Comparative effects of metal chelating agents on the neuronal cytotoxicity induced by copper (Cu +2), iron (Fe +3) and zinc in the hippocampus

Abstract

The ability of metal chelating agents to prevent neuronal death caused by intra-hippocampal injections of cupric sulphate, ferric citrate and zinc chloride was investigated. Ammonium tetrathiomolybdate was itself toxic after injection into the hippocampus, but this toxicity was reduced by formation of a metal ion/tetrathiomolybdate complex with Cu +2. Disodium bathocuproine disulphonate (BCDS) prevented neuronal death caused by Cu +2, but not that induced by Fe +3 or Zn +2. Desferrioxamine prevented death caused by Fe +3, had no significant effect of the toxicity of Zn +2, and increased that caused by Cu +2. Even though N, N, N′, N′-tetrakis(2-pyridylmethyl)ethylenediamine (TPEN) has a higher affinity for Cu +2 than for Zn +2, TPEN had no effect on the toxicity of Cu +2 while totally preventing damage caused by Fe +3 or Zn +2. Ethylenediaminetetra-acetic acid (EDTA) prevented the toxicity of all three metal ions. Motor seizure activity occurred in most rats after injections of Fe +3; or combinations of Cu +2 plus TPEN, or 4 nmol Fe +3 plus 0.1 nmol desferrioxamine. However, apart from the low dose desferrioxamine/Fe +3 combination, only the occasional brain contained seizure-induced neuronal loss in limbic regions outside the injected hippocampus, and these brains were not used for analysis. Seizure activity was found even with very low levels of Cu +2 with a fixed amount of TPEN (a ratio of Cu +2/TPEN of 1:100), but the extent of hippocampal damage in these brains was not significantly different to that caused by injections of saline. These studies demonstrate that idiosyncratic interactions can occur between metal ions and chelating agents. Thus further investigations are needed before chelating agents can be examined for their protective properties in various neurodegenerative diseases.