Inhibition of the RNA Regulator HuR by SRI-42127 Attenuates Neuropathic Pain After Nerve Injury Through Suppression of Neuroinflammatory Responses

Neurotherapeutics. 2022 Sep;19(5):1649-1661. doi: 10.1007/s13311-022-01278-9. Epub 2022 Jul 21.


Microglial activation with the production of pro-inflammatory mediators such as IL-6, TNF-α, and IL-1β, is a major driver of neuropathic pain (NP) following peripheral nerve injury. We have previously shown that the RNA binding protein, HuR, is a positive node of regulation for many of these inflammatory mediators in glia and that its chemical inhibition or genetic deletion attenuates their production. In this report, we show that systemic administration of SRI-42127, a novel small molecule HuR inhibitor, attenuates mechanical allodynia, a hallmark of NP, in the early and chronic phases after spared nerve injury in male and female mice. Flow cytometry of lumbar spinal cords in SRI-42127-treated mice shows a reduction in infiltrating macrophages and a concomitant decrease in microglial populations expressing IL-6, TNF-α, IL-1β, and CCL2. Immunohistochemistry, ELISA, and qPCR of lumbar spinal cord tissue indicate suppression of these cytokines and other inflammatory mediators. ELISA of plasma samples in the acute phase also shows attenuation of inflammatory responses. In summary, inhibition of HuR by SRI-42127 leads to the suppression of neuroinflammatory responses and allodynia after nerve injury and represents a promising new direction in the treatment of NP.

Keywords: Allodynia; Microglia/macrophages; Nerve injury; Neuroinflammation; Neuropathic pain; RNA regulation.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Cytokines / metabolism
  • Disease Models, Animal
  • Female
  • Hyperalgesia / drug therapy
  • Hyperalgesia / metabolism
  • Inflammation / metabolism
  • Inflammation Mediators / metabolism
  • Interleukin-6 / metabolism
  • Male
  • Mice
  • Microglia / metabolism
  • Neuralgia* / metabolism
  • RNA / metabolism
  • Spinal Cord / metabolism
  • Trauma, Nervous System*
  • Tumor Necrosis Factor-alpha / metabolism


  • Tumor Necrosis Factor-alpha
  • RNA
  • Interleukin-6
  • Cytokines
  • Inflammation Mediators