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Manganese (Mn) is an essential heavy metal. However, Mn’s nutritional aspects are paralleled by its role as a neurotoxicant upon excessive exposure. In this review, we covered recent advances in identifying mechanisms of Mn uptake and its molecular actions in the brain as well as promising neuroprotective strategies. The authors focused on reporting findings regarding Mn transport mechanisms, Mn effects on cholinergic system, behavioral alterations induced by Mn exposure and studies of neuroprotective strategies against Mn intoxication. We report that exposure to Mn may arise from environmental sources, occupational settings, food, total parenteral nutrition (TPN), methcathinone drug abuse or even genetic factors, such as mutation in the transporter SLC30A10. Accumulation of Mn occurs mainly in the basal ganglia and leads to a syndrome called manganism, whose symptoms of cognitive dysfunction and motor impairment resemble Parkinson’s disease (PD). Various neurotransmitter systems may be impaired due to Mn, especially dopaminergic, but also cholinergic and GABAergic. Several proteins have been identified to transport Mn, including divalent metal tranporter-1 (DMT-1), SLC30A10, transferrin and ferroportin and allow its accumulation in the central nervous system. Parallel to identification of Mn neurotoxic properties, neuroprotective strategies have been reported, and these include endogenous antioxidants (for instance, vitamin E), plant extracts (complex mixtures containing polyphenols and non-characterized components), iron chelating agents, precursors of glutathione (GSH), and synthetic compounds that can experimentally afford protection against Mn-induced neurotoxicity.

Background The present investigation assessed the potential ameliorating effect of zinc oxide resveratrol nanoparticles against Levofloxacin-induced liver damage in rats. Methods Fifty adult Wistar rats were split up into five groups at random. ( n  = 10). GI, (control): was orally gavaged with distilled water; G II (LFX): was orally given levofloxacin (LFX) (40 mg/kg BW). G III was orally administered zinc oxide resveratrol nanoparticles (Zn- RSV) (20 mg/kg BW). G IV: was given Zn-RSV as GIII and LFX as GII simultaneously (LFX + Zn-RSV). GV: was given LFX as GII and zinc oxide (20 mg/kg BW) (LFX + Zn). All treatments were given every other day for two months. Results Administration of zinc oxide resveratrol nanoparticles (Zn-RSV NPs) significantly mitigated levofloxacin (LFX)-induced hepatotoxicity in rats. Compared to LFX-treated groups through improved liver function via lowered serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), urea, and creatinine levels. Also, reduced oxidative stress markers, decreased malondialdehyde (MDA) and nitric oxide (NO) levels in hepatic tissue and enhanced antioxidant defenses, increased superoxide dismutase (SOD) and catalase activities, restoring them to near-normal levels. Modulated apoptosis: Downregulated pro-apoptotic BAX expression and upregulated anti-apoptotic Bcl-2 expression, promoting cell survival. Zn-RSV NPs alleviated histopathological changes through mitigated LFX-induced degenerative and necrotic changes in hepatic tissue, preserving tissue architecture. Conclusions This study revealed that zinc oxide resveratrol nanoparticles modulated levofloxacin-induced hepatic damage by lowering inflammation and oxidative stress while increasing the activity of antioxidant enzymes in rat hepatic tissue.

