B may be therapeutically useful in the treatment of CNV and inflammation.
Asunto(s)
Neovascularización de la Córnea/tratamiento farmacológico , Quemaduras Oculares/tratamiento farmacológico , Ginkgólidos/uso terapéutico , Lactonas/uso terapéutico , Éteres Fosfolípidos/uso terapéutico , Inhibidores de Agregación Plaquetaria/uso terapéutico , Glicoproteínas de Membrana Plaquetaria/antagonistas & inhibidores , Receptores Acoplados a Proteínas G/antagonistas & inhibidores , Álcalis/efectos adversos , Animales , Movimiento Celular/efectos de los fármacos , Células Cultivadas , Lesiones de la Cornea/inducido químicamente , Neovascularización de la Córnea/patología , Opacidad de la Córnea/tratamiento farmacológico , Quemaduras Oculares/inducido químicamente , Quemaduras Oculares/patología , Femenino , Ginkgólidos/farmacología , Células Endoteliales de la Vena Umbilical Humana/efectos de los fármacos , Células Endoteliales de la Vena Umbilical Humana/fisiología , Humanos , Lactonas/farmacología , Ratones , Neovascularización Fisiológica/efectos de los fármacos , Neutrófilos/efectos de los fármacos , Éteres Fosfolípidos/farmacología , Inhibidores de Agregación Plaquetaria/farmacología , Glicoproteínas de Membrana Plaquetaria/genética , ARN Mensajero/metabolismo , Receptores Acoplados a Proteínas G/genéticaRESUMEN
INTRODUCTION: The literature on complementary and alternative medicine (CAM) is expanding. One of the most common conditions for which CAM is studied in the pediatric population is migraine. Nutraceuticals are a form of CAM that is being used for pediatric migraine prophylaxis. METHODS: A literature search was carried out in order to identify both observational studies and randomized controlled trials on the use of nutraceuticals for the prophylaxis of pediatric migraine. Adult studies on included nutraceuticals were also reviewed. REVIEW: Thirty studies were reviewed on six different nutraceuticals: butterbur, riboflavin, ginkgolide B, magnesium, coenzyme Q10 and polyunsaturated fatty acids. CONCLUSION: Overall, the quality of the evidence for the use of nutraceuticals in pediatric migraine prophylaxis is poor. Further research needs to be done in order to study the efficacy of nutraceuticals for the prophylaxis of pediatric migraine.
Asunto(s)
Suplementos Dietéticos , Medicina Basada en la Evidencia , Trastornos Migrañosos/prevención & control , Niño , Ácidos Grasos Insaturados/uso terapéutico , Ginkgólidos/uso terapéutico , Humanos , Lactonas/uso terapéutico , Magnesio/uso terapéutico , Estudios Observacionales como Asunto , Petasites , Ensayos Clínicos Controlados Aleatorios como Asunto , Riboflavina/uso terapéutico , Resultado del Tratamiento , Ubiquinona/análogos & derivados , Ubiquinona/uso terapéuticoRESUMEN
Mitochondria and oxidative stress play important roles in neuronal cell death associated with cerebral ischemia. Elevated level of reactive oxygen species (ROS) and mitochondrial dysfunction are thought to be responsible for cerebral ischemia injury along with neural cells death through several apoptotic mechanisms. In this study, exposure of rat pheochromocytoma (PC12) cells to hydrogen peroxide (H2O2) at the concentration of 0.3 mM for 24 h caused significant loss of cell viability, lactate dehydrogenase (LDH) release from cells, ascent of ROS level and mitochondrial membrane potential (MMP) decrease. Moreover, the activities of caspase-9, caspase-8 and caspase-3 all were increased in H2O2-induced PC12 cells. However, pretreatment with ginkgolide K (GK) solutions of different concentrations (10, 50, 100 µM) for 24 h prior to exposuring to H2O2 significantly increased cells viability, suppressed LDH release, attenuated ROS level, prevented cytochrome c release from mitochondria and boosted MMP expression. In addition, ginkgolide K notably inhibited the caspase-3 and caspase-9 but not caspase-8 activities in exogenous H2O2-treated PC12 cells. These results demonstrated that ginkgolide K protected PC12 cells from H2O2-induced apoptosis by restoring MMP expression, ameliorating oxidative stress and subsequently leading to inhibit the activity of caspase-3 protein. Therefore, the present study supported that ginkgolide K may be a promising neuroprotective compound for cerebral ischemia treatment.
