Will a mitochondrial antioxidant help with Huntington's disease?
Synthetic Mitochondrial Antioxidant Suppresses Huntington's Disease Symptoms
LifeSciencesToday by Lawrence Berkeley National Laboratory:
Berkeley Lab Scientists Help Develop Promising Therapy for Huntington’s DiseaseThere is a new hope in the fight against Huntington's disease.
A group of researchers, including scientists from the Lawrence Berkeley National Laboratory of the U.S. Department of Energy, has proven the effectiveness of a chemical compound that suppresses the symptoms of this neurodegenerative disease in mice with its model.
This compound is a synthetic antioxidant, the target of which are mitochondria, cellular organelles that produce energy. Oxidative damage to mitochondria is involved in the development of many neurodegenerative diseases, including Alzheimer's, Parkinson's and Huntington's diseases.
The introduction of the synthetic antioxidant XJB-5-131 to mice with a genetic mutation that causes Huntington's disease improved mitochondrial function and increased the survival of neurons. In addition, it suppressed weight loss and stopped the deterioration of motor skills. In general, mice with the Huntington's disease model looked and behaved like healthy animals.
Based on the results published online in the journal Cell (Xun et al., Targeting of XJB-5-131 to Mitochondria Suppresses Oxidative DNA Damage and Motor Decline in a Mouse Model of Huntington's Disease), scientists consider XJB-5-131 as a promising therapeutic compound worthy of further study.
Proof that the target of XJB-5-131 is mitochondria. Micrograph of the same primary striatum neuron isolated from the mouse brain with a Huntington's disease model. (Photo: McMurray lab)
"This compound has shown very good results. More research is needed, but it can really have an impact on the treatment of neurodegenerative diseases," says Cynthia McMurray, PhD, (Berkeley Lab Department of Biological Sciences). She conducted this study with other Berkeley Lab scientists, including Zhiyin Xun, as well as with colleagues from the University of Pittsburgh.
Huntington's disease is a genetic disease characterized by the death of neurons in certain areas of the brain. Symptoms of the disease usually appear in middle age. The disease is expressed in a loss of coordination of movements and a decrease in cognitive abilities. There are no means that can affect the cause of the disease. Currently, patients are prescribed antidepressants or compounds that somewhat slow down the deterioration of coordination of movements. None of these drugs stops the progression of the disease.
An alternative line of defense may be therapy aimed at protecting mitochondria from chemically active molecules containing oxygen. Damage to mitochondria by reactive oxygen species leads to disruption of their function and cell death.
But protecting mitochondria from reactive oxygen species is a daunting task, since mitochondria are both the main target of these molecules and their main source. In other words, the mitochondria themselves produce something that causes them irreparable harm.
Scientists already know the answer to the question whether dietary supplements containing natural antioxidants, such as vitamin E and coenzyme Q, can mitigate the harmful effects of reactive oxygen species on mitochondria: mitochondria are not a specific target of natural antioxidants, and the effect of these drugs, evaluated in clinical trials, is insignificant.
These more than modest results forced scientists to develop synthetic antioxidants specifically targeted at mitochondria. A few years ago, a chemist from the University of Pittsburgh, Peter Wipf, synthesized the antioxidant XJB-5-131, which targets bacterial cell membranes very similar to mitochondrial membranes, and found that this compound significantly increases cell survival. But its effectiveness in neurodegenerative diseases remained unknown.
Dr. McMurray's lab, also a few years ago, began looking for ways to study the genetic mutation that causes Huntington's disease. Scientists have managed to breed mice with this mutation, and the model of the disease created by them not only allows us to assess how the disease affects animals, but also quite well represents what is happening in the human body. In addition, researchers have learned to isolate nerve endings and mitochondria from the brain of mice, which makes it possible to study the role of these organelles in the development of the disease.
First, scientists investigated the effect of XJB-5-131 on motor skills. As they aged, the rotating rod test, in which animals are forced to balance, was performed worse and worse by mice with Huntington's disease. Sick mice receiving XJB performed it as confidently as healthy mice.
In another test, the scientists evaluated the strength of the grip, prompting the animals to remain in a hanging state for 30 seconds. Almost all the sick mice "failed" this test, while 85% of the animals receiving XJB coped with the test. In addition, the treatment stopped weight loss, which is another sign of Huntington's disease.
"We have seen an improvement in all areas. The difference was amazing. XJB prevents weight loss and deterioration of motor skills," Dr. McMurray comments on these results.
The researchers studied the results of the effects of XJB-5-131 on mitochondrial DNA: the compound significantly reduced the amount of damage to it, and the number of copies of mitochondrial DNA, sharply falling in sick mice, recovered to normal.
Finally, by isolating nerve endings from the striatum and cortex of diseased mice–the two brain regions most affected by Huntington's disease–Xun found that XJB-5-131 significantly increases the stress resistance of mitochondria in nerve endings.
In addition, mitochondria were exposed to a chemical that induces the formation of reactive oxygen species. As expected, this led to a violation of their function. But when this chemical was injected together with XJB-5-131, mitochondrial function was restored.
Diagram from the article in Cell – VMXun is now trying to establish exactly how XJB-5-131 protects mitochondria from oxidative damage.
In addition, scientists want to test the effectiveness of several of its promising derivatives. They hope that, given the initial successes they have achieved and the severity of the disease, clinical trials of these compounds will not be a distant prospect.
"Huntington's disease is a hopeless disease, so we really want to help find a remedy that can stop its development," concludes Dr. McMurray.
The study was funded by the US National Institutes of Health (National Institutes of Health).
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