Electrochemical evidence of nitrate release from the nitrooxy compound 4-((nitrooxy) methyl)-3-nitrobenzoic acid and its antinociceptive and anti-inflammatory activities in mice

[Display omitted] •Nitrooxy compound 1 (NC1) potentially releases nitric oxide.•Plasma nitrite concentration was increased after administration of NC1.•NC1 inhibited the tactile hypersensitivity and paw edema in mice.•NC1 reduced neutrophil recruitment and IL-6, IL-1β, TNF-α and CXCL-1 concentration...

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Published in:	Biomedicine & pharmacotherapy Vol. 133; p. 110913
Main Authors:	Braga, Alysson Vinícius, da Silva, Roger Ryuler Lisboa, Rodrigues, Ianny Bandeira, Marques, Gabriel Vitor de Lima, Xavier, Andre Felippe de Almeida, Boane, Anastacio, Paiva, Mayara Rodrigues Brandão de, Franco, Pedro Henrique Cavalcanti, Rodrigues, Felipe Fernandes, Melo, Ivo Souza Ferraz, Silva Cunha Júnior, Armando da, César, Isabela da Costa, Goulart, Marília Oliveira Fonseca, Oliveira, Renata Barbosa de, Coelho, Márcio de Matos, Machado, Renes Resende
Format:	Journal Article
Language:	English
Published:	France Elsevier Masson SAS 01-01-2021 Elsevier
Subjects:	4-((Nitrooxy) methyl)-3-nitrobenzoic acid Analgesics - blood Analgesics - pharmacology Animals Anti-Inflammatory Agents - blood Anti-Inflammatory Agents - pharmacology Carrageenan Cytokines Cytokines - blood Disease Models, Animal Electrochemistry Female Hot Temperature Inflammation Inflammation - blood Inflammation - chemically induced Inflammation - prevention & control Inflammation Mediators - blood Mice Nitrate Nitrates - blood Nitric oxide Nitric Oxide Donors - blood Nitric Oxide Donors - pharmacology Nociceptive Pain - blood Nociceptive Pain - etiology Nociceptive Pain - physiopathology Nociceptive Pain - prevention & control Pain Pain Threshold - drug effects 4-((Nitrooxy) methyl)-3-nitrobenzoic acid Inflammation Nitrate Pain Cytokines Nitric oxide
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Summary:	[Display omitted] •Nitrooxy compound 1 (NC1) potentially releases nitric oxide.•Plasma nitrite concentration was increased after administration of NC1.•NC1 inhibited the tactile hypersensitivity and paw edema in mice.•NC1 reduced neutrophil recruitment and IL-6, IL-1β, TNF-α and CXCL-1 concentrations.•NC1 increased the production of IL-10. Considering the many biological activities of nitric oxide (NO), some lines of research focused on the modulation of these activities through the provision of this mediator by designing and synthesizing compounds coupled with an NO donor group. Thus, the objectives of the present study were to carry out an electrochemical investigation of the nitrooxy compound 4-((nitrooxy) methyl)-3-nitrobenzoic acid (1) and evaluate its activities and putative mechanisms in experimental models of pain and inflammation. Voltammetric studies performed in aprotic medium (mimetic of membranes) showed important electrochemical reduction mechanisms: nitroaromatic reduction, self-protonation, and finally reductive elimination, which leads to nitrate release. Systemic administration of the nitrooxy compound (1) inhibited the nociceptive response induced by heat and the tactile hypersensitivity and paw edema induced by carrageenan in mice. The activities in the models of inflammatory pain and edema were associated with reduced neutrophil recruitment and production of inflammatory cytokines, such as interleukin (IL)-1β, IL-6, tumor necrosis factor-α and CXCL-1, and increased production of IL-10. Concluding, electrochemical analysis revealed unequivocally that electron transfer at the nitro group of the nitrooxy compound (1) results in the cleavage of the organic nitrate, potentially resulting in the generation of NO. This electrochemical mechanism may be compared to a biochemical electron-transfer mediated nitrate release that, by appropriate in vivo bioreduction (enzymatic or not) would lead to NO production. Compound (1) exhibits activities in models of inflammatory pain and edema that may be due to reduced recruitment of neutrophils and production of inflammatory cytokines and increased production of IL-10. These results reinforce the interest in the investigation of NO donor compounds as candidates for analgesic and anti-inflammatory drugs.
ISSN:	0753-3322 1950-6007
DOI:	10.1016/j.biopha.2020.110913