SARS-CoV-2 induced neurotoxicity

And how Glutathione helps fix it

I will attempt to simplify a little the content of this one, but it might be a rather comprehensive substack in terms of connections, and I will link to other ones I wrote. But my first will be a “venting” of some sort.

As many readers will be aware not only I am very vocal on the extensive use of antioxidants, suggesting its use for most people, I am a very big “fan” of one specific one, N-Acetyl-Cysteine, a known precursor for Glutathione, the body “master” antioxidant.

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The following image was my literal reaction when reading the paper above.

From very early in the pandemic it was pretty clear, regardless of how “distinct” SARS-CoV-2 was from the first one, it was a virus that put an extremely high oxidative burden on the infected, the more severe the degree of infection, the higher the burden.

Far from being the only one or the first one, this specific part of the response toward the virus can induce some strong rage in me. Of all the counter-productive choices they made, Vitamin D and antioxidants were the biggest ones, with antioxidation being one that could have saved lots of lives (probably millions) at several stages of the disease (Vitamin D for the most part is extremely effective BEFORE infection). This gives me leeway to cover another paper from a more mechanistic insight than a “groundbreaking” aspect.

Association between Glutathione S-Transferases Gene Variants and COVID-19 Severity in Previously Vaccinated and Unvaccinated Polish Patients with Confirmed SARS-CoV-2 Infection

As the outcome of COVID-19 is associated with oxidative stress, it is highly probable that polymorphisms of genes related to oxidative stress were associated with susceptibility and severity of COVID-19. The aim of the study was to assess the association of glutathione S-transferases (GSTs) gene polymorphisms with COVID-19 severity in previously vaccinated and unvaccinated Polish patients with confirmed SARS-CoV-2 infection. A total of 92 not vaccinated and 84 vaccinated patients hospitalized due to COVID-19 were included. The WHO COVID-19 Clinical Progression Scale was used to assess COVID-19 severity. GSTs genetic polymorphisms were assessed by appropriate PCR methods. Univariable and multivariable analyses were performed, including logistic regression analysis. GSTP1 Ile/Val genotype was found to be associated with a higher risk of developing a severe form of the disease in the population of vaccinated patients with COVID-19 (OR: 2.75; p = 0.0398). No significant association was observed for any of the assessed GST genotypes with COVID-19 disease severity in unvaccinated patients with COVID-19. In this group of patients, BMI > 25 and serum glucose level > 99 mg% statistically significantly increased the odds towards more severe COVID-19. Our results may contribute to further understanding of risk factors of severe COVID-19 and selecting patients in need of strategies focusing on oxidative stress.

Months ago I briefly covered a paper where the authors found that vaccinated individuals, on average, took much longer to recover to baseline levels of ROS than unvaccinated, bearing a lot of weight on the dynamics of breakthrough infection, how the immune system could shift, its potential to set off and accelerate a myriad of pathologies and many aspects we covered here.

Here we have a further mechanistic overview of why some vaccinated individuals have a heavier disease burden than others, in simple terms, certain gene mutations are related to genes responsible for an enzyme reaction to detoxify your body. People with this genotype, studied for its role in other diseases, and vaccinated have a higher chance of developing severe Covid-19 than unvaccinated, and among the unvaccinated higher body mass and higher glucose levels increase the odds towards severe disease, in line with now few years of evidence, and much of what I wrote in this substack in 2022.

If you didn’t understand so far why I insist on antioxidation so much, you are about to, perhaps.

The SARS-CoV-2 main protease induces neurotoxic TDP-43 cleavage and aggregates

TDP-43 as described in the image above is argued among experts as one of the main culprits in neurodegeneration, most pertinent in regard to its accumulation in the presence of inflammation and aging. Understanding the exact interactions between the virus and specific proteins can enable us to avoid or find therapeutic approaches toward remediating whatever possible pathology these nasty interactions might set off.

The authors tested all the proteins SARS-CoV-2 produces, from the infamous S, and N to all the Non-Structural proteins, which while “not essential” to the virus replication, can have many different effects, including pathological burden upon infection or post-infection which is often the case and more common among many other viral infections. In their tests, the only protein that had a detectable influence on the levels of TDP-43 was NSP5.

