Dexmedetomidine Reduces Diabetic Neuropathy Pain in Rats through the Wnt 10a/β-Catenin Signaling Pathway

Abstract

Diabetic neuropathy pain (DNP), a spontaneous pain with hyperalgesia and allodynia, greatly compromises patients' quality of life. Our previous study suggested that dexmedetomidine (DEX) can relieve hyperalgesia in rats by inhibiting inflammation and apoptosis at the level of the spinal cord. In the present study, we aimed to evaluate the role of Wnt 10a/β-catenin signaling in DEX-induced alleviation of DNP in rats. Forty-eight rats were randomly allocated to four groups (n=12/group): control, DNP, DEX, and yohimbine groups. The DNP model was established by streptozotocin (STZ) injection. The effects of DEX with or without the α2 adrenergic antagonist yohimbine were assessed by behavior tests (mechanical withdrawal threshold and thermal withdrawal latency). Spinal cord tissue was evaluated by immunofluorescence staining of astrocytes as well as for Wnt 10a and β-catenin expression, western blot analysis of Wnt 10a and β-catenin expression, and enzyme-linked immunosorbent assay measurement of proinflammatory cytokines (tumor necrosis factor-α and interleukin-1β). Rats with STZ-induced DNP had a decreased pain threshold, activated astrocytes, increased expression of Wnt 10a and β-catenin, and increased levels of proinflammatory cytokines compared to the control group, and these effects were ameliorated by treatment with DEX. Yohimbine administration partly abolished the protective effects of DEX in the DNP model rats. In conclusion, DEX alleviated DNP in rats by inhibiting inflammation and astrocyte activation, which may be attributed to downregulation of the Wnt 10a/β-catenin signaling pathway.

Dexmedetomidine alleviates microglial activation of neuropathic pain by modulating miR-23a/PDE10A axis in streptozotocin-induced diabetic mice

“…DEX has been reported to relieve DNP via various inflammatory signals [14,15]. Consistently, DEX alleviated DNP in STZinduced DM mice in the present study.…”

Integrated bioinformatics analysis reveals novel key biomarkers and potential candidate small molecule drugs in diabetic nephropathy

“…A previous study has shown that UBASH3A [85], SIRPG (signal regulatory protein gamma) [86], IKZF3 [87], CD1D [88], CD2 [89], CD48 [90], CD247 [91] and CYP27B1 [92] are liable for progression of type 1 diabetes through in ammation, but these genes might be key for progression of DN. SIT1 [93], JAML (junction adhesion molecule like) [94], TIMP1 [95], PRKCB (protein kinase C beta) [96], MMP7 [97], WNT7B [98], WNT10A [99], DUSP1 [100], WT1 [101], APOC3 [102], ERRFI1 [103], HCN2 [104], MME (membrane metalloendopeptidase) [105], STRA6 [106], SLC12A3 [107] and GC (GC vitamin D binding protein) [108] expedites epithelial to mesenchymal transition and renal brosis in DN. Previous studies have found CFD (complement factor D) [109], DOCK2 [110], LYZ (lysozyme) [111], CD5L [112], SCARA5 [113], VCAN (versican) [114], GDF5 [115], SFRP2 [116], BTG2 [117], ZFP36 [118], GPR3 [119], OLR1 [120], PM20D1 [121] and UGT2B7 [122] to be expressed in obesity, but these genes might be liable for advancement of DN.…”

The complex role of Wnt ligands in type 2 diabetes mellitus and related complications

“… 118 However, Wnt10a and mediated canonical Wnt signalling are also induced in spinal cord of diabetic rat, and dexmedetomidine treatment could alleviate diabetic neuropathy pain by inhibiting the canonical Wnt10a pathway. 119 The role of Wnt10b in the development of T2DM is comparatively well understood. Among all Wnts, Wnt10b is important negative regulator of adipocyte differentiation via activating the canonical Wnt pathway; lower Wnt10b expression and down‐regulation of Wnt10b/β‐catenin pathway are detected in white adipose and skeletal muscle tissues from men with overweight and prediabetes, 120 and inactivation of Wnt10b/β‐catenin pathway promotes the adipogenesis and diet‐induced obesity in mice.…”

“…In another study, disruption of circadian clocks in mice results in increased adipogenesis and obesity through silencing the canonical Wnt10a pathway, indicating the protective role of Wnt10a in the development of obesity 118 . However, Wnt10a and mediated canonical Wnt signalling are also induced in spinal cord of diabetic rat, and dexmedetomidine treatment could alleviate diabetic neuropathy pain by inhibiting the canonical Wnt10a pathway 119 . The role of Wnt10b in the development of T2DM is comparatively well understood.…”