熊果酸对糖尿病周围神经病变大鼠的抗伤害感受作用：行为、生化和分子对接证据

Pharmacological Research - Natural Products Pub Date : 2025-07-09 DOI:10.1016/j.prenap.2025.100305

Varsha Motilal Shende, Deepti Dinesh Bandawane

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引用次数: 0

摘要

糖尿病周围神经病变（DPN）是一种常见的糖尿病致残性并发症，由氧化应激、炎症、神经变性和疼痛致敏引起。在DPN中，PPAR-γ调节炎症和脂质代谢，而TRPV1介导疼痛和神经炎症。熊果酸（UA）是一种天然的三萜，可能通过激活PPAR-γ和抑制TRPV1来减轻这些病理过程。目的评价UA单用及联用阿米替林（AMT）、甲钴胺素（MeCbl）对糖尿病大鼠神经性疼痛及生化失衡的预防作用，并通过对接分析探讨UA的分子机制。方法采用高脂饮食后注射链脲佐菌素诱导大鼠2型糖尿病。糖尿病大鼠（n = 8只/组）分别给予UA（40 mg/kg）、AMT（30 mg/kg）、MeCbl（0.5 mg/kg）或其亚有效组合治疗6周。评估包括疼痛行为、糖代谢指数、脂质谱、氧化应激和炎症生物标志物，以及胰腺和坐骨神经的组织病理学改变。通过分子对接评估UA与PPAR-γ和TRPV1的相互作用。ResultsUA治疗减少了64.0 %的痛觉过敏(P & lt; 0.05 d = 2.02)和冷触诱发痛47.2 % (P & lt; 0.05 d = 2.29),糖尿病控制相比,联合治疗改善疼痛指数超过82 % (P & lt; 0.001 d比;2.5)。UA显著提高握力（+38.4 %）和行走能力（−16.6 %）；P <； 0.05)，与糖尿病对照组相比，OGTT AUC降低了39% %，从而改善了葡萄糖耐量。UA降低il - 6(−18.9 % P & lt; 0.05 d = 2.84)和肿瘤坏死因子-α(−25.3 % P & lt; 0.05 d = 1.76),规范化的血脂(↓胆固醇26.7 %,↓甘油三酯24.4 %,↑HDL 56.9 %),和恢复氧化平衡(MDA 24.7 %,↓↑谷胱甘肽60.4 %,↑过氧化氢酶50.3 %;所有P & lt; 0.01)。组织病理学评分显示，UA和联合治疗保留了胰岛结构和神经完整性。对接结果证实了UA对PPAR-γ的中等亲和力（−6.554 kcal/mol）和与TRPV1的强结合（−8.214 kcal/mol）。结论UA的早期干预，特别是联合AMT和MeCbl，通过调节氧化应激、炎症和神经性疼痛来减轻DPN的进展。这些临床前研究结果表明，UA有潜力作为DPN治疗的补充药物，需要进一步验证。

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Antinociceptive effects of ursolic acid in rats with diabetic peripheral neuropathy: Behavioral, biochemical, and molecular docking evidence

Introduction

Diabetic peripheral neuropathy (DPN) is a common and disabling complication of diabetes, driven by oxidative stress, inflammation, nerve degeneration, and pain sensitization. In DPN, PPAR-γ regulates inflammation and lipid metabolism, while TRPV1 mediates pain and neuroinflammation. Ursolic acid (UA), a natural triterpenoid, may mitigate these pathological processes via PPAR-γ activation and TRPV1 inhibition.

Objective

To evaluate the efficacy of UA alone and in combination with amitriptyline (AMT) and methylcobalamin (MeCbl) in preventing neuropathic pain and biochemical imbalance in diabetic rats, and to investigate UA’s molecular mechanism through docking analysis.

Methods

Type 2 diabetes was induced in Sprague-Dawley rats using a high-fat diet followed by streptozotocin injection. Diabetic rats (n = 8/group) were treated with UA (40 mg/kg), AMT (30 mg/kg), MeCbl (0.5 mg/kg), or their subeffective combinations for 6 weeks. Evaluations included pain behaviors, glycometabolic indices, lipid profile, oxidative stress and inflammatory biomarkers, and histopathological alterations in pancreas and sciatic nerve. UA’s interaction with PPAR-γ and TRPV1 was assessed via molecular docking.

Results

UA treatment reduced hyperalgesia by 64.0 % (P < 0.05, d = 2.02) and cold allodynia by 47.2 % (P < 0.05, d = 2.29), compared to diabetic control, while combination therapy improved both pain indices by over 82 % (P < 0.001, d > 2.5). UA significantly enhanced grip strength (+38.4 %) and walking ability (−16.6 % time; P < 0.05), and improved glucose tolerance by reducing OGTT AUC by 39 % compared to diabetic control. UA lowered IL-6 (−18.9 %, P < 0.05, d = 2.84) and TNF-α (−25.3 %, P < 0.05, d = 1.76), normalized lipid profile (↓cholesterol by 26.7 %, ↓triglycerides by 24.4 %, ↑HDL by 56.9 %), and restored oxidative balance (↓MDA by 24.7 %, ↑GSH by 60.4 %, ↑catalase by 50.3 %; all P < 0.01). Histopathological scores showed preserved islet architecture and nerve integrity with UA and combination treatments. Docking results confirmed moderate affinity of UA for PPAR-γ (−6.554 kcal/mol) and strong binding to TRPV1 (−8.214 kcal/mol).

Conclusion

Early intervention with UA, particularly in combination with AMT and MeCbl, attenuated DPN progression by modulating oxidative stress, inflammation, and neuropathic pain. These preclinical findings suggest UA’s potential as a complementary agent in DPN management, warranting further validation.

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Pharmacological Research - Natural Products

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