Melatonin prevents glucocorticoid inhibition of cell proliferation and toxicity in hippocampal cells by reducing glucocorticoid receptor nuclear translocation.
Glucocorticoids are the main product of the adrenal cortex and participate in multiple cell functions as immunosupressors and modulators of neural function. Within the brain, glucocorticoid activity is mediated by high-affinity mineralocorticoid and low-affinity glucocorticoid receptors. Among brain cells, hippocampal cells are rich in glucocorticoid receptors where they regulate excitability and morphology. Also, elevated glucocorticoid levels suppress hippocampal neurogenesis in adults. The pineal neuroindole, melatonin, reduces the affinity of glucocorticoid receptors in rat brain and prevents glucocorticoid-induced apoptosis. Here, the ability of melatonin to prevent glucocorticoid-induced cell death in hippocampal HT22 cells was investigated in the presence of neurotoxins. Results showed that glucocorticoids reduce cellular growth and also enhance sensitivity to neurotoxins. We found a G(1) cell cycle arrest mediated by an increase of cyclin/cyclin-dependent kinase inhibitor p21(WAF1/CIP1) protein after dexamethasone treatment and incremental change in amyloid beta protein and glutamate toxicity. Melatonin prevents glucocorticoids inhibition of cell proliferation and reduces the toxicity caused by glucocorticoids when cells were treated with dexamethasone in combination with neurotoxins. Although, melatonin does not reduce glucocorticoid receptor mRNA or protein levels, it decreases receptor translocation to nuclei in these cells.
Quiros
Isabel
I
Departamento de Morfología y Biología Celular, Instituto Universitario de Oncología del Principado de Asturias (IUOPA), Universidad de Oviedo, Facultad de Medicina, Julian Claveria 6, 330006 Oviedo, Spain.
Mayo
Juan C
JC
Garcia-Suarez
Olivia
O
Hevia
David
D
Martin
Vanesa
V
Rodríguez
Carmen
C
Sainz
Rosa M
RM
D000818:Animals; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects*; D018844:Cyclin-Dependent Kinases; D003907:Dexamethasone / Q000494:pharmacology; D005938:Glucocorticoids / Q000494:pharmacology*; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D007150:Immunohistochemistry; D008550:Melatonin / Q000494:pharmacology*; D051379:Mice; D009498:Neurotoxins / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects; D011965:Receptors, Glucocorticoid / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction
D005938:Glucocorticoids; D009498:Neurotoxins; D011965:Receptors, Glucocorticoid; D003907:Dexamethasone; D017346:Protein Serine-Threonine Kinases; C521371:Cdkl2 protein, mouse; D018844:Cyclin-Dependent Kinases; D008550:Melatonin