zinc and MS

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jimmylegs
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Re: zinc and MS

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  • Zinc transporter 3 (ZnT3) gene deletion reduces spinal cord white matter damage and motor deficits in a murine MOG-induced multiple sclerosis model (2016)
    https://www.sciencedirect.com/science/a ... 6116301589

    The present study aimed to evaluate the role of zinc transporter 3 (ZnT3) on multiple sclerosis (MS) pathogenesis. Experimental autoimmune encephalomyelitis (EAE), a disease model of multiple sclerosis, was induced by immunization with myelin oligodendrocyte glycoprotein (MOG35–55) in female mice. Three weeks after the initial immunization, demyelination, immune cell infiltration and blood brain barrier (BBB) disruption in the spinal cord were analyzed. Clinical signs of EAE first appeared on day 11 and reached a peak level on day 19 after the initial immunization. ZnT3 gene deletion profoundly reduced the daily clinical score of EAE. The ZnT3 gene deletion-mediated inhibition of the clinical course of EAE was accompanied by suppression of inflammation and demyelination in the spinal cord. The motor deficit accompanying neuropathological changes associated with EAE were mild in ZnT3 gene deletion mice. This reduction in motor deficit was accompanied by coincident reductions in demyelination and infiltration of encephalitogenic immune cells including CD4 + T cells, CD8 + T cells, CD20 + B cells and F4/80 + microglia in the spinal cord. These results demonstrate that ZnT3 gene deletion inhibits the clinical features and neuropathological changes associated with EAE. ZnT3 gene deletion also remarkably inhibited formation of EAE-associated aberrant synaptic zinc patches, matrix metalloproteinases-9 (MMP-9) activation and BBB disruption. Therefore, amelioration of EAE-induced clinical and neuropathological changes by ZnT3 gene deletion suggests that vesicular zinc may be involved in several steps of MS pathogenesis.
  • The Emerging Role of Zinc in the Pathogenesis of Multiple Sclerosis (2017)
    https://www.mdpi.com/1422-0067/18/10/2070

    Our lab has previously demonstrated that multiple sclerosis-induced spinal cord white matter damage and motor deficits are mediated by the pathological disruption of zinc homeostasis. Abnormal vesicular zinc release and intracellular zinc accumulation may mediate several steps in the pathophysiological processes of multiple sclerosis (MS), such as matrix metallopeptidase 9 (MMP-9) activation, blood-brain barrier (BBB) disruption, and subsequent immune cell infiltration from peripheral systems. Oral administration of a zinc chelator decreased BBB disruption, immune cell infiltration, and spinal white matter myelin destruction. Therefore, we hypothesized that zinc released into the extracellular space during MS progression is involved in destruction of the myelin sheath in spinal cord white mater and in generation of motor deficits. To confirm our previous study, we employed zinc transporter 3 (ZnT3) knockout mice to test whether vesicular zinc depletion shows protective effects on multiple sclerosis-induced white matter damage and motor deficits. ZnT3 gene deletion profoundly reduced the daily clinical score of experimental autoimmune encephalomyelitis (EAE) by suppression of inflammation and demyelination in the spinal cord. ZnT3 gene deletion also remarkably inhibited formation of multiple sclerosis-associated aberrant synaptic zinc patches, MMP-9 activation, and BBB disruption. These two studies strongly support our hypothesis that zinc release from presynaptic terminals may be involved in multiple sclerosis pathogenesis. Further studies will no doubt continue to add mechanistic detail to this process and with luck, clarify how these observations may lead to development of novel therapeutic approaches for the treatment of multiple sclerosis.
  • Long-Term Effects of Zinc Deficiency and Zinc Supplementation on Developmental Seizure-Induced Brain Damage and the Underlying GPR39/ZnT-3 and MBP Expression in the Hippocampus (2019)
    https://www.frontiersin.org/articles/10 ... 00920/full

