DIVERSE EFFECTS OF METAL CHELATING-AGENTS ON THE NEURONAL CYTOTOXICITY OF ZINC IN THE HIPPOCAMPUS

Abnormal metabolism of metal ions such as zinc may contribute to neuro pathology. Complexing zinc could reduce this pathology. Thus, to exami ne the effectiveness of metal chelating agents in vivo, a model system was used. This involved determining the ability of chelating agents t o prevent neuronal death caused by zinc chloride injected into the rat hippocampus. Significant protection against zinc toxicity was obtaine d with pyrithione, inositol hexakisphosphate, ethylenediamine tetraace tate (EDTA) and N,N,N',N'-tetrakis(2-pyridylmethyl)ethylenediamine (TP EN). The affinity of these agents for zinc varied between 10(6) M-1 an d 10(18) M-1. Thus, the affinity for zinc within this range does not a ppear to be a major factor affecting the ability of chelators to provi de neuroprotection. While almost complete protection was found with ED TA and TPEN given simultaneously with zinc chloride, poor protection w as obtained if TPEN was given before or after zinc chloride. Other age nts 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 pentaaceta te [DTPA]). Rats showing increased damage after zinc plus BTC-5N or DT PA suffered wet dog-like shakes (WDS), suggesting that these zinc chel ate complexes can induce seizures resulting in seizure-related damage. In contrast, in the 60% of rats treated with zinc chloride and DTPA t hat had no WDS, there was' about an 80% reduction in the size of the z inc-induced lesion. The ability of chelators to cross cell membranes w as 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.