Melatonin from Plants: Going Beyond Traditional Central Nervous System Targeting-A Comprehensive Review of Its Unusual Health Benefits

Abstract

Melatonin is indispensable for the homeostasis of plants and animals. In humans, it can help prevent or be an adjuvant treatment for several diseases mainly related to the immune system, inflammation, and oxidative stress. Moreover, a melatonin-rich diet is linked to several health benefits, such as regulation of circadian rhythm, regulation of the immunological system, epilepsy control, delaying the aging process, and diminishing hormones related to cancer. This review aimed to show the effects of melatonin in diseases beyond its traditional use. The results showed it can present scavenging of free radicals, reducing inflammatory cytokines, and modulating the immune system. Moreover, it can improve insulin resistance, blood pressure, LDL-c, adipose tissue mass, adhesion molecules, endothelial impairment, and plaque formation. These effects result in neuro- and cardioprotection, improvement of liver diseases, rheumatoid arthritis, dermatitis, COVID-19, polycystic ovaries, and sepsis. We conclude that plant melatonin can benefit patients with many diseases besides sleep problems and neurodegeneration. Plant melatonin may be more cost-effective and present fewer adverse events than synthetic. However, more clinical trials should be performed to show adequate doses, formulation, and treatment time.

Keywords: COVID-19; cancer; cardiovascular diseases; dysbiosis; melatonin; plants; polycystic ovary syndrome; rheumatoid arthritis; sepsis.

Figure 1

Melatonin can exert several actions in the human body. These effects can occur in several organs, such as the heart, liver, kidney, skin, and bones. Besides that, melatonin can modulate molecular and systemic actions. ↑: increase; ↓: decrease.

Figure 2

Biosynthesis of melatonin in chloroplasts (A) under heat conditions and in mitochondria (B) under cold temperature. ASMT: N-acetylserotonin methyltransferase; CO₂: carbon dioxide; COMT: caffeic acid O-methyltransferase; Trp: tryptophan.

Figure 3

Mechanism of action for melatonin. This hormone can bind to receptors associated with G protein, named MT1, MT2, and MT3 receptors. The association of melatonin and the receptor leads to several cellular responses, such as sleep regulation, intestinal mucosa protection, glycemia and blood pressure homeostasis, and inflammatory and antioxidant effects. The ligation of melatonin to the Gi-coupled receptors separates alpha from beta and gamma subunits. In this separation, it is observed that the change of guanosine diphosphate (GDP) for guanosine triphosphate (GTP) leads to inhibition of the adenylate cyclase (AC) enzyme and the subsequent cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA)/cAMP response element-binding protein (CREB) route. The activation of the Gq receptors stimulates the enzyme phospholipase C (PLC), increasing IP3 (inositol triphosphate) and diacylglycerol (DAG) and elevating the levels of Ca⁺². The ligation of melatonin to MT3 (cytosolic enzyme quinone reductase 2—QR2) is the third possibility of melatonin binding. QR2 is related to the reductases that act in reducing oxidative stress. Melatonin can also bind to nuclear receptors designated as retinoid-related orphan (ROR) receptors. ↑: increase; ↓: decrease.

Figure 4

Melatonin can positively affect several human conditions, such as cardiovascular and neurodegenerative diseases (NDD), metabolic-associated fatty liver disease (MAFLD), cancer, dysbiosis, polycystic ovary syndrome, rheumatoid arthritis, coronavirus disease 2019 (COVID-19), periodontal diseases, and sepsis.