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      Neuroprotective effects of Scrophularia buergeriana extract against glutamate-induced toxicity in SH-SY5Y cells

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          Abstract

          The aim of this study was to investigate the antioxidant and anti-apoptotic activities, as well as the underlying mechanisms of action, of Scrophularia buergeriana ( S. buergeriana) extract (SBE) in glutamate-induced SH-SY5Y cell death. The roots of S. buergeriana were extracted with 70% ethanol, and standardized SBE was used in this study. To induce cytotoxicity, the SH-SY5Y cells were exposed to glutamate for 3 h, or pre-treated with SBE for 1 h, and subsequently incubated with glutamate for 3 h. The neuro-protective effects were assessed by measuring cell viability and the total glutathione contents using commercial kits. The antioxidant and anti-apoptotic mechanisms of action of SBE were evaluated by western blot analysis. The results confirmed that glutamate-induced toxicity was caused by reactive oxygen species (ROS) production, leading to oxidative stress and DNA damage, thus leading to cell death. However, treatment of the SH-SY5Y cells with SBE significantly increased the viability of the cells exposed to glutamate by upregulating the levels of antioxidant proteins, such as superoxide dismutase (SOD)1, SOD2 and glutathione peroxidase-1 (GPx-1), and directly enhancing the total glutathione contents. Furthermore, SBE attenuated DNA impairment and decreased B-cell lymphoma-2 (Bcl-2)-associated X protein (Bax), cleaved caspase-3 and cleaved poly(adenosine diphosphate (ADP)-ribose) polymerase (PARP) activation. In addition, SBE upregulated Bcl-2 expression via p38 mitogen-activated protein kinases (MAPKs). On the whole, the findings of this study demonstrated that SBE exerts neuroprotective effects against glutamate-induced cell toxicity through its antioxidant and anti-apoptotic activities.

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          Most cited references 37

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          Glutamate-mediated excitotoxicity and neurodegeneration in Alzheimer's disease.

           P Dodd,  R. Dodd,  R F Hynd (2004)
          Alzheimer's disease (AD) is the most common form of dementia, accounting for 60-70% of cases in subjects over 65 years of age. Several postulates have been put forward that relate AD neuropathology to intellectual and functional impairment. These range from free-radical-induced damage, through cholinergic dysfunction, to beta-amyloid-induced toxicity. However, therapeutic strategies aimed at improving the cognitive symptoms of patients via choline supplementation, cholinergic stimulation or beta-amyloid vaccination, have largely failed. A growing body of evidence suggests that perturbations in systems using the excitatory amino acid L-glutamate (L-Glu) may underlie the pathogenic mechanisms of (e.g.) hypoxia-ischemia, epilepsy, and chronic neurodegenerative disorders such as Huntington's disease and AD. Almost all neurons in the CNS carry the N-methyl-D-aspartate (NMDA) subtype of ionotropic L-glutamate receptors, which can mediate post-synaptic Ca2+ influx. Excitotoxicity resulting from excessive activation of NMDA receptors may enhance the localized vulnerability of neurons in a manner consistent with AD neuropathology, as a consequence of an altered regional distribution of NMDA receptor subtypes. This review discusses mechanisms for the involvement of the NMDA receptor complex and its interaction with polyamines in the pathogenesis of AD. NMDA receptor antagonists have potential for the therapeutic amelioration of AD.
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            Role of oxidants in ischemic brain damage.