    The results revealed that the Zinc-deficient diet for 4 weeks aggravated the long-term adverse effects of developmental seizures, evidenced by weight, cognition, seizure threshold and serum zinc concentrations, which were paralleled by expression changes in hippocampal GPR39 and ZnT-3. In contrast, zinc supplementation for 4 weeks significantly improved damage-related changes described above and rescued the abnormal expression of GPR39, ZnT-3, and MBP in the hippocampus. Similar alterations between the expression pattern of MBP and aberrant sprouting of mossy fibers in the hippocampus may indicate that sprouting is a secondary pathological change caused by developmental brain damage rather than the cause of epileptogenesis. Up-regulation of MBP protein levels in the high zinc diet-treated seizure group as well as the corresponding improvement of cognitive impairment and reduced hippocampal mossy fiber regenerative sprouting, may represent a compensatory mechanism for neuronal membrane damage and repair.
ok noted, chronic low zinc and the transporters get out of whack. reminds me of cancer. and supplementation corrects this aberration, you say? fascinating.
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Re: zinc and MS

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parked for future review/study
  • Zinc transporter 3 (ZnT3) and vesicular zinc in central nervous system function (2017)
    https://www.ncbi.nlm.nih.gov/pubmed/28624432

    Zinc transporter 3 (ZnT3) is the sole mechanism responsible for concentrating zinc ions within synaptic vesicles in a subset of the brain's glutamatergic neurons. This vesicular zinc can then be released into the synaptic cleft in an activity-dependent fashion, where it can exert many signaling functions. This review provides a comprehensive discussion of the localization and function of ZnT3 and vesicular zinc in the central nervous system. We begin by reviewing the fundamentals of zinc homeostasis and transport, and the discovery of ZnT3. We then focus on four main topics. I) The anatomy of the zincergic system, including its development and its modulation through experience-dependent plasticity. II) The role of zinc in intracellular signaling, with a focus on how zinc affects neurotransmitter receptors and synaptic plasticity. III) The behavioural characterization of the ZnT3 KO mouse, which lacks ZnT3 and, therefore, vesicular zinc. IV) The roles of ZnT3 and vesicular zinc in health and disease.
    ...
    5. ZNT3 in health and disease
    5.1. Aging and Alzheimer’s disease...
    5.2. Neurodegeneration and cell death
    ...In general, reduced or eliminated ZnT3 expression seems to precipitate – or at least correlate with – certain deleterious health conditions, as described throughout this section. In a few instances, however, elimination of ZnT3 or chelation of vesicular zinc seems to improve outcomes. In a mouse model of multiple sclerosis, ZnT3 KO mice show better motor function, less demyelination, reduced BBB disruption, and reduced immune cell infiltration into the spinal cord (Choi et al., 2016).
    A lack of zinc or ZnT3 is also protective against cell death following injury of the retina or optic nerve. In a model of light-induced retinal damage, ZnT3 KO mice and mice maintained on a zinc-deficient diet exhibit less loss of photoreceptor cells (Bai et al., 2013). In the case of optic nerve injury, retinal zinc homeostasis is perturbed, resulting in zinc accumulation first in the amacrine cells and, ultimately, in the retinal ganglion cells (see Section 2.2). ZnT3 KO mice show reduced zinc accumulation in the amacrine and retinal ganglion cells and increased ganglion cell survival following nerve crush injury (Li et al., 2017). Even more remarkably, post-injury axon regeneration is greatly enhanced in ZnT3 KO mice relative to wild type mice. Similar prosurvival and pro-regenerative effects can be produced by injecting zinc chelators into the eye...
    5.3. Other disorders...
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Re: zinc and MS

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not ms, but
  • Amyloid plaques arise from zinc-enriched cortical layers in APP/PS1 transgenic mice and are paradoxically enlarged with dietary zinc deficiency (2007)
    https://www.sciencedirect.com/science/a ... 2207011608

    The ZnT3 zinc transporter is uniquely expressed in cortical glutamatergic synapses where it organizes zinc release into the synaptic cleft and mediates β-amyloid deposition in transgenic mice. We studied the association of zinc in plaques in relation to cytoarchitectural zinc localization in the APP/PS1 transgenic mouse model of Alzheimer’s disease. The effects of low dietary zinc for 3 months upon brain pathology were also studied. We determined that synaptic zinc distribution within cortical layers is paralleled by amyloid burden, which is heaviest for both in layers 2–3 and 5. ZnT3 immunoreactivity is prominent in dystrophic neurites within amyloid plaques. Low dietary zinc caused a significant 25% increase in total plaque volume in Alzheimer’s mice using stereological measures. The level of oxidized proteins in brain tissue did not changed in animals on a zinc-deficient diet compared with controls. No obvious changes were observed in the autometallographic pattern of zinc-enriched terminals in the neocortex or in the expression levels of zinc transporters, zinc importers or metallothioneins. A small decrease in plasma zinc induced by the low-zinc diet was consistent with the subclinical zinc deficiency that is common in older human populations. While the mechanism remains uncertain, our findings indicate that subclinical zinc deficiency may be a risk factor for Alzheimer’s pathology.
  • Insight into zinc signaling from dietary zinc deficiency (2009)
    https://www.sciencedirect.com/science/a ... 730900085X

