Nickel in the Nervous System

percyval577

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About Nickel isn´t much known. I nevertheless tested it last autumn over some months (threads/a-nickel-effect.60979) and now can confirm the effect in a more advanced enviroment of influences. It is turning out that the metals Zinc, Chromium and Nickel are key, not taking at the same time though, as well as Manganese (which I can now take from nutrition in higher amounts with a rather good effect after I only had bad ones and therefore avoided it). Other stuff is needed though.

Therefore this thread is thought to gather research mainly hopefully to came up.

_______________​

Effect of nickel on the levels of dopamine, noradrenalin and serotnin in different regions of the rat brain
Fatehyab et aql 1980


no abstract and text available
 

percyval577

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The article has been cited six times (https://scholar.google):


L-carnitine protects against nickel-induced neurotoxicity by maintaining mitochondrial function in Neuro-2a cells
MD He, SC Xu, YH Lu, L Li, M Zhong, YW Zhang… - Toxicology and applied …, 2011 - Elsevier
Mitochondrial dysfunction is thought to be a part of the mechanism underlying nickel-
induced neurotoxicity. L-carnitine (LC), a quaternary ammonium compound biosynthesized
from the amino acids lysine and methionine in all mammalian species, manifests its …
Zitiert von: 37 Ähnliche Artikel Alle 8 Versionen

Dietary administration of nickel: Effects on behavior and metallothionein levels
JR Nation, MF Hare, DM Baker, DE Clark… - Physiology & …, 1985 - Elsevier
Adult male rats were fed either 0, 10, or 20 mg Ni/kg body weight (as NiCl 2) via a 10 g daily
food ration. Following 14 days of exposure, animals were trained over a period of 61 days to
lever press for food on a VI-2 operant training schedule while continuing to experience the …
Zitiert von: 20 Ähnliche Artikel Alle 6 Versionen

Short-term exposure to nickel alters the adult rat brain antioxidant status and the activities of crucial membrane-bound enzymes: neuroprotection by L-cysteine
C Liapi, A Zarros, S Theocharis… - Biological trace element …, 2011 - Springer
Nickel (Ni) is an environmental pollutant towards which human exposure can be both
occupational (mainly through inhalation) and dietary (through water and food chain-induced
bioaccumulation). The aim of this study was to investigate the effects of short-term Ni …
Zitiert von: 17 Ähnliche Artikel Alle 12 Versionen

Molecular mechanisms of nickel induced neurotoxicity and chemoprevention
X Song, SSF Kenston, L Kong, J Zhao - Toxicology, 2017 - Elsevier
Nickel (Ni) is widely used in many industrial sectors such as alloy, welding, printing inks,
electrical and electronics industries. Excessive environmental or occupational exposure to
Ni may result in tumor, contact dermatitis, as well as damages to the nervous system. In …
Zitiert von: 13 Ähnliche Artikel Alle 5 Versionen

Effet de l'exposition chronique au nickel sur les fonctions neurocomportementales chez les rats Wistar pendant la période de développement
K Kahloula, DEH Adli, M Slimani, H Terras… - Toxicologie Analytique et …, 2014 - Elsevier
Résumé La présente étude examine l'impact de l'intoxication au sulfate de nickel à une
dose de 0, 2% sur les fonctions neurocomportementales chez des rats Wistar durant la
période de la gestation et de la lactation. L'exposition au nickel pendant la période de …
Zitiert von: 3 Ähnliche Artikel
[PDF] mdpi.com

Effect of Chronic Administration of Nickel on Affective and Cognitive Behavior in Male and Female Rats: Possible Implication of Oxidative Stress Pathway
M Lamtai, J Chaibat, S Ouakki, O Zghari, A Mesfioui… - Brain sciences, 2018 - mdpi.com
Nickel (Ni) toxicity has been reported to produce biochemical and behavioral dysfunction.
The present study was undertaken to examine whether Ni chronic administration can induce
alterations of affective and cognitive behavior and oxidative stress in male and female rats …
Ähnliche Artikel Alle 11 Versionen
 

percyval577

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I think the main question is, where there is an effect too much or an effect requested.

