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Anti-inflammatory effects induced by pharmaceutical substances on inflammatory active brain astrocytespromising treatment of neuroinflammation

Hansson, Elisabeth and Björklund, Ulrika and Skiöldebrand, Eva and Rönnbäck, Lars (2018). Anti-inflammatory effects induced by pharmaceutical substances on inflammatory active brain astrocytespromising treatment of neuroinflammation. Journal of Neuroinflammation. 15, 1-13
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Official URL: http://doi.org/10.1186/s12974-018-1361-8

Abstract

Background: Pharmaceutical treatment with probable anti-inflammatory substances that attack cells in various ways including receptors, ion channels, or transporter systems may slow down the progression of inflammatory conditions. Astrocytes and microglia are the most prominent target cells for inflammation in the central nervous system. Their responses upon inflammatory stimuli work through the NO/cyclic GMP/protein kinase G systems that can downregulate the ATP-induced Ca2+ signaling, as well as G protein activities which alter Na+ transporters including Na+/K+-ATPase pump activity, Toll-like receptor 4 (TLR4), glutamate-induced Ca2+ signaling, and release of pro-inflammatory cytokines. The rationale for this project was to investigate a combination of pharmaceutical substances influencing the NO and the G(i)/G(s) activations of inflammatory reactive cells in order to make the cells return into a more physiological state. The ATP-evoked Ca2+ signaling is important maybe due to increased ATP release and subsequent activation of purinergic receptors. A balance between intercellular Ca2+ signaling through gap junctions and extracellular signaling mediated by extracellular ATP may be important for physiological function.

Methods: Astrocytes in primary cultures were incubated with lipopolysaccharide in a physiological glucose concentration for 24h to induce inflammatory reactivity. The probable anti-inflammatory substances sildenafil and 1,25-Dihydroxyvitamin D3 together with endomorphin-1, naloxone, and levetiracetam, were used in the presence of high glucose concentration in the medium to restore the cells. Glutamate-, 5-HT-, and ATP-evoked intracellular Ca2+ release, Na+/K+-ATPase expression, expression of inflammatory receptors, and release of tumor necrosis factor alpha were measured.

Results: Sildenafil in ultralow concentration together with 1,25-Dihydroxyvitamin D3 showed most prominent effects on the ATP-evoked intracellular Ca2+ release. The -opioid agonist endomorphin-1, the -opioid antagonist naloxone in ultralow concentration, and the antiepileptic agent levetiracetam downregulated the glutamate-evoked intracellular Ca2+ release and TLR4. The combination of the pharmaceutical substances in high glucose concentration downregulated the glutamate- and ATP-evoked Ca2+ signaling and the TLR4 expression and upregulated the Na+/K+-ATPase pump.

Conclusion: Pharmaceutical treatment with the combination of substances that have potential anti-inflammatory effects, which attack different biochemical mechanisms in the cells may exert decisive effects to downregulate neuroinflammation in the nervous system.

Authors/Creators:Hansson, Elisabeth and Björklund, Ulrika and Skiöldebrand, Eva and Rönnbäck, Lars
Title:Anti-inflammatory effects induced by pharmaceutical substances on inflammatory active brain astrocytespromising treatment of neuroinflammation
Year of publishing :2018
Volume:15
Page range:1-13
Number of Pages:13
Publisher:Springer Nature
ISSN:1742-2094
Language:English
Publication Type:Journal article
Refereed:Yes
Article category:Scientific peer reviewed
Version:Published version
Full Text Status:Public
Subjects:(A) Swedish standard research categories 2011 > 3 Medical and Health Sciences > 301 Basic Medicine > Pharmaceutical Sciences
(A) Swedish standard research categories 2011 > 3 Medical and Health Sciences > 301 Basic Medicine > Neurosciences
Keywords:Gap junction-coupled cells, Astrocytes, Inflammation, Restoration, Ca2+ signaling, Na+, K+-ATPase, TLR4, Glucose, Pharmaceuticals
URN:NBN:urn:nbn:se:slu:epsilon-p-97189
Permanent URL:
http://urn.kb.se/resolve?urn=urn:nbn:se:slu:epsilon-p-97189
Additional ID:
Type of IDID
DOI10.1186/s12974-018-1361-8
Web of Science (WoS)000450469200001
ID Code:16083
Faculty:VH - Faculty of Veterinary Medicine and Animal Science
Department:(VH) > Dept. of Biomedical Sciences and Veterinary Public Health
Deposited By: SLUpub Connector
Deposited On:13 May 2019 07:37
Metadata Last Modified:13 May 2019 07:37

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