The Cellular State Determines the Effect of Melatonin on the Survival of Mixed Cerebellar Cell Culture

Abstract

The constitutive activation of nuclear factor-κB (NF-κB), a key transcription factor involved in neuroinflammation, is essential for the survival of neurons in situ and of cerebellar granule cells in culture. Melatonin is known to inhibit the activation of NF-κB and has a cytoprotective function. In this study, we evaluated whether the cytoprotective effect of melatonin depends on the state of activation of a mixed cerebellar culture that is composed predominantly of granule cells; we tested the effect of melatonin on cultured rat cerebellar cells stimulated or not with lipopolysaccharide (LPS). The addition of melatonin (0.1 nM–1 µM) reduced the survival of naïve cells while inhibiting LPS-induced cell death. Melatonin (100 nM) transiently (15 min) inhibited the nuclear translocation of both NF-κB dimers (p50/p50, p50/RelA) and, after 60 min, increased the activation of p50/RelA. Melatonin-induced p50/RelA activity in naïve cells resulted in the transcription of inducible nitric oxide synthase (iNOS) and the production of NO. Otherwise, in cultures treated with LPS, melatonin blocked the LPS-induced activation of p50/RelA and the reduction in p50/p50 levels and inhibited iNOS expression and NO synthesis. Therefore, melatonin in vehicle-treated cells induces cell death, while it protects against LPS-induced cytotoxicity. In summary, we confirmed that melatonin is a neuroprotective drug when cerebellar cells are challenged; however, melatonin can also lead to cell death when the normal balance of the NF-κB pathway is disturbed. Our data provide a mechanistic basis for understanding the influence of cell context on the final output response of melatonin.

Mitochondria Transcription Factor A: A Putative Target for the Effect of Melatonin on U87MG Malignant Glioma Cell Line

“…However, in cancer cells, two scenarios have been shown: A pro-oxidant activity in which melatonin induces the increase of intracellular levels of ROS, leading to cell death, as was shown in the present study and by others [ 26 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 ]; and melatonin reducing intracellular levels of ROS and inducing cell death by different mechanisms, such as, for example, inhibiting the nuclear transcription factor kappa B (NF-κB) nuclear activity, as reported in human glioma cells (T98 and U251) by Wang and colleagues [ 55 ], and in rat glioma cells (C6) by Martín and colleagues [ 56 ]. Otherwise, the melatonin activation of NF-κB has also been associated with an increase in intracellular oxidative stress in a model of human monocyte (U937) culture [ 47 , 48 ], and in a primary cerebellar granule cell culture [ 57 ]. In the present study, a known antioxidant, NAC, completely inhibited the decreased viability induced by 1 mM melatonin in a U87MG cell culture.…”

Melatoninergic System in Parkinson’s Disease: From Neuroprotection to the Management of Motor and Nonmotor Symptoms

“…Melatonin inhibits the nuclear translocation of NF- κ B in several cellular models. Furthermore, melatonin exerts a protective effect by blocking NF- κ B activation induced by lipopolysaccharide (LPS) in both rats and cells [63, 64]. NF- κ B inhibitors block either the melatonin-induced neuroprotective or neurorestorative effects.…”

Desenvolvimento de biossensores para auxílio do diagnóstico do mal de Alzheimer, para quantificação rápida de melatonina e para determinação simples do traço genético de anemia falciforme

“…122 Sendo assim, nas últimas décadas, esforços intensos tem sido realizados para entender e descrever as diversas influências da melatonina em outras ações e sistemas fisiológicos. 106,[132][133][134] Um dos principais estudos indica que o hormônio possui papel essencial na organização da resposta imune. 135 Quando produzida em níveis normais pela glândula pineal, a melatonina tem o papel de evitar respostas desnecessárias, inibindo o rolamento e a aderência de leucócitos ao endotélio e reduzindo sua permeabilidade vascular.…”