Zinc Chelation Reduces Hippocampal Neurogenesis after Pilocarpine-Induced Seizure

Abstract

Several studies have shown that epileptic seizures increase hippocampal neurogenesis in the adult. However, the mechanism underlying increased neurogenesis after seizures remains largely unknown. Neurogenesis occurs in the subgranular zone (SGZ) of the hippocampus in the adult brain, although an understanding of why it actively occurs in this region has remained elusive. A high level of vesicular zinc is localized in the presynaptic terminals of the SGZ. Previously, we demonstrated that a possible correlation may exist between synaptic zinc localization and high rates of neurogenesis in this area after hypoglycemia. Using a lithium-pilocarpine model, we tested our hypothesis that zinc plays a key role in modulating hippocampal neurogenesis after seizure. Then, we injected the zinc chelator, clioquinol (CQ, 30 mg/kg), into the intraperitoneal space to reduce brain zinc availability. Neuronal death was detected with Fluoro Jade-B and NeuN staining to determine whether CQ has neuroprotective effects after seizure. The total number of degenerating and live neurons was similar in vehicle and in CQ treated rats at 1 week after seizure. Neurogenesis was evaluated using BrdU, Ki67 and doublecortin (DCX) immunostaining 1 week after seizure. The number of BrdU, Ki67 and DCX positive cell was increased after seizure. However, the number of BrdU, Ki67 and DCX positive cells was significantly decreased by CQ treatment. Intracellular zinc chelator, N,N,N0,N-Tetrakis (2-pyridylmethyl) ethylenediamine (TPEN), also reduced seizure-induced neurogenesis in the hippocampus. The present study shows that zinc chelation does not prevent neurodegeneration but does reduce seizure-induced progenitor cell proliferation and neurogenesis. Therefore, this study suggests that zinc has an essential role for modulating hippocampal neurogenesis after seizure.

Administration of Zinc Chelators Improves Survival of Mice Infected with Aspergillus fumigatus both in Monotherapy and in Combination with Caspofungin

“…Our in vitro assays demonstrated that clioquinol, phenanthroline, and TPEN were the most effective independently of fungal growth stage, and they were selected for use in vivo. They all produced complete inhibition of fungal growth at low concentrations and have been previously used in animal models (18,30,33).…”

“…(i) Clioquinol (5-chloro-7-iodo-quinolin-8-ol) is a halogenated 8-hydroxyquinoline (14). It was selected because it has been extensively used as a zinc chelator both in vitro and in vivo (15)(16)(17)(18)(19). Clioquinol (Fluca, 33931-100MG-R) was diluted to a 0.05 M stock solution in 100% dimethyl sulfoxide (DMSO).…”

“…(vii) N,N,N=,N=-tetrakis(2-pyridylmethyl)ethane-1,2-diamine (TPEN) is a membrane-permeative zinc chelator that has also been used extensively in that role in vivo (18,19,32,33) and on A. fumigatus (25). TPEN (Life Technologies, T1210) was diluted to a 0.05 M stock solution in 100% DMSO.…”

Excess influx of Zn 2+ into dentate granule cells affects object recognition memory via attenuated LTP

“…Zn 2+ release from the Schaffer collateral/ commissural pathway plays a key role for the increase in cytosolic Zn 2+ in the CA1. On the other hand, dentate granule cells are insensitive to neurodegeneration (Kim et al, 2012;Noh et al, 2005). The insensitivity might be due to the minimal innervation of zincergic neurons to dentate granule cells.…”

PI3Kγ deficiency enhances seizures severity and associated outcomes in a mouse model of convulsions induced by intrahippocampal injection of pilocarpine

“…Moreover, in the present study, we did not use an unbiased stereological method to quantify DCX positive cells, that is a limitation of the approach. Most studies evaluate DCX expression after 3 to 4 weeks after seizures, since a marked increase on hippocampal proliferation after pharmacological induction of seizures in rodents is only detected after 7-9 days after the insult (Gu et al, 2010;Jessberger et al, 2005;Kim et al, 2012;Walter et al, 2007). Interestingly, PI3Kγ −/− animals exhibited a significant decrease in the number of hippocampal DCX + cells after pilocarpine.…”