Researchers have found that donepezil (DNP), a drug already approved by the FDA for treating Alzheimer's disease, can induce a reversible torpor-like state, mimicking hibernation, in Xenopus laevis frog tadpoles. This groundbreaking discovery, published in ACS Nano, suggests a potential new approach to prevent irreversible organ damage during emergency medical situations, effectively extending the critical "Golden Hour" after traumatic injury.
Inducing Biostasis with Donepezil
The concept of slowing the body’s metabolic processes to mitigate injury is not new; therapeutic hypothermia has been employed for years. However, this method requires specialized equipment not always available in resource-limited settings. According to Michael Super, Ph.D., Director of Immuno-Materials at the Wyss Institute, DNP offers a more accessible solution. "Achieving a similar state of ‘biostasis’ with an easily administered drug like DNP could potentially save millions of lives every year," Super stated.
The Wyss Institute team initially explored SNC80, which showed promise in reducing metabolic activity but was deemed unsuitable for human use due to potential seizure risks. Using their predictive machine learning tool, NeMoCad, they identified DNP as a viable alternative. DNP's known side effects, such as drowsiness and slowed heart rate, mirrored signs of torpor, suggesting its potential for repurposing.
Torpor-Like Effects
María Plaza Oliver, Ph.D., the study’s first author, explained, "We know DNP can protect neurons from metabolic stress in models of Alzheimer’s disease, but this is the first study to explore leveraging its torpor-like effects as the main clinical response, rather than a side effect."
Experiments administering DNP to X. laevis tadpoles confirmed the induction of a reversible torpor-like state. However, the researchers noted toxicity and drug accumulation issues. To mitigate these problems, they encapsulated DNP within lipid nanocarriers, which reduced toxicity and facilitated drug accumulation in brain tissue—a crucial factor, given the central nervous system's role in hibernation and torpor.
Nanocarrier Encapsulation
The encapsulation of DNP in lipid nanocarriers is a key advancement, potentially making the drug a viable treatment for emergency biostasis. These nanocarriers are already approved for clinical use in other applications, suggesting that the encapsulated version of DNP could be scaled up for use in larger animals and, eventually, humans with relative ease.
Future Implications
Donald Ingber, M.D., Ph.D., Founding Director of the Wyss Institute and senior author of the study, is optimistic about DNP's future applications. "Donepezil has been used worldwide by patients for decades, so its properties and manufacturing methods are well-established. Lipid nanocarriers similar to the ones we used are also now approved for clinical use in other applications," Ingber noted. "This study demonstrates that an encapsulated version of the drug could potentially be used in the future to buy patients critical time to survive devastating injuries and diseases."
While the research is promising, further investigation is needed to fully understand how DNP induces torpor and to scale up production of the encapsulated version for larger animal models and human trials. Nevertheless, the possibility of using a well-established drug like DNP to significantly extend the window for lifesaving medical treatment offers a tantalizing prospect for emergency medicine.
