University of São Paulo: Receptor-blocking drugs could prevent or treat neurological problems

Neurological intomas have been reported in patients with covid-19 and there is growing evidence that the coronavirus has the capacity for neuroinvasion, that is, to enter the central nervous system and infect its cells. An article by USP researchers and collaborators in the journal Molecular Psychiatry discusses possible mechanisms for viruses to access the nervous system and the inflammatory effects they have on the brain, suggesting that the exaggerated activation of a cell receptor called P2X7R is associated with this “inflammatory storm” ”.

Coordinator of the research, professor at the Institute of Chemistry (IQ) at USP Henning Ulrich explains that infection by sars-cov-2 induces a condition of neuroinflammation, and that “chronic inflammation in the brain is a characteristic in psychiatric illnesses such as depression and also neurodegenerative, like Parkinson’s disease ”.

Thus, patients with these disorders, which are associated with the activation of neuroimmune mechanisms, may be more susceptible to developing severe conditions of the central nervous system by covid-19. Drugs to decrease this activation, therefore, could be a way to prevent damage from the disease in the brain.

The brain is right there
The first question we can ask is: how does the coronavirus reach the brain ?. This is an intricate process to be described, but in practice it can occur relatively quickly.

“Studies after death indicate that the virus is capable of infecting brain cells, since it has already been identified in the brain tissue of patients infected with sars-cov-2”, says Deidiane Elisa Ribeiro, who is doing post-doctoral work at IQ and who shares the first authorship of the work with the also postdoctoral researcher Ágatha Oliveira Giacomelli. She explains that, for this, the virus needs to overcome a protection that involves our brain called the blood-brain barrier, and there are some hypotheses about how it manages to do this.

To begin with, the virus enters the body mainly through the nose, and reaches the lungs. And to infect any cell, it needs to bind to proteins that are on the cell membranes, called receptors. But they need to be the right recipients. In the lungs, it uses both TMPRSS2 and ACE2 receptors.

virus in the air
lung virus
After infecting some cells in the lung, and reproducing using cellular machinery (since the virus does not have one), sars-cov-2 spreads through the organ quickly. The cells that were infected release pro-inflammatory proteins and ATP molecules (that molecule best known for being the energy reserve in the cells). When ATP is in large quantities outside the cell, it causes cellular damage.

ATP also activates P2X7 receptors in lung cells and macrophages – defense cells that phagocytize (encompass and destroy) foreign agents such as viruses. This causes macrophages to increase the release of the main substances in the inflammatory process, cytokines, in addition to chemokines – and more ATP, in a cycle that feeds back inducing the famous “cytokine storm”. Various physiological processes are deregulated as a result.

brain virus
Through circulation, both the virus and the pro-inflammatory factors released reach other tissues in the body, including the brain. To do this, it infects blood brain barrier endothelial cells, in addition to infecting astrocytes and neurons adjacent to blood vessels by binding to the ACE2 receptors of these cells.

During infection, the blood-brain barrier becomes more permeable and allows cytokines (pro-inflammatory molecules) and defense cells such as leukocytes to pass into brain tissue. The problem is that many of these leukocytes are infected, filled with viruses, and act like trojans, carrying viruses into the central nervous system. There is one of the routes from sars-cov-2 to the brain, but there is another possible route, which also begins in the nose.

In the nasal cavity, the virus infects and multiplies in sustaining cells, using the TMPRSS2 and ACE2 receptors as access again. These cells also express P2X7 receptors and begin a cycle similar to that already described.

Finally, sars-cov-2 can also infect olfactory sensory neurons, and use its connections to enter the central nervous system.

Once in the brain, the virus can alter brain functions both by infecting neurons and glial cells (other cells in the nervous system that have a number of functions), and by the effects that come from the cytokine storm. The result is an inflammatory process characterized by hyperactivation of glial cells. Still, the cytokine storm induces the formation of clots and increases the permeability of small blood vessels, the capillaries, which can result in a stroke, the stroke.

The importance of the P2X7 receiver
In human physiology, some stimuli can lead to a cycle that reinforces the imbalance. Such cycles are called positive feedback, or positive feedback. The mechanism involved in the damage caused by the coronavirus in the brain tissue can be characterized as positive feedback, triggering a series of harmful events that intensify each other.

First, cell stress induces the release of those pro-inflammatory substances, cytokines, and ATP. ATP, in turn, activates P2X7 receptors, which in the brain are mainly present in glial cells. The first is microglia, which in the central nervous system has, among other roles, the defense function. Another type of glial cells that have P2X7 receptors are astrocytes. With P2X7 receptors activated, calcium intake in these cells increases, which in turn increases the release of a neurotransmitter called glutamate. Glutamate activates other receptors present in astrocytes and nerve terminals in neurons – which also opens the door for calcium to enter these cells, again resulting in the release of glutamate and more ATP. “ATP was recently suggested as a neurotransmitter”,

Thereafter, the calcium that enters the neurons triggers other mechanisms that result in the production of nitric oxide, entering reactions that, in turn, generate the so-called reactive oxygen species, better known as free radicals, extremely damaging to cells, since cell membranes to the DNA itself. “The main effect of this would be the death of neurons”, explains Deidiane Ribeiro.

As calcium enters the cell by activating the P2X7 receptor, potassium leaves it. In microglia, this potassium can trigger the activation of an inflammasome (protein complex that is an inflammation sensor) called NLRP3. “The inflammasome is a kind of danger sensor”, defines Professor Ulrich. NLRP3 then induces a cascade of events that, in the end, results in the worsening of the inflammatory process.

Hyperactivation of the P2X7 receptor and stimulation of the NLRP3 inflammasome are observed in patients with psychiatric disorders and neurodegenerative diseases, such as Parkinson’s. This, the researchers postulate, could increase both the susceptibility of these patients to infection by sars-cov-2 and the severity with which covid-19 manifests itself in them. In addition, infection with sars-cov-2 itself could trigger or aggravate these brain disorders.

Thus, they argue, inhibiting the exaggerated expression of the P2X7 receptor and also of the NLRP3 inflammasome could be promising strategies to prevent or treat psychiatric complications or neurodegenerative diseases associated with covid-19.

High impact
Professor Henning Ulrich highlights the recognition of the researchers’ work, published in a high impact scientific journal belonging to the Nature group . “We have few Brazilian works in this magazine, which also charges a fee of more than 4 thousand dollars for the articles to be available in open access. Due to the importance of our work, recognized by the editors, the article was allowed to remain open without being charged this fee ”, he says, emphasizing that this is the second article in his group published in the journal since last year.

Ulrich is the main name in Brazil in the research of psychiatric and neurodegenerative diseases and neuroregeneration mechanisms involving the so-called purinergic signaling, discovered in the 1990s, and in which purinergic receptors, especially P2X7, activated by ATP, participate.

“What we are investigating is the damaging effect of this receptor on Parkinson’s disease, in which we are seeing characteristics similar to what we are proposing here for covid, such as cell death,” he says. And he adds: “when we inhibit the P2X7 receptor in animal models, we see both an improvement in motor function, affected in Parkinson’s disease, as well as a reduction in neuronal death, specifically in the dopaminergic neurons involved in this disease, in addition to a decrease in neuroinflammation, with reduction of excessive glial activation, which is very damaging to the nervous system ”.

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