Molecular Targets of Manganese-Induced Neurotoxicity: A Five-Year Update.

Understanding of the immediate mechanisms of Mn-induced neurotoxicity is rapidly evolving. We seek to provide a summary of recent findings in the field, with an emphasis to clarify existing gaps and future research directions. We provide, here, a brief review of pertinent discoveries related to Mn-induced neurotoxicity research from the last five years. Significant progress was achieved in understanding the role of Mn transporters, such as SLC39A14, SLC39A8, and SLC30A10, in the regulation of systemic and brain manganese handling. Genetic analysis identified multiple metabolic pathways that could be considered as Mn neurotoxicity targets, including oxidative stress, endoplasmic reticulum stress, apoptosis, neuroinflammation, cell signaling pathways, and interference with neurotransmitter metabolism, to name a few. Recent findings have also demonstrated the impact of Mn exposure on transcriptional regulation of these pathways. There is a significant role of autophagy as a protective mechanism against cytotoxic Mn neurotoxicity, yet also a role for Mn to induce autophagic flux itself and autophagic dysfunction under conditions of decreased Mn bioavailability. This ambivalent role may be at the crossroad of mitochondrial dysfunction, endoplasmic reticulum stress, and apoptosis. Yet very recent evidence suggests Mn can have toxic impacts below the no observed adverse effect of Mn-induced mitochondrial dysfunction. The impact of Mn exposure on supramolecular complexes SNARE and NLRP3 inflammasome greatly contributes to Mn-induced synaptic dysfunction and neuroinflammation, respectively. The aforementioned effects might be at least partially mediated by the impact of Mn on α-synuclein accumulation. In addition to Mn-induced synaptic dysfunction, impaired neurotransmission is shown to be mediated by the effects of Mn on neurotransmitter systems and their complex interplay. Although multiple novel mechanisms have been highlighted, additional studies are required to identify the critical targets of Mn-induced neurotoxicity.

Serum trace elements are associated with hemostasis, lipid spectrum and inflammatory markers in men suffering from acute ischemic stroke.

The primary objective of the study is investigation of the association between trace elements status and hemostasis, lipid spectrum and inflammatory markers in acute ischemic stroke (AIS). A total of 30 men suffering from AIS and 30 healthy controls were involved in the current survey. Blood count, serum lipid spectrum, complement components C4 and C3a, vascular endothelial growth factor (VEGF), S100B protein, NR2 antibodies (NR2Ab), and total antioxidant status (TAS), as well as plasma fibrinogen, and D-dimer levels and activated partial thromboplastin time (APTT) were assessed. Serum trace elements were analyzed using inductively coupled plasma mass spectrometry. AIS patients were characterized by significantly increased fibrinogen, D-dimer, TG, C3a, C4, NR2Ab, and VEGF levels. The leukocyte count, erythrocyte sedimentation rate and serum atherogenic index were also increased in stroke patients. Oppositely, TAS and APTT values, bleeding and blood coagulation time were decreased. AIS patients were characterized by significantly decreased serum Fe and Co concentrations, whereas the level of Cu, I, Li, Mn, Se, Zn, As, Pb, Ni, and especially V and B in serum was significantly increased. Serum V and B tightly correlated with the procoagulant state and inflammatory markers. Multiple regression analysis revealed a significant inverse association between serum Se levels and stroke markers after adjustment for covariates. Therefore, it is hypothesized that elements like vanadium and boron may be closely involved in stroke pathogenesis by modulation of hemostasis and inflammation, whereas the observed increase in Se levels may be considered as a compensatory reaction.

Serum trace elements are interrelated with hormonal imbalance in men with acute ischemic stroke.

The objective of the present study was to assess hormonal and trace element status in men suffering from acute ischemic stroke. METHODS: 21 acute ischemic stroke patients and 21 age- and body mass index-matched healthy volunteers were enrolled in the study. Serum trace elements were assessed using inductively coupled plasma mass spectrometry. Serum hormones and brain damage markers were estimated using enzyme-linked immunosorbent assay. RESULTS: Ischemic stroke patients are characterized by significantly higher levels of total and free triiodothyronine (T3), anti-thyroid peroxidase antibodies (Anti-TPO-Ab), prolactin, and cortisol, whereas the level of thyroid stimulating hormone (TSH) was decreased. Serum B, Cu, Li, Mn, Ni, Pb, Se, V, and Zn in stroke significantly exceeded the control values, whereas the level of Co and Fe was decreased. Correlation analysis revealed a significant association between serum B and T3, Anti-TPO-Ab, and iodine concentration; serum Li and Sr levels - with circulating TSH, free T3, and Anti-TPO-Ab; and V concentration - with total T3 and I levels. The following positive relationships were also revealed: Co - TSH, Mn - free T3, Zn - free T3. Multiple linear regression demonstrated that Co, I, and Li were directly related to circulating TSH levels, whereas V concentration was negatively interrelated. In turn, only serum Li levels were characterized by a significant direct relationship with free T3 values. CONCLUSION: Generally, the obtained data demonstrate that altered serum trace elements are associated with thyroid dysfunction in acute ischemic stroke patients. However, the causal relationship should be estimated.

Serum Trace Element Profiles, Prolactin, and Cortisol in Transient Ischemic Attack Patients.

The primary aim of the present study was to assess the association between trace element status, brain damage biomarkers, cortisol, and prolactin levels in transient ischemic attack (TIA) patients. Ten male and 10 female TIA patients were involved in this study. Age, gender, and BMI-matched volunteers served as the respective control group. Serum samples were examined for complement components C4 and C3a, vascular endothelial growth factor (VEGF), S100B, NR2 antibodies (NR2Ab), total antioxidant status (TAS), cortisol, and prolactin. Trace element concentration in serum samples was assessed using inductively coupled plasma mass spectrometry at NexION 300D. The obtained data indicate that both male and female TIA patients were characterized by the increased C4 and prolactin concentrations. At the same time, serum VEGF levels were elevated in only men, whereas TAS values were decreased in women with TIA. Serum cortisol concentrations were significantly increased only in female TIA patients. Men and women with TIA were characterized by a 32 and 44 % decrease in serum Fe content. A two- and threefold increase in serum V content was observed in TIA females and males, respectively. Women with TIA had 60 % higher values of serum B, whereas male patients were characterized by a sevonfold increase in boron content in comparison to the control values. TIA also resulted in decreased serum Cu content in women and elevation of I, Li, Mn, Se, Zn, As, Pb, Ni, and Sr levels in men. Correlation analysis revealed a significant association between trace elements concentration and the studied parameters.