Arches. Photo by Daniel Chia
HOPES: Huntington's Outreach Project for Education, at Stanford
Jan
27
2013

Melatonin

It has long been known that melatonin, a hormone produced in the brain, plays an important role in regulating the body’s natural sleep-wake cycle by causing drowsiness and inducing sleep. The pineal gland, a small structure located beneath the center of the brain produces and releases melatonin in response to the intensity and type of light detected by the eyes. Darkness causes increased melatonin release, while light inhibits melatonin release. What results is a daytime decline and nighttime rise in melatonin levels that mirrors waking and sleeping. Thus, melatonin plays an important role as a regulator of the biological clock. Because of this, melatonin is sometimes prescribed as a treatment for sleep disorders. Disruption of normal sleep is a common symptom in HD, and more information about sleep and HD can be found here.

Outside of sleep regulation, melatonin is also involved in many human bodily processes including learning, memory, and aging. Some of these functions are brought about by the antioxidant properties of the hormone itself, while others are attributed to melatonin binding with its receptor proteins, MT1 and MT2. There has been a great deal of interest in studying these additional benefits of melatonin, since it is already an FDA-approved drug.  In terms of HD specifically, researchers have recently identified melatonin as a neuroprotective agent due to its role in inhibiting the neuronal death characteristic of HD.  Since melatonin acts through so many different possible mechanisms, how exactly can melatonin produce its therapeutic effects against HD and affect disease progression?

Melatonin as an Antioxidant^

Free Radical Damage in HD^

In order to understand the role of antioxidants like melatonin in HD, we must first briefly review free radical damage, a phenomenon implicated in HD-associated neuron death.  Free radicals are highly reactive molecules that are natural byproducts of biochemical processes in the body, but high levels of free radicals can be toxic to cells in the body because they cause oxidative damage. Neuron cells in the brain, seem to be particularly susceptible to oxidative damage. For more information about free radicals and how they damage cells, click here.

One cause of free radical excess is glutamate excitotoxicity. Glutamate is an important neurotransmitter, a chemical signal used by neurons to communicate with each other.  Normally, binding of glutamate to NMDA receptors on neurons is responsible for processes such as learning and memory in the brain. Scientists believe that in HD, the mutant huntingtin protein causes problems that lead to excess binding of glutamate (for more information about NMDA receptors and glutamate toxicity, click here).  One of the eventual results of this defect is the overproduction of free radicals.

Another mechanism that can lead to free radical damage in HD is dysfunction of the mitochondria, the parts of the cell that act as energy power plants. A normal byproduct of the mitochondria producing energy for the cell is the generation of free radicals. However, if mitochondria are defective they may overproduce free radicals, leading to increased damage in the cell.  This is one possible explanation for the mitochondrial defects observed in some patients with HD.

Melatonin’s Antioxidative Properties^

As a defense mechanism against harmful free radicals that are normally produced, the body employs molecules known as free radical scavengers, which we more commonly refer to as antioxidants.  As their name implies, free radical scavengers encounter free radicals and detoxify them before they can damage cells or tissues.  Melatonin, in addition to being a hormone that regulates sleep-wake cycles, is also a potent antioxidant.  Its antioxidant properties go beyond free radical scavenging.  There is evidence suggesting that melatonin can stabilize cell membranes and thereby increase the cell’s resistance against free radicals, that it can stimulate cellular production of other antioxidants, and that it may even play a role in directly inhibiting production of certain types of free radicals.  Melatonin is also among the few antioxidants that can cross the blood-brain barrier, thus extending its protective properties to neurons in the brain.

Much research has been done to determine whether melatonin is truly effective for reducing oxidative damage.  In order to mimic neuronal damage as a result of uncontrolled free radical levels in HD, scientists use chemicals such as quinolinic acid and 3-nitropropionic acid.  The former is a molecule that binds to NMDA receptors which mimics glutamate, while the latter interrupts mitochondrial activity, and injection of either chemical into animal models result in oxidative damage similar to the neuropathology seen in brains of HD patients.  In a 1999 study performed by Southgate et al., rat brains were treated with quinolinic acid, which caused oxidative damage to cell membranes.  However, after the addition of melatonin, the amount of damage decreased significantly, suggesting that melatonin has protective antioxidative effects.  In a more recent 2005 study by Nam et al., 3-nitropropionic acid was injected directly into the striatum of rats, creating neuronal lesions similar to those seen in HD.  Treatment with melatonin reduced the amount of free radical damage to levels comparable to control mice that did not have a 3-nitropropionic acid injection, and significantly decreased the size of neuronal lesions in 3-nitropropionic acid injected mice.  All of these studies provide evidence that melatonin has protective effects against these chemically-induced HD models through antioxidant action. However, it is important to remember that these chemical treatments do not precisely replicate HD and further research must be done to demonstrate the effects of melatonin on oxidative damage in HD.

