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Low oxygen reverses neurodegenerative disease in mice

Discussion in 'Neurology' started by Nada El Garhy, May 19, 2017.

  1. Nada El Garhy

    Nada El Garhy Golden Member

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    When the cells' mitochondria do not work properly, the human body can develop a mitochondrial disease. New research paves the way for treating mitochondrial diseases that affect the brain, showing that oxygen deprivation has unexpected therapeutic benefits - at least in mice.

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    New research reveals the therapeutic benefits of hypoxia for Leigh syndrome, a neurodegenerative disease.
    Mitochondria are the small compartments within a cell, responsible for turning sugar and oxygen into energy.

    Mitochondrial diseases can take many forms, as cells can be found everywhere in the human body. Mitochondrial disorders can affect the brain, kidneys, eyes, and many other organs.

    "Leigh syndrome" is one such kind of mitochondrial disorder that affects the brain. The condition is rare; it is thought to affect only 1 in 30,000 newborns.

    Leigh syndrome is a neurodegenerative disorder. It is characterized by brain lesions, a progressive loss of motor skills and muscle tone, and delays in development. Complications can lead to poor heart, respiratory, and kidney function.

    Most of the time, Leigh syndrome cannot be treated. A new study in mice, however, suggests that hypoxia - that is, a deprivation of oxygen - may have the unexpected benefit of protecting the brain against this form of mitochondrial disease.

    The study was carried out by researchers from the Massachusetts General Hospital (MGH) in Boston, and the findings were published in the journal PNAS.

    The therapeutic role of hypoxia in mitochondrial disease
    The new research builds on previous work by the same team. In their previous study, the researchers used a traditional mouse model of Leigh syndrome - with mice that had the so-called Ndufs4 gene knocked off - and placed them in an environment that had just 11 percent oxygen. This is the equivalent of roughly half of what is found at sea level.

    The Ndufs4 gene encodes a protein that is key for the mitochondrial complex 1 - an enzyme complex that is part of the respiratory chain of the mitochondria.

    The researchers found that the hypoxic environment significantly decreased typical symptoms of Leigh syndrome and prolonged the rodents' survival.

    By contrast, an environment with levels of oxygen higher than normal caused premature death in the animal model but had no impact on normal, healthy animals.

    In the new study, the team aimed not only to better understand the impact of different levels of oxygen on this mouse model, but also to examine whether practical implementations of hypoxia could replicate the results of the previous study.

    Continuous hypoxia reverses Leigh syndrome in mice
    The new study revealed that the degree of brain damage varied with the levels of oxygen, over time.

    Overall, mice that had been treated with hypoxia lived for an average of 270 days, while those living in an environment with 21 percent oxygen survived for only 58 days, on average.

    Imaging studies showed that Ndufs4-knockout mice in an environment with 11 percent oxygen had no brain lesions when they were 250 days old. By contrast, lesions started to appear at as early as 60 days in mice that inhaled 21 percent oxygen.

    Additionally, mice that inhaled 55 percent oxygen died quickly of pulmonary edema and had lesions in the brain's olfactory bulb.

    A surprising result was that hypoxic treatment seemed to also reverse the already existing damage. The lesions in the mice's brains disappeared after they were switched to a low-oxygen environment and kept there for a month.

    The team also tried to move mice with signs of brain damage that had been housed in an 11 percent oxygen environment into a 21 percent environment, but this led to the progression of the disease and eventual death. This indicates that the treatment needs to be continuous.

    Researchers at work to find more practical hypoxia treatments
    Dr. Vamsi Mootha, of the MGH Department of Molecular Biology, is a co-senior author on the paper. She comments on these results:

    "We found, much to our surprise and delight, that we could actually reverse advanced disease. I don't think anybody thought that these types of neurological diseases could be reversible [...] This is an extremely important next step in our exploration of the therapeutic potential of hypoxia for this neurodegenerative disease."

    However, the researchers note the impracticality of their treatment as it stands. An oxygen level of 11 percent is similar to what is found at very high altitudes, and a continuous treatment with this level of oxygen would certainly not feel very comfortable, the authors concede.

    In the future, Mootha and team hope to understand the molecular mechanism behind the benefits of hypoxia so that they can come up with a more practical therapy that protects the brain and reverses brain damage.

    "We're also working to try and identify other, more practical hypoxia regimens that may be effective," Mootha says. "Our vision is to be able to offer patients and their families a therapy that not only halts but heals disease, but we're still only working in animal models. We're not there yet, but we've got all hands on deck to push this concept forward."

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