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Spinocerebellar ataxia type 17 (SCA 17) is a polyglutamine disease caused by the expansion of CAG/CAA repeats in the TATA box-binding protein (TBP) gene. The Ginkgo biloba extract, EGb 761, contains flavonoids and terpenoids with a potential use for the treatment of neurodegenerative diseases such as Alzheimer’s and Parkinson’s diseases. The neurop...
Citations
... The previously proposed calcium hypothesis of neurodegeneration [4] postulates that the main factor triggering neurodegenerative processes in neurons is a disturbance of intracellular calcium signaling. Indeed, impaired calcium homeostasis has been reported for a wide range of neurodegenerative diseases, in both cellular and animal model studies [5][6][7][8][9][10]. In this review, we have summarized the data accumulated to date on established iPSCs-based models of various neurodegenerative pathologies, focusing on the revealed changes in calcium signaling. ...
The development of cell reprogramming technologies became a breakthrough in the creation of new models of human diseases, including neurodegenerative pathologies. The iPSCs-based models allow for the studying of both hereditary and sporadic cases of pathologies and produce deep insight into the molecular mechanisms underlying neurodegeneration. The use of the cells most vulnerable to a particular pathology makes it possible to identify specific pathological mechanisms and greatly facilitates the task of selecting the most effective drugs. To date, a large number of studies on patient-specific models of neurodegenerative diseases has been accumulated. In this review, we focused on the alterations of such a ubiquitous and important intracellular regulatory pathway as calcium signaling. Here, we reviewed and analyzed the data obtained from iPSCs-based models of different neurodegenerative disorders that demonstrated aberrant calcium signaling.
... It can alleviate ischemia, oxidative stress and β-amyloid-induced toxicity (25). Huang et al have reported that EGb761 can protect SH-SY5Y neuroblastoma cells against glutamate toxicity via inhibiting excitotoxicity and calcium influx as well as reducing the expression of apoptotic markers (26). However, little is known about GBE. ...
Ginkgo biloba extract (GBE), a traditional Chinese herbal medicine component, is widely used to alleviate symptoms of neurodegenerative diseases. It has been confirmed that GBE exerts its pharmacological effect mainly due to its antioxidant activity; however, the molecular mechanism responsible for this effect remains unclear. The aim of the present study was to investigate the detailed mechanism of GBE, the main component of Gingko biloba dropping medicine, against oxidative glutamate toxicity in human neuroblastoma SH-SY5Y cells. The SH-SY5Y cells were untreated or pretreated with GBE followed by glutamate stimulation. Cell viability was assessed using an MTT assay. In addition, oxidative stress indexes, including intracellular ROS generation and NADPH oxidase and caspase activity, were also measured. The protein expression of key signaling factors involved in the redoxosome-p66Shc pathway was evaluated to elucidate the neuroprotective effect of GBE. The results showed that GBE treatment significantly attenuated the glutamate-induced cytotoxicity in SH-SY5Y cells by suppressing oxidative stress. A mechanical study revealed that redoxosome-p66Shc activation was associated with glutamate-induced cytotoxicity, which caused mitochondrial dysfunction and cell death. Interestingly, GBE treatment attenuated the activation of redoxosome-p66Shc in a dose-dependent manner, which suggested that the protective effect of GBE on SH-SY5Y cells against oxidative glutamate toxicity may be mediated by the modulation of redoxosome-p66Shc signaling. The current findings contribute to a better understanding of the therapeutic effect of GBE and indicate that redoxosome-p66Shc signaling might be a novel therapeutic target in the prevention and/or treatment of neurodegenerative diseases.
... The involvement of disturbed intracellular calcium signaling in the pathogenesis of HD and other neurodegenerative diseases is widely discussed (Bezprozvanny, 2009;Wu et al., 2011;Egorova et al., 2015;Huang et al., 2016;Nekrasov et al., 2016;Czeredys et al., 2018;Hisatsune et al., 2018). Numerous potential drugs have demonstrated a pronounced specific effect on the pathological functioning of calcium signaling (Chen et al., 2011;Wu et al., 2011Wu et al., , 2016Weber et al., 2019). ...
