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Anti-inflammatory effects induced by ultralow concentrations of bupivacaine in combination with ultralow concentrations of sildenafil (Viagra) and vitamin D3 on inflammatory reactive brain astrocytes

Journal article
Authors Elisabeth Hansson
Eva Skiöldebrand
Published in PLoS ONE
Volume 14
Issue 10
ISSN 1932-6203
Publication year 2019
Published at Institute of Biomedicine
Institute of Neuroscience and Physiology, Department of Clinical Neuroscience
Language en
Keywords adenosine triphosphate, bupivacaine, colecalciferol, glutamic acid, neurokinin 1 receptor, serotonin, sildenafil, toll like receptor 4, animal tissue, antiinflammatory activity, Article, astrocyte, calcium cell level, calcium signaling, calcium transport, controlled study, cytokine release, down regulation, immunocytochemistry, newborn, nonhuman, polyacrylamide gel electrophoresis, protein expression, rat, Western blotting
Subject categories Rheumatology and Autoimmunity, Neurosciences


Network coupled cells, such as astrocytes, regulate their cellular homeostasis via Ca2+ signals spread between the cells through gap junctions. Intracellular Ca2+ release is controlled by different signaling pathways that can be stimulated by ATP, glutamate and serotonin (5-HT). Based on our findings, all these pathways are influenced by inflammatory agents and must be restored to fully recover the Ca2+ signaling network. An ultralow concentration of the local anesthetic agent bupivacaine reduced 5-HT-evoked intracellular Ca2+ release, and an ultralow concentration of the phosphodiesterase-5 inhibitor sildenafil in combination with vitamin D3 reduced ATP-evoked intracellular Ca2+ release. Combinations of these three substances downregulated 5-HT-, glutamate- and ATP-evoked intracellular Ca2+ release to a more normal Ca2+ signaling state. Furthermore, inflammatory Toll-like receptor 4 expression decreased with a combination of these three substances. Substance P receptor neurokinin (NK)-1 expression was reduced by ultralow concentrations of bupivacaine. Here, bupivacaine and sildenafil (at extremely low concentrations) combined with vitamin D3 have potential anti-inflammatory properties. According to the present study, drug combinations at the right concentrations, especially extremely low concentrations of bupivacaine and sildenafil, affect different cellular biochemical mechanisms and represent a potential solution for downregulating inflammatory parameters, thereby restoring cells or networks to normal physiological homeostasis. © 2019 Hansson, Skiöldebrand. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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