Alzheimer's drug could put patients into a hibernation-like state: ScienceAlert

A drug commonly used to treat Alzheimer's symptoms has the potential to put the body into a “pause” state during emergencies when every second counts.

A team led by researchers from the Wyss Institute for Biologically Inspired Engineering, part of Harvard University, tested the drug donepezil hydrochloride (DNP) on tadpoles, putting them into a dormant state known as torpor.

In nature, many animals enter torpor for days or weeks at a time, during which their body temperature and metabolism drop dramatically to conserve energy. Similar to seasonal hibernation, the short periods of rest in torpor typically occur during times of low food availability.

The ability to induce a torpor-like state in humans has advantages in the medical field, as it gives doctors more time to save their patients. The team behind this research believes that DNP – which is already FDA-approved for use in humans – could help prevent permanent organ damage that sometimes occurs while a person is being transported to the hospital.

“Cooling a patient's body to slow down their metabolic processes has long been used in medicine to reduce injuries and long-term problems in serious illnesses. However, this is currently only possible in well-equipped hospitals,” says immunologist Michael Super of Harvard University..

“Achieving a similar state of 'biostasis' with an easily administered drug such as DNP could potentially save millions of lives each year.”

It is important that an organism that enters torpor can emerge safely from that state. In an earlier study, the researchers found that another drug, SNC80, also induced torpor in African clawed frog tadpoles (Xenopus laevis).

Because these animals do not naturally hibernate or enter a state of torpor, scientists knew the drug was successful when the swimming speed of all the tadpoles decreased, suggesting that their metabolism was suppressed by the drug. Unfortunately, due to its tendency to cause seizures, the compound is not a viable option for use in humans.

To find a safer candidate, the research team used a machine learning-based computer algorithm called Network Models for Causally Aware Discovery (NeMoCAD) to filter out 378 compounds that were likely to elicit similar responses to SNC80 in the frogs.

Of all the possibilities, DNP showed the greatest structural similarity. In some ways, this is not a great surprise – overdoses have been reported to be associated with slowed heart rate and lethargy in Alzheimer's patients.

“Although free DNP drugs can suppress the metabolic activity of tadpoles, their use was limited by their toxicity, which occurred after administration for more than 2 to 3 hours,” the team writes. The torpor in these initial tests, which lasted for more than four hours, was irreversible

When the team noticed that the drug was accumulating in all the tissues of the tadpole's body, they solved the problem by encasing it in a nanoemulsion – essentially a tiny capsule with one liquid as the cap and another as the contents. This “significantly reduced toxicity while maintaining efficacy” by delivering a higher concentration of DNP to the brain but with a slower, more controlled release to the rest of the body.

And that meant the tadpoles could be kept in torpor for longer, temporarily reducing their mobility, heart rate and oxygen uptake. All “fully reversible,” according to the study.

“Other advantages of this approach include the prior FDA approval of DNP for clinical use, the low toxicity of the nanoemulsions, the scalability of manufacturing, and the ability to deliver treatments without trained personnel (e.g., via noninvasive mucosal routes),” the authors write.

We still have a long way to go before DNP can be used in the back of an ambulance to buy valuable time, but the idea that existing drugs could be used for other purposes we haven't yet thought of is exciting.

This research was published in the American Chemical Society ACS Nano.