July 15, 2024

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The drug that can reverse COVID-19-induced cognitive decline in the brain

Researchers have identified the drug that can reverse COVID-19-induced cognitive decline in the brain.

Researchers have identified the drug that can reverse COVID-19-induced cognitive decline in the brain.

Through experiments on lab-cultivated miniature brains and mice, scientists discovered that SARS-CoV-2 infection leads to the accumulation of “zombie” cells, causing brain fog associated with Long-COVID-19.

They also found a drug capable of reversing this virus-related cognitive decline.

Using lab-cultivated brain organoids, researchers determined drugs to reverse COVID-19-induced cognitive decline.

Researchers have identified the drug that can reverse COVID-19-induced cognitive decline in the brain.

While SARS-CoV-2 is primarily a respiratory virus, it can result in a range of neurological complications after the acute phase. Long-COVID is often associated with cognitive impairment or brain fog, and ample evidence suggests significant structural changes in the brains of COVID-19 patients.

Although the role of aging cells or “zombie” cells—cells that stop dividing and contribute to cognitive decline in neurodegenerative diseases and aging—is supported by research, their contribution to COVID-19-related brain aging was unclear.

This prompted researchers at the University of Queensland’s Australian Institute for Bioengineering and Nanotechnology to study the effects of different SARS-CoV-2 variants on brain tissue and search for drugs that could reverse this virus-related aging.

“We found that COVID-19 accelerates the appearance of ‘zombie’ or aging cells, which naturally accumulate in the brain with age,” said the study’s first author and corresponding author Julio Aguado. “As is well known, aging cells cause tissue inflammation and degeneration, leading to cognitive impairments such as brain fog and memory loss.”

The researchers hypothesized that SARS-CoV-2-induced brain aging is related to the virus’s neuroinflammatory effects during the acute phase. To validate their hypothesis, researchers analyzed the brains of patients who died due to severe COVID-19 or non-neurological causes. They found that the number of p16 protein-positive cells in the brains of COVID-19 patients increased more than sevenfold compared to the control group. Cell aging is typically characterized by the expression of p16, and the results suggested that SARS-CoV-2 could induce cell aging, leading to cognitive decline and accelerating neurodegenerative processes associated with Long-COVID.

The researchers then generated brain organoid tissue from embryonic stem cells (lab-manufactured miniature brain models) and subjected the organoids to eight months of physiological aging before testing the efficacy of aging inhibitors or senolytic drugs.

Aguado said, “We screened a range of therapeutic drugs using brain organoid tissue, looking for drugs capable of clearing aging cells.”

They identified four drugs that selectively eliminate aging cells: Navitoclax, ABT-737, Quercetin, and the combination of Dasatinib and Quercetin (D+Q). Navitoclax and ABT-737 inhibit the Bcl-2 protein, inducing apoptosis or programmed cell death in aging cells. Quercetin and D+Q can penetrate the blood-brain barrier, clearing aging cells from the brain. Aging organoid tissues exposed to two doses (every two weeks) of Navitoclax, ABT-737, or D+Q were then subjected to extensive RNA sequencing analysis.

Human stem cell-derived brain organoid tissue enabled researchers to conduct ethical and practical experiments that are challenging in human subjects.

Compared to Navitoclax and ABT-737, D+Q had a broader range of effects, alleviating multiple pro-inflammatory pathways specific to cell aging. In addition to acting as an aging inhibitor, D+Q also restored the gene expression age of nine-month-old organ tissues to levels comparable to eight-month-old tissues. Changes in gene expression induced by D+Q treatment were positively correlated with characteristics of lifespan-extending interventions such as caloric restriction, suggesting the drug’s potential for promoting health in targeting cell aging. In essence, this therapy rejuvenated brain tissue in organ organs.

In addition to normal brain aging, researchers infected brain organoid tissues with SARS-CoV-2 variants and found that they significantly increased cell aging, especially the Delta variant. After treating infected organisms with aging inhibitors, the expression of SARS-CoV-2 viral RNA significantly decreased.

Subsequently, the researchers conducted experiments on mice infected with the SARS-CoV-2 Delta variant. Compared to the control group, mice treated with Quercetin or D+Q showed a significantly increased survival rate, with a 60% increase in median lifespan. All aging interventions significantly reduced COVID-related disease features, especially in the D+Q treatment group, including a reduction in p16 and pro-inflammatory cytokines. Similar to organ experiments, researchers found that mice treated with aging inhibitors had significantly lower virus gene expression compared to untreated mice, reducing the expression of aging genes in infected mice to levels comparable to uninfected brains.

Aguado said, “More research is needed to fully understand the mechanisms involved, but this study marks a significant step forward in understanding the intricate relationship between viral infection, aging, and neural health. In the long run, we can expect these drugs to be widely used in treating post-acute sequelae of persistent infections caused by viruses like COVID-19.”

Researchers noted that using brain organoid tissues allowed them to conduct ethical studies challenging to perform on human subjects, and the same approach could be used to study other aging-related neurodegenerative diseases.

One of the co-authors of the study, Ernst Wolvetang, said, “Our research nicely demonstrates how human brain models can accelerate preclinical screening of therapeutic drugs—advancing beyond animal testing—and may have a global impact. The same drug screening approach also aids in Alzheimer’s disease research and a range of neurodegenerative diseases driven by aging.”

The study was published in the journal “Nature Aging.”

Researchers have identified the drug that can reverse COVID-19-induced cognitive decline in the brain.

(source:internet, reference only)

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