Manganese / Nitric Oxide in the Nervous System

percyval577

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I want to gather some literature regarding actions of Mn in the nervous system, and also to compare it with actions of nitric oxide, guessing that Mn may act sometimes at least in the same direction (if not through NO?). I am not aware of any research having looked at it, and making considerations. It may well be that in the GABA system the actions differ as they are controversial for NO.

The main point though is that I think Mn may be a good candidate for impacts like in ME/CFS, maybe in both direction (too high or too low Mn). My further - unprovabale - guess is that he brain uses metals to encode geometrical actions of great spacial extend, so synaptical over a long distance e.e.g foreward, or foreward-round, or turning-around the vertical axis (mainly being asymmetrical therefore). My impression is that Mn would act in a "pinning" manner, therefore maybe reinforcing other actions, but in itself without direction. This could be unfavourable and leading to disruptions. Albeit unprovable for the next 20 years or so minimum, the following literature is also thought to be able to underly this bold guess.

It might take time to comlete the list, the two most important influences may be:
The linkage from the immune system to the nervous system, see for a summary the introduction by Filipov et al 2008 in this thread, post1. And:


Glutamate synthase from the ovine brain is a manganese (II) enzyme
Wedler et al 1982


from the Abstract
The activation of ovine brain glutamine synthetase by Mn(II) or Mg(II) was studied by steady-state kinetics. The metal ion concentration was varied at several fixed concentrations of ATP, and vice versa, and the resultant kinetic curves were analyzed according to the method of London and Steck [London, W. P., & Steck, T. L. (1969) Biochemistry 8, 1767-1779].

The data for Mg(II) indicated optimal activation at Mg:ATP = 2:1, whereas that for Mn(II) occurred at Mn:ATP = 1:1. This was interpreted as indicating formation of Mg . E . Mg . ATP as the subunit complex of optimum activity with Mg(II) (pHopt 7.5).
...
Thus, it appears that four Mn(II) are very tightly bound per octamer and that four more Mn(II) can bind tightly.

Neither Mg(II) nor Ca(II) at 50 mM can displace Mn(II) from the Mn4 . E complex, but Mn(II) still binds tightly to apoenzyme or Mn4E in the presence of 50 mM Mg(II).
...
The total intracellular concentration of Mn(II) in ovine brain tissue was determined to be 1.9-2.6 microM, whereas the free [Mn(II)] was below 0.5 microM. Since the enzyme binds Mn(II) in preference to other divalent ions, it appears that the enzyme may exist as a manganoenzyme in vivo.
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Biochemistry. 1982 Dec 7;21(25):6389-96.
 

percyval577

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Here is a short documentation of movements from Mn intoxinated miners, from 1967. In Manganism Mn enters the body in high dose and without infection. Parkinson´s disease is guessed to develope from low but chronic exposure, one familar PD may confirm this (shown for the second time this year), when the Mn/Zn-exporter ZnT10 doesn´t function well. For other illnesses it might be very low exposure but through infection, I reason. so with additional impact on the immunesystem.

I link to the video to think about the theory of geometrical action, therefore asking, if the disurbed movements could be seen as a disturbance of a synaptically conducted foreward direction of action potentials, say all along the bean shaped thalamus; or action potential would not go around the round shaped striatum and pallius.

First video (the first guy being most affected): https://www.youtube.com/results?search_query=manganism
 
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percyval577

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Identification of dopaminargic neurons of the substantia nigra pars compacta as a target of manganese accumulation
Robinson et al 2015

Manganese serves as a cofactor to a variety of proteins necessary for proper bodily development and function. However, an overabundance of Mn in the brain can result in manganism, a neurological condition resembling Parkinson's disease (PD).

Bulk sample measurement techniques have identified the globus pallidus and thalamus as targets of Mn accumulation in the brain, however smaller structures/cells cannot be measured. Here, X-ray fluorescence microscopy determined the metal content and distribution in the substantia nigra (SN) of the rodent brain. In vivo retrograde labeling of dopaminergic cells (via FluoroGold™) of the SN pars compacta (SNc) subsequently allowed for XRF imaging of dopaminergic cells in situ at subcellular resolution.

