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

Aims: Explore whether Glycogen synthesis kinase-3 beta (GSK3 beta) involved in the analgesic effect of liraglutide on diabetic neuropathic pain (DNP).Methods: DNP was induced by streptozocin (STZ) in WT and GSK3 beta(S9A) mice, which carried a constitutively active form of GSK3 beta. DNP mice were intracerebroventricularly injected with liraglutide 5 weeks after STZ in-jection. 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 GSK3 beta 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 GSK3 beta(S9A) mice. In BV2 microglia, GSK3 beta inhibitor significantly suppressed NLRP3 inflammasome activation. And activating GSK3 beta through GSK3 beta(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 GSK3 beta(S9A) mice. Conclusion: GSK3 beta involves in the analgesic effect of liraglutide on DNP through NLRP3 inflammasome in microglia.