Huntington's disease (HD) is a severe autosomal-dominant neurodegenerative disorder caused by a mutation within a gene, encoding huntingtin protein. Here we have used the induced pluripotent stem cell technology to produce patient-specific terminally differentiated GABA-ergic medium spiny neurons modeling a juvenile form of HD (HD76). We have shown that calcium signaling is dramatically disturbed in HD76 neurons, specifically demonstrating higher levels of store-operated and voltage-gated calcium uptakes. However, comparing the HD76 neurons with the previously described low-repeat HD models, we have demonstrated that the severity of calcium signaling alterations does not depend on the length of the polyglutamine tract of the mutant huntingtin. Here we have also observed greater expression of huntingtin and an activator of store-operated calcium channels STIM2 in HD76 neurons. Since shRNA-mediated suppression of STIM2 decreased store-operated calcium uptake, we have speculated that high expression of STIM2 underlies the excessive entry through store-operated calcium channels in HD pathology. Moreover, a previously described potential anti-HD drug EVP4593 has been found to attenuate high levels of both huntingtin and STIM2 that may contribute to its neuroprotective effect. Our results are fully supportive in favor of the crucial role of calcium signaling deregulation in the HD pathogenesis and indicate that the cornerstone of excessive calcium uptake in HD-specific neurons is a calcium sensor and store-operated calcium channels activator STIM2, which should become a molecular target for medical treatment and novel neuroprotective drug development.
... A study by Huang et al. [62] investigated the positive effects of EGb 761, a standardised extract of Ginkgo biloba, in in vitro models of SCA17 using HEK 293 and SH-SY5Y cells expressing mutant TATA-box binding protein (TBP), and an in vivo transgenic mouse model overexpressing TBP. Pre-treatment with EGb 761 (20 μg/ mL) for 1 h restored cellular calcium homeostasis and suppressed calcium influx, as indicated by reduced calcium green fluorescence intensity. ...
... Intraperitoneal injection of EGb 761 (100 mg/kg) in transgenic mice demonstrated improved motor function by rotarod test. Moreover, EGb 761 prevented the disruption of calbindin integrity, as indicated by immunohistochemistry analysis [62]. Calbindins are major proteins expressed on neurons such as Purkinje cells, which play a role in motor function, calcium homeostasis and cell survival [99,100]. ...
Background
Hereditary ataxia (HA) represents a group of genetically heterogeneous neurodegenerative diseases caused by dysfunction of the cerebellum or disruption of the connection between the cerebellum and other areas of the central nervous system. Phenotypic manifestation of HA includes unsteadiness of stance and gait, dysarthria, nystagmus, dysmetria and complaints of clumsiness. There are no specific treatments for HA. Management strategies provide supportive treatment to reduce symptoms.
Objectives
This systematic review aimed to identify, evaluate and summarise the published literature on the therapeutic roles of natural remedies in the treatment of HA to provide evidence for clinical practice.
Methods
A systematic literature search was conducted using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). Web of Science, PubMed and Science Direct Scopus were thoroughly searched for relevant published articles from June 2007 to July 2020.
Results
Ten pre-clinical and two clinical studies were eligible for inclusion in this systematic review. We identified the therapeutic roles of medicinal plants Brassica napus, Gardenia jasminoides, Gastrodia elata, Ginkgo biloba, Glycyrrhiza inflata, Paeonia lactiflora, Pueraria lobata and Rehmannia glutinosa ; herbal formulations Shaoyao Gancao Tang and Zhengan Xifeng Tang; and medicinal mushroom Hericium erinaceus in the treatment of HA. In this review, we evaluated the mode of actions contributing to their therapeutic effects, including activation of the ubiquitin–proteasome system, activation of antioxidant pathways, maintenance of intracellular calcium homeostasis and regulation of chaperones. We also briefly highlighted the integral cellular signalling pathways responsible for orchestrating the mode of actions.
