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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


Autoři: Elisabeth Hansson aff001;  Eva Skiöldebrand aff002
Působiště autorů: Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden aff001;  Department of Pathology, Institute of Biomedical Sciences and Veterinary Public Health, Swedish University of Agricultural Sciences, Uppsala, Sweden aff002;  Department of Clinical Chemistry and Transfusion Medicine, Institute of Biomedicine, Sahlgrenska University Hospital, Gothenburg University, Gothenburg, Sweden aff003
Vyšlo v časopise: PLoS ONE 14(10)
Kategorie: Research Article
doi: https://doi.org/10.1371/journal.pone.0223648

Souhrn

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.

Klíčová slova:

Cytokines – Glucose – Glucose signaling – Immune receptor signaling – Inflammation – Toll-like receptors – Vitamins – Astrocytes


Zdroje

1. Hansson E, Skiöldebrand E. Coupled cell networks are target cells of inflammation, which can spread between different body organs and develop into systemic chronic inflammation. J Inflammation 2015; 12:44. doi: 10.1186/s12950-015-0091-2 26213498

2. Hansson E, Skiöldebrand E. Low-grade inflammation causes gap junction-coupled cell dysfunction throughout the body, which can lead to the spread of systemic inflammation. Scand J Pain 2019; (in press).

3. Abbott NJ, Rönnbäck L, Hansson E. Astrocyte-endothelial interactions at the blood-brain barrier. Nat Rev Neurosci 2006; 7: 41–53. doi: 10.1038/nrn1824 16371949

4. Verkhratsky A, Nedergaard M. Physiology of astroglia. Physiol Rev 2018; 98: 239–389, doi: 10.1152/physrev.00042.2016 29351512

5. Hansson E. Long-term pain, neuroinflammation and glial activation. Scand J Pain 2010; 1: 67–72. doi: 10.1016/j.sjpain.2010.01.002 29913949

6. Ikeda H, Kiritoshi T, Murase K. Contribution of microglia and astrocytes to the central sensitization, inflammatory and neuropathic pain in the juvenile rat. Mol Pain 2012; 8: 43. http://www.molecularpain.com/content/8/1/43. doi: 10.1186/1744-8069-8-43 22703840

7. Forshammar J, Block L, Lundborg C, Biber B, Hansson E. Naloxone and ouabain in ultra-low concentrations restore Na+/K+-ATPase and cytoskeleton in lipopolysaccharide-treated astrocytes. J Biol Chem 2011; 286: 31586–31597. doi: 10.1074/jbc.M111.247767 21757727

8. Block L, Björklund U, Westerlund A, Jörneberg P, Biber B, Hansson E. A new concept affecting restoration of inflammation-reactive astrocytes. Neuroscience 2013; 250: 536–545. doi: 10.1016/j.neuroscience.2013.07.033 23892009

9. Lacagnina MJ, Watkins LR, Grace PM. Toll-like receptors and their role in persistent pain. Pharmacol Ther 2017; http://doi.org/10.1016/j.pharmthera.2017.10.006.

10. Cotrina ML, Lin J H-C, López-García JC, Naus CCG, Nedergaard M. ATP-mediated glia signaling. J Neurosci 2000; 20: 2835–2844. 10751435

11. Beamer E, Kovács G, Sperlágh B. ATP released from astrocytes modulates action potential threshold and spontaneous excitatory postsynaptic currents in the neonatal rat prefrontal cortex. Brain Res Bull 2017; 135:129–142. doi: 10.1016/j.brainresbull.2017.10.006 29030320

12. Giaume C, Liu X. From a glial syncytium to a more restricted and specific glial networking. J Physiol 2012; 106: 34–39.

13. Chatton J-Y, Magistretti PJ, Barros LF. Sodium signaling and astrocyte energy metabolism. GLIA 2016; 64: 1667–1676. doi: 10.1002/glia.22971 27027636

14. Rönnbäck C, Hansson E. Gap junction coupled cells, barriers and systemic inflammation. Int J Open Access Ophthalmol 2017; 2(1): 7.

15. Rönnbäck C, Hansson E. The importance and control of low-grade inflammation due to damage of cellular barrier systems that may lead to systemic inflammation. Front Neurol 2019; https://doi.org/10.3389/fneur.2019.00533.

