The hippocampal region of rats and mice after a single i.p. dose of clioquinol: loss of synaptic zinc, cell death and c-Fos induction.
Clioquinol (CQ) is able to chelate synaptic zinc, which can modulate excitatory and inhibitory neurotransmission. In humans, CQ was associated with cases of transient global amnesia (TGA) and with the neurodegenerative syndrome subacute myelo-optico-neuropathy (SMON). We examined the CQ induced loss of synaptic zinc, cell death and c-Fos induction in rats and mice. In rats, we found a strong reduction of histochemically reactive synaptic zinc no later than 4 h after the injection of the lowest dose of CQ (50 mg/kg) and, for all doses used, a return to control levels after 48 h. There was no evidence of cell death for any dose and up to 1 week after CQ injections. Only a slight induction of c-Fos was seen in the hippocampus for the higher doses used (100-200 mg/kg). In mice injected with 100 mg/kg, CQ also resulted in a fast loss of synaptic zinc. c-Fos was induced after 4 h in cell populations of the hippocampal region and other parts of the telencephalon, and substantially increased after 24 h. One day after the injection we found a pattern of cell loss (hilus, parts of CA3, CA1 and layer III of the medial entorhinal cortex) reminiscent of that seen in models of temporal lobe epilepsy. In conjunction with published data on the behavioral effects of zinc chelation and the modulatory effects of zinc in excitatory neurotransmission, our results indicate that the loss of synaptic zinc may have been involved in TGA and the neuropathology associated with SMON.
Department of Anatomy, University of Zürich, Winterthurerstr. 190, 8057 Zürich, Switzerland.
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Ismail
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Mauerhofer
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Slomianka
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D007464:Clioquinol / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006624:Hippocampus / Q000166:cytology* / Q000187:drug effects*; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism*; D051381:Rats; D011921:Rats, Inbred WKY; D017207:Rats, Sprague-Dawley; D013569:Synapses / Q000187:drug effects* / Q000378:metabolism; D013997:Time Factors; D015032:Zinc / Q000378:metabolism*
D016760:Proto-Oncogene Proteins c-fos; D007464:Clioquinol; D015032:Zinc