Department of Pharmacology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.
Oxid Med Cell Longev. 2009 Jan-Mar;2(1):26-35. doi: 10.4161/oxim.2.1.7901.
Hippocampal integrity is essential for cognitive functions. On the other hand, induction of metallothionein (MT) by ZnSO(4) and its role in neuroprotection has been documented. The present study aimed to explore the effect of MT induction on carmustine (BCNU)-induced hippocampal cognitive dysfunction in rats. A total of 60 male Wistar albino rats were randomly divided into four groups (15/group): The control group injected with single doses of normal saline (i.c.v) followed 24 h later by BCNU solvent (i.v). The second group administered ZnSO(4) (0.1 micromol/10 microl normal saline, i.c.v, once) then BCNU solvent (i.v) after 24 h. Third group received BCNU (20 mg/kg, i.v, once) 24 h after injection with normal saline (i.c.v). Fourth group received a single dose of ZnSO(4) (0.1 micromol/10 microl normal saline, i.c.v) then BCNU (20 mg/kg, i.v, once) after 24 h. The obtained data revealed that BCNU administration resulted in deterioration of learning and short-term memory (STM), as measured by using radial arm water maze, accompanied with decreased hippocampal glutathione reductase (GR) activity and reduced glutathione (GSH) content. Also, BCNU administration increased serum tumor necrosis factor-alpha (TNFalpha), hippocampal MT and malondialdehyde (MDA) contents as well as caspase-3 activity in addition to histological alterations. ZnSO(4) pretreatment counteracted BCNU-induced inhibition of GR and depletion of GSH and resulted in significant reduction in the levels of MDA and TNFalpha as well as the activity of caspase-3. The histological features were improved in hippocampus of rats treated with ZnSO(4) + BCNU compared to only BCNU-treated animals. In conclusion, MT induction halts BCNU-induced hippocampal toxicity as it prevented GR inhibition and GSH depletion and counteracted the increased levels of TNFalpha, MDA and caspase-3 activity with subsequent preservation of cognition.
海马完整性对于认知功能至关重要。另一方面，已经有研究证明 ZnSO4诱导金属硫蛋白（MT）及其在神经保护中的作用。本研究旨在探讨 MT 诱导对卡莫司汀（BCNU）诱导的大鼠海马认知功能障碍的影响。将 60 只雄性 Wistar 白化大鼠随机分为四组（每组 15 只）：对照组单次注射生理盐水（i.c.v），24 小时后注射 BCNU 溶剂（i.v）。第二组给予 ZnSO4（0.1 微摩尔/10 微升生理盐水，i.c.v，单次），24 小时后注射 BCNU 溶剂（i.v）。第三组给予 BCNU（20mg/kg，i.v，单次），24 小时后注射生理盐水（i.c.v）。第四组给予单次剂量的 ZnSO4（0.1 微摩尔/10 微升生理盐水，i.c.v），24 小时后注射 BCNU（20mg/kg，i.v，单次）。结果显示，BCNU 给药导致学习和短期记忆（STM）恶化，这可以通过使用放射臂水迷宫来测量，同时伴随着海马谷胱甘肽还原酶（GR）活性降低和谷胱甘肽（GSH）含量减少。此外，BCNU 给药增加了血清肿瘤坏死因子-α（TNFalpha）、海马 MT 和丙二醛（MDA）含量以及半胱氨酸天冬氨酸蛋白酶-3（caspase-3）活性，以及组织学改变。ZnSO4预处理可拮抗 BCNU 诱导的 GR 抑制和 GSH 耗竭，并显著降低 MDA 和 TNFalpha 水平以及 caspase-3 活性。与仅接受 BCNU 治疗的动物相比，ZnSO4+BCNU 治疗的大鼠海马组织学特征得到改善。综上所述，MT 诱导可阻止 BCNU 诱导的海马毒性，因为它可以防止 GR 抑制和 GSH 耗竭，并拮抗 TNFalpha、MDA 和 caspase-3 活性的增加，从而维持认知功能。
