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24 fevereiro 2019, 14:09

Scientists: HIV medication will help people recovering from a stroke

Scientists: HIV medication will help people recovering from a stroke - foto 1

The treatment and rehabilitation of stroke survivors has always been comparable to a race against time. As a result of the termination of the plasminogen activator (tPA), capable of destroying blood clots in the vessels, only a few hours after a stroke, irreversible damage to brain tissue may occur. As numerous studies have shown, no medications have so far resulted in the complete restoration of functions lost by the brain.

However, as a result of a series of experiments, researchers have suggested that perhaps the source of the long-awaited therapy may be the cellular protein CCR5, which allows HIV to enter healthy cells. Scientists have discovered that in mice, disabling this receptor helps surviving neurons create new connections. From this, experts concluded that people who carry the CCR5 mutation have a higher chance of recovering from a stroke than others.

“This is the first real molecular target that improves recovery after a stroke,” says Argie Hillis, a neurologist specializing in stroke from the John Hopkins University School of Medicine in Baltimore (USA).

Clinical trials in which stroke patients will be given drugs for treating HIV infection that block CCR5, according to the scientist, will very soon test this hypothesis.

White blood cells use CCR5 receptors located on the cell surface to intercept the signals of chemokine molecules and coordinate the immune response. However, HIV is able to “capture” these proteins and use them to enter host cells. People with the CCR5 mutation are known to be protected from HIV infection.

New discoveries related to the work of this receptor, made possible by working with "smart mice" - animals that have genetic mutations that increase their ability to learn and memorize.

Neuroscientist Alcino Silva and his team at the University of California at Los Angeles (UCLA) tried to determine which of the 148 variants of mice had such improvements. In 2016, they reported that lowering the level of CCR5 in the brain of a healthy mouse improved memory formation and learning.

Neurologist Thomas Carmichael from UCLA expressed interest in the results.

“When you watch patients recover from a stroke, they seem to learn to walk or talk,” he explains.

Indeed, the surviving neurons germinate next to the lost ones and establish new contacts. The drug, aimed at blocking CCR5, turned out to be promising for the recovery of stroke patients, especially since this drug was already at hand.

Maraviroc, which blocks the work of CCR5, was approved by the United States Food and Drug Administration (FDA) back in 2007 as a drug for treating HIV.

An article appeared in Cell magazine this week where Silva, Carmichael and a number of their colleagues showed that the levels of CCR5 in mouse neurons are rapidly increasing after a stroke and can remain elevated for several weeks — probably a protein that prevents recovery.

The team tried to block CCR5 using Maraviroc, which acts on a gene that interferes with receptor development, and then tested the muscle ability of the mice, counting as an example how many times their legs slid when they walked along the metal grid. At the end of the 9-week test period, the treated mice showed a greater improvement in motility than the control group.

Even 3 weeks after a stroke, according to scientists, the drug improved the performance of animals.

As Dr. Dale Corbett, a neuroscientist at the University of Ottawa who specializes in recovering people from a stroke, commented on the results, no similar results were recorded in previous studies. New conclusions, he said, give hope that "it may be advisable to open this window to restore people."

The blocking of CCR5 seems to have helped maintain the connection between the neurons adjacent to the damaged site. Thus, neurons in the motor areas of the brain germinated noticeably more intense, thereby helping the mice to re-learn the lost movements.

However, much of what happens to the CCR5 receptor in the brain after a stroke is still unknown. According to Robin Klein, a neuroimmunologist at the University of Washington School of Medicine in St. Louis, the surge in CCR5 is part of an inflammatory reaction to a stroke. By energizing molecules can stimulate neurons to express more CCR5.

It is known that in the developing brain chemokines affect the migration and communication of neurons. After a stroke, they seem to reduce the number of junction points on neurons near the damage. How this process impedes the recovery of neurons is not yet clear.

Carmichael notes that blocking CCR5 also causes neurons to express genes that increase their excitability, making them more willing to work. He believes that neurons increase CCR5 production after a stroke for 

can weaken their activity and remain low to avoid neural cell death under the influence of neurotransmitters, known as excitotoxicity. But since the protein then remains in place, this defense mechanism only hinders recovery.

The results of experiments obtained on animals are often meaningless to humans. To test this, the Carmichael group has teamed up with researchers from the Tel Aviv stroke group (TABASCO) in Israel.

According to global estimates, approximately 10% of Europeans have a genetic mutation of CCR5, and this number is even higher among Jews of Eastern European origin.

The TABASCO team identified 68 people in a cohort of stroke survivors who had at least one copy of the CCR5 mutation. The new study showed that, compared to people without mutation, they showed themselves a little better in tests for motor and sensory skills and cognitive abilities both after 6 months and 1 year after a stroke.

“It was slightly better, but ... the fact that they found something is impressive,” says Steven Kramer, a neuroscientist at UC Irvine, who took part in the work.

Carmichael and his colleagues are currently preparing for clinical trials, in which 30 patients after discharge from an inpatient rehabilitation facility — usually 4 weeks after a stroke — will be asked to complete a course of “Maraviroc”. Predictably, tests will pass already this year.

Meanwhile, some researchers believe that the discovery associated with the CCR5 receptor will inspire scientists to broader search for brain repair strategies based on learning and memory genes.

Autor: Ivan Shangin
Foto: Science

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