The answere I have in mind is rather not "in the basal ganglia and the thalamus" (as may be indicated from the article 1980 with dopmine etc.) but more detailed rather somewhere in these strucuteres, where it would induce actions distinct from Zinc, Chromium and Manganese (geometrically, I think) And these actions would have been disturbed by the trigger.

Note, I say again that I don´t know about safety. Mainly Nickel is thought to need to be restricted, and only very selsdom there would be a need for intake. There are supplements to buy, sometimes a warning is announced.
https://www.google.com/search?rlz=1...j0j0i10j0i67j0i131j0i22i30j33i160.ev8OlXf_ZNE
 
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percyval577

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Lamtai et al 2018 from post #2 have a nice introduction:

It is well known that nickel (Ni) is an essential element for human and several animal species [1,2]. Imbalanced Ni homeostasis either by deficiency or by overload of this metal is associated with organ dysfunction that leads to various physiological and behavioral disorders. Ni deficiency inhibits growth, reduces reproductive rate, and alters glucose and lipid metabolism, which are associated with anemia, alternations of other metal ion contents, and reduced activity of several enzymes in animals [3]. In contrast, continuous exposure to high levels of Ni leads to multiple toxic effects in various organs, including the lungs, liver, kidneys, and brain [4,5,6].
The nervous system is one of the systems affected by Ni toxicity [7]. It may be taken up into the brain through failures of the blood–brain barrier (BBB), and also via the olfactory pathway [8,9,10], and then accumulates in the cerebral cortex and whole brain [8,11], leading to a cytotoxicity in different types of nerve cells [7,11,12]; a variety of neurological symptoms such as headaches, giddiness, tiredness, lethargy, and ataxia [6]; apoptosis of olfactory sensory and cerebral cortex neurons and behavioral deficiencies; and disrupts neurotransmitters [13,14,15,16].
It is known that changes in neurochemistry often correlate with behavioral disturbance [17]. Animal studies have shown that Ni exposure leads to increased aggressive behavior and affective disorders, and impaired memory processes and exploring activity [11,18]. It has been also demonstrated that Ni has a neuromodulatory role; it can interfere with acetylcholine release from peripheral nerve terminals in vitro [19] and decrease dopamine, norepinephrine, and serotonin levels in certain rat brain regions and change the gene expression of the glutamate receptors [7,16,20,21].
Among the many mechanisms implicated in nickel-mediated neurotoxicity, oxidative stress has been proposed to play a central role; it can damage tissue, including central nervous system (CNS), leading to impaired neuronal function and alteration in the physicochemical properties of cell membranes, and eventually disrupt the vital functions and overall brain activity [6,22]. As a result, it can alter neurotransmission [23]. Importantly, oxidative stress reduces gamma-Aminobutyric acid (GABA) levels [24] and alters GABA uptake [25]. Certain diseases associated with oxidative stress disturbances such as neurodegenerative diseases like Alzheimer’s and Parkinson’s Diseases [26,27], and neuropsychiatric diseases including schizophrenia and some forms of behavior, such as aggressiveness, depression, and anxiety, and also to deterioration of short-term spatial memory [23,28,29,30,31].
...
According to this intro the article Fatehyab reports a decrease of DA, NA and SER in some region of the rat brain. In possible conflict is:


Effect of nickel on aromatic acids and biogenetic amines in brain of guinesa pigs
Girja S. Shukla and Satya V. Chandra 1979

Nickel chloride was administered daily for 60 days to male guinea pigs. The levels of tyrosine and tryptophan were increased in both serum and brain after this treatment. Brain dopamine levels increased by 18%, but norepinephrine (NE), 5-hydroxytryptamine (5-HT) and their metabolites did not show significant change. The increased level of dopamine induced by nickel may be of significance in view of evidence that metal ions play a rôle in the metabolism of brain biogenic amines.
 

percyval577

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The following article might again sound not promising.

