16 February 2010

Seasickness pills will help with heart attack and stroke

With the help of a new method of screening potential drugs, scientists at the Massachusetts General Hospital, working under the leadership of Vamsi Mootha, have discovered in several drugs that have already received official approval from the US Food and Drug Administration (FDA), a previously unknown ability to rearrange energy metabolism in cells, protecting them from the effects of oxygen starvation in a heart attack and a stroke. The results of the work, published on February 14 in the preliminary on-line version of the journal Nature Biotechnology in the article "Nutrient-sensitized screening for drugs that shift energy metabolism from mitochondrial respiration to glycolysis", open up new therapeutic possibilities in the treatment of a number of serious diseases.

Normally, a cell receives the energy it needs from nutrients using two mechanisms. The main of these mechanisms is glycolysis, the anaerobic breakdown of carbohydrates to lactic acid, which allows you to quickly obtain a small amount of adenosine triphosphate (ATP) molecules that act as an energy carrier in the cell. A slower, but also more efficient process is cellular respiration, in which carbohydrates, lipids and amino acids are oxidized to form more ATP molecules.

Natural shifts towards one of these mechanisms occur during the development of the body, as well as depending on the type of its activity, for example, glycolysis is indispensable for fast running for short distances, whereas cellular respiration is indispensable for marathon running. The preferred use of glycolysis is characteristic of all actively dividing cells, including tumor cells, therefore, an artificial shift of energy metabolism towards cellular respiration can suppress tumor growth. On the other hand, animal experiments have shown that the result of cellular respiration suppression is similar to the result of so-called ischemic preparation, the idea of which is that short episodes of ischemia (reduced blood flow) prevent the development of irreversible tissue damage with subsequent complete blockage of blood flow.

To search for compounds capable of shifting the energy metabolism of the cell towards glycolysis, the authors have developed a new screening method. They cultured skin fibroblasts in two types of media. One medium contained glucose, suitable for cleavage by both mechanisms, and the other contained galactose, cleavable only during cellular respiration. In such a system, a drug capable of shifting the energy metabolism of a cell towards glycolysis completely stops the growth of cells in a galactose-containing medium, without affecting the growth of cells in a medium containing glucose. As a result of a test screening of 3,700 drugs (almost half of all drugs approved by the FDA, scientists identified several compounds capable of suppressing cellular respiration, and several anti-tumor drugs with the opposite effect that stop the growth of actively dividing cells.

Most of the compounds used to reproduce ischemic preparation in animal models are too toxic for use in clinical practice, so the authors devoted their work to finding agents that cause less pronounced metabolic shifts. As a result of experimental screening, they identified eight drugs that cause weaker, but rather pronounced shifts in energy metabolism towards glycolysis. One of these drugs turned out to be meclizine, an over–the-counter remedy for nausea and dizziness that does not have negative side effects. The therapeutic effect of this drug indicates its ability to penetrate the blood-brain barrier.

To study the ability of meclizine to prevent tissue damage during heart attack and stroke, researchers, together with colleagues from the University of Rochester, conducted a series of experiments on rats and mice with artificially induced heart attacks and strokes. In both cases, the results obtained demonstrated the ability of meclizine to significantly reduce the severity of ischemic cell damage. In addition, the authors found that the protective effect of the drug is not due to the known mechanisms of its action.

The results obtained indicate that meclizine and similar drugs can be used in the future to prevent tissue damage resulting from a heart attack or stroke. However, Muta emphasizes that extensive animal testing is necessary in order to select optimal intake and dosage regimens, as well as a detailed study of the mechanisms of action of the drug. He also notes that the screening strategy developed by his group can help in identifying unknown positive and negative effects of other medications used in clinical practice.

Evgeniya Ryabtseva
Portal "Eternal youth" http://vechnayamolodost.ru Based on ScienceDaily: Shifting Cellular Energy Metabolism May Help Treat Cardiovascular Disease.


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