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      Tetrandrine protects mouse retinal ganglion cells from ischemic injury

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          Abstract

          This study aimed to determine the protective effects of tetrandrine (Tet) on murine ischemia-injured retinal ganglion cells (RGCs). For this, we used serum deprivation cell model, glutamate and hydrogen peroxide (H 2O 2)-induced RGC-5 cell death models, and staurosporine-differentiated neuron-like RGC-5 in vitro. We also investigated cell survival of purified primary-cultured RGCs treated with Tet. An in vivo retinal ischemia/reperfusion model was used to examine RGC survival after Tet administration 1 day before ischemia. We found that Tet affected RGC-5 survival in a dose- and time-dependent manner. Compared to dimethyl sulfoxide treatment, Tet increased the numbers of RGC-5 cells by 30% at 72 hours. After 48 hours, Tet protected staurosporine-induced RGC-5 cells from serum deprivation-induced cell death and significantly increased the relative number of cells cultured with 1 mM H 2O 2 ( P<0.01). Several concentrations of Tet significantly prevented 25-mM-glutamate-induced cell death in a dose-dependent manner. Tet also increased primary RGC survival after 72 and 96 hours. Tet administration (10 μM, 2 μL) 1 day before retinal ischemia showed RGC layer loss (greater survival), which was less than those in groups with phosphate-buffered saline intravitreal injection plus ischemia in the central ( P=0.005, n=6), middle ( P=0.018, n=6), and peripheral ( P=0.017, n=6) parts of the retina. Thus, Tet conferred protective effects on serum deprivation models of staurosporine-differentiated neuron-like RGC-5 cells and primary cultured murine RGCs. Furthermore, Tet showed greater in vivo protective effects on RGCs 1 day after ischemia. Tet and ciliary neurotrophic factor maintained the mitochondrial transmembrane potential (ΔΨm) of primary cultured RGCs and inhibited the expression of activated caspase-3 and bcl-2 in ischemia/reperfusion-insult retinas.

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          Most cited references 45

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          Retinal ischemia: mechanisms of damage and potential therapeutic strategies.

          Retinal ischemia is a common cause of visual impairment and blindness. At the cellular level, ischemic retinal injury consists of a self-reinforcing destructive cascade involving neuronal depolarisation, calcium influx and oxidative stress initiated by energy failure and increased glutamatergic stimulation. There is a cell-specific sensitivity to ischemic injury which may reflect variability in the balance of excitatory and inhibitory neurotransmitter receptors on a given cell. A number of animal models and analytical techniques have been used to study retinal ischemia, and an increasing number of treatments have been shown to interrupt the "ischemic cascade" and attenuate the detrimental effects of retinal ischemia. Thus far, however, success in the laboratory has not been translated to the clinic. Difficulties with the route of administration, dosage, and adverse effects may render certain experimental treatments clinically unusable. Furthermore, neuroprotection-based treatment strategies for stroke have so far been disappointing. However, compared to the brain, the retina exhibits a remarkable natural resistance to ischemic injury, which may reflect its peculiar metabolism and unique environment. Given the increasing understanding of the events involved in ischemic neuronal injury it is hoped that clinically effective treatments for retinal ischemia will soon be available.
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            Oxidative stress induced-neurodegenerative diseases: the need for antioxidants that penetrate the blood brain barrier.

            Oxidative stress (OS) has been implicated in the pathophysiology of many neurological, particularly neurodegenerative diseases. OS can cause cellular damage and subsequent cell death because the reactive oxygen species (ROS) oxidize vital cellular components such as lipids, proteins, and DNA. Moreover, the brain is exposed throughout life to excitatory amino acids (such as glutamate), whose metabolism produces ROS, thereby promoting excitotoxicity. Antioxidant defense mechanisms include removal of O(2), scavenging of reactive oxygen/nitrogen species or their precursors, inhibition of ROS formation, binding of metal ions needed for the catalysis of ROS generation and up-regulation of endogenous antioxidant defenses. However, since our endogenous antioxidant defenses are not always completely effective, and since exposure to damaging environmental factors is increasing, it seems reasonable to propose that exogenous antioxidants could be very effective in diminishing the cumulative effects of oxidative damage. Antioxidants of widely varying chemical structures have been investigated as potential therapeutic agents. However, the therapeutic use of most of these compounds is limited since they do not cross the blood brain barrier (BBB). Although a few of them have shown limited efficiency in animal models or in small clinical studies, none of the currently available antioxidants have proven efficacious in a large-scale controlled study. Therefore, any novel antioxidant molecules designed as potential neuroprotective treatment in acute or chronic neurological disorders should have the mandatory prerequisite that they can cross the BBB after systemic administration.
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              Molecular mechanisms of glutamate receptor-mediated excitotoxic neuronal cell death.

              Excitotoxicity is one of the most extensively studied processes of neuronal cell death, and plays an important role in many central nervous system (CNS) diseases, including CNS ischemia, trauma, and neurodegenerative disorders. First described by Olney, excitotoxicity was later characterized as an excessive synaptic release of glutamate, which in turn activates postsynaptic glutamate receptors. While almost every glutamate receptor subtype has been implicated in mediating excitotoxic cell death, it is generally accepted that the N-methyl-D-aspartate (NMDA) subtypes play a major role, mainly owing to their high calcium (Ca2+) permeability. However, other glutamate receptor subtypes such as 2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl) propionate (AMPA) or kainate receptors have also been attributed a critical role in mediating excitotoxic neuronal cell death. Although the molecular basis of glutamate toxicity is uncertain, there is general agreement that it is in large part Ca(2+)-dependent. The present review is aimed at summarizing the molecular mechanisms of NMDA receptor and AMPA/kainate receptor-mediated excitotoxic neuronal cell death.
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                Author and article information

                Journal
                Drug Des Devel Ther
                Drug Des Devel Ther
                Drug Design, Development and Therapy
                Dove Medical Press
                1177-8881
                2014
                21 March 2014
                : 8
                : 327-339
                Affiliations
                [1 ]Department of Ophthalmology, Peking University Third Hospital, Peking University Eye Center, Beijing, People’s Republic of China
                [2 ]Department of Neural and Behavioral Sciences, Penn State University, Hershey, PA, USA
                [3 ]Singapore Eye Research Institute, Singapore National Eye Centre, Singapore
                Author notes
                Correspondence: Chun Zhang, Department of Ophthalmology, Peking University Third Hospital, Peking University Eye Center, 49 North Garden Rd, Beijing 100191, People’s Republic of China, Email zhangchun99@ 123456gmail.com
                Samuel S Zhang, Department of Neural and Behavioral Sciences, Penn State University, 500 University Drive, Hershey, PA 17036, USA, Email ssz3@ 123456psu.edu
                Article
                dddt-8-327
                10.2147/DDDT.S55407
                3968085
                © 2014 Li et al. This work is published by Dove Medical Press Limited, and licensed under Creative Commons Attribution – Non Commercial (unported, v3.0) License

                The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

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                Original Research

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