Chronic Mn exposure resulted in a significant Mn increase in both the SN pars reticulata (>163%) and the SNc (>170%) as compared to control; no other metal concentrations were significantly changed. Subcellular imaging of dopaminergic cells demonstrated that Mn is located adjacent to the nucleus.

Measured intracellular manganese concentrations range between 40–200 μM; concentrations as low as 100 μM have been observed to cause cell death in cell cultures. Direct observation of Mn accumulation in the SNc could establish a biological basis for movement disorders associated with manganism, specifically Mn caused insult to the SNc. Accumulation of Mn in dopaminergic cells of the SNc may help clarify the relationship between Mn and the loss of motor skills associated with manganism.
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Manganese Exposure Induces Microglia Activation and Dystrophy in the Substantia Nigra of Non-Human Primates
Verina et al 2010


abstract
Chronic manganese (Mn) exposure produces neurological deficits including a form of parkinsonism that is different from Parkinson's disease (PD). In chronic Mn exposure, dopamine neurons in the substantia nigra (SN) do not degenerate but they appear to be dysfunctional.

Further, previous studies have suggested that the substantia nigra pars reticulata (SNr) is affected by Mn. In the present study, we investigated whether chronic Mn exposure induces microglia activation in the substantia nigra pars compacta (SNc) and SNr in Cynomolgus macaques. Animals were exposed to different weekly doses of Mn (3.3-5.0, 5.0-6.7, 8.3-10 mg Mn/kg body weight) and microglia were examined in the substantia nigra using LN3 immunohistochemistry.

We observed that in control animals, LN3 labeled microglia were characterized by a resting phenotype. However, in Mn-treated animals, microglia increased in number and displayed reactive changes with increasing Mn exposure. This effect was more prominent in the SNr than in the SNc.

In the SNr of animals administered the highest Mn dose, microglia activation was the most advanced and included dystrophic changes. Reactive microglia expressed increased iNOS, L-ferritin, and intracellular ferric iron which were particularly prominent in dystrophic compartments. Our observations indicate that moderate Mn exposure produces structural changes on microglia, which may have significant consequences on their function.
open access
doi: 10.1016/j.neuro.2010.11.003. Epub 2010 Nov 26.
 

percyval577

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Effects of Manganese on Tyrosine Hydroxylase (TH) Activity and TH-phosphorylation in a dopminergic Neural Cell Line
Zhang et al 2011


abstract, may paragraphing
Manganese (Mn) exposure causes manganism, a neurological disorder similar to Parkinson’s disease. However, the cellular mechanism by which Mn impairs the dopaminergic neurotransmitter system remains unclear.

We previously demonstrated that caspase-3-dependent proteolytic activation of protein kinase C delta (PKCδ) plays a key role in Mn-induced apoptotic cell death in dopaminergic neurons. Recently, we showed that PKCδ negatively regulates tyrosine hydroxylase (TH), the rate-limiting enzyme in dopamine synthesis, by enhancing protein phosphatase-2A activity in dopaminergic neurons.

Here we report that Mn exposure can affect the enzymatic activity of TH, the rate-limiting enzyme in dopamine synthesis, by activating PKCδ - PP2A signaling pathway in a dopaminergic cell model. Low dose Mn (3–10 μM) exposure to differentiated mesencephalic dopaminergic neuronal cells for 3 h induced a significant increase in TH activity and phosphorylation of TH-Ser40.

The PKCδ specific inhibitor rottlerin did not prevent Mn-induced TH activity or TH-Ser40 phosphorylation. On the contrary, chronic exposure to 0.1–1 μM Mn for 24 h induced a dose-dependent decrease in TH activity.

Interestingly, chronic Mn treatment significantly increased PKCδ kinase activity and protein phosphatase 2A (PP2A) enzyme activity. Treatment with the PKCδ inhibitor rottlerin almost completely prevented chronic Mn-induced reduction in TH activity, as well as increased PP2A activity.