MiRNA-210 modulates a nickel-induced cellular energy metabolism shift by repressing the iron-sulfur cluster assembly proteins ISCU1/2 in Neuro-2a cells
He et al. 2014


page 6:
In our study, HIF-1α stabilization and miR-210 overexpression induced by NiCl2 were observed in dose- and time-dependent manners. Moreover, CoCl2 and DFX, the well-established hypoxia-mimic compounds, increased the expression of miR-210. Therefore, miR-210 may contribute to the chemical hypoxia responses, in addition to the low oxygen content.
The energy metabolism shift is an important cellular response to hypoxia. When oxygen is abundant, cellular ATP is primarily generated through OXPHOS that generates 32 moles of ATP from 1 mole of glucose. Under hypoxic conditions, OXPHOS is suppressed and cellular energy production shifts to the glycolytic pathway that only generates 2 moles of ATP from 1 mole of glucose. Although glycolysis is not economic for ATP generation, it provides the minimum energy supplement for cell survival under hypoxic conditions.36 Recently, the energy metabolic shift regulated by the HIF-1α-miR-210-ISCU1/2 pathway has been revealed to participate in multiple hypoxia-related physiological and pathological processes.18, 21 In our study, Ni exposure resulted in the downregulation of ISCU1/2 protein levels, which was connected to the changes in HIF-1α and miR-210. The results of the reporter gene assay for the predicted miR-210 bonding site on ISCU1/2 and the western blot analysis of ISCU1/2 protein levels after miR-210 transfection further supported that ISCU1/2 was regulated by miR-210 in Ni exposure conditions. The lack of change in ISCU1/2 mRNA levels after Ni exposure revealed the post-transcriptional regulatory effects of miR-210 on ISCU1/2.15 Moreover, the activation of HIF-1α/miR-210/ISCU1/2 regulation pathway was universal in different Ni-treated cells. The downstream effects of this regulation pathway may underlie the Ni-mediated hypoxia-mimic response.
The energy metabolism shift, characterized by glycolysis enhancement under normoxic conditions, is considered to be involved in the toxicity of Ni. In the central nervous system, Ni-mediated inhibition of OXPHOS resulted in energy supplement stress.12 Inhibition of glycolysis with 2-DG or BrPA increased the cytotoxicity of NiCl2 in Neuro-2a cells in the present study. In addition, the cellular phenotype of preferential glycolytic energy generation, known as the Warburg effect, is implicated in the carcinogenesis of Ni.2 The elucidation of the impacts of Ni on cellular energy metabolism may be important for studying Ni toxicity. We found that miR-210 was an essential modulator of Ni-induced energy metabolism shift, resulting in oxygen consumption decrease, ATP deficit, alteration of HK activity, and accumulation of lactic acid. The key enzymes for OXPHOS, aconitase for the Krebs cycle and complex I for mitochondrial electron transfer, were suppressed by miR-210 without a protein level change of their component elements. It means that the inactivation of these enzymes accounts for the ISC deficit, rather than the inhibition of protein expression.
open access
Cell Death Dis. 2014 Feb 27;5:e1090. doi: 10.1038/cddis.2014.60.
 

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likewise:

Nickel Inhibits Mitochondrial Fatty acid Oxidation
Uppala et al 2015


Abstract
Nickel exposure is associated with changes in cellular energy metabolism which may contribute to its carcinogenic properties. Here, we demonstrate that nickel strongly represses mitochondrial fatty acid oxidation-the pathway by which fatty acids are catabolized for energy-in both primary human lung fibroblasts and mouse embryonic fibroblasts. At the concentrations used, nickel suppresses fatty acid oxidation without globally suppressing mitochondrial function as evidenced by increased glucose oxidation to CO2. Pre-treatment with l-carnitine, previously shown to prevent nickel-induced mitochondrial dysfunction in neuroblastoma cells, did not prevent the inhibition of fatty acid oxidation. The effect of nickel on fatty acid oxidation occurred only with prolonged exposure (>5 h), suggesting that direct inhibition of the active sites of metabolic enzymes is not the mechanism of action. Nickel is a known hypoxia-mimetic that activates hypoxia inducible factor-1α (HIF1α). Nickel-induced inhibition of fatty acid oxidation was blunted in HIF1α knockout fibroblasts, implicating HIF1α as one contributor to the mechanism. Additionally, nickel down-regulated the protein levels of the key fatty acid oxidation enzyme very long-chain acyl-CoA dehydrogenase (VLCAD) in a dose-dependent fashion. In conclusion, inhibition of fatty acid oxidation by nickel, concurrent with increased glucose metabolism, represents a form of metabolic reprogramming that may contribute to nickel-induced carcinogenesis.
open access
Biochem Biophys Res Commun. 2015 Aug 7;463(4):806-10. doi: 10.1016/j.bbrc.2015.06.017. Epub 2015 Jun 5.
 

