The Antinociceptive, Antioxidant and Anti-Inflammatory Effects of 5-Fluoro-2-Oxindole during Inflammatory Pain

Abstract

Recent studies demonstrate that 5-fluoro-2-oxindole inhibits neuropathic pain but the antinociceptive actions of this drug and its effects on the plasticity, oxidative and inflammatory changes induced by peripheral inflammation as well as on the effects and expression of µ-opioid receptors (MOR) have not been evaluated. In C57BL/6 male mice with inflammatory pain provoked by the subplantar administration of complete Freund’s adjuvant (CFA), we evaluated: (1) the antinociceptive actions of 5-fluoro-2-oxindole and its reversion with the HO-1 inhibitor, tin protoporphyrin IX (SnPP); (2) the effects of 5-fluoro-2-oxindole in the protein levels of mitogen-activated protein kinase (MAPK), Nrf2, NADPH quinone oxidoreductase1 (NQO1), heme oxygenase 1 (HO-1), oxidative stress marker (4-hydroxy-2-nonenal; 4-HNE), inducible nitric oxide synthase (NOS2), microglial markers (CD11b/c and IBA-1), and MOR in the spinal cord and/or paw of animals with inflammatory pain; (3) the antinociceptive effects of morphine in 5-fluoro-2-oxindole pre-treated animals. Treatment with 5 and 10 mg/kg of 5-fluoro-2-oxindole inhibited the allodynia and hyperalgesia induced by CFA in a different, time-dependent manner. These effects were reversed by SnPP. Treatment with 5-fluoro-2-oxindole increased the expression of NQO1, HO-1 and MOR and inhibited the CFA-induced upregulation of phosphorylated MAPK, 4-HNE, NOS2, CD11b/c and IBA-1 in spinal cords and/or paws. The local effects of morphine were improved with 5-fluoro-2-oxindole. This work reveals that 5-fluoro-2-oxindole inhibits the plasticity, oxidative and inflammatory responses provoked by peripheral inflammation and potentiates the antinociceptive effects of morphine. Thus, treatment with 5-fluoro-2-oxindole alone and/or combined with morphine are two remarkable new procedures for chronic inflammatory pain management.

Hydrogen Sulfide Inhibits Inflammatory Pain and Enhances the Analgesic Properties of Delta Opioid Receptors

“…Our results confirmed the oxidative stress induced by CFA in the paw, as previously demonstrated [ 39 ], with the increased expression of 4-HNE, an oxidative stress marker, in paw tissues. Interestingly, both treatments, DADS and P-ITC, normalized these increased levels of 4-HNE-positive proteins in this tissue, thus revealing the antioxidative properties of both compounds.…”

“…Interestingly, both treatments, DADS and P-ITC, normalized these increased levels of 4-HNE-positive proteins in this tissue, thus revealing the antioxidative properties of both compounds. In accordance with this finding, the administration of other antioxidants, such as oxindoles, also inhibited the high levels of 4-HNE-positive proteins in the paw of CFA-injected mice [39].…”

“…Interestingly, both treatments, DADS and P-ITC, normalized these increased levels of 4-HNE-positive proteins in this tissue, thus revealing the antioxidative properties of both compounds. In accordance with this finding, the administration of other antioxi-dants, such as oxindoles, also inhibited the high levels of 4-HNE-positive proteins in the paw of CFA-injected mice [39]. In accordance with Guo et al, (2020) [5], our results also demonstrated the reversion of the antiallodynic and antihyperalgesic effects induced by high doses of DADS and P-ITC after administrating selective Nrf2 (ML-385), HO-1 (SnPP), and NQO1 (dicoumarol) inhibitors.…”

[Et3NH][HSO4] catalyzed solvent‐free synthesis of new 1,2,3‐triazolidene‐indolinone derivatives

“…Also, the positional isomer of indigo dye, indirubin 11, [ 22 ] is well known in traditional Chinese medicine. The arylidene‐indolinone is found in many biologically active scaffolds with biological activities as calcium channel blockers, [ 23 ] β 3 adrenergic receptor agonist, [ 24 ] inhibitor of FGFR, [ 25 ] antiangiogenic, [ 26 ] anticancer, [ 27 ] analgesic properties, [28 ] and neuroprotective activities. [ 29 ]…”

“…ones pharmacophore in various medicaments of FGFR, [25] antiangiogenic, [26] anticancer, [27] analgesic properties, [28] and neuroprotective activities. [29] The arylidene-indolinones were prepared by using harsh conditions and/or toxic reagents, for example, organic bases such as piperidine.…”