Melatonin and Melatonin Receptor Interactions^

The reasons why melatonin demonstrates neuroprotective effects are still unknown, but aside from its antioxidant properties, researchers have also shown that the interaction of the hormone with its receptors could be another way it protects the brain from damage by HD.  Like all hormones, melatonin is a chemical signal, and in order to bring about responses, melatonin must bind to one of its two receptors in the body – MT1 and MT2. Since altered levels of MT1 and MT2 receptors have been observed in other neurodegenerative disorders such as Alzheimer’s and Parkinson’s disease, it is possible that the melatonin receptors can play a role in HD as well.

In 2011, Friedlander’s research group conducted a study on the interaction between melatonin and its receptors in HD models and the therapeutic potential of melatonin treatment.  Their results shed light on the means by which melatonin might protect neurons.  Firstly, they found that in addition to its free radical scavenging abilities, melatonin treatment in vitro also blocked cellular pathways that lead to neuron death, or apoptosis, which some research suggests is increased by the mutant huntingtin protein in HD.  More importantly, they found that this effect is achieved by melatonin binding specifically to MT1 receptor.  However, in brain tissue samples of both mice carrying the mutant huntingtin gene and patients with HD, levels of MT1 receptor seemed to decline along with HD progression – samples that had more severe, late-stage HD pathology also had significantly lower levels of MT1.  This fact, coupled with the earlier findings that melatonin provides cell survival signals via the MT1 receptor, suggests that this interaction is disrupted in HD and is a potential target for HD therapeutics.

The Friedlander research group subsequently tested the effect of melatonin treatment in HD mouse models.  In contrast to the earlier animal models mentioned which were induced by chemicals to exhibit HD-like symptoms, they chose to employ transgenic mice that carry a version of the mutant huntingtin gene.  Daily melatonin treatment showed a beneficial effect on HD mice.  Not only did melatonin-treated mice retain normal movement control longer before onset of disease, but they also survived 21% longer than HD mice with no treatment.  Brain tissues were also less damaged in melatonin-treated mice than in untreated mice.  However, some key characteristics of HD – such as weight loss and levels of mutant huntingtin protein aggregates – remained unaffected by melatonin.  Nevertheless, the results of this in vivo study was a physiological reflection of the in vitro findings that melatonin binding with MT1 may help protect neurons by inhibiting certain pathways that cause cell death.

Conclusion^

Melatonin’s antioxidative properties and its interaction with MT1 receptors both seem to contribute to its protection of neurons in HD and make it a promising therapeutic candidate for the disease.  However, research on melatonin’s effect on HD progression is still in its early stages and further work must be done to validate these results before melatonin can potentially be studied in clinical trials.  On the bright side, the fact that melatonin is already an approved drug for treating certain sleep-related conditions could expedite the approval process required for future clinical studies in human patients.

Further Reading^

  1. Wang X, Zhu S, Pei Z, Drozda M, Stavrovskaya IG, Del Signore SJ, Cormier K, Shimony EM, Wang H, Ferrante RJ, Kristal BS, Friedlander RM (2008)  Inhibitors of cytochrome c release with therapeutic potential for Huntington’s Disease. J Neuro 28: 9473-9485.
  2. Reiter RJ, Manchester LC, Tan D-X (2010)  Neurotoxins:  Free radical mechanisms and melatonin protection. Curr Neuropharmacol 8: 194-210.
  3. Reiter RJ, Cabrera J, Sainz RM, Mayo JC, Manchester LC, Tan D-X (1999) Melatonin as a pharmacological agent against neuronal loss in experimental models of Huntington’s disease, Alzheimer’s disease, and Parkinsonism. Annals of New York Academy of Sciences 890: 471-485.
  4. Southgate G, Daya S (1999) Melatonin reduces quniolinic acid-induced lipid peroxidation in rat brain homogenate. Metabolic Brain Disease 14: 165-171.
  5. Nam E, Lee SM, Koh SE, Joo WS, Maeng S, Im HI, Kim YS (2005) Melatonin protects against neuronal damage induced by 3-nitropropionic acid in rat striatum. Brain Research 1046: 90-96.
  6. Wang X, Siranni A, Pei Z, Cormier K, Smith K, Jiang J, Zhou S, Wang H, Zhao R, Yano H, Kim JE, Li W, Kristal BS, Ferrante RJ, Friedlander RM (2011) The melatonin MT1 receptor axis modulates mutant huntingtin-mediated toxicity. J Neuro 31: 14496-14507.

-J. Choi, 1-27-13