Background Neutrophilic chronic rhinosinusitis (CRS) is characterized by persistent inflammation and often responds poorly to corticosteroid therapy. In this disease, neutrophil extracellular traps (NETs) are increasingly recognized as key mediators of mucosal damage and polypogenesis. The removal of NETs by deoxyribonuclease 1 could be a potential therapeutic approach to overcome steroid resistance in neutrophilic CRS. In this study, we established a mouse model of neutrophilic CRS and evaluated the effect of a genetically engineered deoxyribonuclease 1 ‘AR-CR8 Dnase1’ on NETs and polyp formation in the mice. Methods Human neutrophils were isolated and treated with LPS to induce NET formation. An animal model for neutrophilic CRS and polyps was developed by intranasal administration of LPS and Staphylococcal toxin. H&E staining and immunofluorescence were performed to identify polyps, NETs, and immune cells in nasal cavities. Results AR-CR8 Dnase1 effectively degraded NET-like structures in LPS-stimulated human neutrophils. In the mouse CRS model, the intranasal administration of AR-CR8 Dnase1 noticeably reduced the burden of nasal polyps. The intranasal treatment of Dnase1 was effective as much as an injection of dexamethasone in reducing polyp number and NET accumulation in this model. Conclusions These results suggest that an engineered deoxyribonuclease 1 like AR-CR8 Dnase1 be an emerging bio-drug to inhibit inflammatory reaction and polyp formation in patients with neutrophilic CRS. AR-CR8 Dnase1 may be an alternative therapeutic for patients with CRS who are not suitable for steroid therapy, and further studies comparing dosing, durability, and safety are needed before considering clinical use. Trial registration Not applicable.

Background Transport of methylmercury (MeHg) across the blood-brain barrier towards the brain side is well discussed in literature, while ethylmercury (EtHg) and inorganic mercury are not adequately characterized regarding their entry into the brain. Studies investigating a possible efflux out of the brain are not described to our knowledge. Methods This study compares, for the first time, effects of organic methylmercury chloride (MeHgCl), EtHg-containing thiomersal and inorganic Hg chloride (HgCl 2 ) on as well as their transfer across a primary porcine in vitro model of the blood-brain barrier. Results With respect to the barrier integrity, the barrier model exhibited a much higher sensitivity towards HgCl 2 following basolateral incubation (brain-facing side) as compared to apical application (blood-facing side). These HgCl 2 induced effects on the barrier integrity after brain side incubation are comparable to that of the organic species, although MeHgCl and thiomersal exerted much higher cytotoxic effects in the barrier building cells. Hg transfer rates following exposure to organic species in both directions argue for diffusion as transfer mechanism. Inorganic Hg application surprisingly resulted in a Hg transfer out of the brain-facing compartment. Conclusions In case of MeHgCl and thiomersal incubation, mercury crossed the barrier in both directions, with a slight accumulation in the basolateral, brain-facing compartment, after simultaneous incubation in both compartments. For HgCl 2 , our data provide first evidence that the blood-brain barrier transfers mercury out of the brain.

Background All living cells display a rapid molecular response to adverse environmental conditions, and the heat shock protein family reflects one such example. Hence, failing to activate heat shock proteins can impair the cellular response. In the present study, we evaluated whether the loss of different isoforms of heat shock protein ( hsp ) genes in Caenorhabditis elegans would affect their vulnerability to Manganese (Mn) toxicity. Methods We exposed wild type and selected hsp mutant worms to Mn (30 min) and next evaluated further the most susceptible strains. We analyzed survival, protein carbonylation (as a marker of oxidative stress) and Parkinson’s disease related gene expression immediately after Mn exposure. Lastly, we observed dopaminergic neurons in wild type worms and in hsp-70 mutants following Mn treatment. Analysis of the data was performed by one-way or two way ANOVA, depending on the case, followed by post-hoc Bonferroni test if the overall p value was less than 0.05. Results We verified that the loss of hsp-70, hsp-3 and chn-1 increased the vulnerability to Mn, as exposed mutant worms showed lower survival rate and increased protein oxidation. The importance of hsp-70 against Mn toxicity was then corroborated in dopaminergic neurons, where Mn neurotoxicity was aggravated. The lack of hsp-70 also blocked the transcriptional upregulation of pink1 , a gene that has been linked to Parkinson’s disease. Conclusions Taken together, our data suggest that Mn exposure modulates heat shock protein expression, particularly HSP-70, in C. elegans . Furthermore, loss of hsp-70 increases protein oxidation and dopaminergic neuronal degeneration following manganese exposure, which is associated with the inhibition of pink1 increased expression, thus potentially exacerbating the vulnerability to this metal.

