Copper Brain Damage is similar to that caused by Endotoxin and they Synergize

Be careful with your use of supplements or contaminants that can carry too much of this element into your brain or that of your foetus

As people seek ways of improving their health through ensuring adequate essential trace minerals, they might be tempted to self medicate with products that will do more harm than good.

A 2022 paper is locked behind a paywall, but enough of the “snippets” can be read, including the references and a nice graphical abstract showing Copper damage pathways.¹

Some quotes from the article:

TH and IBA-1 immunofluorescence double staining showed that high-dose copper exposure caused decreased dopaminergic neurons and activation of microglia in the substantia nigra of mice, and they were both dose-dependent

The authors are interested in Parkinson’s Disease (PD) and refer to the standard animal model that uses Endotoxin (LPS) to induce it.²

Regarding the microglial activation phenotypes, there are currently widely recognized classifications such as the pro-inflammatory M1 phenotype and the anti-inflammatory M2 phenotype (Boche et al., 2013; Subhramanyam et al., 2019; Tang and Le, 2016).

Microglia in the “classical activated state”, called M1-type microglia, activated by Endotoxin (LPS), IFN-γ, Aβ, α-syn, can induce NF-κB pathways and produce multiple pro-inflammatory factors such as TNF-α and IL-6 (Subhramanyam et al., 2019; Tang and Le, 2016), resulting in CNS damage.

Microglia-mediated neuroinflammation is an important component of the pathogenesis of PD, negatively correlated with survival of dopaminergic neurons in patients (Ouchi et al., 2005).

and another reference to Endotoxin

In PD model induced by LPS or MPTP, the induction of Parkin/PINK1-mediated mitophagy in microglia is often used as a target for studying the neuroprotective effects of new drugs (Ahmed et al., 2021; Han et al., 2021; Qin et al., 2021).

Parkin is an E3 ubiquitin ligase that cooperates with the serine-threonine protein kinase PINK1 to remove the damaged mitochondrial (Dickson, 2012).

The blockage of the mitophagy pathway will cause accumulation of damaged mitochondria, increased ROS production and decreased ATP levels, ultimately leading to cell death (Chen et al., 2020).

Cell pyroptosis is a new type of programmed cell death discovered in recent years.

Many studies have shown that pyroptosis is closely related to autophagy (Guo et al., 2021; Lv et al., 2021; Yan et al., 2020). NLRP3 inflammasome is activated under cell infection or stress (Kumari et al., 2020), which leads to the secretion of Caspase1-dependent proinflammatory cytokines, and ultimately induces pyroptosis (Fu et al., 2019; Sun et al., 2019).

I have mentioned that research is underway to try to ameliorate Endotoxin induced Brain damage.³

The US Comparative Toxicogenomics Database has a very useful collection of 5,959 line entries for Copper in relation to disease, many of which have been curated by Humans with links to peer reviewed papers.⁴ Here is their summary chart.

Among the references under Copper are 21 papers reporting studies on Autism and Copper exposure.⁵ However opening some of the papers, I found more curation is needed because they discussed other elements including Cadmium and Mercury that cause Brain damage via similar pathways.

Some are simply epidemiology papers like a Norway/USA collaboration that looked at gestational levels of 11 metals/elements that showed a “U-shaped” response for Copper.⁶

As mentioned before, we have to look at factors that cause Austism in 3 ways - prenatal, postnatal and combined exposures while the Brain develops.⁷

It is complicated.

Searching Copper and Endotoxin together is one approach to reducing the number of papers to read.⁸ That turns up 398 papers showing Copper damage to numerous organs such as the Liver where there are genetic factors that must be considered.⁹

It was shown in 1982 that Endotoxin increases serum Copper levels in Hamsters.¹⁰

Searching Copper Lipopolysaccharide together pulls up 410 papers.¹¹

With Copper LPS we find 299 papers.¹²

The first on that list is interesting, showing the combined effects of the two toxins and addition of a Copper Chelator to the mix.¹³ It is behind a paywall but the references are visible and the abstract tells us much:

Inflammation is a complex physiological process that enables the clearance of pathogens and repairing damaged tissues. Elevated serum copper concentration has been reported in cases of inflammation, but the role of copper in inflammatory responses remains unclear. This study used bovine macrophages to establish lipopolysaccharide (LPS, Endotoxin)-induced inflammation model.

There were five groups in the study: a group treated with LPS (100 ng/ml), a group treated with either Copper Chelator (TetraThioMolybdate, TTM) (20 μmol) or CuSO₄ (25 μmol or 50 μmol) after LPS stimulation, and a control group.