    ..Zinc deficiency elicits neuropsychological symptoms and affects cognitive performance. It may also aggravate glutamate excitotoxicity in neurological diseases. Abnormal glucocorticoid secretion is associated with these symptoms in zinc deficiency. Furthermore, the decrease in Zn2+ pool may cooperate with glucocorticoid action in zinc deficiency. Judging from susceptibility of Zn2+ pool in the brain to zinc deficiency, it is possible that the decrease in Zn2+ pool in the peripheral tissues triggers abnormal glucocorticoid secretion. To understand the importance of zinc as a signaling factor, this paper analyzes the relationship among the changes in hippocampal functions, abnormal behavior and pathophysiological changes in zinc deficiency, based on the data from experimental animals.
  • The role of zinc in the pathogenesis and treatment of central nervous system (CNS) diseases. Implications of zinc homeostasis for proper CNS function (2014)
    https://www.ncbi.nlm.nih.gov/pubmed/25265815

    Abstract
    Zinc, the essential trace element, is known to play multiple biological functions in human organism. This metal is a component of many structural as well as regulatory and catalytic proteins. The precise regulation of zinc homeostasis is essential for central nervous system and for the whole organism. Zinc plays a significant role in the brain development and in the proper brain function at every stage of life. This article is a review of knowledge about the role of zinc in central nervous system (CNS) function. The influence of this biometal on etiopathogenesis, prevention and treatment of selected brain diseases and disorders was discussed. Zinc imbalance can result not only from insufficient dietary intake, but also from impaired activity of zinc transport proteins and zinc dependent regulation of metabolic pathways. It is known that some neurodegenerative processes are connected with zinc dyshomeostasis and it may influence the state of Alzheimer's disease, depression and ageing-connected loss of cognitive function. The exact role of zinc and zinc-binding proteins in CNS pathogenesis processes is being under intensive investigation. The appropriate zinc supplementation in brain diseases may help in the prevention as well as in the proper treatment of several brain dysfunctions.
  • Fishy Business: Effect of Omega-3 Fatty Acids on Zinc Transporters and Free Zinc Availability in Human Neuronal Cells (2014)
    https://www.mdpi.com/2072-6643/6/8/3245/htm

    5. DHA and Zinc Homeostasis
    ...Dietary DHA deficiency resulted in increased zinc levels in the hippocampus and elevated expression of the putative zinc transporter, ZnT3, in the rat brain [71]. In this study, rats were raised under control diets, which were either omega-3 enriched or DHA-deficient. Rats raised under the deficient diet demonstrated an up-regulation of ZnT3 mRNA levels and free zinc in the hippocampus. Although this study reports an increase in ZnT3 mRNA levels, it lacks protein data to assess the functionality or availability of the ZnT3 protein since changes at the RNA level do not necessarily equate to changes at the protein expression level. In addition, altered zinc metabolism in neuronal cells has been linked to neurodegenerative conditions such as AD [30]. Another study conducted with transgenic mice has shown a significant link between ZnT3 transporter levels and cerebral amyloid plaque pathology. When the ZnT3 transporter was silenced in transgenic mice expressing cerebral amyloid plaque pathology, a significant reduction in plaque load and the presence of insoluble amyloid were observed [72]. In addition to the decrease in plaque load, ZnT3 silenced mice also exhibited a significant reduction in free zinc availability in the hippocampus and cerebral cortex. Collectively, the findings from this study are very interesting and indicate a clear connection between zinc availability and amyloid plaque formation, thus indicating a possible link to AD. DHA supplementation has also been reported to limit the following: amyloid presence, synaptic marker loss, hyper-phosphorylation of Tau, oxidative damage and cognitive deficits in transgenic mouse model of AD [73]. In addition, studies by Stoltenberg, Flinn and colleagues report on the modulation of zinc and the effect in transgenic mouse models of AD [74,75]. Given that all of these are classic pathological features of AD, and considering the limiting nature of DHA in these processes, it can be argued that DHA is a key candidate in preventing or even curing this debilitating disease.
    In order to better understand the possible links and pathways of zinc and DHA with neurodegeneration, we designed a study that incorporates all three of these aspects, to study their effects at the cellular level. In this study, we were able to demonstrate a possible link between omega-3 fatty acid (DHA) concentration, zinc availability and zinc transporter expression levels in cultured human neuronal cells [7]. When treated with DHA over 48 h, ZnT3 levels were markedly reduced in the human neuroblastoma M17 cell line. Moreover, in the same study, we were able to propose a possible neuroprotective mechanism of DHA, which we believe is exerted through a reduction in cellular zinc levels (through altering zinc transporter expression levels) that in turn inhibits apoptosis [7]. DHA supplemented M17 cells also showed a marked depletion of zinc uptake (up to 30%) [7], and free zinc levels in the cytosol were significantly low compared to the control treatment (unpublished data). This reduction in free zinc availability was specific to DHA; cells treated with EPA had no significant change in free zinc levels (unpublished data). Moreover, DHA-repleted cells had low levels of active caspase-3 and high Bcl-2 levels compared to the control treatment [7]. These findings are consistent with previous published data and further strengthen the possible correlation between zinc, DHA and neurodegeneration [30,71,72,73,74,75]....
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Re: zinc and MS