Conclusion
We reviewed the therapeutic roles of natural remedies in improving or halting the progression of HA, which warrant further study for applications into clinical practice.
... Huang et al., 48 observed suppression of excitotoxicity and apoptosis by treatment with extract EGb761 from Ginkgo biloba in a model of type 17 spinocerebellar ataxia. This is a polyglutamine disease caused by the expansion of CAG/CAA repeated groups in the TATA box-binding protein (TBP) gene that leads to protein aggregates in these patients. ...
... In a dopamine-induced PD model, it suggestively upregulates NR4A2 expression but downregulates expression of α-synuclein [125]. EGb 761, a standard extract which is prepared from Ginkgo biloba leaves [130,131], has several effects against several neurological disorders, such as AD, PD, and spinocerebellar ataxia type 17 [131][132][133][134][135]. Moreover, EGb 761 activity has been indicated by clinical trials for treating numerous neuropsychiatric diseases [136,137]. ...
... In a dopamine-induced PD model, it suggestively upregulates NR4A2 expression but downregulates expression of α-synuclein [125]. EGb 761, a standard extract which is prepared from Ginkgo biloba leaves [130,131], has several effects against several neurological disorders, such as AD, PD, and spinocerebellar ataxia type 17 [131][132][133][134][135]. Moreover, EGb 761 activity has been indicated by clinical trials for treating numerous neuropsychiatric diseases [136,137]. ...
NR4A2 is a nuclear receptor and a transcription factor, with distinctive physiological features. In the cell nuclei of the central nervous system, it is widely expressed and identified as a crucial regulator of dopaminergic (DA) neuronal differentiation, survival, and maintenance. Importantly, it has regulated different genes crucial for dopaminergic signals, and its expression has been diminished in both aged and PD post-mortem brains and reduced in PD patients. In microglia and astrocytes, the expression of NR4A2 has been found where it can be capable of inhibiting the expression of proinflammatory mediators; hence, it protected inflammation-mediated DA neuronal death. In addition, NR4A2 plays neuroprotective role via regulating different signals. However, NR4A2 has been mainly focused on Parkinson’s research, but, in recent times, it has been studied in Alzheimer’s disease (AD), multiple sclerosis (MS), and stroke. Altered expression of NR4A2 is connected to AD progression, and activation of its may improve cognitive function. It is downregulated in peripheral blood mononuclear cells of MS patients; nonetheless, its role in MS has not been fully clear. miR-145-5p known as a putative regulator of NR4A2 and in a middle cerebral artery occlusion/reperfusion model, anti-miR-145-5p administration promoted neurological outcomes in rat. To date, various activators and modulators of NR4A2 have been discovered and investigated as probable therapeutic drugs in neuroinflammatory and neuronal cell death models. The NR4A2 gene and cell-based therapy are described as promising drug candidates for neurodegenerative diseases. Moreover, microRNA might have a crucial role in neurodegeneration via affecting NR4A2 expression. Herein, we present the role of NR4A2 in neuroinflammation and neuronal cell death focusing on neurodegenerative conditions and display NR4A2 as a promising therapeutic target for the therapy of neuroprotection.
... Recently, SS was shown to elevate intracellular Ca 2+ concentration and activate the Ca 2+ /CaMKII/ CREB signaling cascade in AC, causing tinnitus in rats [20]. Conversely, EGb appeared to ameliorate glutamate-induced excitotoxicity and apoptosis by regulating intracellular Ca 2+ concentration [21]. In line with these findings, we demonstrated that EGb pretreatment attenuated GluN2B upregulation in the rat IC immediately after SS administration. ...
