Melatonin Acts as an Antidepressant by Inhibition of the Acid Sphingomyelinase/Ceramide System

Abstract

Background: Melatonin has been shown to have antidepressive effects. We tested whether melatonin inhibits the acid sphingomyelinase/ceramide system and mediates its antidepressive effects via inhibition of the acid sphingomyelinase and a reduction of ceramide in the hippocampus. Antidepressants such as amitriptyline and fluoxetine were previously shown to inhibit the acid sphingomyelinase/ceramide system, which mediates neurogenesis and behavioral changes induced by these drugs. Methods: The effect of melatonin on the activity of the acid sphingomyelinase prior to and after treatment with melatonin was determined in cultured neurons and in vivo in the hippocampus of mice by measuring the consumption of [¹⁴C] sphingomyelin. Ceramide was measured by DAG kinase assay and fluorescence microscopy of the hippocampus and of cultured neurons. Neurogenesis in the hippocampus was analyzed by in vivo labeling with bromodeoxyuridine. Behavior was assessed in standardized tests. Results: Melatonin treatment inhibited acid sphingomyelinase in vitro in cultured pheochromocytoma cells and in vivo in the hippocampus, which resulted in a reduction of ceramide in vitro and in vivo. The inhibition of the acid sphingomyelinase/ceramide system translated into increased neurogenesis in glucocorticosterone-stressed mice after treatment with melatonin, an effect that is abrogated in acid sphingomyelinase-deficient mice. Likewise, melatonin improved the depressive behavior of stressed mice, a therapeutic effect that was again absent in acid sphingomyelinase-deficient animals. Conclusion: These data indicate that the antidepressive effects of melatonin as well as the induction of neurogenesis triggered by this drug are mediated by an inhibition of the acid sphingomyelinase/ceramide system. This is the first study to identify melatonin as an inhibitor of the acid sphingomyelinase.

Protective Effects of Melatonin on Neurogenesis Impairment in Neurological Disorders and Its Relevant Molecular Mechanisms

“…It was shown that 3-week daily treatment of 10 mg/kg BW melatonin prevented CORT-induced reduction in cell proliferation in the DG and reduced depression- and anxiety-like behavior of the mice in the forced swim test, open field test, and novelty suppressed feeding test [ 51 ]. The anti-depressive and neurogenetic effects of melatonin was potentially brought about by the inhibition of the acid sphingomyelinase/ceramide system as well as the decrease in vesicular monoamine transporter 2 (VMAT2) levels and increase in the monoamine oxidase A MAO-A levels in the hippocampus [ 52 , 53 ]. Using combination treatment of melatonin and citalopram (MLTCITAL), 14-day daily treatment of 2.57 mg/kg BW MLTCITAL promoted neurogenesis and reduced depression-like behavior in adult mice [ 54 ] ( Table 3 ).…”

Role of Janus-Kinases in Major Depressive Disorder

“…Thus, it has been previously shown that inhibition of the acid sphingomyelinase/ceramide systems prevents the effects of stress in the hippocampus [10,[25][26][27] and functions upstream of stress-activated kinases such as p38Kinase [25].…”

Melatonin and the Programming of Stem Cells

“…These observations are in accordance with the multiple results on NSC protection, proliferation, and differentiation both in vivo and in vitro (Table 1). Rat midbrain NSCs None Viability↑ dopaminergic differentiation (tyrosine hydroxylase↑), BDNF↑ GDNF↑ [110] Mouse NSCs from ganglionic eminence None Differentiation to neurons↑ in FBS-stimulated proliferation, but not in differentiation period [111] Murine induced pluripotent stem cells None Differentiation to NSCs↑ and further to neurons↑ PI3K/AKT signaling [112] Mouse hippocampal NSCs None Survival↑ differentiation↑ [113] NSCs from adult murine SVZ None Proliferation↑ differentiation↑; ERK/MAPK signaling [114,115] Rat adult hippocampal NSCs None Proliferation↑ phosphorylation of ERK1/2 andc-Raf [116] Mouse adult spinal cord NSPCs None Proliferation↑ PI3K/AKT signaling [117] Murine hippocampus in vivo None Neurogenesis↑ [118] Murine dentate gyrus in vivo None NeuN+ cells↑ DCX+ cells↑ [108,113,[119][120][121][122][123][124] Rat dentate gyrus in vivo Pinealectomy Neurogenesis↑ [125] Rat embryonal NSCs IL-18 Proliferation↑ differentiation↑ BDNF↑ GDNF↑ [126] Mouse embryonic cortical NSCs LPS Sox2 expression↑ PI3K/Akt/Nrf2 signaling [20] Mouse cortical NSCs in vitro Hypoxia Proliferation↑ differentiation to neurons↑ MT 1 dependence, pERK1/2↑ [19] Mouse embryonic cortical NSCs Hyperglycemia Proliferation↑ self-renewal↑ autophagy↓ [127] Murine dentate gyrus in vivo Corticosterone Attenuation of proliferation suppression [128] Rat adult hippocampal NSCs Dexamethasone Reversal of inhibition of nestin and Ki67 expression [129] Murine dentate gyrus in vivo Dexamethasone Attenuation of suppressed DCX expression [130] Murine dentate gyrus in vivo Cuprizone Restoration of Ki67+ proliferative cells and DCX+ NPCs; BNDF↑ [131] Murine dentate gyrus in vivo Scopolamine Restoration of Ki67+ proliferative cells and DCX+ NPCs [132] Murine dentate gyrus in vivo d-Galactose (aging model) Restoration of Ki67+ proliferative cells and DCX+ NPCs…”