Neither acute nor chronic Mn exposures induced any cytotoxic cell death or altered TH protein levels. Collectively, these results demonstrate that low dose Mn exposure impairs TH activity in dopaminergic cells through activation of PKCδ and PP2A activity.
open access​
 

percyval577

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For the following findings the answer may be that nitric oxide inhibits transporters, see then Kiss et al 2004 although they only mention the regular NO from the nNOS not the one from the Mn modulated iNOS which belongs to the immunesystem.

Manganese catalyzes auto-oxidation of dopamine to 6-Hydroxydopamine in vitro
Garner and Nachtman 1989


abstract
Manganese (Mn) is an essential trace element which, upon excessive exposure, produces a neurological syndrome similar to chronic Parkinson's disease in animals and humans. Previous work demonstated that Mn was more potent than other transition metals in stimulating dopamine (DA) auto-oxidation. In these experiments, DA was incubated under physiological conditions in the presence and absence of Mn for up to 60 min. 6-Hydroxydopamine (6-OHDA) was produced in the presence of Mn, while the incubation mixture without Mn showed no DA oxidation. 6-Hydroxydopamine is a neurotoxicant which exerts its effects by destroying DA nerve terminals in the CNS. Therefore, this work suggests that the Mn catalyzed increase in DA auto-oxidation could be linked mechanistically to the appearance of Mn-induced neurotoxic effects.
paywalled​

Manganese increases L-DOPA auto-oxidation in the striatum of the freely moving rat: implications to L-DOPA long-term therapy of [PD]
Serru et al 2000

open access
 
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percyval577

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Inhibitory effects of nitric oxide on dopamine transporters: interneuronal communication without receptors
Kiss et al 2004


Previously we observed that Nomega-nitro-L-arginine methyl ester (l-NAME) decreased the striatal dopamine (DA) release in microdialysis experiments and this effect was completely diminished in the presence of the DA uptake inhibitor nomifensine, indicating that the effect was mediated via the DA transporter.

The aim of the present work was to study the direct effect of nitrergic compounds on DA uptake. We measured the uptake of [3H]DA in striatal slices and found that the nitric oxide (NO) generator sodium nitroprussid (100 microM) decreased the uptake by 66%. In contrast, the NO synthase inhibitor L-NAME (100 microM) increased the DA uptake by 80%, while the inactive D-NAME had no effect on uptake.

Our data indicate that NO exerts an inhibitory effect on DA transporters. Since the production of NO by neuronal NO synthase is closely related to the activation of NMDA receptors, the level of NO around synapses reflects the activity of glutamatergic neurotransmission. The strength of excitatory input, therefore, can be nonsynaptically signaled by NO to the surrounding dopaminergic neurons via the inhibitory tone on transporters.

The concomitant elevation of DA concentration around the activated synapse represents the response of dopaminergic system, which can adapt to the changing excitatory activity without receiving glutamatergic input and without expressing glutamate receptors.

Thus, the effect of NO on transporters represents a new form of interneuronal communication, a nonsynaptic interaction without receptors.
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Here a theoretical work. It finds eg, that in the small synaptical clefts in the striatum DA autoxidation is meaningless, though in the cortex not. But could it become to some extent meaningful when transporters are inhibited?

Dopamine Autoxidation is controlled by Acidic pH
Umek et al 2018

open access
 

percyval577

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Defective Mitochondrial Dynamics Underlie Manganese-Induced Toxicity
Morcillo et al 2021

abstract, my breaks and bold
Perturbations in mitochondrial dynamics have been observed in most neurodegenerative diseases. Here, we focus on manganese (Mn)-induced Parkinsonism-like neurodegeneration, a disorder associated with the preferential of Mn in the basal ganglia where the mitochondria are considered an early target. Despite the extensive characterization of the clinical presentation of manganism, the mechanism by which Mn mediated mitochondrial toxicity is unclear.

