Abstract
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.
Highlights
Gap junction-coupled cell networks can be targets when the body or different organs are exposed to inflammatory stimuli, such as bacteria or viruses [1,2]
We previously demonstrated that sildenafil attenuates adenosine triphosphate (ATP)-evoked intracellular Ca2+ release in LPS-induced inflammatory reactive astrocytes [28]
Our experiments revealed the necessity of a specific number of microglia to obtain reactive inflammatory astrocytes
Summary
The purpose of the present study was to attenuate inflammation-induced LPS effects on astrocytes to return the cells to a more physiological state with a drug combination that primarily affects 5-HT- and ATP-evoked Ca2+ signaling. The purpose of the present study was to reduce 5-HT-evoked Ca2+ signaling in astrocytes that were treated with LPS to induce inflammatory reactivity
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