16. Toda S, Sakaim A, Ikeda Y, Sakamoto A, Suzuki H. A local anesthetic, ropivacaine, suppresses activated microglia via a nerve growth factor-dependent mechanism and astrocytes via a nerve growth factor-independent mechanism in neuropathic pain. Mol Pain 2011; 7:1–11. doi: 10.1186/1744-8069-7-1

17. Block L, Jörneberg P, Björklund U, Westerlund A, Biber B, Hansson E. Ultralow concentrations of bupivacaine exert anti-inflammatory effects on inflammation-reactive astrocytes. Eur J Neurosci 2013; 38: 3669–3678. doi: 10.1111/ejn.12364 24083665

18. Zhang J, Deng X. Bupivacaine effectively relieves inflammation-induced pain by suppressing activation of the NF-қB signaling pathway and inhibiting the activation of spinal microglia and astrocytes. Exp Ther Med 2017; 13: 1074–1080. doi: 10.3892/etm.2017.4058 28450945

19. Thakur KK, Saini J, Mahajan K, Singh D, Jayswal DP, Mishra S, et al. Therapeutic implications of toll-like receptors in peripheral neuropathic pain. Pharmacol Res 2017; 115: 224–232. doi: 10.1016/j.phrs.2016.11.019 27894923

20. DeLuca GC, Kimball SM, Kolasinski J, Ramagopalan SV, Ebers GC. Review: The role of vitamin D in nervous system health and disease. Neuropath Appl Neurobiol 2013; 39: 458–484.

21. Jo WK, Zhang Y, Emrich HM, Dietrich DE. Glia in the cytokine-mediated onset of depression: fine tuning the immune response. Front Cell Neurosci 2015; 9: doi: 10.3389/fncel.2015.00268 26217190

22. Jiao K-P, Li S-M, Lv W-Y, Jv M-L, He H-Y. Vitamin D3 repressed astrocyte activation following lipopolysaccharide stimulation in vitro and in neonatal rats. NeuroReport 2017; 28: 492–497. doi: 10.1097/WNR.0000000000000782 28430709

23. Enkhjargal B, McBride DW, Manaenko A, Reis C, Sakai Y, Tang J, et al. Intranasal administration of vitamin D attenuates blood-brain barrier disruption through endogenous upregulation of osteopontin and activation of CD44/P-gp glycosylation signaling after subarachnoid hemorrhage in rats. J Cereb Blood Flow Metab 2017; 37: 2555–2566. doi: 10.1177/0271678X16671147 27671249

24. Shim S, Shuman M, Duncan E. An emerging role of cGMP in the treatment of schizophrenia: A review. Schozphrenia Res 2016; 170: 226–231.

25. Peixoto CA, Gomes FOS. The role of phosphodiesterase-5 inhibitors in prostatic inflammation: a review. J Inflammation 2015; 12: 54. doi: 10.1186/s12950-015-0099-7 26379476

26. Rapôso C, Luna RLA, Nunes AKS, Thomé R, Peixoto CA. Role of iNOS-NO-cGMP signaling in modulation of inflammatory and myelination processes. Brain Res Bull 2014; 104: 60–73. doi: 10.1016/j.brainresbull.2014.04.002 24727400

27. Peixoto CA, Nunes AKS, Garcia-Osta A (2015) Phosphodiesterase-5 inhibitors: Action on the signaling pathways of neuroinflammation, neurodegeneration, and cognition. Med Inflammation ID 940207,http://dx.doi.org/10.1155/2015/940207.

28. Nunes AKS, Rapôso C, Björklund U, Cruz-Höfling MA, Peixoto CA, Hansson E. Sildenafil (Viagra) prevents and restores LPS-induced inflammation in astrocytes. Neurosci Lett 2016; 630: 59–65. doi: 10.1016/j.neulet.2016.07.029 27466020

29. Hansson E, Björklund U, Skiöldebrand E, Rönnbäck L. Anti-inflammatory effects induced by pharmaceutical substances on inflammatory active brain astrocytes–promising treatment of neuroinflammation. J Neuroinflam 2018; 15: 321–333.

