Melatonin N-acetyl-5-methoxytriptamine is an ancient molecule which synchronizes the internal biological activity with the environmental photoperiod. It is synthesized by the pineal gland during the night and released to the general circulation where it reaches nanomolar concentrations. The indolamine acts through melatonin receptors and binds to nearly 18 different proteins. Among these is calmodulin, a phylogenetically conserved protein which is the main transductor of the calcium signaling. In this review, we will describe evidence in support that melatonin binds to calmodulin in presence of calcium, as well as the implications in the activity of Calmodulin kinase II as an antagonist and stimulating its activity. Also, we review literature that support the relevance on melatonin binding to calmodulin in the regulation of circadian rhythms in unicellular organisms, as well as in neuronal development in mammals as an ancient conserved mechanism. Finally, it is remarked the importance of antioxidant effects of melatonin on calmodulin preservation. Significance StatementThis review compiled evidence in support that melatonin binds to calmodulin. We discuss the dual effect of melatonin on the activity of CaM binding proteins, the possible mechanisms involved and the relevance on regulation of circadian rhythms. Finally, we describe evidence in support that binding of melatonin to CaM hydrophobic pockets may prevent the oxidation of methionine species through a shielding effect, in addition to its antioxidant capabilities, preserving the functionality of CaM.

Forty per cent of major depression patients are resistant to antidepressant medication. Thus, it is necessary to search for alternative treatments. Melatonin (N-acetyl-5-hydroxytryptamine) enhances neurogenesis and neuronal survival in the adult mouse hippocampal dentate gyrus. Additionally, melatonin stimulates the activity of Ca²⁺/Calmodulin-dependent Kinase II (CaMKII), promoting dendrite formation and neurogenic processes in human olfactory neuronal precursors and rat organotypic cultures. Similarly, ketamine, an N-methyl-D-aspartate receptor (NMDAR) antagonist, modulates CaMKII activity. Importantly, co-treatment of low doses of ketamine (10⁻⁷ M) in combination with melatonin (10⁻⁷ M) produces additive effects on neurogenic responses in olfactory neuronal precursors. Importantly, enhanced neurogenic responses are produced by conventional antidepressants like ISSRs. The goal of this study was to investigate whether hippocampal CaMKII participates in the signaling pathway elicited by combining doses of melatonin with ketamine acutely administered to mice, 30 min before being subjected to the forced swimming test. The results showed that melatonin, in conjunction with ketamine, significantly enhances CaMKII activation and changes its subcellular distribution in the dentate gyrus of the hippocampus. Remarkably, melatonin causes nuclear translocation of the active form of CaMKII. Luzindole, a non-selective MT₁ and MT₂ receptor antagonist, abolished these effects, suggesting that CaMKII is downstream of the melatonin receptor pathway that causes the antidepressant-like effects. These findings provide molecular insights into the combined effects of melatonin and ketamine on neuronal plasticity-related signaling pathways and pave the way for combating depression using combination therapy.

Neoponcirin causes anxiolytic-like effects in mice when administered intraperitoneally but not orally. Neoponcirin is non-water-soluble and insoluble in solvents, and in medium acid, it isomerizes, reducing its bioavailability. To improve the pharmacological properties of neoponcirin, we formed a neoponcirin complex with beta-cyclodextrin (NEO/βCD), which was characterized by FT-IR, UV-Vis, and NMR, and their solubility profile. We evaluated the antidepressant-like effects of NEO/βCD acutely administered to mice orally in the behavioral paradigms, the tail suspension (TST) and the forced swimming (FST) tests. We also analyzed the benefits of repeated oral doses of NEO/βCD on depression- and anxiety-like behaviors induced in mice by chronic unpredictable mild stress (CUMS), using the FST, hole board, and open field tests. We determined the stressed mice’s expression of stress-related inflammatory cytokines (IL-1β, IL-6, and TNFα) and corticosterone. Results showed that a single or chronic oral administration of NEO/βCD caused a robust antidepressant-like effect without affecting the ambulatory activity. In mice under CUMS, NEO/βCD also produced anxiolytic-like effects and avoided increased corticosterone and IL-1β levels. The effects of the NEO/βCD complex were robust in both the acute and the stress chronic models, improving brain neurochemistry and recovering immune responses previously affected by prolonged stress.

Smell dysfunction affects quality of life and is considered an early clinical sign of Alzheimer’s and Parkinson’s diseases. Olfactory loss increases with age and is associated with certain ciliopathies, a group of genetic disorders characterized by a wide spectrum of multisystemic disturbances. The dysfunction of mature olfactory sensory neurons (OSNs) in the olfactory neuronal pathway remains poorly understood. Previous evidence suggests that primary cilia proteins are involved in the maturation of olfactory sensory neurons (OSNs). In this study, we obtained olfactory neuronal precursors (ONPs) from the olfactory mucosa of young and older healthy volunteers who reported smell impairment (hyposmia) without neurological deficits or underlying airflow issues (conductive olfactory loss) and from normosmic individuals. In vitro analysis of ONPs showed that these cells can form primary cilia in normosmic individuals, while in hyposmic participants, there is a reduction in cilia frequency and a shorter length. In addition, ONPs from hyposmic individuals had a decrease in proliferation and cell differentiation. Our data indicate that alterations in molecular pathways related to primary cilia formation and the proliferation of ONPs lead to defects in neuronal maturation. These changes may hinder the differentiation of olfactory sensory neurons OSNs and contribute, at least in part, to olfactory loss.