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      Neuroprotective effects of an extract from the inflamed skin of rabbits inoculated with vaccinia virus on glutamate-induced neurotoxicity in cultured neuronal cell line

      research-article
      , , , , ,
      Neurological Research
      Taylor & Francis
      N18-RE-105, NON-NMDA-TYPE RECEPTOR, L-GLUTAMIC ACID, VACCINIA VIRUS, CHRONIC PAIN

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          Abstract

          Objective: Protein-free extracts from the inflamed skin of rabbits inoculated with vaccinia virus (Rosemorgen ® and Neurotropin ®) are widely employed to combat chronic pain and treat allergic conditions in human subjects in Japan. However, the pharmacologic mechanisms of Rosemorgen ® and Neurotropin ® remain unclear.

          Methods: In this study, we examined the effects of Rosemorgen ® on L-glutamic acid (Glu)-induced cell death in N18-RE-105 neural cell line, which only possessed non-N-methyl-D-aspartate (NMDA)-type receptors.

          Results: There were many large cytoplasmic cells and elongation of fivers in phosphate-buffered saline (PBS) additional group without Glu. In PBS and Glu simultaneous additional group, the survival ratio was decrease significantly compared with PBS alone group. Moreover, there were dead cells which did not have cytoplasm and aggregated nucleus. The Glu-induced cell death of N18-RE-105 cells was inhibited by both pre-treatment (24 hours before Glu treatment) and simultaneous treatment with Rosemorgen ®. There were many large cytoplasmic cells and elongation of fivers in Rosemorgen ® group.

          Discussion: From this finding in N18-RE-105 cells, Rosemorgen ® was concluded to inhibit Glu-induced cell death via non-NMDA type receptors. One of the pharmacologic mechanisms of Rosemorgen ® has been clear. These results suggest that Rosemorgen ® depresses allodynia and chronic pain through interaction with non-NMDA type receptors.

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          Most cited references25

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          Cell survival promoted by the Ras-MAPK signaling pathway by transcription-dependent and -independent mechanisms.

          A mechanism by which the Ras-mitogen-activated protein kinase (MAPK) signaling pathway mediates growth factor-dependent cell survival was characterized. The MAPK-activated kinases, the Rsks, catalyzed the phosphorylation of the pro-apoptotic protein BAD at serine 112 both in vitro and in vivo. The Rsk-induced phosphorylation of BAD at serine 112 suppressed BAD-mediated apoptosis in neurons. Rsks also are known to phosphorylate the transcription factor CREB (cAMP response element-binding protein) at serine 133. Activated CREB promoted cell survival, and inhibition of CREB phosphorylation at serine 133 triggered apoptosis. These findings suggest that the MAPK signaling pathway promotes cell survival by a dual mechanism comprising the posttranslational modification and inactivation of a component of the cell death machinery and the increased transcription of pro-survival genes.
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            Glutamate toxicity in a neuronal cell line involves inhibition of cystine transport leading to oxidative stress.

            Glutamate binds to both excitatory neurotransmitter binding sites and a Cl(-)-dependent, quisqualate- and cystine-inhibited transport site on brain neurons. The neuroblastoma-primary retina hybrid cells (N18-RE-105) are susceptible to glutamate-induced cytotoxicity. The Cl(-)-dependent transport site to which glutamate and quisqualate (but not kainate or NMDA) bind has a higher affinity for cystine than for glutamate. Lowering cystine concentrations in the cell culture medium results in cytotoxicity similar to that induced by glutamate addition in its morphology, kinetics, and Ca2+ dependence. Glutamate-induced cytotoxicity is directly proportional to its ability to inhibit cystine uptake. Exposure to glutamate (or lowered cystine) causes a decrease in glutathione levels and an accumulation of intracellular peroxides. Like N18-RE-105 cells, primary rat hippocampal neurons (but not glia) in culture degenerate in medium with lowered cystine concentration. Thus, glutamate-induced cytotoxicity in N18-RE-105 cells is due to inhibition of cystine uptake, resulting in lowered glutathione levels leading to oxidative stress and cell death.
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              A Multiple Comparison Procedure for Comparing Several Treatments with a Control

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                Author and article information

                Journal
                Neurol Res
                Neurol Res
                Neurological Research
                Taylor & Francis
                0161-6412
                1743-1328
                19 July 2013
                2008
                : 30
                : 4 , Stroke research in China
                : 430-434
                Affiliations
                Department of Pathology Kinki University School of Medicine, Osaka, Japan
                Department of Pathology Kinki University School of Medicine, Osaka, Japan; Division of Sports Medicine, Institute of Life Science, Kinki University, Osaka, Japan; Division of Hospital Pathology, Hospital of Kinki University School of Medicine, Osaka, Japan
                Kinki University School of Pharmaceutical Sciences Osaka, Japan
                Department of Pathology PL Hospital, Osaka, Japan
                Article
                11734414
                10.1179/016164107X251763
                9491247
                18241529
                cc2599ed-492b-4e35-ba70-3bd120a289ec
                © 2008 Maney Publishing

                This article is made available via the PMC Open Access Subset for unrestricted re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the monkeypox public health emergency or until permissions are revoked in writing. Upon expiration of these permissions, PMC is granted a perpetual license to make this article available via PMC and Europe PMC, consistent with existing copyright protections.

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                Figures: 0, Tables: 0, References: 25, Pages: 5
                Categories
                Research Article
                Articles

                n18-re-105,non-nmda-type receptor,l-glutamic acid,vaccinia virus,chronic pain

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