Background: Melatonin, a neurohormone secreted from the pineal gland, circulates throughout the
body and then mediates several physiological functions. The pharmacological effects of melatonin can
be mediated through its direct antioxidant activity and receptor-dependent signaling.
Objective: This article will mainly review receptor-dependent signaling. Human melatonin receptors
include melatonin receptor type 1 (MT1) and melatonin receptor type 2 (MT2), which are widely
distributed throughout the brain.
Result: Several lines of evidence have revealed the involvement of the melatonergic system in
different neurodegenerative diseases. Alzheimer’s disease pathology negatively affects the
melatonergic system. Melatonin effectively inhibits β-amyloid (Aβ) synthesis and fibril formation.
These effects are reversed by pharmacological melatonin receptor blockade. Reductions in MT1 and
MT2 expression in the amygdala and substantia nigra pars compacta have been reported in
Parkinson’s disease patients. The protective roles of melatonin against ischemic insults via its
receptors have also been demonstrated. Melatonin has been reported to enhance neurogenesis
through MT2 activation in cerebral ischemic/reperfusion mice. The neurogenic effects of melatonin on
mesenchymal stem cells are particularly mediated through MT2.
Conclusion: Understanding the roles of melatonin receptors in neuroprotection against diseases may
lead to the development of specific analogues with specificity and potency greater than those of the
original compound. These successfully developed compounds may serve as candidate preventive and
disease-modifying agents in the future.