Diverse effects of metal chelating agents on the neuronal cytotoxicity of zinc in the hippocampus
Diverse effects of metal chelating agents on the neuronal cytotoxicity of zinc in the hippocampus
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DOI：
10.1016/s0006-8993(98)00482-x
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发表时间：
1998-07-13
期刊：
影响因子：
2.9
通讯作者：
Lees, GJ
中科院分区：
文献类型：
--
作者：
Cuajungco, MP;Lees, GJ
锌等金属离子代谢异常可能导致神经病理学改变。复合锌可以减少这种病理。因此，为了检查金属螯合剂在体内的有效性，使用了模型系统。这涉及到确定螯合剂的能力，以防止注射到大鼠海马体的氯化锌引起的神经元死亡。用嘧啶核苷、肌醇六磷酸、乙二胺四乙酸盐（EDTA）和N，N，N ′，N ′-四（2-吡啶基甲基）乙二胺（TPEN）对锌毒性有显著的保护作用。这些试剂对锌的亲和力在10（6）M-1和10（18）M-1之间变化。因此，在此范围内对锌的亲和力似乎不是影响螯合剂提供神经保护能力的主要因素。虽然EDTA和TPEN与氯化锌同时给药时发现几乎完全的保护作用，但如果在氯化锌之前或之后给药TPEN，则保护作用较差。其他药物要么不能防止锌诱导的神经元死亡（zincon），要么加重锌毒性（BTC-5 N和约40%的大鼠注射了氯化锌和二亚乙基三胺五乙酸盐[DTPA]的组合）。在锌加BTC-5 N或DTPA后表现出增加的损伤的大鼠遭受湿狗样颤抖（WDS），表明这些锌螯合物可以诱导癫痫发作，导致癫痫相关的损伤。相比之下，在60%接受氯化锌和DTPA治疗的大鼠中，没有WDS，锌诱导的病变大小减少了约80%。螯合剂穿过细胞膜的能力进行了检查，通过确定是否Timm的染色泡状锌减少后，注射到海马体的螯合剂。TPEN和吡嘧磺隆减少了锌的Timm染色。然而，细胞渗透性对于螯合剂保护免受锌毒性是不必要的。(C)1998 Elsevier Science B. V.保留所有权利。
Abnormal metabolism of metal ions such as zinc may contribute to neuropathology. Complexing zinc could reduce this pathology. Thus, to examine the effectiveness of metal chelating agents in vivo, a model system was used. This involved determining the ability of chelating agents to prevent neuronal death caused by zinc chloride injected into the rat hippocampus. Significant protection against zinc toxicity was obtained with pyrithione, inositol hexakisphosphate, ethylenediamine tetraacetate (EDTA) and N,N,N',N'-tetrakis(2-pyridylmethyl)ethylenediamine (TPEN). The affinity of these agents for zinc varied between 10(6) M-1 and 10(18) M-1. Thus, the affinity for zinc within this range does not appear to be a major factor affecting the ability of chelators to provide neuroprotection. While almost complete protection was found with EDTA and TPEN given simultaneously with zinc chloride, poor protection was obtained if TPEN was given before or after zinc chloride. Other agents either did not protect against zinc-induced neuronal death (zincon), or exacerbated zinc toxicity (BTC-5N and about 40% of rats injected with a combination of zinc chloride and diethylenetriamine pentaacetate [DTPA]). Rats showing increased damage after zinc plus BTC-5N or DTPA suffered wet dog-like shakes (WDS), suggesting that these zinc chelate complexes can induce seizures resulting in seizure-related damage. In contrast, in the 60% of rats treated with zinc chloride and DTPA that had no WDS, there was' about an 80% reduction in the size of the zinc-induced lesion. The ability of chelators to cross cell membranes was examined by determining whether Timm's staining for vesicular zinc was reduced following the injection of a chelator into the hippocampus. TPEN and pyrithione reduced Timm's staining for zinc. However, cell permeability was not necessary for a chelator to protect against zinc toxicity. (C) 1998 Elsevier Science B.V. All rights reserved.