PMID- 35121012
OWN - NLM
STAT- MEDLINE
DCOM- 20220407
LR  - 20220407
IS  - 1872-9754 (Electronic)
IS  - 0197-0186 (Linking)
VI  - 154
DP  - 2022 Mar
TI  - Dimethyl itaconate inhibits neuroinflammation to alleviate chronic pain in mice.
PG  - 105296
LID - S0197-0186(22)00021-3 [pii]
LID - 10.1016/j.neuint.2022.105296 [doi]
AB  - 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-1beta, 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.
CI  - Copyright (c) 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.
FAU - Ren, Jinxuan
AU  - Ren J
AD  - Department of Anesthesiology, Second Affiliated Hospital, School of Medicine, 
      Zhejiang University, Hangzhou, China.
FAU - Yu, Lina
AU  - Yu L
AD  - Department of Anesthesiology, Second Affiliated Hospital, School of Medicine, 
      Zhejiang University, Hangzhou, China.
FAU - Lin, Jiaqi
AU  - Lin J
AD  - Department of Anesthesiology, Second Affiliated Hospital, School of Medicine, 
      Zhejiang University, Hangzhou, China.
FAU - Ma, Longfei
AU  - Ma L
AD  - Department of Anesthesiology, Second Affiliated Hospital, School of Medicine, 
      Zhejiang University, Hangzhou, China.
FAU - Gao, Dave Schwinn
AU  - Gao DS
AD  - Department of Anesthesiology, Second Affiliated Hospital, School of Medicine, 
      Zhejiang University, Hangzhou, China.
FAU - Sun, Na
AU  - Sun N
AD  - Department of Anesthesiology, Second Affiliated Hospital, School of Medicine, 
      Zhejiang University, Hangzhou, China.
FAU - Liu, Ying
AU  - Liu Y
AD  - Department of Anesthesiology, Second Affiliated Hospital, School of Medicine, 
      Zhejiang University, Hangzhou, China.
FAU - Fang, Lili
AU  - Fang L
AD  - Department of Anesthesiology, Second Affiliated Hospital, School of Medicine, 
      Zhejiang University, Hangzhou, China.
FAU - Cheng, Zhenzhen
AU  - Cheng Z
AD  - Department of Anesthesiology, Second Affiliated Hospital, School of Medicine, 
      Zhejiang University, Hangzhou, China.
FAU - Sun, Kai
AU  - Sun K
AD  - Department of Anesthesiology, Second Affiliated Hospital, School of Medicine, 
      Zhejiang University, Hangzhou, China.
FAU - Yan, Min
AU  - Yan M
AD  - Department of Anesthesiology, Second Affiliated Hospital, School of Medicine, 
      Zhejiang University, Hangzhou, China. Electronic address: zryanmin@zju.edu.cn.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20220202
PL  - England
TA  - Neurochem Int
JT  - Neurochemistry international
JID - 8006959
RN  - 0 (Succinates)
RN  - 11JIB0YI93 (dimethyl itaconate)
SB  - IM
MH  - Animals
MH  - *Chronic Pain/drug therapy
MH  - Ganglia, Spinal/metabolism
MH  - Hyperalgesia/metabolism
MH  - Mice
MH  - *Neuralgia/metabolism
MH  - Neuroinflammatory Diseases
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Spinal Cord/metabolism
MH  - Spinal Cord Dorsal Horn
MH  - Succinates
OTO - NOTNLM
OT  - Dimethyl itaconate
OT  - Inflammatory pain
OT  - Neuroinflammation
OT  - Neuropathic pain
OT  - Nuclear factor-erythroid 2 p45-related factor 2
EDAT- 2022/02/06 06:00
MHDA- 2022/04/08 06:00
CRDT- 2022/02/05 05:37
PHST- 2021/09/01 00:00 [received]
PHST- 2022/01/21 00:00 [revised]
PHST- 2022/01/29 00:00 [accepted]
PHST- 2022/02/06 06:00 [pubmed]
PHST- 2022/04/08 06:00 [medline]
PHST- 2022/02/05 05:37 [entrez]
AID - S0197-0186(22)00021-3 [pii]
AID - 10.1016/j.neuint.2022.105296 [doi]
PST - ppublish
SO  - Neurochem Int. 2022 Mar;154:105296. doi: 10.1016/j.neuint.2022.105296. Epub 2022 
      Feb 2.