Gautam Pratham, Singh Varinder, Kanwar Navjot, Shri Richa, Singh Tanveer, Singh Manjinder, Singh Thakur Gurjeet, Grewal Amarjot Kaur, Kumar Amit, Singh Ravinder, Ahmad Sheikh F, Al-Mazroua Haneen A
Department of Pharmaceutical Sciences and Technology, Maharaja Ranjit Singh Punjab Technical University, Bathinda, Punjab, India.
Department of Pharmaceutical Sciences and Technology, Maharaja Ranjit Singh Punjab Technical University, Bathinda, Punjab, India.
Neurotoxicology. 2025 Aug 30;111:103310. doi: 10.1016/j.neuro.2025.103310.
Lead (Pb) neurotoxicity remains a global concern, causing irreversible cognitive and motor impairments through mechanisms like mitochondrial dysfunction, oxidative stress and inflammation. Transcription Factor EB (TFEB), a master regulator of lysosomal biogenesis and autophagy that also coordinates mitochondrial function, has emerged as a novel target in neuroprotection. This study evaluated the neuroprotective potential of hesperidin (natural flavonoid) against Pb-induced neurotoxicity, with a focus on the role of TFEB. Rats were orally administered lead acetate (100 mg/kg) once daily for 30 days to induce neurotoxicity, followed by hesperidin (50 and 100 mg/kg, p.o.) treatment. Cognitive and motor functions were assessed through Morris Water Maze and rotarod tests, while biochemical analyses measured oxidative stress markers (TBARS, GSH), inflammatory cytokines (TNF-α, IL-6, NF-κB), and mitochondrial complex I-III activities. Pb exposure significantly impaired learning, memory, and motor coordination, increased oxidative and inflammatory markers, and reduced mitochondrial function. Hesperidin treatment improved behavioral outcomes and restored redox balance, inflammatory markers and mitochondrial enzyme activity. However, co-treatment with eltrombopag, a TFEB inhibitor, abolished these protective effects, confirming TFEB's involvement. These findings highlight hesperidin's ability to mitigate Pb neurotoxicity through TFEB-mediated restoration of mitochondrial function and suppression of oxidative stress and inflammation. Targeting TFEB may offer a novel therapeutic strategy for heavy metal-induced neurodegeneration.
铅（Pb）神经毒性仍是全球关注的问题，它通过线粒体功能障碍、氧化应激和炎症等机制导致不可逆的认知和运动障碍。转录因子EB（TFEB）是溶酶体生物发生和自噬的主要调节因子，也协调线粒体功能，已成为神经保护的新靶点。本研究评估了橙皮苷（天然类黄酮）对铅诱导的神经毒性的神经保护潜力，重点关注TFEB的作用。大鼠每天口服醋酸铅（100 mg/kg），持续30天以诱导神经毒性，随后进行橙皮苷（50和100 mg/kg，口服）治疗。通过莫里斯水迷宫和转棒试验评估认知和运动功能，同时通过生化分析测量氧化应激标志物（TBARS、GSH）、炎性细胞因子（TNF-α、IL-6、NF-κB）和线粒体复合体I-III活性。铅暴露显著损害学习、记忆和运动协调能力，增加氧化和炎症标志物，并降低线粒体功能。橙皮苷治疗改善了行为结果，恢复了氧化还原平衡、炎症标志物和线粒体酶活性。然而，与TFEB抑制剂艾曲泊帕共同治疗消除了这些保护作用，证实了TFEB的参与。这些发现突出了橙皮苷通过TFEB介导的线粒体功能恢复以及氧化应激和炎症抑制来减轻铅神经毒性的能力。靶向TFEB可能为重金属诱导的神经退行性变提供一种新的治疗策略。