Asunto(s)
Isquemia Encefálica , Supervivencia Celular/efectos de los fármacos , Ginkgo biloba/química , Ginkgólidos/farmacología , Lactonas/farmacología , Mitocondrias/efectos de los fármacos , Fármacos Neuroprotectores/farmacología , Estrés Oxidativo/efectos de los fármacos , Animales , Antioxidantes/metabolismo , Antioxidantes/farmacología , Antioxidantes/uso terapéutico , Apoptosis/efectos de los fármacos , Isquemia Encefálica/tratamiento farmacológico , Isquemia Encefálica/metabolismo , Caspasas/metabolismo , Citocromos c/metabolismo , Ginkgólidos/uso terapéutico , Peróxido de Hidrógeno , L-Lactato Deshidrogenasa/metabolismo , Lactonas/uso terapéutico , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Mitocondrias/fisiología , Fármacos Neuroprotectores/uso terapéutico , Células PC12 , Fitoterapia , Extractos Vegetales/farmacología , Extractos Vegetales/uso terapéutico , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Ratas , Especies Reactivas de Oxígeno/metabolismoRESUMEN
The use of herbal therapies is ancient and increasing worldwide. There is a growing body of evidence supporting the efficacy of various "complementary" and alternative medicine approaches in the management of headache disorders. Promising tools to treat migraine patients are herbal products. In particular constituents of Petasites hybridus, Tanacetum Parthenium and Ginkgo Biloba have shown antimigraine action in clinical studies. A miscellaneous of recreational drugs and other herbal remedies have been supposed to have a role in headache treatment but quality of clinical studies in this field is low and inconclusive. Further research is warranted in this area.
Asunto(s)
Trastornos Migrañosos/tratamiento farmacológico , Fitoterapia , Animales , Terapias Complementarias , Ginkgólidos/uso terapéutico , Humanos , Lactonas/uso terapéutico , Petasites , Extractos Vegetales/uso terapéutico , Tanacetum partheniumRESUMEN
OBJECTIVE: To systemically evaluate the efficacy and safety of diterpene ginkgolides meglumine injection (DGMI) on cerebral infarction (CI). METHODS: Comprehensively collect randomized controlled trials of DGMI in the treatment of CI in 7 databases including Embase, PubMed, the Cochrane Library, the China National Knowledge Infrastructure Database, the WanFang Database, the China Science and Technology Journal Database, and the China Biology Medicinedisc as of January 2023. The studies were screened according to the inclusion and exclusion criteria and evaluated according to the criteria recommended by the Cochrane Handbook, then RevMan 5.3, Stata 12.0 software were used for Meta-analysis. RESULTS: A total of 22 randomized controlled trials with 2194 patients were included. Meta analysis showed that: the total effective rate of treatment (relative riskâ =â 1.29, 95% confidence interval (1.21, 1.38), Pâ <â .001), National Institute of Health stroke scale score, Barthel index and Modified Rankin Scale were better in DGMI group than in Conventional Western Medicine Treatment group. The included studies reported 42 adverse events, 25 of which belonged to DGMI groups. CONCLUSION: Available evidence suggested that DGMI can significantly improve the clinical efficiency in the treatment of CI. DGMI is an ideal treatment for CI, which has high clinical application value.
