Zhang X, Wang X, Wang J, Shao N, Cai B, Xie D
School of Integrated Chinese and Western Medicine, Anhui University of Chinese Medicine, Hefei 230012, China.
First Clinical Medical College, Anhui University of Chinese Medicine, Hefei 230012, China.
Nan Fang Yi Ke Da Xue Xue Bao. 2024 Mar 20;44(3):447-454. doi: 10.12122/j.issn.1673-4254.2024.03.05.
To investigate the neuroprotective effect of Capsule (HPTQ) in a rat model of Wilson disease (WD) and explore the underlying mechanisms.
SD rat models of WD were established by feeding of coppersupplemented chow diet and drinking water for 12 weeks, and starting from the 9th week, the rats were treated with low-, moderate- and high-dose HPTQ, penicillamine, or normal saline by gavage on a daily basis for 3 weeks. Copper levels in the liver and 24-h urine of the rats were detected, and their learning and memory abilities were evaluated using Morris water maze test. HE staining was used to observe morphological changes of CA1 region neurons in the hippocampus, and neuronal apoptosis was detected with TUNEL staining. Hippocampal expressions of endoplasmic reticulum stress (ERS)-mediated apoptosis pathway-related proteins GRP78, CHOP, caspase-12, cleaved caspase-9, and cleaved caspase-3 at both the mRNA and protein levels were detected using RT-qPCR, immunofluorescence assay or Western blotting.
Compared with normal control rats, the rat models with copper overload-induced WD exhibited significantly increased copper levels in both the liver and 24-h urine, impaired learning and memory abilities, obvious hippocampal neuronal damage in the CA1 region and increased TUNEL-positive neurons (<0.01), with also lowered mRNA and protein expressions of GRP78, CHOP, caspase-12, cleaved caspase-9, and cleaved caspase-3 in the hippocampus (all <0.01). Treatments with HPTQ and penicillamine significantly lowered copper level in the liver but increased urinary copper level, improved learning and memory ability, alleviated neuronal damage and apoptosis in the hippocampus, and decreased hippocampal expressions of GRP78, CHOP, caspase-12, cleaved caspase-9, and cleaved caspase-3 in the rat models (<0.01 or 0.05).
HPTQ Capsule has neuroprotective effects in rat models of WD possibly by inhibiting ERS-mediated apoptosis pathway.
研究[药物名称]胶囊（HPTQ）对威尔逊病（WD）大鼠模型的神经保护作用，并探讨其潜在机制。
通过喂食含铜饲料和饮水12周建立WD的SD大鼠模型，从第9周开始，大鼠每日分别灌胃低、中、高剂量的HPTQ、青霉胺或生理盐水，持续3周。检测大鼠肝脏和24小时尿液中的铜水平，并使用莫里斯水迷宫试验评估其学习和记忆能力。采用HE染色观察海马CA1区神经元的形态变化，并用TUNEL染色检测神经元凋亡。使用RT-qPCR、免疫荧光分析或蛋白质印迹法检测海马中内质网应激（ERS）介导的凋亡途径相关蛋白GRP78、CHOP、caspase-12、裂解的caspase-9和裂解的caspase-3在mRNA和蛋白质水平的表达。
与正常对照大鼠相比，铜过载诱导的WD大鼠模型肝脏和24小时尿液中的铜水平显著升高，学习和记忆能力受损，海马CA1区神经元明显受损，TUNEL阳性神经元增加（<0.01），海马中GRP78、CHOP、caspase-12、裂解的caspase-9和裂解的caspase-3的mRNA和蛋白质表达也降低（均<0.01）。HPTQ和青霉胺治疗可显著降低肝脏铜水平，但增加尿铜水平，改善学习和记忆能力，减轻海马神经元损伤和凋亡，并降低大鼠模型中海马GRP78, CHOP, caspase-12, 裂解的caspase-9和裂解的caspase-3的表达（<0.01或0.05）。
HPTQ胶囊对WD大鼠模型具有神经保护作用，可能是通过抑制ERS介导的凋亡途径实现的。
