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

Hanssoń, Elisabeth; Skiöldebrand, Eva

doi:10.1371/journal.pone.0223648

Cited by 3 publications

(2 citation statements)

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“…The reduced glucose uptake found in OA chondrocytes compared to control chondrocytes ( Rotter Sopasakis et al., 2019 ) was restored by incubation of the cells with metformin along with the different drug combinations. This is in accordance with a previous study in astrocytes in which the combination of these drugs restored elevated 5-HT- and ATP-evoked intracellular Ca 2+ signaling through gap junctions ( Hansson and Skiöldebrand, 2019a ). Bupivacaine (1 pM) was shown to attenuate 5-HT-evoked intracellular Ca 2+ release in gap junction-coupled astrocytes ( Block et al., 2013 ), and sildenafil (1 μM) also attenuated ATP-evoked intracellular Ca 2+ release in these cells ( S Nunes et al., 2016 ).…”

Section: Discussionsupporting

confidence: 93%

“…An enhanced extracellular ATP concentration has been observed in inflammatory diseases ( Beamer et al., 2017 ). We also observed increased ATP-evoked Ca 2+ signaling in inflammatory-induced chondrocytes ( Skiöldebrand et al., 2018 ) as well as inflammatory-induced astrocytes ( Hansson and Skiöldebrand, 2019a ), and we hypothesized that ATP-evoked Ca 2+ signaling could be decreased to the physiological level.…”

Section: Discussionmentioning

confidence: 99%

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Bupivacaine in combination with sildenafil (Viagra) and vitamin D3 have anti-inflammatory effects in osteoarthritic chondrocytes

Hanssoń

Skiöldebrand

2021

Current Research in Pharmacology and Drug Discovery

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Aims To treat osteoarthritic chondrocytes and thereby reduce the inflammation with a drug combination that primarily affects 5-HT- and ATP-evoked Ca 2+ signaling. In osteoarthritic chondrocytes, Ca 2+ signaling is elevated, resulting in increased production of ATP and inflammatory mediators. The expression of TLR4 and Na + /K + -ATPase was used to evaluate the inflammatory status of the cells. Main methods Equine chondrocytes were collected from joints with mild structural osteoarthritic changes and cultured in monolayers. The cells were treated with a combination of bupivacaine (1 pM) and sildenafil (1 μM) in combination with vitamin D3 (100 nM). A high-throughput screening system, the Flexstation 3 microplate reader, was used to measure intra- and extracellular Ca 2+ signaling after exposure to 5-HT, glutamate, or ATP. Expression of inflammatory receptors was assessed by Western blotting. Key findings Drug treatment substantially reduced 5-HT- and ATP-evoked intracellular Ca 2+ release and TLR4 expression compared to those in untreated chondrocytes. The combination of sildenafil, vitamin D3 together with metformin, as the ability to take up glucose is limited, increased Na + /K + -ATPase expression. Significance The combination of these three therapeutic substances at concentrations much lower than usually used, reduced expression of the inflammatory receptor TLR4 and increased the cell membrane enzyme Na + /K + -ATPase, which regulates cell volume and reduces increased intracellular Ca 2+ concentrations. These remarkable results indicate that this drug combination has disease-modifying osteoarthritis drug (DMOAD) properties and may be a new clinical therapy for osteoarthritis (OA).

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