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Melatonin Delays Onset, and Prolongs Survival in an HD Mouse Model
Dr Robert Friedlander
In 2008, we covered research by Dr. Robert Friedlander and colleagues which showed that inhibiting the release of cytochrome c was neuroprotective in the R6/2 mice.
When the mitochrondria, the energy factories of the cell, are damaged in neurodegenerative disease, they release cytochrome c into the cytoplasm of the cell. Cytochrome c is a small protein associated with the membrane of the mitochondria. Its release activates caspases. The word caspase comes from cysteine-aspartic-acid-proteases. These enzymes play a role in apoptosis, programmed cell death. Specifically, cytochrome c release activates caspase 9 which in turn activates caspase 3 which brings about the death of the cell.
Dr. Friedlander and colleagues conducted a screen of drugs from the National Institute of Neurological Disorders and Stroke. Their Neurodegeneration Drug Consortium maintains a library of 1040 compounds, most of which are FDA approved for other purposes and many of which cross the blood brain barrier. Of the 16 promising drugs which were identified, they initially selected methazolamide, a drug which crosses the blood brain barrier and is approved to treat glaucoma, to test in the R6/2 mice. Disease onset was delayed and survival time prolonged. In addition, neurodegeneration was reduced.
The new study presents the results of a preclinical study of melatonin, another inhibitor of cytochrome c. The mice were injected daily with either melatonin or a placebo, evaluated weekly for signs of the disease, and their brain tissue was examined after death. Melatonin treatment delayed the onset of disease, slowed disease progression, reduced neurodegeneraion, and prolonged life span by 21 percent.
This is an important finding since melatonin has a good safety profile and crosses the blood brain barrier. However, the researchers did not simply assume that inhibition of cytochrome c was the only mechanism by which melatonin conferred neuroprotection but did further research with cell models to explore the mechanisms involved. It has become increasingly important to know why a drug is expected to work so that good decisions can be made about which drugs should go into clinical trials and to learn from any failures. A drug which has been shown to address a significant therapeutic target effectively and safely should be given priority. If a trial fails it is important to know whether the drug failed to affect the target or whether the target might not have been well-chosen.
The researchers found that melatonin does indeed inhibit the cytochrome c and the activation of caspases 9 and 3. In addition, melatonin inhibits the Rip2 protein which activates caspase 1. Rip2 is known to be elevated in the brains of the R6/2 mice. Melatonin also inhibits the loss of mitochondria membrane potential, a pathology found in HD models as well as models of other neurodegenerative disorders.
In addition, melatonin preserves melatonin (MT1) receptors which are known to be reduced in HD models and HD patients as the disease progresses. MT1 receptors are found on the mitochondria. Administration of an agent that prevents melatonin from binding to the MT1 receptor accelerates cell death, while gene-engineering to increase the number of receptors delays it.
On the issue of mechanism, the researchers suggest that melatonin exerts its neuroprotective effects by inhibiting cell death pathways by preserving the MT1 receptors as well as through its antioxidant properties.
Lower levels of melatonin are found in Huntington’s disease as well as in Parkinson’s and Alzheimer’s diseases. In addition, melatonin levels decline with age.
"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."
One of the limitations of melatonin is that it has a short half-life of 20 to 50 minutes. However, it has some analogues with a longer half –life and there are also drugs which increase the MT1 receptors; these are likely to be explored as potential treatments.
Xin Wang, Ana Sirianni, Zhijuan Pei, Kerry Cormier, Karen Smith, Jiying Jiang, Shuanhu Zhou, Hui Wang, Rong Zhao, Hiroko Yano, Jeong Eun Kim, Wei Li, Bruce S. Kristal, Robert J. Ferrante, and Robert M. Friedlander. “The Melatonin MT1 Receptor Axis Modulates Mutant Huntingtin-Mediated Toxicity.” The Journal of Neuroscience 12 October 2011, 31(41):14496-14507.
Zin Wang, Shan Zhu, Zhijuan Pei, Martin Drozda, Irina Stavrovskaya, Steven DelSignore, Kerry Cormier, Ethan Shimony, Hongyan Wang, Robert Ferrante, Bruce Kristal, and Robert M. Friedlander. “Inhibitors of cytochrome c release with therapeutic potential for Huntington's disease.“ The Journal of Neuroscience 2008 Sep 17;28(38):9473-85.
- Marsha L. Miller, October 21, 2011