Vol.:(0123456789) 1 3 Infammation Research (2020) 69:1257–1270 https://doi.org/10.1007/s00011-020-01407-0 ORIGINAL RESEARCH PAPER Methyl gallate attenuates infammation induced by Toll‑like receptor ligands by inhibiting MAPK and NF‑Κb signaling pathways Luana Barbosa Correa 1,2  · Leonardo Noboru Seito 1,2  · Marília F. Manchope 3  · Waldiceu A. Verri Jr 3  · Thiago Mattar Cunha 4  · Maria G. Henriques 1,2  · Elaine Cruz Rosas 1,2 Received: 18 February 2020 / Revised: 20 July 2020 / Accepted: 1 October 2020 / Published online: 9 October 2020 © Springer Nature Switzerland AG 2020 Abstract Objective and design Methyl gallate (MG) is a prevalent polyphenol in the plant kingdom, which may be related to the efects of several medicinal plants. Although it is widely reported that polyphenols have therapeutic efects, there are few studies demonstrating that MG has anti-infammatory action. This study aimed to investigate the molecular mechanism behind the anti-infammatory activity of MG and its efect on hyperalgesia. Methods Swiss mice were pretreated orally with diferent doses of MG and subjected to i.pl. injection of zymosan to induce paw edema. RAW264.7 macrophages and BMDMs stimulated with diferent TLR agonists such as zymosan, LPS, or Pam3CSK 4 were used to investigate the molecular mechanisms of MG Results MG inhibits zymosan-induced paw edema and hyperalgesia and modulates molecular pathways crucial for infamma- tion development. Pretreatment with MG inhibited cytokines production and NF-κB activity by RAW 264.7 cells stimulated with zymosan, Pam3CSK 4 or LPS, but not with PMA. Moreover, pretreatment with MG decreased IκB degradation, nuclear translocation of NF-κBp65, c-jun and c-fos and ERK1/2, p38 and JNK phosphorylation. Conclusion Thus, the results of this study demonstrate that MG has a promising anti-infammatory efect and suggests an explanation of its mechanism of action through the inhibition of NF-κB signaling and the MAPK pathway. Keywords Methyl gallate · Polyphenols · Hyperalgesia · Tlrs · NF-κB signaling · MAPKs quinases Introduction Arthritis conditions comprise over 100 diseases and syn- dromes, which are usually progressive and associated with pain and edema. Among them, osteoarthritis (OA) and rheu- matoid arthritis (RA) are the most common pathologies with important infammatory components, which can lead to tis- sue injury. Damage-associated molecular patterns (DAMPs) are released from these injuries and operate as endogenous signals to activate TLRs amplifying the infammatory pro- cess [1]. Furthermore, the activation of TLR signaling plays a signifcant role in initiating and maintaining pain [2–4]. In this context, targeting TLRs may provide a pharmacological tool to develop novel therapies for managing pathological infammation and pain. Polyphenols are secondary metabolites of plants with a broad range of therapeutic efects due to their potent anti- oxidant, immunomodulatory, and anti-infammatory actions with a potential role in diferent oxidative stress-induced complications, such as cardiovascular disease, cancer, and Inflammation Research Responsible Editor: M. Teixeira Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00011-020-01407-0) contains supplementary material, which is available to authorized users. * Maria G. Henriques mariahenriques.focruz@gmail.com * Elaine Cruz Rosas elaine.rosas@far.focruz.br 1 Laboratory of Applied Pharmacology, Farmanguinhos, Oswaldo Cruz Foundation, Rio de Janeiro, RJ, Brazil 2 National Institute for Science and Technology on Innovation on Diseases of Neglected Populations (INCT/IDPN), Oswaldo Cruz Foundation, Rio de Janeiro, Brazil 3 Department of Pathology, Center for Biological Sciences, State University of Londrina, Paraná, Brazil 4 Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, São Paulo, Brazil