Ali Syed Afroz, Datusalia Ashok Kumar
Laboratory of Molecular NeuroTherapeutics, Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, Raebareli, Uttar Pradesh, India.
Department of Regulatory Toxicology, National Institute of Pharmaceutical Education and Research, Raebareli, Uttar Pradesh, India.
Phytother Res. 2025 Mar;39(3):1422-1437. doi: 10.1002/ptr.8430. Epub 2025 Jan 10.
Hepatic encephalopathy (HE) is a complex neurological disorder in individuals with liver diseases, necessitating effective neuroprotective interventions to alleviate its adverse outcomes. Berberine (BBR), a natural compound with well-established anti-fibrotic and neuroprotective properties, has not been extensively studied in the context of glial activation under hyperammonaemic conditions. This study evaluates the neuroprotective potential of BBR in a thioacetamide (TAA)-induced HE rat model, focusing on its effects on glial activation and NLRP3 inflammasome signalling.
Neurological impairments were assessed using open field tests and sensory analysis. Western blotting was performed to evaluate the expression of glial and neuronal markers, tight junction proteins and NLRP3 inflammasome components in the cortex and hippocampus. Histopathological and molecular changes were further examined using H&E, immunohistochemistry and immunofluorescence staining.
BBR treatment significantly improved behavioural abnormalities and reduced systemic ammonia levels in TAA-exposed rats. It restored blood-brain barrier integrity, as evidenced by reduced tight junction protein degradation. BBR inhibited the expression of NLRP3 inflammasome markers, including caspase-1, IL-1β, ASC, and NF-κB, while reducing glial cell activation (IBA-1 and GFAP). Notably, BBR diminished NLRP3 expression in glial cells, indicating its potent anti-inflammatory effects. Additionally, BBR preserved neuronal integrity, as demonstrated by the maintained expression of MAP-2 and NeuN and reduced cleaved Gasdermin D levels.
These findings suggest that BBR alleviates behavioural and molecular abnormalities in HE through NLRP3 inflammasome inhibition, highlighting its potential as a therapeutic agent for managing HE.
肝性脑病（HE）是一种发生于肝病患者的复杂神经紊乱疾病，需要有效的神经保护干预措施来减轻其不良后果。黄连素（BBR）是一种具有公认的抗纤维化和神经保护特性的天然化合物，在高氨血症条件下神经胶质细胞激活的背景下尚未得到广泛研究。本研究评估了BBR在硫代乙酰胺（TAA）诱导的HE大鼠模型中的神经保护潜力，重点关注其对神经胶质细胞激活和NLRP3炎性小体信号传导的影响。
使用旷场试验和感觉分析评估神经功能障碍。进行蛋白质免疫印迹法以评估皮质和海马中神经胶质细胞和神经元标志物、紧密连接蛋白和NLRP3炎性小体成分的表达。使用苏木精-伊红染色、免疫组织化学和免疫荧光染色进一步检查组织病理学和分子变化。
BBR治疗显著改善了TAA暴露大鼠的行为异常并降低了全身氨水平。它恢复了血脑屏障的完整性，紧密连接蛋白降解减少证明了这一点。BBR抑制了NLRP3炎性小体标志物的表达，包括半胱天冬酶-1、白细胞介素-1β、凋亡相关斑点样蛋白（ASC）和核因子κB，同时减少了神经胶质细胞激活（离子钙结合衔接分子1和胶质纤维酸性蛋白）。值得注意的是，BBR降低了神经胶质细胞中NLRP3的表达，表明其具有强大的抗炎作用。此外，BBR保持了神经元的完整性，微管相关蛋白2和神经元核抗原的持续表达以及裂解的Gasdermin D水平降低证明了这一点。
这些发现表明，BBR通过抑制NLRP3炎性小体减轻了HE中的行为和分子异常，突出了其作为治疗HE的治疗药物的潜力。
