Bone Marrow-derived Mesenchymal Stem Cells Alleviate Neuropathic Pain Through Inhibiting ERK5/CREB Pathway In The Mouse CCI Model

Background:Neuropathic pain,as a kind of chronic pain induced by peripheral or central nerve injury,is the result of complicated pathological changes.In recent years,mesenchymal stem cells(MSCs)have been regarded as the new therapeutic approaches for chronic pain,but the specific mechanisms remain to be elucidated.In this study,we demonstrated that bone marrow-derived mesenchymal stem cells(BMSCs)inhibited the pathway of extracellular regulated proteins kinase 5(ERK5)/c AMP response element binding protein(CREB)to relieve neuropathic pain in the mouse model.Methods:Chronic constriction injury(CCI)of sciatic nerve in C57BL/6 mice was established to simulate neuropathic pain.Mice were randomly divided into 2 groups(n=6/group):Sham group and CCI group.The pain-like behaviors of mice were detected.The dorsal root ganglion and spinal cord were collected on day 7 after CCI injury for p-ERK5 and p-CREB protein examination.For BMSCs therapy experiments,mice were randomly divided into 3 groups(n=6/group): Sham group,CCI group,CCI treated with BMSCs group.The pain-like behaviors of mice were evaluated.The dorsal root ganglion and spinal cord were collected on day 7 after BMSCs intervention for detection of p-ERK5,p-CREB,IBA-1 and inflammatory cytokines.In vitro experments,microglial cells were divided into 3 groups: PBS group,LPS group and LPS stimulated cocultured with BMSCs group.The medium supernatant and microglia were collected 24 hours after stimulation for inflammatory cytokines detection and p-ERK5 examination.Results:(1)The thermal pain threshold of mice with CCI model was reduced,and the expressions of p-ERK5 and p-CREB in dorsal root ganglia and spinal cord were increased.(2)BMSCs increased the mechanical and thermal pain thresholds of CCI mice,inhibited the expression of p-ERK5,p-CREB and IBA-1 in dorsal root ganglia and spinal cord,and downregulated proinflammatory factors.(3)BMSCs cocultured with microglia decreased the secretion of proinflammatory cytokines stimulated by LPS and the content of p-ERK5 in the microglia.Conclusion BMSCs relieve neuropathic pain by inhibiting ERK5/CREB pathway in the mouse CCI model.BMSCs may provide therapeutic benefits for patients with neuropathic pain in the future.