Asunto(s)
Medicamentos Herbarios Chinos , Ginkgólidos , Humanos , Infarto Cerebral/tratamiento farmacológico , Medicamentos Herbarios Chinos/efectos adversos , Medicamentos Herbarios Chinos/uso terapéutico , Ginkgólidos/efectos adversos , Ginkgólidos/uso terapéutico , Meglumina/efectos adversos , Meglumina/uso terapéutico , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
Neuropathic pain is a pathological state induced by the aberrant generation of pain signals within the nervous system. Ginkgolide B(GB), an active component found of Ginkgo. biloba leaves, has neuroprotective properties. This study aimed to explore the effects of GB on neuropathic pain and its underlying mechanisms. In the in vivo study, we adopted the rat chronic constriction injury model, and the results showed that GB(4â¯mg/kg) treatment effectively reduced pain sensation in rats and decreased the expressions of Iba-1 (a microglia marker), NLRP3 inflammasome, and inflammatory factors, such as interleukin (IL)-1ß, in the spinal cord 7 days post-surgery. In the in vitro study, we induced microglial inflammation using lipopolysaccharide (500â¯ng/mL) / adenosine triphosphate (5â¯mM) and treated it with GB (10, 20, and 40⯵M). GB upregulated the expression of mitophagy proteins, such as PINK1, Parkin, LC3 II/I, Tom20, and Beclin1, and decreased the cellular production of reactive oxygen species. Moreover, it lowered the expression of inflammation-related proteins, such as Caspase-1, IL-1ß, and NLRP3 in microglia. However, this effect was reversed by Parkin shRNA/siRNA or the autophagy inhibitor 3-methyladenine (5â¯mM). These findings reveal that GB alleviates neuropathic pain by mitigating neuroinflammation through the activation of PINK1-Parkin-mediated mitophagy.
Asunto(s)
Ginkgólidos , Inflamasomas , Lactonas , Microglía , Mitofagia , Proteína con Dominio Pirina 3 de la Familia NLR , Neuralgia , Ratas Sprague-Dawley , Animales , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Ginkgólidos/farmacología , Ginkgólidos/uso terapéutico , Mitofagia/efectos de los fármacos , Lactonas/farmacología , Lactonas/uso terapéutico , Inflamasomas/metabolismo , Neuralgia/tratamiento farmacológico , Neuralgia/metabolismo , Masculino , Ratas , Microglía/efectos de los fármacos , Microglía/metabolismo , Modelos Animales de Enfermedad , Especies Reactivas de Oxígeno/metabolismoRESUMEN
The review presents an analysis of experimental data on the study of neurobiological effects of ginkgolide B, which may find application in the therapy of Alzheimer's disease (AD). Ginkgolide B is a diterpene trilactone isolated from the leaves of the relict woody plant Ginkgo biloba L., which has been used for thousands of years in traditional Chinese medicine as a neuroprotective agent. In recent years, this compound has attracted attention because of its wide range of neurobiological effects. The neuroprotective effect of ginkgolide B on brain neurons when exposed to various neurotoxins has been established. This compound has also been shown to effectively protect neurons from the effects of beta-amyloid. Studies have revealed the ability of ginkgolide B to reduce microglia activity and regulate neurotransmitter release. In vivo experiments have shown that this substance significantly increases the expression of brain-derived neurotrophic factor (BDNF) and improves cognitive functions, including memory and learning. It is concluded that ginkgolide B, apparently, may find application in the future as a multi-targeted agent of complex therapy of AD.
