Current nonsurgical treatments of discogenic lumbar radiculopathy are neither effective nor safe. Our prior studies have suggested that hydroxylated fullerene (fullerol) nanomaterial could attenuate proinflammatory cytokine tumor necrosis factor alpha (TNF-α)-induced neuroinflammation and oxidative stress in mouse dorsal root ganglia (DRG) and primary neurons. Here, we aim to investigate the analgesic effect of fullerol in a clinically relevant lumbar radiculopathy mouse model and to understand its underlying molecular mechanism in mouse DRGs and neurons. Surprisingly, single and local application of fullerol solution (1 μM, 10 μL) was sufficient to alleviate ipsilateral paw pain sensation in mice up to 2 weeks postsurgery. In addition, microCT data suggested fullerol potentially promoted disc height recovery following injury-induced disc herniation. Alcian blue/picrosirius red staining also suggested that fullerol promoted regeneration of extracellular matrix proteins visualized by the presence of abundant newly formed collagen and proteoglycan in herniated discs. For in vitro DRG culture, fullerol attenuated TNF-α-elicited expression of transient receptor potential cation channel subfamily V member 1 (TRPV-1) and neuropeptides release (substance P and calcitonin gene-related peptide). In addition, fullerol suppressed TNF-α-stimulated increase in intracellular Ca²⁺ concentrations in primary neurons. Moreover, Western blot analysis in DRG revealed that fullerol’s beneficial effects against TNF-α might be mediated through protein kinase B (AKT) and extracellular protein-regulated kinase (ERK) pathways. These TNF-α antagonizing and analgesic effects indicated therapeutic potential of fullerol in treating lumbar radiculopathy, providing solid preclinical evidence toward further translational studies.

中文翻译：

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羟基化富勒烯：一种通过拮抗TNF-α诱导的离子通道激活，钙信号传导和神经肽产生来治疗腰椎神经根疾病的恒星纳米药物。

椎间盘源性神经根神经病的当前非手术治疗既无效也不安全。我们以前的研究表明羟基化富勒烯（fullerol）纳米材料可以减轻促炎性细胞因子肿瘤坏死因子α（TNF-α）诱导的小鼠背根神经节（DRG）和原代神经元的神经炎症和氧化应激。在这里，我们旨在调查富勒醇在临床相关的腰神经根病小鼠模型中的镇痛作用，并了解其在小鼠DRG和神经元中的潜在分子机制。令人惊讶的是，在手术后最多两周内，一次和局部施用富勒醇溶液（1μM，10μL）足以减轻小鼠的同侧爪痛感。此外，microCT数据表明，富乐醇可能在损伤引起的椎间盘突出症后促进椎间盘高度恢复。阿尔辛蓝色/ picrosiriirius红色染色还表明，富勒醇促进了椎间盘突出的大量新形成的胶原蛋白和蛋白聚糖的存在，从而可视化了胞外基质蛋白的再生。对于体外DRG培养，富勒醇减弱了TNF-α诱导的瞬时受体电位阳离子通道亚家族V成员1（TRPV-1）的表达和神经肽的释放（P物质和降钙素基因相关肽）。此外，富勒醇抑制了TNF-α刺激的细胞内Ca的增加 阿尔辛蓝/ picrosiriirius红染色还表明，富勒醇促进了椎间盘中大量新形成的胶原蛋白和蛋白聚糖的存在，从而使胞外基质蛋白再生。对于体外DRG培养，富勒醇减弱了TNF-α诱导的瞬时受体电位阳离子通道亚家族V成员1（TRPV-1）的表达和神经肽的释放（P物质和降钙素基因相关肽）。此外，富勒醇抑制了TNF-α刺激的细胞内Ca的增加 阿尔辛蓝色/ picrosiriirius红色染色还表明，富勒醇促进了椎间盘突出的大量新形成的胶原蛋白和蛋白聚糖的存在，从而可视化了胞外基质蛋白的再生。对于体外DRG培养，富勒醇减弱了TNF-α诱导的瞬时受体电位阳离子通道亚家族V成员1（TRPV-1）的表达和神经肽的释放（P物质和降钙素基因相关肽）。此外，富勒醇抑制了TNF-α刺激的细胞内Ca的增加原代神经元中²⁺浓度。此外，DRG中的蛋白质印迹分析表明，富勒醇对TNF-α的有益作用可能是通过蛋白激酶B（AKT）和细胞外蛋白调节激酶（ERK）途径介导的。这些TNF-α拮抗和镇痛作用表明富勒醇在治疗腰椎神经根病方面具有治疗潜力，为进一步的翻译研究提供了坚实的临床前证据。