Preclinical Study Sheds Light on How Melatonin May Protect Neurons

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by Marta Figueiredo PhD |

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Treatment with melatonin — a hormone best known for its role in sleep regulation — lessened neurodegeneration and motor symptoms in a mouse model of Parkinson’s disease, a study shows.

These benefits were associated with the suppression of a death-inducing inflammatory pathway called NLRP3 inflammasome in microglia, the immune cells of the central nervous system (CNS, comprising the brain and spinal cord).

The data, which shed light on the mechanisms behind melatonin’s neuroprotective effects, may help identify new therapeutic targets and approaches for Parkinson’s disease.

The study, “Melatonin Attenuates Neuroinflammation by Down-Regulating NLRP3 Inflammasome via a SIRT1-Dependent Pathway in MPTP-Induced Models of Parkinson’s Disease,” was published in the Journal of Inflammation Research.

The progressive loss of dopamine-producing, or dopaminergic, neurons in Parkinson’s disease is associated with the buildup of toxic clumps of the alpha-synuclein protein, neuroinflammation, and excessive microglial activation.

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Microglia play a crucial role in the CNS during immune responses to infection or injury, and may release either pro- or anti-inflammatory signals in response to changes in the brain’s environment.

Previous studies have shown that both alpha-synuclein aggregates and dopaminergic neuron loss trigger the activation of the NLRP3 inflammasome in microglia, highlighting a key role of inflammasomes — protein complexes within cells that drive inflammation in response to certain triggers — in Parkinson’s.

The NLRP3 inflammasome, also implicated in several other diseases, is known to trigger the release of pro-inflammatory molecules such as interleukin-1 beta (IL-1 beta) and to initiate an inflammatory form of cell death.

Melatonin is a hormone produced by the small pea-shaped pineal gland in the brain and mainly known for its role in regulating the body’s internal clock (circadian rhythm) and sleep-awake cycles.

However, this molecule is also involved in several biological activities, and was shown to exert anti-inflammatory effects by increasing the levels of silence information regulator 1 (SIRT1), an enzyme that acts against chronic inflammation and whose activity is reduced in Parkinson’s patients and rat models.

“[P]reclinical and clinical studies have shown that melatonin decreases neuroinflammation in [Parkinson’s disease], but the mechanism underlying this effect remains to be explored,” the researchers wrote.

To shed light on melatonin’s potential anti-inflammatory effects in Parkinson’s, researchers in China evaluated the effects of melatonin treatment in a mouse model of the disease as well as in lab-grown mouse and rat microglia.

Results showed that melatonin reversed Parkinson’s-associated weight loss and motor deficits, and significantly reduced dopaminergic-neuron loss and microglia activation in the brain of these mice.

Moreover, melatonin was found to prevent NLRP3 inflammasome activation and to reduce the levels of IL-1 beta in both the mouse model and lab-grown microglia, suggesting that the hormone’s neuroprotective effects are linked to its ability to suppress NLRP3 inflammasome in the brain, particularly in microglia.

Further analysis revealed that this anti-inflammasome effect was associated with a melatonin-induced restoration of SIRT1 levels in lab-grown microglia. Higher doses of melatonin were found to reduce SIRT1 levels, suggesting a fine-tuned balance for melatonin to exert beneficial effects.

“Our data demonstrated that melatonin attenuates neuroinflammation by negatively regulating NLRP3 inflammasome activation via a SIRT1-dependent pathway,” the researchers wrote.

However, no significant differences in SIRT1 levels were detected between untreated and treated mice, highlighting that further research in animal models is needed to clarify the mechanisms behind melatonin’s neuroprotective, anti-inflammatory effects, the team noted.

“Collectively, our results demonstrated a previously unrecognized mechanism through which melatonin suppresses inflammasome-induced neuroinflammation” in Parkinson’s disease, the team concluded.

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