A new spin on energy independence

An over-the-counter drug interferes with the metabolic processes that take place in the mitochondrion (like the one pictured here) and could lead to a new way to treat heart attacks and strokes.
Image courtesy of the Dartmouth Electron Microscope Facility, Dartmouth College

In a world addicted to oil, the notion of a pill that could shift countries' dependence on oil to another form of energy seems far-fetched - and it is. But a similar idea, rooted in the biology of the human body, has gained traction in recent years. The goal: to find a drug that can coax cells to change the way they use their energy resources.

In a paper appearing in the February 14 advance online issue of the journal Nature Biotechnology, a team of scientists reports the discovery of a well-known compound that seems to do just that. Their findings could someday spur new ways of preventing or treating a variety of illnesses, including stroke, heart attack and maybe even cancer.

Unlike people, most cells are remarkably flexible in the ways they use, or metabolize, energy, and can readily shift from one method to another depending on the circumstances. For example, cells can switch back and forth from glycolysis, a form of metabolism that relies on the sugar glucose, to another type of metabolism known as mitochondrial respiration, which is more efficient, occurs inside special compartments called mitochondria, and requires the presence of oxygen.

Beyond just a simple observation, this flexibility has garnered attention for its potential utility in treating human disease.

For instance, researchers have known for decades that in cancer, cells show a strong preference for glycolysis over other forms of metabolism, and that the way glycolysis proceeds is distinct from normal human cells. Some recent studies suggest that thwarting this cancer cell tendency (known as the "Warburg effect") might help slow tumor growth.

At the other end of the metabolic pendulum, a growing body of evidence suggests that interfering with mitochondrial respiration might help protect tissues that suffer damage due to lack of blood flow (called "ischemia"), which often occurs during a heart attack or stroke. The idea stems from an experimental phenomenon first described in the 1980s.

"It's a pretty amazing observation. In an animal model, if you tie off a blood vessel to the heart for 40 minutes, you infarct, or kill, a large portion of the tissue fed by that vessel," said Vamsi Mootha, the senior author of the Nature Biotechnology study, who is an associate professor at Massachusetts General Hospital and Harvard Medical School, and a senior associate member at the Broad Institute.

"If however, you first come in and provide brief, nonlethal episodes of ischemia to that region, then you tie off the blood vessel in the exact same way, the amount of tissue that dies is only 30 percent of that which would die otherwise."

Researchers later extended this observation with an important chemical discovery. They identified chemicals that offer the same kind of protection - that is, they mimic the protective effects of briefly interrupting blood flow prior to the sustained ischemia that accompanies a stroke or heart attack. Although the details of how these so-called tool compounds work remain poorly understood, many of them interfere with mitochondrial respiration.

These discoveries raise the possibility that a drug based upon them might someday become available and, if given to patients prone to strokes or heart attacks, might provide some protection against tissue damage as a result of these conditions. Yet the chemicals are very toxic, even at low doses, making them unlikely candidates for use in humans. So, Mootha and his colleagues wondered if they could unearth more promising drug candidates.

With support from the Smith Family Foundation as well as other funding organizations, the scientists devised an approach to survey, or screen, thousands of chemicals. Their method, which they call "nutrient-sensitized screening," takes advantage of cells' ability to shift between different modes of energy metabolism based on what sugars are available, and can pinpoint chemicals that coax cells away from mitochondrial respiration and toward glycolysis.

"Our screen rediscovered almost all the known inhibitors of mitochondrial respiration including the previously identified tool compounds," said Mootha. "But what is particularly exciting is that we also found several FDA-approved drugs and over-the-counter agents" that yield similar effects.

Mootha and his colleagues, including first authors Vishal Gohil and Sunil Sheth, were especially intrigued by one drug in particular - meclizine. The drug, used to alleviate dizziness and nausea, has been available as an over-the-counter medication in the US for roughly 40 years, said Mootha, yet it has never before been linked to energy metabolism.

A handful of the drug's properties stoked the researchers' enthusiasm. With its long history of use, there is already considerable information about the drug's safety and side effects, which in principle could accelerate its journey through the drug development pipeline. In addition, since meclizine treats symptoms that are generally thought to originate in the central nervous system, it is likely that the drug penetrates the blood-brain barrier - a key capability for a candidate drug to minimize brain tissue damage from stroke.

To gather data that supports their zeal, the team sought experimental proof that meclizine treatment can offer protection against tissue damage, whether in the heart, the brain or both.

Through collaborations with Cenk Ayata of the Stroke and Neurovascular Regulation Laboratory at Massachusetts General Hospital and Paul Brookes of the University of Rochester Medical Center, the scientists found that pre-treatment with meclizine can offer protection to brain and heart tissue in mouse models of stroke and heart attack, respectively.

The result is an important step forward in understanding meclizine and its effects. However, many other steps remain before the drug can be considered suitable for use in humans for protection against stroke and heart attack. "All of our work is preclinical, which means we don't yet know whether the compound will have the same effects in humans as it does in animal models."

Still, he acknowledges that the discovery holds promise. "What is exciting is the fact that meclizine is an over-the-counter drug. Although a great deal of work is still needed, including extensive toxicity studies, you could imagine initiating human clinical trials in the not-so-distant future."