Modulation of inhibitory and excitatory amino acid receptor ion channels by zinc

Human activities can cause zinc (Zn) contamination of aquatic environments. Zn is an essential trace metal, but effects of environmentally relevant Zn exposure on the brain–intestine axis in fish are poorly understood. Here, six-month-old female zebrafish (Danio rerio) were exposed to environmentally relevant Zn concentrations for six weeks. Zn significantly accumulated in the brain and intestine, causing anxiety-like behaviors and altered social behaviors. Zn accumulation altered levels of neurotransmitters, including serotonin, glutamate, and γ-aminobutyric acid, in the brain and intestine, and these changes were directly associated with changes in behavior. Zn caused oxidative damage and mitochondrial dysfunction, and impaired NADH dehydrogenase, thereby dysregulating the energy supply in brain. Zn exposure resulted in nucleotide imbalance and dysregulation of DNA replication and the cell cycle, potentially impairing the self-renewal of intestinal cells. Zn also disturbed carbohydrate and peptide metabolism in the intestine. These results indicate that chronic exposure to Zn at environmentally relevant concentrations dysregulates the bidirectional interaction of the brain–intestine axis with respect to neurotransmitters, nutrients, and nucleotide metabolites, thereby causing neurological disorder-like behaviors. Our study highlights the necessity to evaluate the negative impacts of chronic environmentally relevant Zn exposure on the health of humans and aquatic animals.

Zinc is a transition metal that is particularly abundant in the mossy fibers of the hippocampal CA3 area. Despite the large number of studies about the zinc role in mossy fibers, the action of zinc in synaptic mechanisms is only partly known. The use of computational models can be a useful tool for this study. In a previous work, a model was developed to evaluate zinc dynamics at the mossy fiber synaptic cleft, following weak stimulation, insufficient to evoke zinc entry into postsynaptic neurons. For intense stimulation, cleft zinc effluxes must be considered. Therefore, the initial model was extended to include postsynaptic zinc effluxes based on the Goldman-Hodgkin-Katz current equation combined with Hodgkin and Huxley conductance changes. These effluxes occur through different postsynaptic escape routes, namely L- and N-types voltage-dependent calcium channels and NMDA receptors. For that purpose, various stimulations were assumed to induce high concentrations of cleft free zinc, named as intense (10 μM), very intense (100 μM) and extreme (500 μM). It was observed that the main postsynaptic escape routes of cleft zinc are the L-type calcium channels, followed by the NMDA receptor channels and by N-type calcium channels. However, their relative contribution for cleft zinc clearance was relatively small and decreased for higher amounts of zinc, most likely due to the blockade action of zinc in postsynaptic receptors and channels. Therefore, it can be concluded that the larger the zinc release, the more predominant the zinc uptake process will be in the cleft zinc clearance.

Benzodiazepines and carbamazepine are mental disorder treatment-related contaminants of emerging concern (CECs) routinely detected in water bodies. Electrochemical oxidation (EO) processes have been proven effective in reducing CECs levels, although the toxic effects of residual compounds formed after EO are still scarcely studied. Herein, ultrapure water (UP), surface water (SW), municipal wastewater (MWW), and industrial pharmaceutical wastewater (IWW) were spiked with four benzodiazepines (alprazolam, clonazepam, diazepam, lorazepam) and carbamazepine (100 μg L⁻¹ each) and treated by an EO process employing two electrodes: a platinum-coated titanium (Ti/Pt) and a boron-doped diamond (BDD). Neurotoxicity tests were performed by exposing rat hippocampus slices to EO-treated waters to investigate the effects of residual compounds on neuronal activity. The EO results indicate that both electrodes were efficient in completely removing the studied drugs from UP and SW, but that <50 % removal was achieved for MWW. For IWW, total organic carbon (up to 71 %) and total nitrogen (up to 82 %) removals were achieved at 1000 A m⁻². UP exposure significantly reduced ROS production, likely due to the presence of transformation by-products. SW and MWW EO-treated waters led to slight neurotoxicity. Decreased neurotoxicity was mainly observed for the IWW after EO using both the BDD and Ti/Pt anodes. A ROS production evaluation following the application of several untreated effluent cycles demonstrated that long-term effects may alter cell functionality and that recovery responses decrease over time.

Zinc in one of the most abundant trace minerals in human body which is involved in numerous biological pathways and has variety of roles in the nervous system. It has been assumed that zinc exerts its role in nervous system through increasing brain derived neurotrophic factor (BDNF) concentrations.