In this study we hypothesized whether Mn exposure alters mitochondrial activity, including axonal transport of mitochondria and mitochondrial dynamics, morphology, and network. Using primary neuron cultures exposed to 100 μM Mn (which is considered the threshold of Mn toxicity in vitro) and intraperitoneal injections of MnCl2 (25mg/kg) in rat,

we observed that Mn increased mitochondrial fission mediated by phosphorylation of dynamin-related protein-1 at serine 616 (p-s616-DRP1) and decreased mitochondrial fusion proteins (MFN1 and MFN2) leading to mitochondrial fragmentation, defects in mitochondrial respiratory capacity, and mitochondrial ultrastructural damage in vivo and in vitro.

Furthermore, Mn exposure impaired mitochondrial trafficking by decreasing dynactin (DCTN1) and kinesin-1 (KIF5B) motor proteins and increasing destabilization of the cytoskeleton at protein and gene levels. In addition, mitochondrial communication may also be altered by Mn exposure, increasing the length of nanotunnels to reach out distal mitochondria.

These findings revealed an unrecognized role of Mn in dysregulation of mitochondrial dynamics providing a potential explanation of early hallmarks of the disorder, as well as a possible common pathway with neurological disorders arising upon chronic Mn exposure.
paywalled​

Though I think the effect has not been unrecognized, sadly I am currently not able to find the paper back, where I have read Mn-induced fission mentioned. I think, there was no degenerative problem a necessary part.

Deregulation of Mitochondria-Shaping Proteins Opa-1 and Drp-1 in Manganese-induced Apoptosis
Alaimo et al 2014
open access

Manganese exposure induces neuroinflammation by impairing mitochondrial dynamics in astrocytes
Sakar et al 2017

google.com/search?=manganese+mitochondrial+fission
 

percyval577

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The following finding could be interesting as the TSPO receptor - here with its old name - has been reported to be elevated in ME/CFS, Nakatomi et al 20014 and now a publication to come (from Australian researchers, if I remember rightly)

Upregulation of 'peripheral-type' benzodiazepine receptors in the globus pallidus in a subacute rat model of manganese neurotoxiticity
Hazell et al 2003


abstract, my pragraphing
Manganese neurotoxicity (MN) is a neurological disorder characterized by selective neuronal loss in the globus pallidus together with characteristic morphological changes known as Alzheimer type II astrocytosis. In order to understand the underlying mechanisms responsible for these processes, we studied early effects of this metal in a sub-acute rat model.

Levels of manganese in the globus pallidus were increased by 81% after 1 day of treatment and elevated by 551% compared to controls after 4 days. In addition, manganese treatment led to a 60% increase in ptbr expression, and a 105% increase in levels of its product, the isoquinoline-carboxamide binding protein, a major constituent of the 'peripheral-type' benzodiazepine receptor (PTBR) that is localized to astrocytes, in this brain region after 4 days.

These results indicate that PTBRs, and possibly neurosteroids, are an early response to manganese exposure and may play a major role in the pathophysiology of MN.
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Three more papers freely accessibly. Two may be interesting in the context of ME/CFS, as the cell cycle has been observed a couple of times, I think, to be elevated:

TSPO: An Evolutionary Conserved Protein with Elusive Function
Bonsack and Sukumari-Ramesh 2018

TSPO interacts VDAC1 and triggers a ROS-dependent inhibition of mitochondrial quality control
Gatliff et al 2014

TSPO is a REDOX regulator of cell mitophagy
Gatliff and Campanella 2015

google search tspo+manganese
 

percyval577

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Another finding on astrocytes and Mn:

Manganese exposure induces neuroinflammation by impairing mitochondrial dynamics in astrocytes
Sakar et al 2018


abstract, my paragraphing
Chronic manganese (Mn) exposure induces neurotoxicity, which is characterized by Parkinsonian symptoms resulting from impairment in the extrapyramidal motor system of the basal ganglia. Mitochondrial dysfunction and oxidative stress are considered key pathophysiological features of Mn neurotoxicity. Recent evidence suggests astrocytes as a major target of Mn neurotoxicity since Mn accumulates predominantly in astrocytes. However, the primary mechanisms underlying Mn-induced astroglial dysfunction and its role in metal neurotoxicity are not completely understood.