Asunto(s)
Enfermedad de Alzheimer , Factor Neurotrófico Derivado del Encéfalo , Ginkgo biloba , Ginkgólidos , Lactonas , Fármacos Neuroprotectores , Ginkgólidos/farmacología , Ginkgólidos/uso terapéutico , Enfermedad de Alzheimer/tratamiento farmacológico , Humanos , Fármacos Neuroprotectores/uso terapéutico , Fármacos Neuroprotectores/farmacología , Lactonas/uso terapéutico , Lactonas/farmacología , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Animales , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Péptidos beta-Amiloides/metabolismo , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Microglía/efectos de los fármacos , Microglía/metabolismo , Memoria/efectos de los fármacosRESUMEN
This study aimed to investigate the correlation between ginkgolide B (GB) and the JAK/STAT signaling pathway and to explore its regulating effect on secondary cell apoptosis following spinal cord injury (SCI), to elucidate the protective mechanism GB against acute SCI. Sprague-Dawley rats were randomly divided into a sham-operated group, an SCI group, an SCI + GB group, an SCI + methylprednisolone (MP) group, and an SCI + specific JAK inhibitor AG490 group. A rat model of acute SCI was established using the modified Allen's method. At 4 h, 12 h, 1 day, 3 days, 7 days and 14 days after injury, injured T10 spinal cord specimens were harvested. GB significantly increased inclined plane test scores and Basso, Beattie, and Bresnahan scale scores in SCI rats from postoperative day 3 to day 14. The effect was equal to that of the positive control drug, MP. Western blot analysis showed that JAK(2) was significantly phosphorylated from 4 h after SCI, peaked at 12 h and gradually decreased thereafter, accompanied by phosphorylation of STAT(3) with a similar time course. GB was shown to significantly inhibit the phosphorylation of JAK(2) and STAT(3) in rats with SCI. It significantly increased the ratio of B cell CLL/lymphoma-2 (Bcl-2)/Bcl-2-associated X protein (Bax) protein expression at 24 h, led to an obvious down-regulation of caspase-3 gene and protein expression at 3 days, and significantly decreased the cell apoptosis index at each time point after SCI. This effect was similar to that obtained with the JAK-specific inhibitor, AG490. Our experimental findings indicated that GB can protect rats against acute SCI, and that its underlying mechanism may be related to the inhibition of JAK/STAT signaling pathway activation, improvement of the Bcl-2/Bax ratio, decreased caspase-3 gene and protein expression and further inhibition of secondary cell apoptosis following SCI.
Asunto(s)
Ginkgólidos/uso terapéutico , Lactonas/uso terapéutico , Transducción de Señal/efectos de los fármacos , Traumatismos de la Médula Espinal/tratamiento farmacológico , Animales , Apoptosis/efectos de los fármacos , Caspasa 3/metabolismo , Regulación hacia Abajo , Janus Quinasa 2/metabolismo , Masculino , Metilprednisolona/uso terapéutico , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Distribución Aleatoria , Ratas , Recuperación de la Función/efectos de los fármacos , Factor de Transcripción STAT3/metabolismo , Médula Espinal/metabolismo , Traumatismos de la Médula Espinal/metabolismo , Traumatismos de la Médula Espinal/patología , Tirfostinos/farmacología , Proteína X Asociada a bcl-2/metabolismoRESUMEN
Standardized Ginkgo biloba extract EGb 761 has been shown to inhibit inflammatory hyperalgesia in rats; however, the mechanism of action is not known. This study set out to investigate the anti-inflammatory and analgesic potential of bilobalide, a unique G. biloba constituent, in three well-characterized models of acute inflammatory pain. The effect of oral, intraplantar or intrathecal administration of bilobalide or drug-vehicle (0.25% agar; 10% ethanol in H2O) on responses to noxious thermal and mechanical stimulation of the hindpaw, and paw oedema were assessed in adult male Wistar rats before and after intradermal hindpaw injection of carrageenan (3%; 50 µl) or capsaicin (10 µg; 50 µl) or after hindpaw incision (n=6-8/group). Oral administration of bilobalide (10-30 mg/kg) significantly inhibited thermal hyperalgesia in response to carrageenan, capsaicin and paw incision, independent of dose, with an efficacy similar to that of diclofenac. In the carrageenan model, mechanical hypersensitivity and paw oedema were also significantly reduced after treatment with bilobalide (10-30 mg/kg). Intrathecal administration of bilobalide (0.5-1 µg) inhibited carrageenan-induced thermal hyperalgesia, but had no effect on mechanical hypersensitivity or paw oedema (application≥2 µg induced adverse effects, precluding testing of higher doses). Intraplantar administration of bilobalide (30-100 µg) had no effect. These data show that bilobalide is a potent anti-inflammatory and antihyperalgesic agent, the therapeutic effects of which are mediated in part through a central site of action, and may account for the therapeutic action of the whole extract G. biloba.