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  3. Pharmacological modulation of Sigma-1 receptor ameliorates pathological neuroinflammation in rats with diabetic neuropathic pain via the AKT/GSK-3β/NF-κB pathway

Pharmacological modulation of Sigma-1 receptor ameliorates pathological neuroinflammation in rats with diabetic neuropathic pain via the AKT/GSK-3β/NF-κB pathway

  • Brain Res Bull. 2025 Feb:221:111226. doi: 10.1016/j.brainresbull.2025.111226.
Yuyu An 1,  Shanshan Cao 2,  Leilei Shi 3,  Yuhan Zhang 4,  Xin Wang 5,  Shiyu Yuan 6,  Yongheng Shi 7,  Bin Wang 8,  Jiping Liu 9,  Chao-Jun Han 10
Affiliations

Affiliations

  • 1 Department of Pharmacology, Shaanxi University of Chinese Medicine, Xianyang 712046, PR China. Electronic address: 3054919731@qq.com.
  • 2 Department of Pharmacology, Shaanxi University of Chinese Medicine, Xianyang 712046, PR China. Electronic address: 2297660423@qq.com.
  • 3 Department of Pharmacology, Shaanxi University of Chinese Medicine, Xianyang 712046, PR China. Electronic address: 1397730057@qq.com.
  • 4 Department of Pharmacology, Shaanxi University of Chinese Medicine, Xianyang 712046, PR China. Electronic address: 1052184664@qq.com.
  • 5 Department of Pharmacology, Shaanxi University of Chinese Medicine, Xianyang 712046, PR China. Electronic address: 1792686826@qq.com.
  • 6 Department of Pharmacy, The Second affiliated hospital of Shaanxi University of Chinese Medicine, Xianyang 712046, PR China. Electronic address: shiyu_yuan@163.com.
  • 7 Department 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. Electronic address: yhshi@sntcm.edu.cn.
  • 8 Department 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. Electronic address: wangbin812@126.com.
  • 9 Department 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. Electronic address: ljp0711@sntcm.edu.cn.
  • 10 Department 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. Electronic address: hanchaojun@sntcm.edu.cn.
PMID: 39870326 DOI: 10.1016/j.brainresbull.2025.111226
Abstract

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.

Keywords

Dorsal root ganglia; GSK-3β; Lipopolysaccharide (LPS); Microglia-like cell; Neuroinflammation; PRE-084; Sigma-1 receptor.

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