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Pharmacology

Clean-up of the arteries

Compound developed in Rio Grande do Sul dissolves plaques that obstruct blood vessels

eduardo cesarOur arteries are sometimes reminiscent of old metal pipes, which, with time, rust and accumulate dirt until they are completely clogged. This is how it is, at least with arteriosclerosis, the most frequent of the diseases that damage the blood vessels, which is associated with 17 million deaths a year in the world.  Marked by the formation of plaques of fat that prevent the passage of the blood, arteriosclerosis in general is fatal, when it affects the arteries of the heart or of the brain, organs that resist only a few minutes without oxygen. It seems paradoxical, but researchers from the Federal University of Grande do Sul (UFRGS) have discovered that a kind of hormone produced by the organism, the prostaglandins, may assist in the treatment, and even in the prevention, of this problem.

Using prostaglandins, the team led by biochemist Paulo Ivo Homem de Bittencourt Júnior produced a compound that, in experiments with mice, proved to be capable of dissolving the fat deposits that build up in the arteries – the atheromas, as doctors say.  This formulation, which has been given the temporary  name of LipoCardium, also prevented the formation of plaques, a consequence of the consumption of fatty foods, smoking and lack of exercise.

Should the safety and effectiveness of this compound be demonstrated in the future tests with rabbits, dogs and human beings, it is possible that in up to ten years a new medicine may reach the pharmacies, to avoid the formation of the plaques that prevent the normal circulation of the blood. Made in extremely small quantities inside the cells, the prostaglandins form a vast family of small molecules – each one of them made up of a mere 20 carbon atoms -, with different actions in different parts of the body, which range from the control of blood pressure to the activation of the pain center in the brain to inducing childbirth.

Among the 36 known natural prostaglandins, the researcher from the UFRGS selected the cyclopentenone (CP-PGs, for short), in whose structure five of the 20 carbon atoms are joined together to form a ring. It was not a random choice. During his doctorate, supervised by biochemist Rui Curi, of the University of São Paulo, Homem de Bittencourt spent a year in the laboratory of biologist Maria Gabriella Santoro, from the University of Rome, Italy. It was she who discovered a fundamental property of these prostaglandins: once inside the cells, these molecules prevent two phenomena connected with the emergence of atheromas, inflammation and cell multiplication.

It is easier to understand the value of this compound with a quick explanation of how these fat deposits are formed on the walls of the arteries. Chronic arterial hypertension, the consumption of  fat foods, or smoking, for example, produce imperceptible lesions in the endothelium, the layer of cells that cover the inside of the veins and arteries. It is a restricted effect, but one that echoes through the organism. In the damaged cells, a chemical signal induces the production of proteins typical of inflammation, which, exposed on the surface of the cells, act like an light  sign, indicating to the defense system: “There are problems here!” Defense cells are relocated to the affected region of the blood vessels and destroy the sick cells.

But the chemical signal that sets off the production of these proteins also indicates to the cells of the endothelium that they should multiply. The new cells of the arteries covering then start to involve the defense cells, which keep pouring into the region of the wound. If that were not enough, the fat molecules in excess in the blood – and not put to good use by the organism in the production of energy – join this clump of cells that grows towards the inside of the veins and arteries.  That is the atheroma, which is not made up just of fat molecules, as is usually imagined. There are also electrically charged atoms (ions) of calcium, which are deposited on the atheroma and make the artery less elastic and more inclined to burst.

With the cyclopentenone prostaglandins, Homem de Bittencourt imagined, it would, in theory, be possible to lock the trigger that sets off the formation of the atheroma and eliminate the evil before its appearance. This is because these molecules link up with a key protein in the process of cell multiplication and inflammation, the I-kappaB kinase enzyme, or IKK for short. Like a goalkeeper who intercepts the ball on its way to the goal, the prostaglandins tackle the IKK and prevent the sending of a signal for the cells to multiply and the defense system to come into action. There is an extra beneficial effect: the CP-PGs assist in repairing the proteins damaged by the lesions in the cell.

Safe packaging
It was the perfect choice. But what was missing was to find a way of taking the cyclopentenone prostaglandins to the atheroma. The problem is that, although they are naturally produced by the organism, these molecules cannot be injected directly into the blood. Because of their potent antiproliferative action, these prostaglandins would cause the same side effects as conventional chemotherapy with anticancer medicines, such as the loss of hair and intestinal problems, besides an intense general indisposition. “The solution was to wrap the prostaglandins in liposomes, capsules of fat produced artificially, with a structure similar to that of a soccer ball”, explains Homem de Bittencourt.

But even the use of liposomes did not guarantee the action of the prostaglandins in the right place. As these fatty capsules have the same electrical charge as the cells of the endothelium, they would be repelled by the walls of the arteries and remain in the blood until they were consumed by the defense cells. A way still had to be found to bring the capsules to the place of the lesion. The team from UFRGS only found the way out when it noted a peculiarity of the damaged cells of the endothelium: they show on their surface a protein that is not found in any other place of the body. They are the vascular adhesion molecules, that illuminated sign that attracts the attention of the defense cells and which they link up with. The researcher from Rio Grande do Sul then had the idea of adding to the liposomes laden with prostaglandins, a protein that is a perfect fit for the vascular adhesion molecules.

Punctual action
As a result, the liposomes immersed in the blood tangle up with the adhesion molecules when they pass the wound and, like the horse filled with warriors that the Greeks offered the Trojans, are absorbed by the damaged cells.  Accordingly, the prostaglandins act only on the desired spot, without generating the unwanted effects. There is the main difference between the compound developed by the group from Rio Grande do Sul and the other medicines used in the fight against arteriosclerosis – the statins, for example, act in another way and reduce the risk of arteriosclerosis because they inhibit the production of cholesterol, particularly in the liver. “Besides being used to treat arteriosclerosis, the prostaglandin-based compound may perhaps prevent the formation of atheromas in the cases in which there is a family history of high cholesterol”, says Homem de Bittencourt, who has already obtained a patent registration for the new formulation with the National Industrial Property Institute (INPI).

In the first battery of tests, the compound from UFRGS showed encouraging results. Experiments with mice genetically modified to develop arteriosclerosis and fed for four month on a fat rich diet showed that the prostaglandin-based compound eliminated the plaques of the atheroma after two weeks of daily use – the animals that were not given the formulation generally died in 15 days. According to the researcher, this result – keeping, of course, the proper proportions – would correspond to the case of a person with 80% of the arteries of his heart blocked being cured of the disease after a year and a half of treatment with the compound.

According to Homem de Bittencourt, a Brazilian pharmaceutical company, whose name is kept secret, is currently negotiating with UFRGS’s technology transfer office to make the prostaglandin-based compound in fact a new medicine. It is a fundamental partnership, since the tests necessary for proving the effectiveness and safety of the compound should cost about R$ 5 million, almost eight times more than has been spent up to now. The institutions that have supported this research up until now – the National Council for Scientific and Technological Development (CNPq), the Rio Grande do Sul State Research Support Foundation (Fapergs) and UFRGS itself – would hardly have the conditions for financing, on their own, the development stage of this artery cleaner.

The Project
Cyclopentanone prostaglandins in the cardiovascular system: therapeutic potential in arterial hypertension and arteriosclerosis by cytoprotection and redirectioning of the lipidic metabolism; Coordinator Paulo Ivo Homem de Bittencourt Júnior – UFRGS; Investment R$ 497,000.00 (CNPq), R$ 34,250.00 (UFRGS) e R$ 61,050.00 (Fapergs)

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