Researchers led by Hidetoshi Masumoto and Genshiro Sunagawa of the RIKEN Center for Biosystems Dynamics Research (BDR) in Japan have developed a new method of protecting organs during cardiac and aortic surgery when blood flow needs to be blocked. Rather than relying on cold temperatures to induce hypometabolism and reduce the need for oxygen, the technique works by stimulating Q neurons in the brain, which slow metabolism to a hibernation-like state. In this proof-of-concept study, the procedure protected the mice’s kidneys from damage due to lack of oxygen and avoided the harmful side effects associated with prolonged hypothermia. The findings could lead to new ways to perform similar surgeries in people.
For some types of heart and aortic surgery, doctors must cut off blood flow while they work to repair the aorta. For the past 50 years, this type of surgery has been performed after using cold temperatures to induce deep hypothermia, which slows the body’s metabolism so that organs can survive on very little oxygen. While this is effective in protecting organs like the kidneys, it also reduces blood clotting, causing excessive bleeding and the need for blood transfusions.
Masumoto and his team at RIKEN BDR looked for ways to slow metabolism without inducing hypothermia. We know that many animals, such as bears and squirrels, can hibernate, and despite the extremely slow metabolism during hibernation, they are healthy when they wake up. However, like most animals, humans do not hibernate. That was the end of the story until a few years ago, when Sunagawa’s group discovered a way to induce a state of hibernation in mice – animals that don’t normally hibernate. “If we can induce them, there are many possibilities for using hibernation-like states in cardiovascular medicine, resuscitation medicine, or other cases where organ protection by hypothermia is insufficient or inappropriate,” says Sunagawa.
But first, the effectiveness of the technique must be verified in animal models. The new study is the first clinical implementation of the technique and tested its effectiveness using a mouse model of aortic surgery requiring circulatory arrest. The team’s previous studies have shown that hibernation-level hypometabolism can be achieved by activating special neurons in the brain’s hypothalamus called Q neurons. these specific neurons by injection. They compared four groups of model mice that varied on whether or not cold temperatures were used to induce hypometabolism and whether or not Q neurons were activated.
Kidney damage and kidney function were assessed by examining the levels of biomarkers in the blood. The analysis showed that hypometabolism induced by Q neurons at normal temperatures protected the kidneys as well as that induced by hypothermia. “With these results, we now know that hibernation-like states induced by Q neurons can be used to protect organs,” says Masumoto.
The ultimate goal of Masumoto and Sunagawa’s research is to slow people’s metabolism during heart surgery or for other medical reasons, using a variation of this technique. But because Q neurons in humans cannot be selectively activated like they can in experimentally modified mice, the team is now looking for ways to protect organs downstream of the brain. “Activation of Q neurons triggers a sequence of biological events that allows organs to exist in a hypometabolic state for days,” says Sunagawa. “Once we know precisely what these events are, we are confident that we can pharmacologically induce them in the body, without needing to activate Q neurons first.”
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