Pharmacological modulation of Sigma-1 receptor ameliorates pathological neuroinflammation in rats with diabetic neuropathic pain via the AKT/GSK-3β/NF-κB pathway
Diabetic neuropathic pain (DNP) is a common complication of diabetes mellitus (DM) and is characterized by spontaneous pain and neuroinflammation. The Sigma-1 receptor (Sig-1R) has been proposed as a target for analgesic development. It is an important receptor with anti-inflammatory properties and...
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Elsevier
2025-02-01
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| Series: | Brain Research Bulletin |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S0361923025000383 |
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| author | Yuyu An Shanshan Cao Leilei Shi Yuhan Zhang Xin Wang Shiyu Yuan Yongheng Shi Bin Wang Jiping Liu Chao-jun Han |
| author_facet | Yuyu An Shanshan Cao Leilei Shi Yuhan Zhang Xin Wang Shiyu Yuan Yongheng Shi Bin Wang Jiping Liu Chao-jun Han |
| author_sort | Yuyu An |
| collection | DOAJ |
| description | Diabetic neuropathic pain (DNP) is a common complication of diabetes mellitus (DM) and is characterized by spontaneous pain and neuroinflammation. The Sigma-1 receptor (Sig-1R) has been proposed as a target for analgesic development. It is an important receptor with anti-inflammatory properties and has been found to regulate DNP. However, it is not known whether Sig-1R can ameliorate pathological neuroinflammation in DNP. The present study used a rat model of DNP and a highly selective agonist of Sig-1R to assess the effects of the protein on neuropathic pain in rats with type 2 diabetes mellitus. The rats were divided into Control, Model, Sig-1R agonist PRE-084 (0.3, 0.6, 1 mg/kg), and metformin (Met, 20 mg/kg) groups, with seven rats per group, and their body weight, fasting blood glucose, mechanical withdrawal threshold and thermal withdrawal latency were tested weekly for two weeks. After treatment with PRE-084, the pain thresholds in the DNP rats were significantly improved, together with pathological changes in the dorsal root ganglion, reductions in the serum levels of TNF-α, IL-1β, IL-6, MOD, and prostaglandin E2 (PGE2), and the activity of superoxide dismutase was increased. The mRNA levels of TNF-α, IL-1β, and cyclooxygenase 2 (COX-2) were reduced. Pharmacological inhibition of Sig-1R with BD1047 (10 μM) abolished Sig-1R-mediated activation of lipopolysaccharide-treated BV-2 microglial cells. It was also found that PRE-084 increased phosphorylation of serine/threonine protein kinase B (AKT) and glycogen synthase kinase 3β (GSK-3β) at Ser9, inhibiting nuclear factor kappa B (NF-κB)-mediated neuroinflammation in the dorsal root ganglion, thus reducing DNP. The findings suggest that the effect of Sig-1R agonist PRE-084 on DNP may reduce the level of inflammation through the up-regulation of AKT/GSK-3β and down-regulation of the NF-κB signaling, thereby contributing to the treatment of the disease. |
| format | Article |
| id | doaj-art-dec65fe497e94448b38b761d4efd113c |
| institution | Kabale University |
| issn | 1873-2747 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Elsevier |
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| series | Brain Research Bulletin |
| spelling | doaj-art-dec65fe497e94448b38b761d4efd113c2025-02-07T04:46:47ZengElsevierBrain Research Bulletin1873-27472025-02-01221111226Pharmacological modulation of Sigma-1 receptor ameliorates pathological neuroinflammation in rats with diabetic neuropathic pain via the AKT/GSK-3β/NF-κB pathwayYuyu An0Shanshan Cao1Leilei Shi2Yuhan Zhang3Xin Wang4Shiyu Yuan5Yongheng Shi6Bin Wang7Jiping Liu8Chao-jun Han9Department of Pharmacology, Shaanxi University of Chinese Medicine, Xianyang 712046, PR ChinaDepartment of Pharmacology, Shaanxi University of Chinese Medicine, Xianyang 712046, PR ChinaDepartment of Pharmacology, Shaanxi University of Chinese Medicine, Xianyang 712046, PR ChinaDepartment of Pharmacology, Shaanxi University of Chinese Medicine, Xianyang 712046, PR ChinaDepartment of Pharmacology, Shaanxi University of Chinese Medicine, Xianyang 712046, PR ChinaDepartment of Pharmacy, The Second affiliated hospital of Shaanxi University of Chinese Medicine, Xianyang 712046, PR ChinaDepartment of Pharmacology, Shaanxi University of Chinese Medicine, Xianyang 712046, PR China; Key Laboratory of Pharmacodynamic Mechanism and Material Basis of Traditional Chinese Medicine, Shaanxi Administration of Traditional Chinese Medicine, Xianyang 712046, PR ChinaDepartment of Pharmacology, Shaanxi University of Chinese Medicine, Xianyang 712046, PR China; Key