2-Allylphenol Reduces IL-1βand TNF-α, Promoting Antinociception through Adenosinergic, Anti-Inflammatory, and Antioxidant Mechanisms

Abstract

2-Allylphenol (2-AP) is a synthetic phenylpropanoid, structurally related to cardanol, thymol, and ortho-eugenol. Phenylpropanoids are described in the literature as being capable of promoting biological activity. Due to the similarity between 2-AP and other bioactive phenylpropanoids, the present research aims at evaluating the antioxidant, antinociceptive, and anti-inflammatory potential of 2-AP in silico, in vitro, and in vivo. At 30 min prior to the start of in vivo pharmacological testing, administration of 2-AP (25, 50, 75, and 100 mg/kg i.p.), morphine (6 mg/kg i.p.), dexamethasone (2 mg/kg s.c.), or vehicle alone was performed. In the acetic acid-induced abdominal writhing tests, pretreatment with 2-AP significantly reduced the number of abdominal writhes, as well as decreased licking times in the glutamate and formalin tests. Investigation of the mechanism of action using the formalin model led to the conclusion that the opioid system does not participate in its activity. However, the adenosinergic system is involved. In the peritonitis tests, 2-AP inhibited leukocyte migration and reduced releases of proinflammatory mediators TNF-α and IL-1β. In vitro antioxidant assays demonstrated that 2-AP presents significant ability to sequester superoxide radicals. In silico docking studies confirmed interaction between 2-AP and the adenosine A2a receptor through hydrogen bonds with the critical asparagine 253 residues present in the active site. Investigation of 2-AP demonstrated its nociception inhibition and ability to reduce reactive oxygen species. Its interaction with A2a receptors may well be related to proinflammatory cytokines TNF-α and IL-1β reduction activity, corroborating its antinociceptive effect.

A 9-aminoacridine derivative induces growth inhibition of Ehrlich ascites carcinoma cells and antinociceptive effect in mice

“…The second phase, related to local inflammation, is more continual and durable and involves the release of pro-inflammatory agents (TNF-α, interleukins, bradykinin, prostaglandins, and serotonin) ( Hunskaar and Hole, 1987 ; Silva et al, 2017 ; Andrade et al, 2020 ). In general, analgesic agents with central action inhibit both phases of the formalin test, such as opioid analgesics, while peripheral analgesic drugs suppress only the second phase ( Aragão Neto et al, 2019 ).…”

Novel derivatives of eugenol as potent anti-inflammatory agents via PPARγ agonism: rational design, synthesis, analysis, PPARγ protein binding assay and computational studies

“…Several studies have shown that eugenol inhibits pro-inflammatory mediators including interleukins IL-1β and IL-6, tumor necrosis factor-alpha (TNF-α) and prostaglandin E2 (PGE2), inducible expression of oxide nitric synthase (iNOS) and activation of cyclooxygenase-2 (COX-2), nuclear factor kappa B (NF-κB), leukotriene C4 and 5-lipoxygenase (5-LOX). 17–19 …”

“…Several studies have shown that eugenol inhibits pro-inammatory mediators including interleukins IL-1b and IL-6, tumor necrosis factoralpha (TNF-a) and prostaglandin E2 (PGE2), inducible expression of oxide nitric synthase (iNOS) and activation of cyclooxygenase-2 (COX-2), nuclear factor kappa B (NF-kB), leukotriene C4 and 5-lipoxygenase (5-LOX). [17][18][19] In this backdrop, we aimed at developing new eugenol derivatives to study their potential anti-inammatory activity. Therefore, we rationally designed eugenol based PPARg agonists, synthesized, puried, analyzed, screened for PPARg binding, and evaluated for in vitro anti-inammatory activity.…”

Computational analysis of eugenol inhibitory activity in lipoxygenase and cyclooxygenase pathways

“…According to the literature, eugenol can inhibit the generation of superoxide anion in neutrophils, by inhibiting the Raf/MEK/ERK1/2/p47phox-phosphorylation pathway 9 . In parallel, aliphenols such as eugenol have been reported as inhibitors of proinflammatory mediators such as, interleukins IL-1 β and IL-6, tumor necrosis factor alpha (TNF-α) and prostaglandin E2 (PGE2), inducible expression of oxide nitric synthase (iNOS) and expression of cyclooxygenase-2 (COX-2), nuclear factor kappa B (NF-κB), leukotriene C4 and 5-lipoxygenase (5-LOX) [9][10][11][12] .Numerous diseases such as osteoarthritis, Crohn's disease, colon cancer, breast cancer and prostate cancer are associated with the progression of chronic inflammation with activation of pro inflammatory mediators such as interleukins and intracellular enzymes such as COX and LOX [12][13][14][15][16][17][18][19][20][21][22] . The inflammatory process is associated with an increase in the production of prostaglandins.COX is the main enzyme in catalyzing the metabolic conversion of arachidonic acid to prostaglandins, which mediates homeostatic functions in different physiological systems [23][24][25] .…”

“…According to the literature, eugenol can inhibit the generation of superoxide anion in neutrophils, by inhibiting the Raf/MEK/ERK1/2/p47phox-phosphorylation pathway 9 . In parallel, aliphenols such as eugenol have been reported as inhibitors of proinflammatory mediators such as, interleukins IL-1 β and IL-6, tumor necrosis factor alpha (TNF-α) and prostaglandin E2 (PGE2), inducible expression of oxide nitric synthase (iNOS) and expression of cyclooxygenase-2 (COX-2), nuclear factor kappa B (NF-κB), leukotriene C4 and 5-lipoxygenase (5-LOX) [9][10][11][12] .…”