Abo-Elsoud Reda A A, Ali Eman A, Al-Gholam Marwa A, Rizk Mohamed S, Elseadawy Rasha S A, Ameen Omnia
Medical Physiology Department, Faculty of Medicine, Menoufia University, Shebin El Kom, Menoufia, Egypt.
Clinical Pharmacology Department, Faculty of Medicine, Menoufia University, Shebin El Kom, Menoufia, Egypt.
Naunyn Schmiedebergs Arch Pharmacol. 2025 Apr;398(4):4019-4036. doi: 10.1007/s00210-024-03496-8. Epub 2024 Oct 15.
Multiple sclerosis (MS) is a demyelinating disease affecting the central nervous system associated with progressive neurodegeneration. Pirfenidone (Pir) is a well-known antifibrotic agent; however, Pir's function in MS is little explored. We evaluated the neuroprotective effects of Pir in MS and its possible underlying mechanisms. Forty male Swiss mice were divided equally into control, cuprizone (CPZ), Pir, and CPZ + Pir groups. Assessment of motor function was conducted using neurobehavioral tests, EMG, and nerve conduction velocity (NCV). Mice's brains were extracted to measure oxidative stress, neuroinflammatory markers, and the expression of neurotrophic genes. The corpus callosum and the sciatic nerve were subjected to histopathological and immunohistochemical studies. The CPZ group was associated with significant reductions in muscle power, frequency of contraction, sciatic NCV, SOD, IL-10, SIRT1, NGF, and neuregulin-1. Significant increases in MDA, TNF-α, INF-γ, IL-17, TGF-β, and NF-κB were also detected. Multiple areas of partially demyelinated nerve fibers in the corpus callosum, the loss of oligodendrocyte nuclei, and increased microglia and astrocytes were also observed. The sciatic nerve revealed partial demyelination with significantly reduced myelin basic protein (MBP) expression. Pir significantly restored motor function, demyelination, and neurodegenerative changes induced by CPZ. Besides the antifibrotic action of Pir, we concluded that it improves motor function in MS by alleviating the demyelinating process and neurodegeneration. Its potential anti-inflammatory, antioxidant, and antifibrotic properties could be contributing factors. These effects could be mediated by modulating the NF-κB, SIRT1, NGF, and neuregulin-1 pathways. Pir is a promising agent for treating MS.
多发性硬化症（MS）是一种影响中枢神经系统的脱髓鞘疾病，与进行性神经退行性变有关。吡非尼酮（Pir）是一种著名的抗纤维化药物；然而，Pir在MS中的作用鲜少被研究。我们评估了Pir在MS中的神经保护作用及其可能的潜在机制。40只雄性瑞士小鼠被平均分为对照组、铜螯合剂（CPZ）组、Pir组和CPZ + Pir组。使用神经行为测试、肌电图和神经传导速度（NCV）评估运动功能。提取小鼠大脑以测量氧化应激、神经炎症标志物和神经营养基因的表达。对胼胝体和坐骨神经进行组织病理学和免疫组织化学研究。CPZ组与肌肉力量、收缩频率、坐骨神经NCV、超氧化物歧化酶（SOD）、白细胞介素-10（IL-10）、沉默信息调节因子1（SIRT1）、神经生长因子（NGF）和神经调节蛋白-1显著降低有关。还检测到丙二醛（MDA）、肿瘤坏死因子-α（TNF-α）、干扰素-γ（INF-γ）、白细胞介素-17（IL-17）、转化生长因子-β（TGF-β）和核因子-κB（NF-κB）显著增加。在胼胝体中还观察到多个部分脱髓鞘神经纤维区域、少突胶质细胞核的丧失以及小胶质细胞和星形胶质细胞的增加。坐骨神经显示部分脱髓鞘，髓鞘碱性蛋白（MBP）表达显著降低。Pir显著恢复了CPZ诱导的运动功能、脱髓鞘和神经退行性变化。除了Pir的抗纤维化作用外，我们得出结论，它通过减轻脱髓鞘过程和神经退行性变来改善MS中的运动功能。其潜在的抗炎、抗氧化和抗纤维化特性可能是促成因素。这些作用可能通过调节NF-κB、SIRT1、NGF和神经调节蛋白-1途径来介导。Pir是一种有前途的治疗MS的药物。
