1. Academic Validation
  2. Dimethyl itaconate inhibits neuroinflammation to alleviate chronic pain in mice

Dimethyl itaconate inhibits neuroinflammation to alleviate chronic pain in mice

  • Neurochem Int. 2022 Mar;154:105296. doi: 10.1016/j.neuint.2022.105296.
Jinxuan Ren 1 Lina Yu 1 Jiaqi Lin 1 Longfei Ma 1 Dave Schwinn Gao 1 Na Sun 1 Ying Liu 1 Lili Fang 1 Zhenzhen Cheng 1 Kai Sun 1 Min Yan 2
Affiliations

Affiliations

  • 1 Department of Anesthesiology, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
  • 2 Department of Anesthesiology, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China. Electronic address: zryanmin@zju.edu.cn.
Abstract

The metabolite itaconate has both anti-inflammatory and immunomodulatory effects. However, its influence on chronic pain is unclear. Here, we demonstrated that intraperitoneal injection of the itaconate derivative dimethyl itaconate (DI) alleviated chronic pain symptoms, such as allodynia and hyperalgesia, in spinal nerve ligation (SNL) and inflammatory pain models. Moreover, intraperitoneal DI reduced the secretion of inflammatory cytokines (i.e., interleukin-1β, tumour necrosis factor-alpha) in dorsal root ganglion (DRG), spinal cord and hind paw tissues, suppressed the activation of macrophages in the DRG and glial cells in the spinal dorsal horn and decreased the phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2) in the DRG and spinal cord. DI boosted nuclear factor-erythroid 2 p45-related factor 2 (Nrf2) levels in the DRG and spinal cord of SNL mice. Intraperitoneal administration of the Nrf2 inhibitor ML385 abolished the analgesic effect of DI and decreased the expression of Nrf2 in the DRG and spinal cord. Similarly, administration of DI potently reversed the lipopolysaccharide (LPS)-induced inflammatory effect in microglia. Reduction of endogenous itaconate levels by pretreatment with immune-responsive gene 1 (IRG1) siRNA blocked Nrf2 expression, which impaired the analgesic and anti-inflammatory effects of DI in vitro. Therefore, our findings revealed for the first time that intraperitoneal DI elicited anti-inflammatory effect and sustained chronic pain relief, which may be regarded as a promising therapeutic agent for chronic pain treatment.

Keywords

Dimethyl itaconate; Inflammatory pain; Neuroinflammation; Neuropathic pain; Nuclear factor-erythroid 2 p45-related factor 2.

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