Melatonin (MEL), an indolamine with diverse functions in the brain, has been shown to produce antidepressant-like effects, presumably through stimulating neurogenesis. We recently showed that the combination of MEL with ketamine (KET), an NMDA receptor antagonist, has robust antidepressant-like effects in mice, at doses that, by themselves, are non-effective and have no adverse effects. Here, we show that the KET/MEL combination increases neurogenesis in a clone derived from human olfactory neuronal precursors, a translational pre-clinical model for effects in the human CNS. Neurogenesis was assessed by the formation of cell clusters > 50 µm in diameter, positively stained for nestin, doublecortin, BrdU and Ki67, markers of progenitor cells, neurogenesis, and proliferation. FGF, EGF and BDNF growth factors increased the number of cell clusters in cultured, cloned ONPs. Similarly, KET or MEL increased the number of clusters in a dose-dependent manner. The KET/MEL combination further increased the formation of clusters, with a maximal effect obtained after a triple administration schedule. Our results show that the combination of KET/MEL, at subeffective doses that do not produce adverse effects, stimulate neurogenesis in human neuronal precursors. Moreover, the mechanism by which the combination elicits neurogenesis is meditated by melatonin receptors, CaM Kinase II and CaM antagonism. This could have clinical advantages for the fast treatment of depression.
Melatonin (N-acetyl-5-methoxytryptamine) is an indoleamine synthesized by the pineal gland in the dark phase of the photoperiod. Released melatonin into the pineal recess and the cerebrospinal fluid is the chemical signal that conveys information about the environmental illumination to the brain. In recent years, it was described that melatonin stimulates the neurodevelopment in the adult brain. During this complex process, new neurons are formed and differentiate to form synaptic connections. Neuropsychiatric disorders are characterized by the loss of neuronal connectivity and diminished levels of melatonin, among other features. Importantly, these patients have impaired circadian rhythms. In recent years, evidence aroused indicating that neurodevelopment occurs in the adult brain, making important the study of chemical compounds and endogenous molecules that stimulate neurodevelopment to reestablish synaptic connectivity. In this chapter, we will review the evidence that supports the circadian melatonin modulatory effects on neurodevelopment and its importance for the treatment of neuropsychiatric diseases.
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