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Nickel block of a family of neuronal alcium channels: subtype- and subunit-dependent action at multiple sites
Zamponi e al 1996


abstract
Nickel ions have been reported to exhibit differential effects on distinct subtypes of voltage-activated calcium channels. To more precisely determine the effects of nickel, we have investigated the action of nickel on four classes of cloned neuronal calcium channels (alpha1A, alpha1B, alpha1C, and alpha1E) transiently expressed in Xenopus oocytes.

Nickel caused two major effects: (i) block detected as a reduction of the maximum slope conductance and (ii) a shift in the current-voltage relation towards more depolarized potentials which was paralleled by a decrease in the slope of the activation-curve. Block followed 1:1 kinetics and was most pronounced for alpha1C, followed by alpha1E > alpha1A > alpha1B channels. In contrast, the change in activation-gating was most dramatic with alpha1E, with the remaining channel subtypes significantly less affected. The current-voltage shift was well described by a simple model in which nickel binding to a saturable site resulted in altered gating behavior.

The affinity for both the blocking site and the putative gating site were reduced with increasing concentration of external permeant ion. Replacement of barium with calcium reduced both the degree of nickel block and the maximal effect on gating for alpha1A channels, but increased the nickel blocking affinity for alpha1E channels. The coexpression of Ca channel beta subunits was found to differentially influence nickel effects on alpha1A, as coexpression with beta2a or with beta4 resulted in larger current-voltage shifts than those observed in the presence of beta1b, while elimination of the beta subunit almost completely abolished the gating shifts. In contrast, block was similar for the three beta subunits tested, while complete removal of the beta subunit resulted in an increase in blocking affinity.

Our data suggest that the effect of nickel on calcium channels is complex, cannot be described by a single site of action, and differs qualitatively and quantitatively among individual subtypes and subunit combinations.
paywalled
J Membr Biol. 1996 May;151(1):77-90.
Subunit dependend effect of nickel on NMDA receptor channels
Machetti and glavazzo 2003


abstract
Nickel (Ni2+) is a transition metal that affects different neuronal ionic channels. We investigated its effects on glutamate channels of the NMDA-type in the presence of saturating concentration of glutamate or NMDA (50 microM), in 0 external Mg and in the continuous presence of saturating glycine (30 microM).

In neonatal rat cerebellar granule cells, Ni2+ inhibited the current evoked by NMDA at -60 mV with an IC50 close to 40 microM. The inhibition was weakly voltage-dependent and the current at +40 mV was inhibited with IC50=86 microM. Wash out of the metal unmasked a stimulatory effect which persisted for a few seconds. In HEK293 cells transiently transfected with recombinant NR1a-NR2A receptors, Ni2+ inhibited the current elicited by glutamate with an IC50=52 microM at -60 mV and 90 microM at +40 mV. In HEK293 expressing NR1a-NR2B receptors, 0.1-100 microM Ni2+ caused a potentiation of the current, with EC50=4 microM, while with 300 microM, a voltage-dependent block became apparent (IC50=170 microM).

As previously reported, the current through both classes of recombinant receptors was steeply dependent on external pH, and in both cases the protonic block had an IC50 close to pH 7.2. Application of Ni2+ showed that stimulation of NR1a-NR2B receptor channels was dependent on external pH, while voltage-independent inhibition of NR1a-NR2A was less sensitive to pH change.

