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

Abstract

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.

The pharmacological perturbation of brain zinc impairs BDNF-related signalling and the cognitive performances of young mice

“…route is highly effective in reducing the pool of chelatable Zn 2+ in the brain and the hippocampus in particular 33,39 . In agreement with previous studies [33][34][35][36][37][38] , we obtained a significant decrease of hippocampal Zn 2+ levels (Supplementary fig. 1; normalized TSQ fluorescence in control: 1.00±0.08 vs 0.49±0.04 in CQ-treated mice, p<0.001).…”

“…In this study, we investigated the cognitive effects of Zn 2+ chelation in young mice. Previous studies have shown that intraperitoneal CQ administration promotes a robust reduction of the pool of chelatable Zn 2+ in rodents [33][34][35][36][37][38] . The main finding of the study is that a 2-week administration of CQ exerts adverse effects on learning and memory performances of treated mice.…”

Blockade of intracellular Zn2+signaling in the dentate gyrus erases recognition memory via impairment of maintained LTP

“…Cell death is observed in the dentate granule cell layer 24 h after i.p. injection of CQ (100 mg/kg) into mice, while there is no evidence of cell death for any dose (50–200 mg/kg) and up 1 week after CQ injections into rats (Ismail et al, ). Thus CQ‐induced cell death may not occur in the dentate gyrus of rats.…”

Chemical Blocking of Zinc Ions in CNS Increases Neuronal Damage Following Traumatic Brain Injury (TBI) in Mice

“…Studies using the antibiotic/zinc chelator Clioquinol have revealed an association with this zinc chelating agent and transient global amnesia and neurodegenerative disorders [51]. In related areas of neurobiology, studies on Alzheimer diseased brains have shown a rather deleterious effect when removing zinc from the diet, with a subsequently increased plaque load especially in the neocortex which contains high amounts of ZEN neurons [52].…”