3,5-Dicaffeoylquinic acid attenuates microglial activation-mediated inflammatory pain by enhancing autophagy through the suppression of MCP3/JAK2/STAT3 signaling

• Published in: Biomedicine & pharmacotherapy Vol. 153; p. 113549
• Main Authors: Park, Joon, Kim, Yongeun, Lee, Changho, Kim, Yun Tai
• Format: Journal Article
• Language: English
• Published: Elsevier Masson SAS 01.09.2022; Elsevier
• Subjects: 3,5-dicaffeoylquinic acid; Inflammatory pain; Microglia; Monocyte chemotactic protein 3; Neuroinflammation; Neuroinflammation; 3,5-dicaffeoylquinic acid; Inflammatory pain; Monocyte chemotactic protein 3; Microglia
• ISSN: 0753-3322; 1950-6007
• DOI: 10.1016/j.biopha.2022.113549

Microglial activation in the spinal cord contributes to the development of inflammatory pain. Monocyte chemotactic protein 3 (MCP3) can induce microglial activation, resulting in increased pain sensitivity; however, the underlying mechanism remains poorly understood. 3,5-dicaffeoylquinic acid (3,5-DCQA) has shown protective effects against inflammation-related diseases, but the effect of 3,5-DCQA on microglial activation and inflammatory pain is not evaluated. This study aimed to investigate the effects of 3,5-DCQA on microglial activation-induced inflammatory pain. Furthermore, the underlying mechanism inhibited by 3,5-DCQA via MCP3 suppression was studied. To induce microglial activation, LPS was treated in BV2 microglial cells. The LPS-induced microglial activation and pro-inflammatory cytokines production were significantly reduced by 3,5-DCQA treatment in BV2 cells. Moreover, 3,5-DCQA suppressed LPS-induced MCP3 expression, resulting in reduced phosphorylation of JAK2/STAT3. Interestingly, the suppressed JAK2/STAT3 signaling enhanced autophagy induction in BV2 cells. The increased autophagy by 3,5-DCQA and knockout of MCP3 inhibited LPS-induced inflammatory response in BV2 cells. To establish the inflammatory pain, CFA was injected into the right paw of mice. The CFA-induced pain hypersensitivity and foot swelling were attenuated by the oral administration of 3,5-DCQA. Moreover, CFA-induced microglial activation was reduced and the autophagy markers were recovered in the spinal cord of 3,5-DCQA-administered mice. Similar results were observed in cultured primary microglia. Our findings indicate that 3,5-DCQA attenuates inflammation-mediated pain hypersensitivity by enhancing autophagy through inhibition of MCP3-induced JAK2/STAT3 signaling. Therefore, 3,5-DCQA could be a potential therapeutic agent for alleviating inflammatory pain. [Display omitted] •3,5-DCQA significantly inhibited LPS-induced microglial activation in microglia.•3,5-DCQA prevented LPS-induced MCP3, resulting in suppressed JAK2/STAT3 signaling.•The suppressed STAT3 recovered LPS-induced disruption of autophagy in microglia.•Oral administration of 3,5-DCQA attenuated CFA-induced pain hypersensitivity.