These results indicate that Ni2+ has multiple and complex effects on NMDA channels, which are largely dependent on the NR2 subunit.
paywalled
Brain Res Mol Brain Res. 2003 Oct 7;117(2):139-44.
 

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Nickel modulates the elecrical activity of cultured cortical neurons through a specific effect on [NMDA] receptor channels
Gavazzo et al 2011


from the abstract
Nickel (Ni(2+)) is a toxic metal that affects the function of several ionic channels. In the N-methyl-d-aspartate (NMDA) subtype of glutamate receptor (NR), it causes activity enhancement of the channels containing the NR2B subunit and voltage-independent inhibition of those containing NR2A.
.....
These results demonstrate that, in these cultured cells, the NR spontaneous current is almost entirely due by NR2B-containing receptors and that Ni(2+) affects the electrical activity through a specific effect on NR channels.
paywalled
Neuroscience. 2011 Mar 17;177:43-55. doi: 10.1016/j.neuroscience.2010.12.018. Epub 2010 Dec 21



The influence of calcium ions on nickel modulation of NMDA receptor currents
Gavazzo et al 2011


from he abstract
These observations indicate that Ni-mediated potentiation is not dependent on Ca influx and internal Ca concentration, but it is dependent on external Ca, which possibly interacts with the extracellular portion of the protein through a modulatory binding site.
paywalled
Metallomics
 

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Nickel block of three Cloned T-type Calcium Channels: Low Concentrations Selectivily Block alpha1H
Lee et al 1999

Nickel has been proposed to be a selective blocker of low-voltage-activated, T-type calcium channels. However, studies on cloned high-voltage-activated Ca2+ channels indicated that some subtypes, such as α1E, are also blocked by low micromolar concentrations of NiCl2. There are considerable differences in the sensitivity to Ni2+ among native T-type currents, leading to the hypothesis that there may be more than one T-type channel. We confirmed part of this hypothesis by cloning three novel Ca2+ channels, α1G, H, and I, whose currents are nearly identical to the biophysical properties of native T-type channels. In this study we examined the nickel block of these cloned T-type channels expressed in both Xenopus oocytes and HEK-293 cells (10 mM Ba2+). Only α1H currents were sensitive to low micromolar concentrations (IC50 = 13 μM). Much higher concentrations were required to half-block α1I (216 μM) and α1G currents (250 μM). Nickel block varied with the test potential, with less block at potentials above −30 mV. Outward currents through the T channels were blocked even less. We show that depolarizations can unblock the channel and that this can occur in the absence of permeating ions. We conclude that Ni2+ is only a selective blocker of α1H currents and that the concentrations required to block α1G and α1I will also affect high-voltage-activated calcium currents.

Ni(2+) affects dopamine uptake which limits suitability as inhibitor of T-type volage gated Ca(2+) channels
Brimblecombe and Cragg 2015


abstract
Neuronal T-type voltage-gated Ca(2+) channels are reported to have physiological roles that include regulation of burst firing, Ca(2+) oscillations, and neurotransmitter release. These roles are often exposed experimentally by blocking T-type channels with micromolar Ni(2+).

We used Ni(2+) to explore the role of axonal T-type channels in dopamine (DA) release in mouse striatum, but identified significant off-target effects on DA uptake. Ni(2+) (100 μM) reversibly increased electrically evoked DA release and markedly extended its extracellular lifetime, detected using fast-scan cyclic voltammetry. Prior inhibition of the DA transporter (DAT) by cocaine (5 μM) occluded the facilitatory action of Ni(2+) on DA release and conversely, allowed Ni(2+) to inhibit release, presumably through T-channel inhibition. Ni(2+) further prolonged the timecourse of DA clearance suggesting further inhibition of DA uptake.

In summary, Ni(2+) has major effects on DA transmission besides those due to T-channels that likely involve inhibition of the DAT.
paywalled
ACS Chem Neurosci. 2015 Jan 21;6(1):124-9. doi: 10.1021/cn500274g. Epub 2014 Dec 5.