A new function for an old drug known as meclizine has been elucidated by Dr. Vishal M. Gohil, a Texas A&M AgriLife Research biochemist. Meclizine (an antihistamine) is an over-the-counter (OTC) drug synthesized in the 1950s and later used to treat nausea, motion sickness, and vertigo. It is now known that meclizine has potential to treat certain infectious diseases and some forms of cancer.
Gohil and colleagues found an enzyme that is inhibited by meclizine that had been proposed previously to be a drug target for the treatment in a number of diseases such as malaria and African sleeping sickness. This particular pathway had also been proposed to be important for the proliferation of cancer cells.
In previous research, Gohil and researchers from Harvard Medical School and Massachusetts General Hospital, the University of Rochester and the University of Guelph, demonstrated that meclizine can be used as a therapy for heart attack and stroke.
Gohil initially identified meclizine in a drug-screening experiment aimed at finding drugs that inhibit mitochondrial respiration. Mitochondria are membrane bound vesicles inside all eukaryotic cells that are responsible for generating ATP, the energy currency of the cell.
Gohil was surprised when the drug-screening identified meclizine as inhibiting mitochondrial function as the drug had been on the market for decades and used as an antihistamine. However, unlike other antihistamines, meclizine has a unique property that allows it to treat nausea and motion sickness, which most other antihistamines can’t.
Gohil notes, “… when we saw it in our drug screen we got excited about it because we could see that it decreases cellular oxygen consumption or respiration. We started trying to figure out the mechanism and to see if it could have any clinical benefit and application.” It is known for certain diseases such as stroke, heart attack, and some neurological diseases that if mitochondrial respiration can be inhibited, this could be a beneficial treatment.
Some initial testing and observations were made in terms of how mitochondrial respiration was inhibited in the presence of meclizine. When they added meclizine to whole cells, they saw a reduced respiration, but very slowly. Then they decided to add meclizine to isolated mitochondria and found no effect whatsoever. This suggested to the researchers that meclizine may not be directly targeting one of the enzymes associated with mitochondria that are needed for oxygen consumption. Knowing this, they used an unbiased metabolic profiling method to determine how non-mitochondrial pathways could be targeted by meclizine. The metabolic profiling method gave them snapshots of metabolite levels before and after treatment so they could get an idea of how meclizine was perturbing metabolites.
Gohil and associates found one metabolite known as phosphoethanolamine was in high concentrations within a few hours of treatment. Phosphoethanolamine is an intermediate metabolite in a biosynthetic pathway of a common phospholipid which is an important component of cell membranes. This suggested to the researchers that there was a link between in this biosynthetic pathway and mitochondrial respiration.
According to Gohil, “Our research showed that if we just take this metabolite and directly add it to mitochondria, it actually inhibits the respiration. The reason we could use the drug for infectious disease or cancer is not because it inhibits respiration but because it inhibits a phospholipid biosynthetic enzyme that is required to form the building blocks of membranes.”