In this study, we examined the interrelationship between mitochondrial dysfunction and astrocytic inflammation in Mn neurotoxicity. We first evaluated whether Mn exposure alters mitochondrial bioenergetics in cultured astrocytes. Metabolic activity assessed by MTS assay revealed an IC50 of 92.68 μM Mn at 24 h in primary mouse astrocytes (PMAs) and 50.46 μM in the human astrocytic U373 cell line.

Mn treatment reduced mitochondrial mass, indicative of impaired mitochondrial function and biogenesis, which was substantiated by the significant reduction in mRNA of mitofusin-2, a protein that serves as a ubiquitination target for mitophagy. Furthermore, Mn increased mitochondrial circularity indicating augmented mitochondrial fission. Seahorse analysis of bioenergetics status in Mn-treated astrocytes revealed that Mn significantly impaired the basal mitochondrial oxygen consumption rate as well as the ATP-linked respiration rate. The effect of Mn on mitochondrial energy deficits was further supported by a reduction in ATP production. Mn-exposed primary astrocytes also exhibited a severely quiescent energy phenotype, which was substantiated by the inability of oligomycin to increase the extracellular acidification rate.

Since astrocytes regulate immune functions in the CNS, we also evaluated whether Mn modulates astrocytic inflammation. Mn exposure in astrocytes not only stimulated the release of proinflammatory cytokines, but also exacerbated the inflammatory response induced by aggregated α-synuclein. The novel mitochondria-targeted antioxidant, mito-apocynin, significantly attenuated Mn-induced inflammatory gene expression, further supporting the role of mitochondria dysfunction and oxidative stress in mediating astrogliosis.

Lastly, intranasal delivery of Mn in vivo elevated GFAP and depressed TH levels in the olfactory bulbs, clearly supporting the involvement of astrocytes in Mn-induced dopaminergic neurotoxicity. Collectively, our study demonstrates that Mn drives proinflammatory events in astrocytes by impairing mitochondrial bioenergetics.
open access​
 

percyval577

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Manganese neurotoxicity and protective effects of resveratrol and quercetin in preclinical studies
Gawlik et al 2017


abstract
Background: Exposure to Mn results in a neurological syndrome known as manganism.
Methods: We examined how 4-week Mn exposure (20mg/kg MnCl2po, 5days/week) induces neurotoxic effects in rats. Oxidized-to-reduced glutathione ratio (GSSG/GSH), malondialdehyde (MDA), superoxide dismutase (SOD) activity, catalase (CAT) activity, vitamin E content and caspase-3 activity were measured in several rat brain structures. Further, we examined protective effects of the polyphenols: resveratrol (R) or quercetin (QCT) against Mn-induced neurotoxicity.


Results: After exposure to Mn, we found a rise in GSSG/GSH ratio and a reduction in SOD activity in the rat striatum (STR),

while in the nucleus accumbens (NAC) decreases in alpha-tocopherol content and in SOD activity were noted.

In the frontal cortex (FCX), an enhancement in GSSG/GSH ratio and a reduction in SOD and CAT activities were observed.

In the cerebellum (CER), a significant increase in the caspase-3 activity paralleled a rise in the GSSG/GSH ratio and a diminution of SOD activity.

In the rat hippocampus (HIP), Mn evoked an enhancement in GSSG/GSH ratio. There were no changes in the MDA levels.

Pretreatment with R and QCT protected against the Mn-induced (i) enhancement in GSSG/GSH ratio in the STR, (ii) decreases in the NAC alpha-tocopherol content and (iii) reduction in SOD activity in FCX, NAC and CER.


Conclusion: Repeated Mn administration induces toxic effects in several rat brain structures and treatment with R and QCT may be a potential therapeutic strategy to attenuate the metal neurotoxicity.
Keywords: Manganese; Neuroprotection; Quercetin; Rat brain; Resveratrol.