Copper concentrations increased in macrophages after the LPS treatment.

TTM decreased mRNA expression of pro-inflammatory factors (IL-1β, TNF-α, IL-6, iNOS, and COX-2), whereas Copper supplement increased them.

Compared to the control group, TLP4 and MyD88 protein levels were increased in the TTM and copper groups. However, TTM treatment decreased p-p65 and increased IкB-α while the copper supplement showed reversed results. In addition, the phagocytosis and migration of bovine macrophages decreased in the TTM treatment group while increased in the copper treatment groups. Results mentioned above indicated that Copper could promote the LPS-induced inflammatory response in bovine macrophages, promote pro-inflammatory factors by activating the NF-кB pathway, and increase phagocytosis capacity and migration. Our study provides a possible targeted therapy for bovine inflammation.

I would not recommend swallowing a Molybdenum compound to try to treat Copper poisoning!

Ceruloplasmin

Thanks to Martha for mentioning the Copper Transporter Ceruloplasmin that is synthesized in the liver containing 6 atoms of copper.¹⁴

Searching PubMed for Ceruloplasmin with Endotoxin brings up 72 papers.¹⁵

The top of the list is one from China, covering Endotoxin (LPS) induced Cardiac Death unfortunately behind a paywall.¹⁶

The abstract is useful:

Background: Currently, sepsis induced cardiotoxicity is among the major causes of sepsis-related death. The specific molecular mechanisms of sepsis induced cardiotoxicity are currently unknown. Therefore, the purpose of this paper is to identify the key molecule mechanisms for sepsis induced cardiotoxicity.

Methods: Original data of sepsis induced cardiotoxicity was derived from Gene Expression Omnibus (GEO; GSE63920; GSE44363; GSE159309) dataset. Functional enrichment analysis was used to analysis sepsis induced cardiotoxicity related signaling pathways. Our findings also have explored the relationship of cuproptosis and N6-Methyladenosine (m6A) in sepsis induced cardiotoxicity. Mice are randomly assigned to 3 groups: saline treatment control group, LPS group administered a single 5 mg/kg dose of LPS for 24 h, LPS + CD274 inhibitor group administered 10 mg/kg CD274 inhibitor for 24 h.

Results: Overall, expression of cuproptosis-related genes (CRGs) CD274, Ceruloplasmin (CP), Vascular endothelial growth factor A (VEGFA), Copper chaperone for cytochrome c oxidase 11 (COX11), chemokine C-C motif ligand 8 (CCL8), Mitogen-activated protein kinase kinase 1(MAP2K1), Amine oxidase 3 (AOC3) were significantly altered in sepsis induced cardiotoxicity. The results of spearman correlation analysis was significant relationship between differentially regulated genes (DEGs) of CRGs and the expression level of m6A methylation genes.

GO and KEGG showed that these genes were enriched in response to interferon-beta, MHC class I peptide loading complex, proteasome core complex, chemokine receptor binding, TAP binding, chemokine activity, cytokine activity and many more. These findings suggest that cuproptosis is strongly associated with sepsis induced cardiotoxicity.

Conclusion: In the present study, we found that cuproptosis were associated with sepsis induced cardiotoxicity. The CD274, CP, VEGFA, COX11, CCL8, MAP2K1, AOC3 genes are showing a significant difference expression in sepsis induced cardiotoxicity. Our studies have found significant correlations between CRGs and m6A methylation related genes in sepsis induced cardiotoxicity. These results provide insight into mechanism for sepsis induced cardiotoxicity.

Keywords: Cardiotoxicity; Cuproptosis; N6-methyladenosine; Sepsis.

Searching PubMed for Ceruloplasmin with Lipopolysaccharide finds 72 papers.¹⁷

Searching PubMed for Ceruloplasmin with LPS finds 59 papers.¹⁸

Cuproptosis

Quick look at Cuproptosis is exceedingly interesting, with a free paper from China where they used Elesciomol¹⁹ to induce Cuproptosis.²⁰

Here is their Figure showing the pathways to Death.

