Enhanced seizures and hippocampal neurodegeneration following kainic acid-induced seizures in metallothionein-I plus II-deficient mice
Enhanced seizures and hippocampal neurodegeneration following kainic acid-induced seizures in metallothionein-I plus II-deficient mice
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DOI：
10.1046/j.1460-9568.2000.00128.x
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发表时间：
2000-07-01
影响因子：
3.4
通讯作者：
Hidalgo, J
中科院分区：
文献类型：
--
作者：
Carrasco, J;Penkowa, M;Hidalgo, J
金属硫蛋白（MTs）是中枢神经系统中主要的锌结合蛋白，可能参与锌代谢的控制以及抗氧化应激的保护。由于靶基因失活而缺乏MT- i和MT-II （MT- i + II缺陷）的小鼠注射了kainic酸（KA），一种有效的惊厥剂，以检查这些MT亚型的神经生物学重要性。在35 mg/kg KA剂量下，MT-I + II缺陷雄鼠的惊厥次数和惊厥时间均高于对照组。3天后，注射ka的小鼠海马出现神经胶质瘤和神经元损伤。通过末端脱氧核苷酸转移酶介导的原位末端标记（TUNEL）、单链DNA （ssDNA）检测以及白细胞介素-1 β转换酶（ICE）和caspase-3水平的升高显示，MT-I + II缺乏可减少星形胶质细胞和小胶质细胞的形成，并增强神经元的损伤和凋亡。与对照小鼠相比，MT-I + ii缺乏小鼠海马组织化学反应性锌的增加程度更大。通过丙二醛（MDA）和蛋白酪氨酸硝化（NITT）水平以及MT-I + II、核因子κ B （nf - κ B）和Cu/ zn -超氧化物歧化酶（Cu/Zn-SOD）的表达，ka诱导的癫痫发作也引起氧化应激增加。MT-I + II缺乏增强了KA引起的氧化应激。KA和MT-I + II缺乏均显著影响MT-III、粒细胞-巨噬细胞集落刺激因子（GM-CSF）及其受体（GM-CSFr）的表达。目前的研究结果表明，MT-I + II对ka诱导癫痫发作期间神经元的存活很重要，并且表明锌调节受损和抗氧化活性受损都有助于观察到MT-I + II缺陷小鼠的神经病理。
Metallothioneins (MTs) are major zinc binding proteins in the CNS that could be involved in the control of zinc metabolism as well as in protection against oxidative stress. Mice lacking MT-I and MT-II (MT-I + II deficient) because of targeted gene inactivation were injected with kainic acid (KA), a potent convulsive agent, to examine the neurobiological importance of these MT isoforms. At 35 mg/kg KA, MT-I + II deficient male mice showed a higher number of convulsions and a longer convulsion time than control mice. Three days later, KA-injected mice showed gliosis and neuronal injury in the hippocampus. MT-I + II deficiency decreased both astrogliosis and microgliosis and potentiated neuronal injury and apoptosis as shown by terminal deoxynucleotidyl transferase-mediated in situ end labelling (TUNEL), detection of single stranded DNA (ssDNA) and by increased interleukin-1 beta-converting enzyme (ICE) and caspase-3 levels. Histochemically reactive zinc in the hippocampus was increased by KA to a greater extent in MT-I + II-deficient compared with control mice. KA-induced seizures also caused increased oxidative stress, as suggested by the malondialdehyde (MDA) and protein tyrosine nitration (NITT) levels and by the expression of MT-I + II, nuclear factor-kappa B (NF-kappa B), and Cu/Zn-superoxide dismutase (Cu/Zn-SOD). MT-I + II deficiency potentiated the oxidative stress caused by KA. Both KA and MT-I + II deficiency significantly affected the expression of MT-III, granulocyte-macrophage colony stimulating factor (GM-CSF) and its receptor (GM-CSFr). The present results indicate MT-I + II as important for neuron survival during KA-induced seizures, and suggest that both impaired zinc regulation and compromised antioxidant activity contribute to the observed neuropathology of the MT-I + II-deficient mice.