30. Rotter Sopasakis V, Wickelgren R, Sukonina V, Brantsing C, Svala E, Hansson E, et al. Elevated glucose levels preserve glucose uptake, hyaluronan production and low glutamate release following IL-1β stimulation of differentiated chondrocytes. Cartilage 2018; 1–13. doi: 10.1177/ǀ9476035ǀ8770256

31. Li F, Zhang A, Shi Y, Ma Y, Du Y. 1α,25-Dihydroxyvitamin D3 prevents the differentiation of human lung fibroblasts via microRNA-27b targeting the vitamin D receptor. Int J Mol Med 2015; 36: 967–974. doi: 10.3892/ijmm.2015.2318 26311239

32. Berridge MJ. Inositol trisphosphate and calcium oscillations. Biochem Soc Symp 2007; 74:1–7.

33. Lowry OH, Rosebrough NJ, Farr AL, Randall RJ. Protein measurement with the Folin phenol reagent. J Biol Chem 1951; 193, 265–275. 14907713

34. Persson M, Brantefjord M, Hansson E, Rönnbäck L. Lipopolysaccharide increases microglial GLT-1 expression and glutamate uptake capacity in vitro by a mechanism dependent on TNF-α. GLIA 2005; 51: 111–120. doi: 10.1002/glia.20191 15789431

35. Watkins LR, Maier SF. Glia: A novel drug discovery target for clinical pain. Nat Rev Drug Discov 2003; 2: 973–985. doi: 10.1038/nrd1251 14654796

36. Watkins LR, Maier SF. Immune regulation of central nervous system functions: from sickness responses to pathological pain. J Int Med 2005; 257: 139–155.

37. Hansson E. Could chronic pain and spread of pain sensation be induced and maintained by glial activation? Acta Physiol 2006; 187: 321–327.

38. Hansson E, Werner T, Björklund U, Skiöldebrand E. Therapeutic innovation: inflammatory-reactive astrocytes as targets of inflammation. IBRO Reports 2016; 1: 1–9. doi: 10.1016/j.ibror.2016.06.001 30135924

39. Block L, Lundborg C, Bjersing J, Dahm P, Hansson E, Biber B. Ultralow dose of naloxone as an adjuvant to intrathecal morphine infusion improves perceived quality of sleep but fails to alter persistent pain. A randomized, double-blind, controlled study. Clin J Pain 2015; 31: 968–975. doi: 10.1097/AJP.0000000000000200 25629634

40. Nunes AKS, Rapôso C, Rocha SWS, de Sousa Barbosa KP, de Almeida RL, da Cruz-Höfling MA, et al. Involvement of AMP, IKβα-NFқB and eNOS in the sildenafil anti-inflammatory mechanism in a demyelination model. Brain Res 2015; 162: 119–133.

41. Hansson E, Westerlund A, Björklund U, Olsson T. μ-Opioid agonists inhibit the enhanced intracellular Ca2+ responses in inflammatory activated astrocytes co-cultured with brain endothelial cells. Neuroscience 2008; 155: 1237–1249. doi: 10.1016/j.neuroscience.2008.04.027 18692967

42. Hildebrand KR, Elsberry DD, Deer TR. Stability, compatibility, and safety of intrathecal bupivacaine administered chronically via an imputable delivery system. Clin J Pain 2001; 17: 239–244. 11587115

43. Vardjan N, Zorec R. Excitable astrocytes: Ca2+- and cAMP-regulated exocytosis. Neurochem Res 2015; 40: 2414–2424. doi: 10.1007/s11064-015-1545-x 25732760

44. Borán MS, Garcia A. The cyclic GMP-protein kinase G pathway regulates cytoskeleton dynamics and motility in astrocytes. J Neurochem 2007; 102: 216–230. doi: 10.1111/j.1471-4159.2007.04464.x 17564679

45. Adamczak DM. The role of toll-like receptors and vitamin D in cardiovascular diseases–a review. Int J Molec Sci 2017; 18: 2252. doi: 10.3390/ijms18112252 29077004

46. Haussler MR, Whitfield GK, Kaneko I, Haussler CA, Hsieh D, Hsieh J-C, et al. Molecular mechanisms of vitamin D action. Calcif Tissue Int 2013; 92: 77–98. doi: 10.1007/s00223-012-9619-0 22782502


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