The Interactions Of Notch1 And TLR4 Signaling Pathways In Diabetic Neuropathy

Painful diabetic neuropathy is a common complication of diabetes which significantly affects the quality of life of the patients. Unfortunately, symptomatic treatment options have limited efficacy, and often carry significant risk of systemic adverse effects. Intervevtion of nociceptive pathway is a novel therapeutic option for the treatment of painful diabetic neuropathy. Alterations of toll-like receptor 4 (TLR4) may occur in diabetes and are implicated in the development of diabetic peripheral neuropathy. There is close relationship between Notch1 and TLR4 signaling pathways in mediating inflammatory response. Whether the interactions exist between Notchl and TLR4 signaling pathways in dorsal root ganglion (DRG) neurons in diabetic neuropathy needs to be further clarified. In the present study, the interactions of Notchl and TLR4 signaling pathways in DRG from streptozotocin (STZ)-induced diabetic neuropathic pain rat model and in cultured DRG neurons with high glucose-induced neurotoxicity were investigated. The results showed that:(1) Mechanical allodynia and thermal hyperalgesia were observed in STZ-induced diabetic neuropathic pain rats; (2) High glucose induced not only Notchl mRNA, HES1 mRNA, and TLR4 mRNA expression, but also Notchl intracellular domain (NICD1) and TLR4 protein expression in DRG of in vivo and in vitro models of diabetic neuropathy; (3) The expression of tumor necrosis factor-a (TNF-a) levels increased in DRG of painful diabetic neuropathic rats; (4) The elevated NICD1, TLR4, and TNF-a protein levels was closely relaed to mechanical allodynia and thermal hyperalgesia; (5) The proportion of NICD1-immunoreactive (IR) and TLR4-IR neurons in DRG cultures was also increased after high glucose challenge in vitro; (6) The above alterations could be partially reversed by inhibition of either Notch1 or TLR4 signaling pathway; (7) Inhibition of one of the Notchl and TLR4 signaling pathways could affect another signaling pathway suggesting the interactions between Notchl and TLR4 signaling pathways. These data imply that the interactions between Notchl and TLR4 signaling pathways and their relations to production TNF-a are specific important in the development or progression of diabetic neuropathy. A better understanding of the interactions of Notch1 and TLR4 signaling pathways in primary sensory neurons may lead to interpretation of the mechanisms and novel approaches for preventing or inhibiting the development or progression of diabetic neuropathy and promoting the relief of diabetic neuropathic pain behaviors.