Objectives:
Sodium salicylate (SS) is well known for its ototoxic properties that induce functional and morphological changes in the cochlea and brain. Ginkgo biloba extract (GBE) has been widely used for treatment of various neurodegenerative diseases; however, its effects on salicylate-induced ototoxicity remain unclear. Herein, we examined the effects of EGb 761 (EGb), a standard form of GBE, on the plasticity of the N-methyl-D-aspartate receptor subunit 2B (GluN2B) in the inferior colliculus (IC) following SS administration.
Methods:
Seven-week-old Sprague Dawley rats (n=24) were randomly allocated to control, SS, EGb, and EGb+SS groups. The SS group received a single intraperitoneal SS injection (350 mg/kg), the EGb group received EGb orally for 5 consecutive days (40 mg/kg), and the EGb+SS group received EGb for 5 consecutive days, followed by an SS injection. The auditory brainstem responses (ABRs) were assessed at baseline and 2 hours after SS administration. GluN2B expression was examined by Western blot and immunohistochemistry.
Results:
There were no significant differences in ABR threshold shifts among the groups. The expression of the GluN2B protein normalized by which of glyceraldehyde 3-phosphate dehydrogenase (GAPDH) was significantly lower in the EGb+SS group, as compared to the SS group (P=0.012). Weak and diffused GluN2B immunoreactivity was detected in the IC neural cells of the EGb+SS group, while those of the SS group exhibited strong and diffused GluN2B positivity.
Conclusion:
EGb may play a role in regulating the GluN2B expression in the IC of salicylate-induced ototoxicity model.
... Extracts of these plants have been found to have antioxidant, anti-inflammatory, anti-apoptotic, anti-atheroscleotic, anticancer and neuroprotective effects. It was reported that KMP was one of the major constituent ACCEPTED MANUSCRIPT A C C E P T E D M A N U S C R I P T present in the extracts from these plants and was responsible for their observed pharmacological actions (Singh et al. 2009;Lim et al. 2011;Yang et al. 2011;Singh et al. 2014;Oboh et al. 2015;Huang et al. 2016). Furthermore, studies have also shown that KMP, by itself, exhibits various beneficial effects such as reduction of oxidative stress in streptozotocin-induced diabetes (Al-Kumar et al. 2015); attenuation of apoptosis in doxorubicin-induced cardiotoxicity (Xiao et al., 2012); alleviation of insulin resistance in type 2 diabetes (Luo et al. 2015); anticancer activity (Jo et al. 2015) and protection against glutamate-induced neurotoxicity (Yang et al. 2014). ...
Background:
Myocardial infarction (MI) continues to be associated with high morbidity and mortality worldwide despite the availability of current therapeutic modalities. Kaempferol (KMP), a dietary flavonoid, possesses good antioxidant, immunomodulatory and anti-apoptotic properties and has been evaluated in the present study for its role in mitigating myocardial injury following MI.
Purpose:
In this study, the ability of KMP to protect heart against isoproterenol (ISO) induced oxidative stress and myocardial infarction was evaluated.
Material and methods:
Male Wistar rats (n=48) were administered KMP (5, 10 & 20mg/kg/day, i.p.) or vehicle for 15 days with ISO, 85mg/kg, subcutaneously, for 2 consecutive days was also administered at 24h interval on the 13th and 14th days. On the 15th day, rats were anaesthetized and right coronary artery was cannulated to record hemodynamic parameters. Later on blood sample was collected and heart was removed to estimate biochemical, histopathological, ultrastructural and immuohistochemical studies respectively.
Results:
ISO-treated rats showed a significant reduction in arterial pressure, maximum rate of development of left ventricular pressure and increase in left ventricular end-diastolic pressure. Also, there was a significant decrease in antioxidant enzyme levels such as superoxide dismutase, catalase and glutathione and increase in the level of malondialdehyde and serum TNF-α and IL-6 levels. In addition, the cardiac injury markers such as creatine kinase-MB and lactate dehydrogenase were increased in the serum. Furthermore, immunohistochemistry revealed an increased Bax/Bcl-2 ratio in the myocardium. KMP (5, 10 and 20mg/kg) dose dependently restored hemodynamic, left ventricular functions, decreased cardiac injury marker enzymes in serum, increased antioxidant levels, reduced lipid peroxidation and TNF-α level and apoptosis. Histopathological and ultrastructural studies support the protective effect of KMP in ISO-induced myocardial infarcted rats.