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interesting title encounter:

Zinc deficiency and its repletion following liver transplantation in humans.
https://www.ncbi.nlm.nih.gov/pubmed/8826662

(related older topic i have yet to reread in detail viewtopic.php?t=6906)

stream-of-consciousness follow-up search titles, parked for future review:

Correction of hypozincemia following liver transplantation in children is associated with reduced urinary zinc loss
https://www.ncbi.nlm.nih.gov/pubmed/10051486

Serum and urine zinc response in head-injured patients
https://www.ncbi.nlm.nih.gov/pubmed/3944632

Increased urinary zinc excretion after thermal injury
https://www.ncbi.nlm.nih.gov/pubmed/1744502

A Syndrome of Acute Zinc Loss
Cerebellar Dysfunction, Mental Changes, Anorexia, and Taste and Smell Dysfunction
https://jamanetwork.com/journals/jamane ... act/574032

Zinc Homeostasis in Humans
https://www.ncbi.nlm.nih.gov/pubmed/10801944
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Re: zinc and MS

Post by Petr75 »

2019 Oct 30
Institute of Immunology, Medical Faculty, RWTH Aachen University, Aachen, Germany
Micronutrients in autoimmune diseases: possible therapeutic benefits of zinc and vitamin D.
https://www.ncbi.nlm.nih.gov/pubmed/31841960

Abstract

A functional immune system is essential for healthy life. This is achieved by the coordinate activation and interaction of different immune cells. One should be aware that activation of the immune response is as important as its deactivation when the pathogens are cleared, as otherwise host tissue can be damaged up to life-threatening levels. Autoimmune diseases (AID) represent a phenomenon of immune cells attacking host cells and tissue. Five to eight percent of the world's population are currently affected by 80-100 AID. In recent years, the incidence has been constantly increasing, reaching alarmingly high numbers particularly for type 1 diabetes mellitus, Crohn's disease, rheumatoid arthritis, Sjogren's syndrome and multiple sclerosis. This indicates a higher societal burden of AID for the future. This article provides an overview of general concepts of triggers and underlying mechanisms leading to self-destruction. Lately, several original concepts of disease etiology were revised, and there is a variety of hypotheses on triggers, underlying mechanisms and preventive actions. This article concentrates on the importance of nutrition, especially zinc and vitamin D, for balancing the immune function. Homespun nutritional remedies seem to reenter today's therapeutic strategies. Current treatment approaches are largely symptomatic or suppress the immune system. However, recent studies reveal significant benefits of nutrition-related therapeutic approaches including prevention and treatment of established disease, which offer a cost-efficient and trigger-unspecific alternative addressing balancing rather than suppression of the immune system. Zinc and vitamin D are currently the best studied and most promising candidates for therapeutic intervention.
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Re: zinc and MS

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posted elsewhere previously, but deserves its own flag to interested readers' attention:

The emerging role of serum zinc in motor disability and radiological findings in patients with multiple sclerosis (2019)
https://ejnpn.springeropen.com/articles ... 019-0107-6

"... [se zn] is negatively correlated with disease duration, number of relapses, motor disability, fatigue, and MRI lesion load."
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