Melatonin is a naturally occurring hormone that is best known for its role in sleep regulation. However, after screening more than a thousand FDA-approved drugs several years ago, a team of researchers has determined that melatonin, which is relatively inexpensive and available over the counter, is also a powerful antioxidant that blocks the release of enzymes that activate apoptosis, or programmed cell death.
Annually about 5,000 people are diagnosed with Amyotrophic Lateral Sclerosis (ALS), also known as Lou Gehrig’s disease, which damages motor nerve cells that control muscles, leading to muscle weakness, paralysis and eventually — death. No known treatment can slow the progress of ALS, and there is no cure. As ALS kills nerves, the muscles they control begin to wither. The damaged muscles, however, can “re-innervate” themselves by prompting healthy nerves to send new branches their way, like limbs in a damaged hedge filling in a gap.
A paper with the somewhat cumbersome title:”Melatonin inhibits the caspase-1/cytochrome c/caspase-3 cell death pathway, inhibits MT1 receptor loss and delays disease progression in a mouse model of amyotrophic lateral sclerosis,” published published online ahead of print in the journal Neurobiology of Disease (Volume 55, July 2013, Pages 26–35 doi: 10.1016/j.nbd.2013.03.00 Pages 26–35), reports that mice bred to develop ALS-like disease, when treated with melatonin injections, demonstrated later symptoms onset, survived longer, and manifested less degeneration of motor neurons in the spinal cord.
According to the paper’s abstract, by screening a drug library the researchers found that Melatonin inhibited cytochrome c release in purified mitochondria and prevented cell death in cultured neurons. a team of scientists at several U.S. universities and medical institutions, including the University of Pittsburgh, Harvard Medical School, Ohio State University, Weifang Medical University; University of Texas Medical School at Houston, VA Pittsburgh Health Care System, Bedford VA Medical System in Boston, and St. Joseph’s Hospital and Medical Center in Phoenix. One of the co-authors is Professor and Vice Chairman Arthur L. Day, M.D. of the Vivian L. Smith Department of Neurosurgery at The University of Texas Medical School at Houston. The study was led by senior investigator Robert Friedlander, M.D. at the University of Pittsburgh School of Medicine, evaluated whether Melatonin would slow disease progression in SOD1G93A mice, and were able to demonstrate that Melatonin significantly delayed disease onset, with neurological deterioration and mortality in ALS mice inhibited by Melatonin treatment. Moreover, for the first time, the researchers determined that disease progression was associated with the loss of both melatonin and the melatonin receptor 1A (MT1) in the spinal cord of ALS mice, thereby demonstrating that Melatonin is neuroprotective in transgenic ALS mice, and this protective effect is mediated through its effects on the caspase-mediated cell death pathway, and that furthermore, their data suggest that Melatonin and MT1 receptor loss may play a role in the pathological phenotype observed in ALS — these observations being an indication that Melatonin and modulation of Rip2/caspase-1/cytochrome c or MT1 pathways may yield promising novel therapeutic approaches for treating ALS.
“Our experiments show for the first time that a lack of melatonin and melatonin receptor 1, or MT1, is associated with the progression of ALS,” Dr. Friedlander is cited commenting. “We saw similar results in a Huntington’s disease model in an earlier project, suggesting similar biochemical pathways are disrupted in these challenging neurologic diseases.”
This latest research builds on findings of a study, published in the Dec. 11, 2009 issue of the journal Science by researchers at the University of Texas Southwestern Medical Center who found that a molecule produced naturally by muscles in response to nerve damage can reduce symptoms and prolong life in a mouse model of ALS.
“We believe we can apply this research toward drug development,” Dr. Eric Olson, chairman of molecular biology at UT Southwestern and senior author of the study commented at the time.
“Our experiments show for the first time that a lack of melatonin and melatonin receptor 1, or MT1, is associated with the progression of ALS,” says UPMC’s Dr. Friedlander. “We saw similar results in a Huntington’s disease model in an earlier project, suggesting similar biochemical pathways are disrupted in these challenging neurologic diseases.”
The research them hopes to stop neuron death in ALS similarly to as was done with Huntington’s, although Dr. Friedlander cautions that much more work has to be done to unravel how these mechanisms work before human trials of melatonin or a drug akin to it can be conducted to determine its usefulness as an ALS treatment.
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