Department of Molecular and Translational Medicine, Center of Emphasis in Diabetes and Metabolism, Texas Tech University Health Sciences Center El Paso, El Paso, TX 79912, USA.
Int J Mol Sci. 2020 Jan 30;21(3):881. doi: 10.3390/ijms21030881.
Diabetes is a global epidemic and more than 50% diabetic patients are also diagnosed with neuropathy, which greatly affects the quality of life of the patients. Available treatments are not always successful due to the limited efficacy and complications, such as addiction and dependency. Studies have implicated that high mobility group box1 (HMGB1) protein plays a crucial role in neuroinflammation and the development of neuropathic conditions. HMGB1 is a proinflammatory cytokine that can be released from necrotic cells in passive form or in response to inflammatory signals as an active form. HMGB1 is the ligand for the receptor for advanced glycation end products (RAGE), and toll-like receptors, (TLR)-2 and TLR4, which also indirectly activates C-X-C chemokine receptor type 4 (CXCR4). We investigated whether blocking of HMGB1 can reduce pain and inflammation in diabetic neuropathic animals to further understand the role of HMGB1 in diabetic neuropathy. Type 2 diabetic rats and mice were treated with natural inhibitor of HMGB1, glycyrrhizin (GLC) for five days/week for four weeks at a dose of 50 mg/kg per day by intraperitoneal injection. The animals were divided into three categories: naïve control, diabetic alone, diabetic with GLC treatment. All of the behavioral analyses were conducted before and after the treatment. The expression of inflammatory markers and changes in histone acetylation in the peripheral nervous system were measured by immunohistochemistry and Western blot analysis after the completion of the treatment. Our study revealed that TLR4, HMGB1, CXCR4, and Nod-like receptor protein 3 (NLRP3) levels were increased in the spinal and dorsal root ganglia (DRG) neurons of Type 2 diabetic mice and rats with painful neuropathy. GLC treatment inhibited the increases in TLR4, NLRP3, and CXCR4 expressions and improved the mechanical and thermal pain threshold in these animals. Immunohistochemical studies revealed that hyperglycemia mediated inflammation influenced HMGB1 acetylation and its release from the neurons. It also altered histone 3 acetylation in the microglial cells. The inhibition of HMGB1 by GLC prevented the release of HMGB1 as well as H3K9 acetylation. These findings indicate that the interruption of HMGB1 mediated inflammation could ameliorate diabetic neuropathy and might exhibit a unique target for the treatment.
糖尿病是一种全球性的流行病，超过 50%的糖尿病患者还被诊断患有神经病变，这极大地影响了患者的生活质量。由于疗效有限和存在成瘾和依赖等并发症，现有的治疗方法并不总是有效。研究表明，高迁移率族蛋白 B1（HMGB1）蛋白在神经炎症和神经病变的发展中起着关键作用。HMGB1 是一种促炎细胞因子，可作为无活性形式从坏死细胞中释放，也可作为活性形式响应炎症信号释放。HMGB1 是晚期糖基化终产物（RAGE）受体、Toll 样受体（TLR）-2 和 TLR4 的配体，也间接激活 C-X-C 趋化因子受体 4（CXCR4）。我们研究了阻断 HMGB1 是否可以减轻糖尿病神经病变动物的疼痛和炎症，以进一步了解 HMGB1 在糖尿病神经病变中的作用。2 型糖尿病大鼠和小鼠每周腹腔注射 50mg/kg 的天然 HMGB1 抑制剂甘草酸（GLC），连续 5 天/周，共 4 周。动物分为三组：正常对照组、糖尿病组、糖尿病加 GLC 治疗组。所有行为分析均在治疗前后进行。治疗完成后，通过免疫组织化学和 Western blot 分析测量外周神经系统中炎症标志物的表达和组蛋白乙酰化的变化。我们的研究表明，TLR4、HMGB1、CXCR4 和 Nod 样受体蛋白 3（NLRP3）在 2 型糖尿病小鼠和伴有痛性神经病变的大鼠的脊髓和背根神经节（DRG）神经元中表达增加。GLC 治疗抑制了 TLR4、NLRP3 和 CXCR4 表达的增加，并改善了这些动物的机械和热痛阈值。免疫组织化学研究表明，高血糖介导的炎症影响 HMGB1 的乙酰化及其从神经元中的释放，并改变小胶质细胞中的组蛋白 3 乙酰化。GLC 抑制 HMGB1 可防止 HMGB1 的释放以及 H3K9 的乙酰化。这些发现表明，阻断 HMGB1 介导的炎症可能改善糖尿病神经病变，并可能为治疗提供一个独特的靶点。