Laboratory of Pharmacodynamic Mechanism and Material Basis of Traditional Chinese Medicine, Shaanxi Administration of Traditional Chinese Medicine, Xianyang 712046, PR ChinaDepartment of Pharmacology, Shaanxi University of Chinese Medicine, Xianyang 712046, PR China; Key Laboratory of Pharmacodynamic Mechanism and Material Basis of Traditional Chinese Medicine, Shaanxi Administration of Traditional Chinese Medicine, Xianyang 712046, PR ChinaDepartment of Pharmacology, Shaanxi University of Chinese Medicine, Xianyang 712046, PR China; Key Laboratory of Pharmacodynamic Mechanism and Material Basis of Traditional Chinese Medicine, Shaanxi Administration of Traditional Chinese Medicine, Xianyang 712046, PR China; Correspondence to: Shaanxi University of Chinese Medicine, No. 1 Middle Section of Century Avenue, Xianyang 712046, PR China.Diabetic neuropathic pain (DNP) is a common complication of diabetes mellitus (DM) and is characterized by spontaneous pain and neuroinflammation. The Sigma-1 receptor (Sig-1R) has been proposed as a target for analgesic development. It is an important receptor with anti-inflammatory properties and has been found to regulate DNP. However, it is not known whether Sig-1R can ameliorate pathological neuroinflammation in DNP. The present study used a rat model of DNP and a highly selective agonist of Sig-1R to assess the effects of the protein on neuropathic pain in rats with type 2 diabetes mellitus. The rats were divided into Control, Model, Sig-1R agonist PRE-084 (0.3, 0.6, 1 mg/kg), and metformin (Met, 20 mg/kg) groups, with seven rats per group, and their body weight, fasting blood glucose, mechanical withdrawal threshold and thermal withdrawal latency were tested weekly for two weeks. After treatment with PRE-084, the pain thresholds in the DNP rats were significantly improved, together with pathological changes in the dorsal root ganglion, reductions in the serum levels of TNF-α, IL-1β, IL-6, MOD, and prostaglandin E2 (PGE2), and the activity of superoxide dismutase was increased. The mRNA levels of TNF-α, IL-1β, and cyclooxygenase 2 (COX-2) were reduced. Pharmacological inhibition of Sig-1R with BD1047 (10 μM) abolished Sig-1R-mediated activation of lipopolysaccharide-treated BV-2 microglial cells. It was also found that PRE-084 increased phosphorylation of serine/threonine protein kinase B (AKT) and glycogen synthase kinase 3β (GSK-3β) at Ser9, inhibiting nuclear factor kappa B (NF-κB)-mediated neuroinflammation in the dorsal root ganglion, thus reducing DNP. The findings suggest that the effect of Sig-1R agonist PRE-084 on DNP may reduce the level of inflammation through the up-regulation of AKT/GSK-3β and down-regulation of the NF-κB signaling, thereby contributing to the treatment of the disease.http://www.sciencedirect.com/science/article/pii/S0361923025000383Sigma-1 receptorDorsal root gangliaNeuroinflammationMicroglia-like cellPRE-084GSK-3β |
| spellingShingle | Yuyu An Shanshan Cao Leilei Shi Yuhan Zhang Xin Wang Shiyu Yuan Yongheng Shi Bin Wang Jiping Liu Chao-jun Han Pharmacological modulation of Sigma-1 receptor ameliorates pathological neuroinflammation in rats with diabetic neuropathic pain via the AKT/GSK-3β/NF-κB pathway Brain Research Bulletin Sigma-1 receptor Dorsal root ganglia Neuroinflammation Microglia-like cell PRE-084 GSK-3β |
| title | Pharmacological modulation of Sigma-1 receptor ameliorates pathological neuroinflammation in rats with diabetic neuropathic pain via the AKT/GSK-3β/NF-κB pathway |
| title_full | Pharmacological modulation of Sigma-1 receptor ameliorates pathological neuroinflammation in rats with diabetic neuropathic pain via the AKT/GSK-3β/NF-κB pathway |
| title_fullStr | Pharmacological modulation of Sigma-1 receptor ameliorates pathological neuroinflammation in rats with diabetic neuropathic pain via the AKT/GSK-3β/NF-κB pathway |
| title_full_unstemmed | Pharmacological modulation of Sigma-1 receptor ameliorates pathological neuroinflammation in rats with diabetic neuropathic pain via the AKT/GSK-3β/NF-κB pathway |
| title_short | Pharmacological modulation of Sigma-1 receptor ameliorates pathological neuroinflammation in rats with diabetic neuropathic pain via the AKT/GSK-3β/NF-κB pathway |
| title_sort | pharmacological modulation of sigma 1 receptor ameliorates pathological neuroinflammation in rats with diabetic neuropathic pain via the akt gsk 3β nf κb pathway |
| topic | Sigma-1 receptor Dorsal root ganglia Neuroinflammation Microglia-like cell PRE-084 GSK-3β |
| url | http://www.sciencedirect.com/science/article/pii/S0361923025000383 |
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