The Durk Pearson & Sandy Shaw®
Life Extension NewsTM
Volume 13 No.
2 • April 2010
Emerging Medicine: Cardioprotection and
Neuroprotection Against Ischemia-Reperfusion
New Use for a Very Old Drug: Shifts Cellular Energy
Mitochondrial Respiration to Glycolysis
A very interesting paper appeared in the March 2010 Nat Biotechnol. In ischemic diseases, such as stroke, angina, heart attacks, and sleep apnea, cells are exposed to hypoxia (deficiency of oxygen) with resulting adaptations, such as the induction of HIF (hypoxia inducible factor). One method that cells use to adapt to oxygen or nutrient deficiency is to shift energy metabolism from mitochondrial oxidative phosphorylation (the efficient ATP-generating pathway in which glucose is metabolized to CO2 and water) to glycolysis (a less efficient pathway for generating ATP in which glucose is metabolized to lactate under conditions of hypoxia). “... studies in animal models have shown that attenuating mitochondrial respiration can prevent the pathological consequences of ischemia-reperfusion injury in myocardial infarction and stroke.” It has also been suggested that, because mitochondrial respiration is the major source of reactive oxygen species, glucose to lactate (glycolysis) conversion may protect cells that depend upon it (such as rapidly reproducing cells and cancer cells) from oxidative stress.
The authors devised a small-molecule screen for detecting agents that shift energy metabolism from mitochondrial respiration to glycolysis in fibroblasts. They were particularly interested in molecules that induced very small shifts in metabolism, as “they may represent particularly safe drugs with which to manipulate energy metabolism.” As a result of this screen, the authors identified meclizine (Antivert), “which has been approved for the treatment of nausea and vertigo for decades, is available over the counter, has a favorable safety profile, and likely penetrates the blood-brain barrier given its efficacy in disorders of the central nervous system.”
Meclizine, they found, acts as a mild uncoupler of cellular oxygen consumption, without an effect on HIF. The researchers tested meclizine in an adult rat ventricular cardiomyocyte model of simulated ischemia-reperfusion injury and found that a 20 minute meclizine pre-incubation followed by washout before ischemia resulted in a dose-dependent protection of cardiomyocytes against cell death. “As with other cell types, meclizine inhibited oxygen consumption in cardiomyocytes in a dose-dependent manner.” The authors also found meclizine to preserve heart pump function after an ischemic event in perfused rat hearts. In another paper, the author suggests that “... persistent glycolysis is deleterious due to the generation of MG [methylglyoxal, a metabolite of glucose, and a potent glycating agent*], but brief periods of glycolysis could be hormetic.” In other words, brief periods of glycolysis induced by a mild mitochondrial uncoupler could act similarly to ischemic preconditioning. This might suggest using a mild uncoupler like meclizine at bedtime for people who suffer from intermittent hypoxia during sleep (sleep apnea).
As the authors explain, the potency of meclizine in attenuating mitochondrial respiration appears to vary across different cell types and, moreover, it is not clear whether the currently approved doses of meclizine (for nausea and vertigo) would achieve dose levels adequate for cardioprotection or neuroprotection. Hence, they suggest that more research be done on optimal dosing for efficacy and safety. However, it is unlikely that there will be much (if any) funding available for such research (though we would love to see it) on a 40 year old drug long beyond patent protection.
The use of meclizine at its current approved doses has a 40 year record of safety; hence, for those with ischemic diseases who are interested in experimenting with this drug, we would suggest you first discuss this with your physician and, if you do decide to use it, do NOT exceed the currently approved dose. If you have cancer, it would probably be a good idea to avoid any substance that would induce continuous glycolysis, as many cancer cells rely on glycolysis (called the Warburg effect in cancer cells) for generating energy, though it is not clear how a substance that induced short periods of glycolysis would affect glycolysis-addicted cancers. We do not recommend experimenting with meclizine if you have cancer.
1a. Gohil et al. Nutrient-sensitized screening for drugs that shift energy metabolism from mitochondrial respiration to glycolysis. Nat Biotechnol 28(3):249-55 (2010).
1b. Brand and Hermifisse. Aerobic glycolysis by proliferating cells, a protective strategy against reactive oxygen species. FASEB J 11:388-95 (1997).
2. Hipkiss. On the mechanisms of ageing suppression by dietary restriction — is persistent glycolysis the problem? Mech Ageing Dev 127:8-15 (2006).