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      Monosialoganglioside protects against bupivacaine-induced neurotoxicity caused by endoplasmic reticulum stress in rats

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          Abstract

          Background

          Local anesthetics in spinal anesthesia have neurotoxic effects, resulting in severe neurological complications. Intrathecal monosialoganglioside (GM1) administration has a therapeutic effect on bupivacaine-induced neurotoxicity. The aim of this study was to determine the underlying mechanisms of bupivacaine-induced neurotoxicity and the potential neuroprotective role of GM1.

          Materials and methods

          A rat spinal cord neurotoxicity model was established by injecting bupivacaine (5%, 0.12 μL/g) intrathecally. The protective effect of GM1 (30 mg/kg) was evaluated by pretreating the animals with it prior to the bupivacaine regimen. The neurological and locomotor functions were assessed using standard tests. The histomorphological changes, neuron degeneration and apoptosis, and endoplasmic reticulum stress (ERS) relevant markers were analyzed using immunofluorescence, quantitative real-time PCR, and Western blotting.

          Results

          Bupivacaine resulted in significant neurotoxicity in the form of aberrant neurolocomoter functions and spinal cord histomorphology and neuronal apoptosis. Furthermore, the ERS specific markers were significantly upregulated during bupivacaine-induced neurotoxicity. These neurotoxic effects were ameliorated by GM1.

          Conclusion

          Pretreatment with GM1 protects against bupivacaine-induced neurotoxicity via the inhibition of the GRP78/PERK/eIF2α/ATF4-mediated ERS.

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          Most cited references 41

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          Chronic catheterization of the spinal subarachnoid space.

          To administer drugs into the spinal subarachnoid space of unanesthetized and intact rats and rabbits, a procedure is described whereby a polyethylene catheter (PE-10) may be inserted through a puncture of the atlanto-occipital membrane and secured to the skull. Calibration experiments carried out with bromophenol blue dye, 3H-naloxone and 14C-urea revealed first, that there was little rostro-caudal diffusion of the injectate along the spinal axis and secondly, that even for compounds such as naloxone which can rapidly permeate neural tissues, the levels which do appear in the brain are small following the spinal subarachnoid administration of the drug. Control injections, administered either acutely or repeatedly over a prolonged period of time, had no detectable effect on the animal's behavior. These observations, as well as the lack of pathology in the spinal cords of rats having such catheters for periods of up to 4 months suggests that the implant is well tolerated.
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            Neurological complications after regional anesthesia: contemporary estimates of risk.

            Regional anesthesia (RA) provides excellent anesthesia and analgesia for many surgical procedures. Anesthesiologists and patients must understand the risks in addition to the benefits of RA to make an informed choice of anesthetic technique. Many studies that have investigated neurological complications after RA are dated, and do not reflect the increasing indications and applications of RA nor the advances in training and techniques. In this brief narrative review we collate the contemporary investigations of neurological complications after the most common RA techniques. We reviewed all 32 studies published between January 1, 1995 and December 31, 2005 where the primary intent was to investigate neurological complications of RA. The sample size of the studies that investigated neurological complications after central and peripheral (PNB) nerve blockade ranged from 4185 to 1,260,000 and 20 to 10,309 blocks, respectively. The rate of neuropathy after spinal and epidural anesthesia was 3.78:10,000 (95% CI: 1.06-13.50:10,000) and 2.19:10,000 (95% CI: 0.88-5.44:10,000), respectively. For common PNB techniques, the rate of neuropathy after interscalene brachial plexus block, axillary brachial plexus block, and femoral nerve block was 2.84:100 (95% CI 1.33-5.98:100), 1.48:100 (95% CI: 0.52-4.11:100), and 0.34:100 (95% CI: 0.04-2.81:100), respectively. The rate of permanent neurological injury after spinal and epidural anesthesia ranged from 0-4.2:10,000 and 0-7.6:10,000, respectively. Only one case of permanent neuropathy was reported among 16 studies of neurological complications after PNB. Our review suggests that the rate of neurological complications after central nerve blockade is <4:10,000, or 0.04%. The rate of neuropathy after PNB is <3:100, or 3%. However, permanent neurological injury after RA is rare in contemporary anesthetic practice.
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              Multiple Mechanisms of Unfolded Protein Response-Induced Cell Death.

              Eukaryotic cells fold and assemble membrane and secreted proteins in the endoplasmic reticulum (ER), before delivery to other cellular compartments or the extracellular environment. Correctly folded proteins are released from the ER, and poorly folded proteins are retained until they achieve stable conformations; irreparably misfolded proteins are targeted for degradation. Diverse pathological insults, such as amino acid mutations, hypoxia, or infection, can overwhelm ER protein quality control, leading to misfolded protein buildup, causing ER stress. To cope with ER stress, eukaryotic cells activate the unfolded protein response (UPR) by increasing levels of ER protein-folding enzymes and chaperones, enhancing the degradation of misfolded proteins, and reducing protein translation. In mammalian cells, three ER transmembrane proteins, inositol-requiring enzyme-1 (IRE1; official name ERN1), PKR-like ER kinase (PERK; official name EIF2AK3), and activating transcription factor-6, control the UPR. The UPR signaling triggers a set of prodeath programs when the cells fail to successfully adapt to ER stress or restore homeostasis. ER stress and UPR signaling are implicated in the pathogenesis of diverse diseases, including neurodegeneration, cancer, diabetes, and inflammation. This review discusses the current understanding in both adaptive and apoptotic responses as well as the molecular mechanisms instigating apoptosis via IRE1 and PERK signaling. We also examine how IRE1 and PERK signaling may be differentially used during neurodegeneration arising in retinitis pigmentosa and prion infection.
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                Author and article information

                Journal
                Drug Des Devel Ther
                Drug Des Devel Ther
                Drug Design, Development and Therapy
                Drug Design, Development and Therapy
                Dove Medical Press
                1177-8881
                2019
                19 February 2019
                : 13
                : 707-718
                Affiliations
                [1 ]Department of Anesthesiology, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi, People’s Republic of China, jingchenliu@ 123456yeah.net
                [2 ]Department of Anesthesiology, Langdong Hospital of Guangxi Medical University, Nanning 530021, Guangxi, People’s Republic of China
                Author notes
                Correspondence: Jingchen Liu, Department of Anesthesiology, The First Affiliated Hospital of Guangxi Medical University, 22 Shuangyong Road, Nanning 530021, Guangxi, People’s Republic of China, Tel +86 077 1535 6250, Email jingchenliu@ 123456yeah.net
                Article
                dddt-13-707
                10.2147/DDDT.S192225
                6387603
                © 2019 Liu et al. This work is published and licensed by Dove Medical Press Limited

                The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

                Categories
                Original Research

                Pharmacology & Pharmaceutical medicine

                bupivacaine, gm1 ganglioside, ers, neurotoxicity

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