Participation of Ca2+-Calmodulin-Dependent Protein Kinase II in the Antidepressant-Like Effects of Melatonin.

Melatonin, a hormone that regulates sleep-wake cycles, also shows antidepressant-like effects in animal studies. These effects appear to involve activation of an enzyme called calcium-calmodulin-dependent kinase II (CaMKII), which plays roles in learning, memory, and brain cell adaptability. Patients with major depression have lower nighttime melatonin levels. This review describes evidence that melatonin may work partly through CaMKII to support neuroplasticity—the brain's ability to form new connections—and that combining melatonin with other antidepressants like ketamine could enhance these benefits.

Study at a glance

Abstract

Melatonin (N-acetyl-5-methoxytryptamine) is an indoleamine secreted by the pineal gland during the dark phase of the photoperiod. Its main function is the synchronization of different body rhythms with the dark-light cycle. Research on melatonin has significantly advanced since its discovery and we now know that it has considerable significance in various physiological processes, including immunity, aging, and reproduction. Moreover, in recent years evidence of the pharmacological possibilities of melatonin has increased. Indoleamine, on the other hand, has antidepressant-like effects in rodents, which may be mediated by the activation of calcium-calmodulin-dependent kinase II (CaMKII) and are also related to the regulation of neuroplasticity processes, including neurogenesis, synaptic maintenance, and long-term potentiation. Remarkably, patients with major depression show decreased levels of circulating melatonin in plasma. This review presents evidence of the antidepressant-like effects of melatonin in preclinical models and the participation of CaMKII in these actions. CaMKII's role in cognition and memory processes, which are altered in depressive states, are part of the review, and the effects of melatonin in these processes are also reviewed. Furthermore, participation of CaMKII on structural and synaptic plasticity and the effects of melatonin are also described. Finally, the advantages of using melatonin in combination with other antidepressants such as ketamine for neuroplasticity are described. Evidence supports that CaMKII is activated by melatonin and downstream melatonin receptors and may be the common effector in the synergistic effects of melatonin with other antidepressants. SIGNIFICANCE STATEMENT: This review compiled evidence supporting that melatonin causes antidepressant-like effects in mice through calmodulin kinase II stimulation of downstream melatonin receptors as well as the participation of this enzyme in neuroplasticity, memory, and cognition. Finally, we describe evidence about the effectiveness of antidepressant-like effects of melatonin in combination with ketamine.