To search for compounds that shift cells from respiration to glycolysis, Mootha's team devised a novel screening strategy. They cultured skin cells in two different nutrient environments glucose, which provides energy through both glycolysis and respiration, or galactose, which forces cells to rely on mitochondrial respiration alone. A drug that redirects energy metabolism from respiration to glycolysis would stop growth in the galactose-cultured cells while having little effect on cells grown in glucose. Their initial screen of almost 3,700 compounds, including nearly half of all FDA-approved drugs, identified several drugs known to inhibit cellular respiration on one end of the scale and several anti-cancer drugs that halt the growth of rapidly proliferating cells at the other, which verified the approach.
Because most agents known to mimic ischemic preconditioning in animal models are too toxic to use in human patients, the researchers were most interested in finding drugs that cause subtle metabolic shifts. The screen identified eight approved drugs that produced a less pronounced but still significant shift away from cellular respiration. One of those agents was meclizine, an over-the-counter drug used to treat nausea and vertigo suggesting that it passes the blood-brain barrier with few negative side effects.
To investigate meclizine's potential to prevent tissue damage in heart attack or stroke, Mootha's team collaborated with University of Rochester researchers who had developed rat models of heart attack damage and an MGH Pathology group with a mouse model of stroke damage. Blinded experiments using both animal models showed that pretreatment with meclizine dramatically reduced ischemic damage to cardiac cells in the heart attack model and to brain cells in the stroke model. They also found that meclizine's i
|Contact: Sue McGreevey|
Massachusetts General Hospital