Glycogen synthesis kinase-3β involves in the analgesic effect of liraglutide on diabetic neuropathic pain

J Diabetes Complications. 2023 Mar;37(3):108416. doi: 10.1016/j.jdiacomp.2023.108416. Epub 2023 Feb 4.

Abstract

Aims: Explore whether Glycogen synthesis kinase-3β (GSK3β) involved in the analgesic effect of liraglutide on diabetic neuropathic pain (DNP).

Methods: DNP was induced by streptozocin (STZ) in WT and GSK3β(S9A) mice, which carried a constitutively active form of GSK3β. DNP mice were intracerebroventricularly injected with liraglutide 5 weeks after STZ injection. The behavior of neuropathic pain was evaluated 2 h after drugs administration. The microglial activation and the expression of NOD-like receptor protein 3 (NLRP3) in microglia in cortex were evaluated. The role of GSK3β in the inhibitory effect of liraglutide on the NLRP3 inflammasome was explored in BV2 microglia.

Results: Intracerebroventricular administration of liraglutide significantly relieved neuropathic pain and inhibited the activation of cortical microglia in WT mice with DNP. But the effect of liraglutide disappeared in GSK3β(S9A) mice. In BV2 microglia, GSK3β inhibitor significantly suppressed NLRP3 inflammasome activation. And activating GSK3β through GSK3β(S9A) lentivirus significantly blocked the inhibitory effect of liraglutide on NLRP3 inflammasome in BV2 microglia. Intracerebroventricular administration of liraglutide significantly inhibited the expression of NLRP3 in cortex microglia of DNP group in WT mice but failed in GSK3β(S9A) mice.

Conclusion: GSK3β involves in the analgesic effect of liraglutide on DNP through NLRP3 inflammasome in microglia.

Keywords: Diabetic neuropathic pain; Glycogen synthesis kinase-3β; Liraglutide; NOD-like receptor protein 3 inflammasome.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analgesics
  • Animals
  • Diabetes Mellitus*
  • Diabetic Neuropathies*
  • Glycogen
  • Glycogen Synthase Kinase 3 beta
  • Inflammasomes / metabolism
  • Liraglutide
  • Mice
  • NLR Family, Pyrin Domain-Containing 3 Protein / metabolism
  • Neuralgia*

Substances

  • Liraglutide
  • Inflammasomes
  • Glycogen Synthase Kinase 3 beta
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Glycogen
  • Analgesics