Abstract
Purpose: To investigate the effect of dexmedetomidine on streptozotocin (STZ)-induced diabetic neuropathy pain (DNP) in rats and elucidate its mechanism of action.Methods: The DNP rat model was established by injecting STZ (70 mg/kg) following dexmedetomidine treatment. Next BV-2 cells were stimulated using lipopolysaccharide (LPS, 200 ng/mL) and then administered 20 μM dexmedetomidine. Blood glucose levels, body weight, and paw withdrawal threshold (PWT) were measured once a week in DNP rats. Transfection was performed, and luciferasereporter assay was used to verify microRNA (miR)-337 binding to Rap1A mRNA. Reverse transcriptionpolymerase chain reaction (RT-PCR) was used to measure the levels of miR-618 and P2Y12 while the protein levels of P2Y12 and ionized calcium-binding adaptor molecule 1 (IBA-1) were determined by western blot analysis.Results: Dexmedetomidine treatment significantly increased PWT (p < 0.01) in DNP rats and decreased miR-618 expression (p < 0.01) but increased P2Y12 expression (p < 0.01) in the spinal cord of DNP rats. Luciferase reporter assay data showed that the presumed binding site of miR-618 is located in the 3′-untranslated regions of P2Y12. MiR-618 overexpression significantly reduced P2Y12levels (p < 0.01). Dexmedetomidine upregulated P2Y12 expression (p < 0.01) but decreased IBA-1 expression (p < 0.01).Conclusion: Dexmedetomidine application attenuates DNP by inhibiting microglial activation via the regulation of miR-618/P2Y12 pathway. This finding provides a potential therapeutic strategy for DNP management.
 Keywords: Dexmedetomidine, Diabetic neuropathy pain, Paw withdrawal threshold, Calcium-binding adaptor molecule 1, MiR-618, P2Y12
Highlights
Diabetic neuropathy pain (DNP) is one of the most common symptoms in patients with diabetes mellitus [1]
MiR-618 expression was significantly reduced but P2Y12 expression was increased after dexmedetomidine administration in miR-618treated cells (Figure 3 C and D; p < 0.01). miR618 overexpression downregulated P2Y12 expression in LPS-treated cells, while dexmedetomidine upregulated P2Y12 expression (Figure 3 E; p < 0.01)
Dexmedetomidine treatment significantly alleviated neuropathic pain in DNP rats and decreased miR-618 expression, but the level of P2Y12 was increased in the spinal cord of DNP rats
Summary
Diabetic neuropathy pain (DNP) is one of the most common symptoms in patients with diabetes mellitus [1]. Dexmedetomidine attenuated DNP in rats by regulating the Wnt 10a/β-catenin pathway [7]. The DNP rat model was established by the intraperitoneal injection of streptozotocin (STZ, 70 mg/kg, Sigma-Aldrich, St. Louis, MO, USA) 3 times/day. Neuropathic pain in diabetic rats was defined as 50 % PWT < 5 g, measured using the von Frey hair test. For miR-618 and P2Y12 expression in the spinal cord of rats, different concentrations of dexmedetomidine (5, 10, 50, and 100 μg/kg) were administered. A DNP rat model was established by injecting STZ, and BV-2 cells were stimulated by LPS. A dual-reporter luciferase assay system was utilized to determine luciferase activity using a Tecan SpectraFluorPlus plate-reader (Plastic Surgery Laboratory, University of Pittsburgh, Pittsburgh, PA, USA).
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