Present meta-analysis was aimed to review the effect of zinc supplementation on serum concentrations of BDNF.

Four electronic databases (Pubmed, Scopus, Web of Science, Embase) were searched for identifying studies that examined BDNF levels prior and after zinc supplementation up to May 2020. According to the Cochrane guideline, a meta-analysis was performed to pool the effect size estimate (Hedges’ test) of serum BDNF across studies. Risk of publication bias was assessed using a funnel plot and Egger’s test.

Five studies were eligible and 238 participants were included. These studies enrolled subjects with premenstrual syndrome, diabetic retinopathy, major depression disorder, overweight/obese and obese with mild to moderate depressive disorders. Zinc supplementation failed to increase blood BDNF concentrations with effect size of 0.30 (95 % CI: -0.08, 0.67, P = 0.119). Funnel plot did not suggest publication bias.

Zinc supplementation may not significantly increase BDNF levels. However, the small number of included articles and significant heterogeneity between them can increase the risk of a false negative result; therefore, the results should be interpreted with caution.

A new picoline based ligand, namely 2-hydroxy-5-methyl-3-[{(6-methylpyridin-2-yl)imino}methyl]benzaldehyde (L) and it’s zinc(II) complex, Zn(L)₂ (1) have been synthesized and structurally characterized. The ligand (L) selectively interacts with Zn²⁺ ion in presence of series of cations in CH₃CN-H₂O (v/v 1:1) in 1 mM HEPES buffer (pH 7.2). The fluorescence intensity of L is significantly enhanced, and it is increased to 52 times on coordination with Zn(II) ion. The fluorescence intensity value of the L does not show any significant change in the pH range 5 to 9, while the extent of emission phenomenon with Zn(II) ions is observed in the said pH range. The detection limit (0.36 µM) and association constant (log K_app = 13.25) are evaluated by the fluorescence emission experiment. The probe shows reversibility in addition of dihydrogen phosphate (H₂PO₄⁻) ion to the 1. Additionally, the ‘turn-on’ fluorescence probe has sufficient cell permeability and intracellular Zn(II) sensing property as envisaged from the microscopic imaging in HEK293T cells. Both L and ZnL₂ (1) are innocuous against PBMC (peripheral blood mononuclear cells) but effective antitumor agents against U-937 cancer cells.

The present work, using chromaffin cells in rat adrenal slices (RCCs), aims to describe what type of ionic current alterations induced by zinc underlies their effects reported on synaptic transmission. Thus, Zn²⁺ blocked calcium channels of RCCs in a time- and concentration-dependent manner with an IC₅₀ of 391 μM. This blockade was partially reversed upon washout and was greater at more depolarizing holding potentials (i.e. 32 ± 5% at −110 mV, and 43 ± 6% at -50 mV, after 5 min perfusion). In ω-toxins-sensitive calcium channels (N-, P- and Q-types), Zn²⁺caused a lower blockade of I_Ca, 33.3%, than in ω-toxins-resistant ones (L-type, 55.3%; and R-type, 90%). This compound inhibited calcium current at all test potentials and shows a shift of the I-V curve to more depolarized values of about 10 mV. The sodium current was not blocked by acute application of high Zn²⁺concentrations. Voltage-dependent potassium current was marginally affected by high Zn²⁺ concentrations showing no concentration-dependence. Nevertheless, calcium- and voltage-dependent potassium current was drastically depressed in a dose-dependent manner, with an IC₅₀ of 453 μM. This blockade was related to the prevention of Ca²⁺ influx through voltage-dependent calcium channels coupled to BK channels. Under current-clamp conditions, RCCs exhibit a resting potential of -50.7 mV, firing spontaneous APs (1–2 spikes/s) generated by the opening of Na⁺ and Ca²⁺-channels, and terminated by the activation of voltage and Ca²⁺-activated K⁺-channels (BK). We found that the blockade of these ionic currents by Zn²⁺ led to a drastic alteration of cellular excitability with a depolarization of the membrane potential, the slowdown and broadening of the APs and the severe reduction of the after hyperpolarization (AHP) which led to a decrease in the APs firing frequency. Taken together, these results point to a neurotoxic action evoked by zinc that is associated with changes to cellular excitability by blocking the ionic currents responsible for both the neurotransmitter release and the action potentials firing.