             Paul K S Chan (1996)
            Oxygen free radicals or oxidants have been proposed to be involved in acute central nervous system injury that is produced by cerebral ischemia and reperfusion. Because of the transient nature of oxygen radicals and the technical difficulties inherent in accurately measuring their levels in the brain, experimental strategies have been focused on the use of pharmacological agents and antioxidants to seek a correlation between the exogenously supplied specific radical scavengers (ie, superoxide dismutase and catalase) and the subsequent protection of cerebral tissues from ischemic injury. However, this strategy entails problems (hemodynamic, pharmacokinetic, toxicity, blood-brain barrier permeability, etc) that may cloud the data interpretation. This mini-review will focus on the oxidant mechanisms in cerebral ischemic brain injury by using transgenic and knockout mice as an alternative approach. Transgenic and knockout mutants that either overexpress or are deficient in antioxidant enzyme/protein levels have been successfully produced. The availability of these genetically modified animals has made it possible to investigate the role of certain oxidants in ischemic brain cell damage in molecular fashion. It has been shown that an increased level of CuZn-superoxide dismutase and antiapoptotic protein Bcl-2 in the brains of transgenic mice protects neurons from ischemic/reperfusion injury, whereas a deficiency in CuZn-superoxide dismutase or mitochondrial Mn-superoxide dismutase exacerbates ischemic brain damage. Target disruption of neuronal nitric oxide synthase in mice also provides neuronal protection against permanent and transient focal cerebral ischemia. I conclude that molecular genetic approaches in modifying antioxidant levels in the brain offer a unique tool for understanding the role of oxidants in ischemic brain damage.
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              Protection of SH-SY5Y Neuronal Cells from Glutamate-Induced Apoptosis by 3,6′-Disinapoyl Sucrose, a Bioactive Compound Isolated from Radix Polygala

              The neuroprotective effects of 3,6′-disinapoyl sucrose (DISS) from Radix Polygala against glutamate-induced SH-SY5Y neuronal cells injury were evaluated in the present study. SH-SY5Y neuronal cells were pretreated with glutamate (8 mM) for 30 min followed by cotreatment with DISS for 12 h. Cell viability was determined by (3,4,5-dimethylthiazol-2-yl)-2,5-diphenylte-trazolium bromide (MTT) assay, and apoptosis was confirmed by cell morphology and flow cytometry assay, evaluated with propidium iodide dye. Treatment with DISS (0.6, 6, and 60 μmol/L) increased cell viability dose dependently, inhibited LDH release, and attenuated apoptosis. The mechanisms by which DISS protected neuron cells from glutamate-induced excitotoxicity included the downregulation of proapoptotic gene Bax and the upregulation of antiapoptotic gene Bcl-2. The present findings indicated that DISS exerts neuroprotective effects against glutamate toxicity, which might be of importance and contribute to its clinical efficacy for the treatment of neurodegenerative diseases.
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                Author and article information

                Journal
                Int J Mol Med
                Int. J. Mol. Med
                IJMM
                International Journal of Molecular Medicine
                D.A. Spandidos
                1107-3756
                1791-244X
                May 2019
                19 March 2019
                19 March 2019
                : 43
                : 5
                : 2144-2152
                Affiliations
                [1 ]Department of Biotechnology, Chonnam National University, Yeosu 59626, Republic of Korea
                [2 ]Laboratory of Clinical Virology, and Forensics, School of Medicine, University of Crete, Heraklion 71003, Greece
                [3 ]Department of Toxicology and Forensics, School of Medicine, University of Crete, Heraklion 71003, Greece
                [4 ]Department of Analytical and Forensic Medical Toxicology, Sechenov University, Moscow 119991, Russia
                [5 ]Department of Biochemistry, Carol Davila University of Medicine and Pharmacy, Faculty of Pharmacy, Bucharest 020956, Romania
                Author notes
                Correspondence to: Professor Aristidis Tsatsakis, Department of Toxicology and Forensics, School of Medicine, University of Crete, Heraklion 71003, Greece, E-mail: tsatsaka@ 123456uoc.gr
                Dr Seung Hwan Yang, Department of Biotechnology, Chonnam National University, Yeosu 59626, Republic of Korea, E-mail: ymichigan@ 123456jnu.ac.kr
                Article
                ijmm-43-05-2144
                10.3892/ijmm.2019.4139
                6443351
                30896788
                Copyright: © Lee et al.

                This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

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