Elesclomol binds copper (Cu²⁺) in the extracellular environment and transports it to intracellular compartments. Increased Cu accumulation causes cuproptosis mainly through FDX1-mediated mitochondrial proteotoxic stress. On the one hand, FDX1 reduces Cu²⁺ to Cu⁺, facilitating the lipoylation (LA) and aggregation of enzymes (especially DLAT) involved in the regulation of mitochondrial TCA cycle. On the other hand, FDX1 causes the destabilization of Fe–S cluster proteins. In addition to Cu ionophores, Cu importers (e.g., SLC31A1) and exporters (e.g., ATP7B) regulate cuproptosis sensitivity by affecting intracellular Cu⁺ levels. GSH functions as a thiol-containing copper chelator that blocks cuproptosis, whereas BSO promotes cuproptosis by depleting GSH. The mitochondrial pyruvate carrier (MPC) inhibitor UK5099 and electron transport chain (ETC) complex I/III inhibitors (e.g., rotenone and antimycin A) attenuate elesclomol-induced cuproptosis.

We see that Iron Sulfur bonds are important.

Other Substack authors are interested in the interplay of Zinc and Copper.

Please provide your favourite articles and I will add links later to remain within the current email length limit.

1. Qian Zhou, Ying Zhang, Lu Lu, Hu Zhang, Chao Zhao, Yuepu Pu, Lihong Yin. 2022. Copper induces microglia-mediated neuroinflammation through ROS/NF-κB pathway and mitophagy disorder. https://www.sciencedirect.com/science/article/abs/pii/S0278691522005671

2. Parkinson's Disease after Pfizer jabs most likely due to Endotoxin in every vial

3. Endotoxin Binding Protein as a proposed Treatment for Parkinson's Disease

4. https://ctdbase.org/detail.go?type=chem&acc=D003300&view=disease

5. https://ctdbase.org/detail.go?type=relationship&chemAcc=D003300&diseaseAcc=MESH%3AD000067877&view=reference

6. Thea S Skogheim, Kjell Vegard F Weyde, Stephanie M Engel, Heidi Aase, Pål Surén, Merete G Øie, Guido Biele, Ted Reichborn-Kjennerud, Ida H Caspersen, Mady Hornig, Line S Haug, Gro D Villanger. 2021. Metal and essential element concentrations during pregnancy and associations with autism spectrum disorder and attention-deficit/hyperactivity disorder in children. https://www.sciencedirect.com/science/article/pii/S0160412021000933

7. Autism is Caused by Endotoxin in Jabs

8. https://pubmed.ncbi.nlm.nih.gov/?term=Copper+endotoxin

9. Rolf Teschke. 2022. Aluminum, Arsenic, Beryllium, Cadmium, Chromium, Cobalt, Copper, Iron, Lead, Mercury, Molybdenum, Nickel, Platinum, Thallium, Titanium, Vanadium, and Zinc: Molecular Aspects in Experimental Liver Injury. https://www.mdpi.com/1422-0067/23/20/12213

10. Etzel Kenneth R., Swerdel Mavis R., Swerdel Joel N., Cousins Robert J. 1982. Endotoxin-Induced Changes in Copper and Zinc Metabolism in the Syrian Hamster. https://www.sciencedirect.com/science/article/abs/pii/S0022316623197057

11. https://pubmed.ncbi.nlm.nih.gov/?term=Copper+lipopolysaccharide

12. https://pubmed.ncbi.nlm.nih.gov/?term=Copper+LPS

13. Hongrui Guo, Lin Jing, Chenglong Xia, Yanqiu Zhu, Yue Xie, Xiaoping Ma, Jing Fang, Zhisheng Wang, Zhicai Zuo. 2024. Copper Promotes LPS-Induced Inflammation via the NF-кB Pathway in Bovine Macrophages. https://link.springer.com/article/10.1007/s12011-024-04107-6

14. https://en.wikipedia.org/wiki/Ceruloplasmin

15. https://pubmed.ncbi.nlm.nih.gov/?term=ceruloplasmin+endotoxin

16. Jingru Yan, Zhangyi Li, Yilan Li, Yao Zhang. 2024. Sepsis induced cardiotoxicity by promoting cardiomyocyte cuproptosis. https://www.sciencedirect.com/science/article/abs/pii/S0006291X23013396

17. https://pubmed.ncbi.nlm.nih.gov/?term=ceruloplasmin+lipopolysaccharide+

18. https://pubmed.ncbi.nlm.nih.gov/?term=ceruloplasmin+LPS

19. https://en.wikipedia.org/wiki/Elesclomol

20. Daolin Tang, Xin Chen and Guido Kroemer. 2022. Cuproptosis: a copper-triggered modality of mitochondrial cell death. https://www.nature.com/articles/s41422-022-00653-7