Department of Biochemistry, PGIMER, Chandigarh, India 160012.
Biol Trace Elem Res. 2013 Jun;153(1-3):257-68. doi: 10.1007/s12011-013-9665-0. Epub 2013 Apr 24.
Animal models of copper toxicosis rarely exhibit neurological impairments and increased brain copper accumulation impeding the development of novel therapeutic approaches to treat neurodegenerative diseases having high brain Cu content. The aim of this study was to investigate the effects of intraperitoneally injected copper lactate (0.15 mg Cu/100 g body weight) daily for 90 days on copper and zinc levels in the liver and hippocampus, on biochemical parameters, and on neurobehavioral functions (by Morris water maze) of male Wistar rats. Copper-administered animals exhibited significantly decreased serum acetylcholinesterase (AChE) activity and impaired neuromuscular coordination and spatial memory compared to control rats. Copper-intoxicated rats showed significant increase in liver and hippocampus copper content (99.1 and 73 % increase, respectively), 40.7 % reduction in hepatic zinc content, and interestingly, 77.1 % increase in hippocampus zinc content with concomitant increase in copper and zinc levels in serum and urine compared to control rats. Massive grade 4 copper depositions and grade 1 copper-associated protein in hepatocytes of copper-intoxicated rats were substantiated by rhodanine and orcein stains, respectively. Copper-intoxicated rats demonstrated swelling and increase in the number of astrocytes and copper deposition in the choroid plexus, with degenerated neurons showing pyknotic nuclei and dense eosinophilic cytoplasm. In conclusion, the present study shows the first evidence in vivo that chronic copper toxicity causes impaired spatial memory and neuromuscular coordination, swelling of astrocytes, decreased serum AChE activity, copper deposition in the choroid plexus, neuronal degeneration, and augmented levels of copper and zinc in the hippocampus of male Wistar rats.
动物铜中毒模型很少出现神经损伤和大脑铜积累增加，这阻碍了开发治疗富含大脑铜的神经退行性疾病的新疗法。本研究旨在研究每天腹腔注射乳酸铜（0.15mgCu/100g 体重）90 天对雄性 Wistar 大鼠肝脏和海马中铜和锌水平、生化参数以及神经行为功能（通过 Morris 水迷宫）的影响。与对照组大鼠相比，给予铜的动物表现出显著降低的血清乙酰胆碱酯酶（AChE）活性和神经肌肉协调及空间记忆受损。铜中毒大鼠的肝脏和海马铜含量分别显著增加（分别增加 99.1%和 73%），肝脏锌含量减少 40.7%，有趣的是，海马锌含量增加 77.1%，同时血清和尿液中铜和锌水平也增加，与对照组大鼠相比。铜中毒大鼠的肝细胞中存在大量 4 级铜沉积物和 1 级铜相关蛋白，这分别通过罗丹明和鞣酸红染色得到证实。铜中毒大鼠表现出星形胶质细胞肿胀和数量增加，脉络丛铜沉积，变性神经元出现固缩核和浓密嗜酸性细胞质。总之，本研究首次在体内证明慢性铜中毒会导致空间记忆和神经肌肉协调受损、星形胶质细胞肿胀、血清 AChE 活性降低、脉络丛铜沉积、神经元变性以及雄性 Wistar 大鼠海马中铜和锌水平升高。