To find out the exact mechanism by that SARS-CoV-2 NSP5 can cleave TDP-43 (an important step for its pathological effects) they used several inhibitors and found that SARS-CoV-2 can use different strategies to cleave TDP-43 using NSP5.

The exact position at which NSP5 cleaves TDP-43, it is important to know

NSP5 is a protein that doesn’t change much among different viruses (SARS and MERS), and they found that SARS-CoV-2 has lower expression (quantity) but higher efficiency in cleaving TDP-43 than the other two infamous coronaviruses, and both Beta and Omicron can do the same.

An important aspect of “proteinopathies” is the change in solubility in specific proteins, and to the surprise of no one this is precisely what they found, the presence of NSP5 significantly decreased the solubility of TDP-43, both “full-length” meaning the entire protein, and the cleaved protein (broken into smaller pieces) and the byproduct of such interaction can work to further amplify the effects of NSP5 on TDP-43. Basically creating a feedback loop.

To clarify as a personal observation based on all the research I have done so far in the last few years, while there is evidence of SARS-CoV-2 presence and pathological effects in the brain, brain tropism in the majority of cases is relegated to the severity of infection, outliers do exist but this often the case. Now I want to cover aspects outside the scope of this paper, but I do think they are of incredible importance in regard to this specific pathological effect (TDP).


I have covered SARS-CoV-2 and the brain before, and at the core of the issue lies the same dynamic. Excessive oxidative burden, depletion of specific and uniquely important nutrients, and mitochondrial dysfunction. Also as a rather annoying habit for ages, I left small hints to the following, and by ages I mean almost 2 years.

Oxidative stress induced by glutathione depletion reproduces pathological modifications of TDP-43 linked to TDP-43 proteinopathies

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While the field of neurodegeneration is very complex and can get extremely complex when you use an interdisciplinary approach, any person can scour dozens upon dozens of papers on this subject and somewhere in the paper, at a random paragraph you will find the same words. Oxidative stress, ROS, and mitochondrial dysfunction all play a central role in proteinopathies. Here is a paper on the aggregation of TDP-43 induced by oxidative stress causing significant mitochondrial dysfunction.

By merely supplementing anything related to Glutathione production (NAC together with Glycine, Glutathione itself, and Quercetin, among others) one can easily abrogate the potential damage arising from complex interactions between viral proteins and our own bodies. For the herbal aficionado here is a paper on the use of a Chinese herb, Bojungikgi-tang, and riluzole (treatment for ALS). I still personally prefer the Glutathione approach because of many other reasons, but as they say “never hurts to know more”.

To anyone interested in neurodegeneration, I would say especially in regards to SARS-CoV-2 and its neurodegenerative potential, I recommend you read the following paper.

In regards to the following.

Spike Protein as a endotoxin delivery system

There is also the microbiome aspect of both neurodegeneration, endotoxins, and what we discussed here, with special attention to Akkermansia muciniphila, the very same microbe Omicron disrupts long-term in many individuals, a lower level of Akkermansia is found in many people suffering from neurodegenerative conditions, and amelioration of their conditions are present when Akkermansia levels are raised.

And as an FYI, this is still the most important aspect, following the endotoxin interaction with the Spike Protein, among all of this. Galectin-3 plays a central role in many diseases, especially neurodegenerative ones.

Chimeric nature of Galectin-3 and SARS-CoV-2

As the oddity of the day, this.

NAC and Vitamin D Restore CNS Glutathione in Endotoxin-Sensitized Neonatal Hypoxic-Ischemic Rats

Within 1 h of administration, NVD increased GSH close to baseline and suppressed GLX. The combination of NVD with hypothermia rapidly improved cellular redox status after LPS-HI, potentially inhibiting important secondary injury cascades and allowing more time for hypothermic neuroprotection.

Hypothermia + the administration of NAC and Vitamin rapidly rescued the antioxidant capacity of the rats (in which LPS, the most famous endotoxin basically drained), allowing it to avoid secondary injury.

In case you are new here, the following is a helpful start on NAC+Glycine.

The powerful effects of GlyNAC

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