Conclusion:
Thus, the present study revealed that KMP mitigates myocardial damage in ISO-induced cardiac injury by maintaining hemodynamic and biochemical parameters and reducing inflammation owing to its anti-apoptotic, anti-inflammatory and antioxidant activities. It may be concluded that a diet containing KMP may be beneficial in those who are at the risk of myocardial injury.
Objective
Alzheimer’s disease (AD) is the most common age-related neurodegenerative disorder. Emerging evidence suggests that synaptic dysfunction is associated with the onset and progression of AD. Interestingly, Ginkgo biloba extract (EGb) is one of the most frequently investigated herbal medicines for enhancing cognition and alleviating neurodegenerative dementia. This study aimed to investigate the effect and the mechanism of EGb on AD-like synaptic disorders.
Methods
Scopolamine (SCO)-induced rats were used to mimic AD-like memory deficits. Morris water maze test and fear conditioning test were conducted to evaluate the memory status of rats in response to different treatments. Then, the synapse alterations were assessed by Golgi staining, and Western blotting was conducted to assess the protein expression of PSD95, GluN2B, synapsin-1, and synaptophysin. Reverse transcription quantitative polymerase chain reaction was applied to detect the mRNA expression of PSD95 and the levels of miR-1-3p/miR-206-3p.
Results
EGb supplement alleviated the learning and memory deficits induced by SCO in behavioral experiments. Moreover, EGb treatment attenuated synaptic damage elicited by SCO, manifested as increased dendritic spine density and the proportion of mushroom-type spines in hippocampal neurons. Further investigation indicated that EGb rescued the expression of synaptic-related proteins, especially PSD95, and decreased the levels of miR-1-3p/miR-206-3p in the rat hippocampus.
Conclusion
The application of EGb effectively treats SCO-induced memory impairments probably by suppressing miR-1-3p/miR-206-3p and elevating the expression of PSD95.
Background: Ginkgo biloba L. (Ginkgoaceae), known as a "living fossil,"has a long history of medicinal use. Both its
leaves and nutshave been widely prescribed for the treatment of various ailments, including pulmonary diseases,
alcohol abuse, bladder inflammation, heart and lung dysfunction, and skin infections. Currently, there are
different forms of G. biloba available in the market, including extracts and isolated compounds such as terpenoids,
flavonoids, bioflavonoids, and organic acids. Despite the significant medicinal importance of this plant,
there is a lack of updated reviews encompassing its pharmacology and other relevant aspects. Therefore, the
objective of this review is to collect and analyze existing literature on the phytochemical, ethnobotanical, and
pharmacological aspects of G. biloba.
Method: Electronic databases including PubMed, Embase, Scopus, and Google Scholar were searched for keywords
“Ginkgo biloba” or “ginkgo” in combination with “phytochemistry”, “ethnobotany”, “pharmacology”,
“nervous system”, and “cardiovascular”, etc. to collect the relevant articles. There was no language restriction.
Results: Retrieved studies showed that the extracts and isolated compounds from G. bilobahave beneficial activities
in cerebrovascular, nervous, cardiovascular, endocrine, muscular and skeletal, renal, respiratory, digestive,
and immunity systems.
Conclusion: Numerous in vitro and in vivo studieshave been conducted to investigate the therapeutic potential of
G. biloba in the treatment and improvement of various diseases. Additionally, there is a substantial body of
clinical research on G. biloba preparations and isolated compounds. However, further investigations, particularly
human-controlled trials, are recommended to determine the efficacy and safety of G. biloba. These trials would
provide more robust evidence regarding the potential benefits and risks associated with the use of G. biloba in
clinical settings.
