Melatonin is Neuroprotective in ALS Mice

by Amy Madsen on Fri, 2013-05-10 11:31

Treatment with the naturally occurring hormone delayed symptom onset, increased life span and inhibited nerve-cell loss in the SOD1 research mouse model of amyotrophic lateral sclerosis

Xin Wang at Harvard Medical School/Brigham and Women's Hospital in Boston and colleagues have published findings showing that the naturally occurring hormone melatonin appears to prevent the loss of nerve cells in mice with an ALS-like disease.
Article Highlights:
  • A team of researchers, funded in part by the Muscular Dystrophy Association, has demonstrated that a naturally occurring hormone called melatonin is associated with disease progression in a mouse model of ALS.
  • Mice with an ALS-like disease that were treated with melatonin experienced a later disease onset, survived longer and had less nerve-cell degeneration than mice that didn't receive treatment.
  • The findings may help identify biological targets at which to aim potential ALS therapies.

Melatonin, a naturally occurring hormone produced by the pineal gland, is best known for its role in regulating sleep. Now, results from a study supported in part by MDA show that treatment with the compound prevents the loss of motor neurons, delays disease onset and prolongs survival in mice with a disease mimicking human amyotrophic lateral sclerosis (ALS).

The neuroprotective properties associated with the drug appear to result from the compound's ability to prevent activation of a cell-death process called apoptosis.

The findings may help identify biological targets at which potential ALS therapies could be aimed.

(Note: Although melatonin is available for purchase over-the-counter in the United States, its effects on people with ALS are still unknown. Therefore, individuals are strongly advised not to use it to treat ALS until it has been proven safe and effective in people with the disease.)

“Over-the-counter medications or supplements and those used in this study are administered differently,” said Valerie Cwik, MDA executive vice president and chief medical and scientific officer. “More research is needed to know if melatonin will benefit people with ALS.”

Always consult with your physician before adding any new medications or supplements to your treatment plan.

About the study

The researchers, led by Robert Friedlander at the University of Pittsburgh School of Medicine, evaluated the effects of melatonin in mice with a disease that mimics ALS caused by a mutation in the SOD1 gene.

The researchers found that melatonin levels in the spinal cords of 120-day-old ALS mice were significantly decreased by approximately 16 percent, compared to levels in age-matched healthy littermates. With daily systemic injection of melatonin for 11 weeks, they were able to restore melatonin in the ALS mice to levels comparable to those seen in unaffected mice.

For the study, mice were divided into two groups and, beginning at six weeks of age, received daily intraperitoneal injections either of melatonin at a dose of 30 milligrams per kilogram of body weight (the treatment group), or placebo (the control group).

The investigators, who did not know which mice received melatonin and which received placebo, monitored the animals' body weight and conducted neurobehavioral tests designed to assess muscle strength and coordination.

Melatonin delayed disease onset and progression

Study results showed that melatonin significantly delayed disease onset and death, and that treatment with melatonin was beneficial during both the early and late stages of disease in the mice.

  • Mice treated with melatonin exhibited disease onset at an average age of 121.4 days, a statistically significant 10.1-percent delay over the average age of onset of 110.3 days in mice that received placebo.  
  • Melatonin also prolonged life span by 7.4 percent (untreated mice survived an average of 136.7 days, while those that received melatonin survived an average of 146.8 days).

Mice belonging to the treatment group showed significant delay in the appearance of disease-related motor symptoms such as hind-limb tremor and gait abnormalities.

Analysis also showed that mice treated with melatonin had less motor neuron loss than those that received placebo, and that tissue loss in the spinal cord was reduced in melatonin-treated animals compared to placebo-treated counterparts.

Melatonin blocked programmed cell death

Melatonin is a powerful antioxidant that blocks damage to cells caused by free radicals (byproducts of cellular energy production). The hormone works to combat oxidative stress, thought by some to play a prominent role in ALS.

The researchers determined, however, that melatonin caused the beneficial effects in the mice through another mechanism — by blocking the release of proteins, particularly one called cytochrome c, that activate apoptosis.

For more information

Findings were published online March 26, 2013, in Neurobiology of Disease. Read the full report, for a fee: 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.

MDA supported Xin Wang at Harvard Medical School/Brigham and Women's Hospital in Boston for her contribution to this work. Read Wang's manuscript on the neuroprotective role of melatonin, published online Oct. 10, 2009, in CNS Neuroscience, for free: The Anti-Apoptotic Activity of Melatonin in Neurodegenerative Diseases.

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