Department of Molecular and Translational Medicine, Center of Emphasis in Diabetes and Metabolism, Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center El Paso, El Paso, TX, USA.
Department of Molecular and Translational Medicine, Texas Tech University Health Sciences Center El Paso, El Paso, TX, USA.
Mol Neurobiol. 2024 Apr;61(4):2283-2296. doi: 10.1007/s12035-023-03701-4. Epub 2023 Oct 24.
Diabetic painful neuropathy (DPN) is one of the most detrimental complications of diabetes. Alterations in neuroinflammatory mediators play significant roles in the development of DPN. Infiltration of the neutrophils and monocyte/macrophages contributes substantial role in the degenerative process of the distal sciatic nerve by forming neutrophil extracellular traps (NETs) under diabetic condition. Citrullination of histones due to increase in protein arginine deiminase (PAD) enzyme activity under hyperglycemia may promote NET formation, which can further increase the cytokine production by activating macrophages and proliferation of neutrophils. This study reveals that the increase in histone deacetylases (HDAC) is crucial in DPN and inhibition of HDAC using HDAC inhibitor (HDACi) FK228 would suppress NETosis and alleviate diabetic nerve degeneration and pain. FK228, also known as romidepsin, is FDA approved for the treatment of cutaneous T-cell lymphoma yet the molecular mechanisms of this drug are not completely understood in DPN. In this study, type 2 diabetic (T2D) mice with pain were treated with HDACi, FK228 1 mg/kg; I.P. 2 × /week for 3 weeks. The results demonstrate that FK228 treatment can alleviate thermal hyperalgesia and mechanical allodynia significantly along with changes in the expression of HDACs in the dorsal root ganglia (DRG) and spinal cord dorsal horn neurons of diabetic animals. The results also indicate that FK228 treatment can alter the expression of neutrophil elastase (NE), extracellular or cell free DNA (cfDNA), citrullinated histone-3 (CitH3), PADI4, growth-associated protein (GAP)-43, and glucose transporter (GLUT)-4. Overall, this study suggests that FK228 could amend the expression of nerve regeneration markers and inflammatory mediators in diabetic animals and may offer an alternative treatment approach for DPN.
糖尿病性痛性神经病（DPN）是糖尿病最具危害性的并发症之一。神经炎症介质的改变在 DPN 的发展中起着重要作用。在高血糖条件下，由于蛋白精氨酸脱亚氨酶（PAD）酶活性增加导致组蛋白瓜氨酸化，可能会促进 NET 的形成，NET 的形成可以通过激活巨噬细胞和中性粒细胞增殖进一步增加细胞因子的产生。本研究表明，组蛋白去乙酰化酶（HDAC）的增加在 DPN 中至关重要，使用 HDAC 抑制剂（HDACi）FK228 抑制 HDAC 会抑制 NET 形成并减轻糖尿病神经变性和疼痛。FK228，也称为罗米地辛，已被 FDA 批准用于治疗皮肤 T 细胞淋巴瘤，但在 DPN 中，该药物的分子机制尚不完全清楚。在这项研究中，患有疼痛的 2 型糖尿病（T2D）小鼠用 HDACi，FK228 1mg/kg；腹腔注射 2×/周，共 3 周。结果表明，FK228 治疗可显著缓解糖尿病动物背根神经节（DRG）和脊髓背角神经元中热痛觉过敏和机械性痛觉过敏，同时改变 DRG 和脊髓背角神经元中 HDAC 的表达。结果还表明，FK228 治疗可以改变中性粒细胞弹性蛋白酶（NE）、细胞外或无细胞 DNA（cfDNA）、瓜氨酸化组蛋白-3（CitH3）、PADI4、生长相关蛋白（GAP）-43 和葡萄糖转运蛋白（GLUT）-4 的表达。总的来说，这项研究表明 FK228 可能改善糖尿病动物神经再生标志物和炎症介质的表达，并可能为 DPN 提供一种替代治疗方法。