Background Metallothioneins (MT) are small proteins, which are crucial for the distribution of heavy and transition metals. Previously, we found in mice that knockout of MT 1 and 2 genes (MTKO) impaired spatial learning and potentiated the learning impairment caused by developmental mercury exposure. The current study examined the neurocognitive and neurochemical effects of MTKO with the developmental copper (Cu) supplementation. Methods Wildtype (WT) and MTKO mice were given supplemental Cu (0, 10 or 50 mg/l) in their drinking water during gestation and until weaning. When the mice were young adults they were trained on the win-shift 8-arm radial maze test of spatial learning and memory. After cognitive testing, their brains were analyzed for norepinepherine, dopamine and serotonin levels. Results In the spatial learning test, wildtype mice showed the normal sex difference with males performing more accurately than the females. This effect was eliminated by MTKO and restored by moderate Cu supplementation during development. In neurochemical studies, MTKO caused a significant overall increase in serotonin in all of the regions studied: the frontal cortex, posterior cortex, hippocampus, striatum, midbrain, and brainstem. MTKO also caused a significant increase in norepinepherine in the brainstem and hippocampus. In wildtype mice, Cu supplementation during development caused a significant decline in dopamine and norepinepherine in the midbrain and dopamine in the frontal cortex. These effects were blocked by MTKO. Conclusions The normal sex difference in spatial working memory accuracy, which was eliminated by MTKO, was restored by moderate copper supplementation. MTKO increased serotonin across all brain areas studied and increased norepinepherine only in the hippocampus and brainstem. MTKO blocked copper-induced decreases in dopamine and norepinepherine in the midbrain and dopamine in the frontal cortex.

Background Lead (Pb 2+ ) exposure has been shown to impair presynaptic neurotransmitter release in both in vivo and in vitro model systems. The mechanism by which Pb 2+ impairs neurotransmitter release has not been fully elucidated. In previous work, we have shown that Pb 2+ exposure inhibits vesicular release and reduces the number of fast-releasing sites in cultured hippocampal neurons. We have also shown that Pb 2+ exposure inhibits vesicular release and alters the distribution of presynaptic vesicles in Shaffer Collateral – CA1 synapses of rodents chronically exposed to Pb 2+ during development. Methods In the present study, we used transmission electron microscopy to examine presynaptic vesicle pools in Mossy Fiber-CA3 synapses and in Perforant Path-Dentate Gyrus synapses of rats to determine if in vivo Pb 2+ exposure altered presynaptic vesicle distribution in these hippocampal regions. Data were analyzed using T -test for each experimental endpoint. Results We found that Pb 2+ exposure significantly reduced the number of vesicles in the readily releasable pool and recycling pool in Mossy Fiber-CA3 terminals. In both Mossy Fiber-CA3 terminals and in Perforant Path-Dentate Gyrus terminals, Pb 2+ exposure significantly increased vesicle nearest neighbor distance in all vesicular pools (Rapidly Releasable, Recycling and Resting). We also found a reduction in the size of the postsynaptic densities of CA3 dendrites in the Pb 2+ exposed group. Conclusions In our previous work, we have demonstrated that Pb 2+ exposure impairs vesicular release in Shaffer Collateral - CA1 terminals of the hippocampus and that the number of docked vesicles in the presynaptic active zone was reduced. Our current data shows that Pb 2+ exposure reduces the number of vesicles that are in proximity to release sites in Mossy Fiber- CA3 terminals. Furthermore, Pb 2+ exposure causes presynaptic vesicles to be further from one another, in both Mossy Fiber- CA3 terminals and in Perforant Pathway – Dentate Gyrus terminals, which may interfere with vesicle movement and release. Our findings provide a novel in vivo mechanism by which Pb 2+ exposure impairs vesicle dynamics and release in the hippocampus.

Metals have many essential functions in the brain and a large body of evidence supports important roles for altered metal stasis in many brain disorders. However, despite this evidence, acceptance of metals as key mediators of brain dysfunction is largely lacking in mainstream biomedicine. This editorial will outline the possible reasons for this and suggest potential means to improve the acceptance of metals as central players in brain disease.