The neuroprotective potential of melatonin

According to a review by Bulgarian researchers in the International Journal of Molecular Sciences​, numerous clinical trials confirm melatonin’s impact on neuroprotection from progressive neurodegenerative disorders. Often these conditions are found with an insomnia comorbidity.

“For optimal neuroprotective effects of melatonin, early supplementation is crucial,” the researchers wrote. “Melatonin, as well as its metabolites, N1-acetyl-N2-formyl-5-methoxykynuramine (AFMK) and N1-acetyl-5-methoxykynuramine (AMK), can reduce oxidative brain damage by shielding mitochondria from dysfunction during the aging process.”

Melatonin also can improve inflammation and enhance circadian rhythm, they added.

Cognitive decline and sleep​

All living species can produce melatonin. Although released by the pineal gland, there are also many extra-pineal sites where melatonin synthesis occurs, including at the bone marrow, retina, lens, cochlea, lungs, liver, kidney, pancreas, thyroid gland, female reproductive organs and skin.

Melatonin plays a critical role in regulating circadian rhythms and seasonal biorhythms. Circadian clocks are critical to regulate human health, choreographing physiological and neuroendocrine functions.

There is a link between cognitive decline and inadequate sleep. When it comes to neurodegenerative diseases, numerous clinical trials of melatonin supplementation administered to separate groups, one Alzheimer’s and the other Parkinson’s disease patients, showed prolonged release of the hormone had beneficial impacts on sleep disruption, non-motor symptoms and quality of life, according to the researchers.

Oxidative stress​

Melatonin secretion decreases with chronobiological aging, which includes a decline in circadian rhythm and a “dampening of circadian gene expression that can augment oxidative damage through an increased generation and accumulation of ROS and RNS,” the researchers wrote.

Scientists have focused on this what is known as a ‘free radical theory of aging’ for more than 50 years. Cellular oxidative metabolism produces ROS and RNS, which are associated with health decline of individuals with neurological disorders.

“At the subcellular level, mitochondria are the major source of generation of OH and ONOO,” the researchers explained. “The excessive production of these destructive species causes enhanced mitochondrial oxidative stress as well as mtDNA mutations and occurs along with human aging and age-related pathologies.”

It is a process that may lead to an accumulation of mutations, increasing mitochondrial impairment and the development of oxidative damage. Ultimately mitochondrial dysfunction dictates the rate of aging.

Oxidative stress may be a contributing factor in neurodegenerative diseases. For example, oxidized proteins and lipid peroxidation were seen in patients with mild cognitive impairment and beginning stage Alzheimer’s disease.

Continued exposure to oxidative stress results in 'inflammaging,' otherwise known as low-grade chronic inflammation. This process can remodel the immune system, causing changes in cellular and humoral immunity as people age. Immunity may play an important role in the process of aging and age-related conditions.

More clinical trials​

Brain aging changes the biological clock’s function, which decreases melatonin synthesis and contributes to emerging neurological irregularities.

The researchers noted that exogenous melatonin may be a potential circadian synchronizer and can regulate homeostasis in the brain during aging.

“Numerous experimental studies and clinical trials confirm the therapeutic neuroprotective potential of melatonin and its derivatives,” they wrote. “They exert powerful neuroprotection through a myriad of different mechanisms, allowing for the prevention of neurodegeneration and/or cognitive improvement, along with sleep maintenance.”

Studies show that melatonin supplementation reduces apoptotic neurons. In a transgenic mouse model of Alzheimer’s disease, it increases the choline acetyltransferase activity in the frontal cortex and hippocampus.

Melatonin also protects the brain from amyloid-beta-induced neurotoxicity.

“More targeted studies of melatonin supplementation in aged individuals with signs of brain aging and neurodegeneration are needed and must be performed in the future,” the researchers suggested. “This need for high-quality clinical trials is necessary for comprehensive research and for an evaluation of the effect of supplemented melatonin in different doses and formulations to design the optimal effective treatment for retardation of neurodegeneration.”

Source: International Journal of Molecular Sciences​
doi: doi.org/10.3390/ijms25105122​
“The Vital Role of Melatonin and Its Metabolites in the Neuroprotection and Retardation of Brain Aging”
Authors: Georgeta Bocheva et al.