PITTSBURGH, Oct. 11 -- Melatonin, best known for its role in sleep regulation, delayed the onset of symptoms and reduced mortality in a mouse model of Huntington's disease, say researchers at the University of Pittsburgh School of Medicine and Harvard Medical School. Their findings, published today in the Journal of Neuroscience, show for the first time that certain receptors for the hormone reside in the mitochondria, and that there are fewer of them both in affected mice and human brains.
Huntington's disease (HD) is an inherited, lethal disorder of involuntary movement, progressive loss of intellectual function and emotional problems, explained senior investigator Robert M. Friedlander, M.D., chair, Department of Neurological Surgery and UPMC Endowed Professor of neurosurgery and neurobiology. A mutant protein, called huntingtin, kills neurons in the brain's striatum and then the cortex.
"In earlier work, we screened more than 1,000 FDA-approved drugs to see which ones could block the release of a small protein called cytochrome c from the mitochondria to interrupt a key step in a chain reaction known as apoptosis, or programmed cell death," he said. "Melatonin, which we know to be a potent antioxidant, was one of the agents that could do this in the test tube, but we needed to determine if it would also be neuroprotective in a transgenic animal model of HD."
For the study, the researchers injected HD mice daily with either melatonin or a placebo, evaluated them weekly for signs of the disease, and examined their brain tissue after death. They found that melatonin treatment delayed the onset of disease by 19 percent, slowed disease progression and prolonged life span by 18 percent.
The researchers determined also that type 1 melatonin (MT1) receptors are found on mitochondria, which supplies energy for the cell, and that they were depleted in both HD-affected human and mice brain tissue samples. In lab experiments, administration of an agent that prevents melatonin from binding to the MT1 receptor encouraged cell death, while gene-engineering to increase the number of receptors led to greater neuroprotection, even when melatonin levels were normal.
"Extra melatonin might help fill all the available MT1 receptors, allowing the hormone to counter the programmed cell death cascade and thus protect neurons," Dr. Friedlander said. "This suggests that melatonin or similar agents that influence the MT1 receptor have potential as an HD treatment, which we've never had before."
Low levels of circulating melatonin have been seen in other neurodegenerative diseases, including Alzheimer's disease and Parkinson's disease. The research team is continuing to explore what might cause the loss of MT1 receptors and to assess other drugs that block cytochrome c and cell death.
"Perhaps the best approach will be to develop a cocktail of drugs that target different molecular pathways that are responsible for creating HD," Dr. Friedlander said. "We plan to see if combining different agents leads to a greater impact on disease progression and mortality."
The team includes lead author Xin Wang, Ph.D., and others from Harvard Medical School, where Dr. Friedlander began the research effort prior to joining Pitt; as well as researchers from the Bedford Veterans Affairs Medical Center, Bedford, Mass.; Boston University School of Medicine; and Seoul National University Hospital.
Grants from the National Institute of Neurological Disorders and Stroke, part of the National Institutes of Health, the Muscular Dystrophy Association, the Huntington's Disease Society of America, and the U.S. Veterans Administration funded the research.
About the University of Pittsburgh School of Medicine
As one of the nation's leading academic centers for biomedical research, the University of Pittsburgh School of Medicine integrates advanced technology with basic science across a broad range of disciplines in a continuous quest to harness the power of new knowledge and improve the human condition. Driven mainly by the School of Medicine and its affiliates, Pitt has ranked among the top 10 recipients of funding from the National Institutes of Health since 1997.
Likewise, the School of Medicine is equally committed to advancing the quality and strength of its medical and graduate education programs, for which it is recognized as an innovative leader, and to training highly skilled, compassionate clinicians and creative scientists well-equipped to engage in world-class research. The School of Medicine is the academic partner of UPMC, which has collaborated with the University to raise the standard of medical excellence in Pittsburgh and to position health care as a driving force behind the region's economy. For more information about the School of Medicine, see http://www.medschool.pitt.edu.
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