Dexmedetomidine attenuates P2X4 and NLRP3 expression in the spine of rats with diabetic neuropathic pain

Liu, Kang; Huang, Yayi; Zhou, Fang; Zhao, Bo; Xia, Zhongyuan

doi:10.1590/s0102-865020190110000005

Cited by 21 publications

(12 citation statements)

References 24 publications

(23 reference statements)

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“…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.…”

Section: Discussionsupporting

confidence: 90%

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

Wu¹,

Qiao²,

Song³

2022

Trop. J. Pharm Res

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Purpose: To elaborate the functional role of dexmedetomidine (DEX) in alleviating microglial activation of diabetic neuropathic pain (DNP) and explore the involved signaling pathways. Methods: The viability of BV-2 cells was measured using a commercial kit. Levels of interleukin 1β (IL- 1β) and tumor necrosis factor-α (TNF-α) were measured using commercial ELISA kit. The mRNA target was predicted and confirmed using TargetScan and luciferase assay. Protein expression levels were determined by western blotting. Diabetes was indiced in C57BL/6J mice using streptozotocin (STZ) and antidiabetic parameters evaluated in vivo. Results: DEX suppressed HG-induced microglial activation in BV-2 cells. The levels of IL-1β and TNF-α increased in HG-treated cells, but this was counteracted following DEX treatment. Phosphorylation of p65 (p-p65) was upregulated in cells treated with HG, while DEX repressed this upregulation. MiR-23a was downregulated in BV-2 cells treated with HG, but upregulated by addition of DEX. MiR-23a mimics repressed the induction of IL-1β and TNF-α levels and expression of p-p65. Results from TargetScan and luciferase assays showed that the 3-untranslated region (UTR) of PDE10A was directly targeted by miR-23a. The in vivo studies showed that miR-23a agomir relieved neuropathic pain and reduced the expressions of PDE10A and p-p65 in STZ-induced diabetic mice, but these effects were aggravated by DEX. Conclusion: The results show that upregulation of miR-23a, DEX alleviates microglial activation of neuropathic pain and reduces levels of inflammatory factors in STZ-induced diabetic C57BL/6J mice. The underlying mechanism was at least partially mediated by PDE10A.

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“…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.…”

Section: Discussionsupporting

confidence: 90%

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

Wu¹,

Qiao²,

Song³

2022

Trop. J. Pharm Res

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“…Both types of diabetes are associated with neuropathic pain. STZ is commonly used to induce DNP in experimental animals [34][35][36] and causes peripheral neuropathy and hyperalgesia when administered at high doses or multiple small doses. Here, we successfully established a rat model of DNP using a single, high dose of STZ.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of phosphorylated calcium/calmodulin-dependent protein kinase IIα relieves streptozotocin-induced diabetic neuropathic pain through regulation of P2X3 receptor in dorsal root ganglia

Kang

Fei

et al. 2022

Purinergic Signalling

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Diabetic neuropathic pain (DNP) is frequent among patients with diabetes. We previously showed that P2X3 upregulation in dorsal root ganglia (DRG) plays a role in streptozotocin (STZ)-induced DNP but the underlying mechanism is unclear. Here, a rat model of DNP was established by a single injection of STZ (65 mg/kg). Fasting blood glucose was significantly elevated from the 1st to 3rd week. Paw withdrawal thresholds (PWTs) and paw withdrawal latencies (PWLs) in diabetic rats significantly reduced from the 2nd to 3rd week. Western blot analysis revealed that elevated p-CaMKIIα levels in the DRG of DNP rats were accompanied by pain-associated behaviors while CaMKIIα levels were unchanged. Immunofluorescence revealed significant increase in the proportion of p-CaMKIIα immune positive DRG neurons (stained with NeuN) in the 2nd and 3rd week and p-CaMKIIα was co-expressed with P2X3 in DNP rats. KN93, a CaMKII antagonist, significantly reduce mechanical hyperalgesia and thermal hyperalgesia and these effects varied dose-dependently, and suppressed p-CaMKIIα and P2X3 upregulation in the DRGs of DNP rats. These results revealed that the p-CaMKIIα upregulation in DRG is involved in DNP, which possibly mediated P2X3 upregulation, indicating CaMKIIα may be an effective pharmacological target for DNP management.

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“…Unfortunately, the study of the molecular mechanisms and, specifically, pathogenic mechanisms involving the inflammasome has lagged somewhat behind other complications of diabetes. To date, a handful of articles on the involvement of NLRP3 in some pathophysiological changes and clinical manifestations of diabetic neuropathy are found in the literature [153][154][155][156][157]. Though suggesting a contribution of the TXNIP [153,154], PR2X4 [155], and HMGB1/TLR4-NLRP3 signaling pathways [156], these studies do not provide conclusive evidence on the role of NLRP3 in diabetic neuropathy and need to be confirmed in larger controlled studies.…”

Section: Diabetic Neuropathymentioning

confidence: 97%

The Inflammasome in Chronic Complications of Diabetes and Related Metabolic Disorders

Menini

Iacobini

Vitale

et al. 2020

Cells

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Diabetes mellitus (DM) ranks seventh as a cause of death worldwide. Chronic complications, including cardiovascular, renal, and eye disease, as well as DM-associated non-alcoholic fatty liver disease (NAFLD) account for most of the morbidity and premature mortality in DM. Despite continuous improvements in the management of late complications of DM, significant gaps remain. Therefore, searching for additional strategies to prevent these serious DM-related conditions is of the utmost importance. DM is characterized by a state of low-grade chronic inflammation, which is critical in the progression of complications. Recent clinical trials indicate that targeting the prototypic pro-inflammatory cytokine interleukin-1β (IL-1 β) improves the outcomes of cardiovascular disease, which is the first cause of death in DM patients. Together with IL-18, IL-1β is processed and secreted by the inflammasomes, a class of multiprotein complexes that coordinate inflammatory responses. Several DM-related metabolic factors, including reactive oxygen species, glyco/lipoxidation end products, and cholesterol crystals, have been involved in the pathogenesis of diabetic kidney disease, and diabetic retinopathy, and in the promoting effect of DM on the onset and progression of atherosclerosis and NAFLD. These metabolic factors are also well-established danger signals capable of regulating inflammasome activity. In addition to presenting the current state of knowledge, this review discusses how the mechanistic understanding of inflammasome regulation by metabolic danger signals may hopefully lead to novel therapeutic strategies targeting inflammation for a more effective treatment of diabetic complications.

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Dexmedetomidine attenuates P2X4 and NLRP3 expression in the spine of rats with diabetic neuropathic pain

Cited by 21 publications

References 24 publications

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

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

Inhibition of phosphorylated calcium/calmodulin-dependent protein kinase IIα relieves streptozotocin-induced diabetic neuropathic pain through regulation of P2X3 receptor in dorsal root ganglia

The Inflammasome in Chronic Complications of Diabetes and Related Metabolic Disorders

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