Anti-inflammatory Properties of Sodium Salicylate: Effects on Intracellular Signaling Pathways and Other Non-Cyclooxygenase Effects

General Description

Sodium salicylate exerts its anti-inflammatory effects through multiple mechanisms. It interferes with kinases, particularly the MAPK cascade, and inhibits several nuclear transcription factors, including NF-nB. The expression of cyclooxygenase-2 is complex, with conflicting results suggesting both inhibitory and stimulatory effects. However, sodium salicylate's ability to induce the release of adenosine is believed to contribute significantly to its anti-inflammatory properties. Adenosine possesses potent anti-inflammatory properties and regulates immune responses. By increasing extracellular adenosine levels, sodium salicylate modulates inflammatory processes. Further research is needed to fully understand the precise mechanisms involved.

Figure 1. Sodium salicylate

Kinases and transcription factors

Sodium salicylate has significant effects on kinases and transcription factors, particularly in the context of inflammatory responses. High concentrations of salicylates have been found to interfere with kinases, such as the mitogen activated protein-kinases (MAPK) cascade, with reported inhibitory effects, except for the activation of p38 MAPK in certain studies. This interference with kinases may contribute to the observed inhibitory effects of salicylates on several nuclear transcription factors. One of the key focuses of research has been the interaction between salicylates and nuclear transcription factor kappa B (NF-nB), which plays a crucial role in cellular response to inflammatory stimuli. NF-nB regulates gene transcription by binding to DNA target sites and is involved in the activation of pro-inflammatory enzymes, cytokines, chemokines, and cell adhesion molecules. Studies have shown that aspirin and salicylate inhibit the NF-nB pathway, contradicting the hypothesis of NF-nB-mediated anti-inflammatory action of salicylate. Additionally, studies suggest that the pharmacological actions of aspirin and salicylates are mediated by inhibiting CCAA T/enhancer –binding protein binding and transactivation. These findings highlight the complex and multifaceted effects of sodium salicylate on kinases and transcription factors, particularly in the context of inflammation. ¹

Expression of cyclooxygenase-2

Sodium salicylate has been the subject of conflicting research regarding its effects on the expression of cyclooxygenase-2. While some studies have suggested that salicylate can inhibit the expression of cyclooxygenase in isolated cells, the majority of research has found no such inhibitory effects. Interestingly, a recent study has shown that sodium salicylate, at concentrations capable of interfering with the nuclear translocation of the transcription factor NF-nB, can actually enhance the expression of cyclooxygenase-2 protein in endotoxin-treated human peripheral blood mononuclear cells. This effect was also observed with aspirin but not with other NSAIDs. Furthermore, it has been reported that NSAIDs can stimulate cyclooxygenase-2 expression through the activation of peroxisome proliferator-activated receptors (PPARs), a mechanism that does not apply to the increase observed with salicylates, as they do not activate PPARs. One possible explanation for this paradoxical stimulation of cyclooxygenase-2 by salicylates is the activation of p38 MAPK, which is required for the transcription and stabilization of cyclooxygenase-2 mRNA. Additionally, the activation of p38 MAPK by salicylate has also been linked to enhancing cytokine-induced expression of inducible nitric oxide synthase, suggesting potential implications for inflammatory responses in infectious diseases. ¹

Release of adenosine

Research has indicated that sodium salicylate's effects on the release of adenosine may play a significant role in its anti-inflammatory properties. In a study conducted on p105 deficient mice, results were consistent with the hypothesis that a substantial portion of the anti-inflammatory effect of salicylates is mediated through an adenosine-dependent mechanism. It has been proposed that salicylates disrupt oxidative phosphorylation, leading to a decrease in intracellular ATP formation. As a consequence, this disruption triggers the release of adenosine into extracellular fluids in quantities that are significant enough to exert anti-inflammatory effects. This suggests that sodium salicylate's anti-inflammatory properties may be attributed not only to its direct effects on cyclooxygenase-2 expression but also to its ability to induce the release of adenosine. Adenosine is known to possess potent anti-inflammatory properties and can regulate immune responses. By increasing the availability of extracellular adenosine, sodium salicylate may contribute to the modulation of inflammatory processes. Further research is needed to fully elucidate the precise mechanisms by which sodium salicylate affects the release of adenosine and its subsequent anti-inflammatory effects. ²

Reference

1. Amann R, Peskar BA. Anti-inflammatory effects of aspirin and sodium salicylate. Eur J Pharmacol. 2002;447(1):1-9.

2. Cronstein BN, Van de Stouwe M, Druska L, Levin RI, Weissmann G. Nonsteroidal antiinflammatory agents inhibit stimulated neutrophil adhesion to endothelium: adenosine dependent and independent mechanisms. Inflammation. 1994;18(3):323-335.

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