CLOCK, SIRT1, and HDAC2 Knockdown along with Melatonin Intervention Significantly Decreased the Level Glucocorticoid Receptor

Abstract

Infantile spasm (IS) is a common catastrophic epilepsy syndromes occurred in infancy and associated with glucocorticoid release, but its etiology is still unknown. Melatonin (MLT) is a natural hormone secreted by pineal gland associated with circadian rhythm and epilepsy. This study intended to figure out the molecular mechanism of IS therapy by analyzing the influence of CLOCK, SIRT1, HDAC2 and MLT on glucocorticoid receptor α (GRα). In the present study, the results showed that the gene of CLOCK, SIRT1 and HDAC2 were successfully knockdown by small interfering RNAs in GT1-7 cells. In addition, gene knockdown of CLOCK, SIRT1 and HDAC2 significantly inhibited the GRα expression and decreased the GRα concentration, which this inhibitory effect was significantly enhanced by MLT intervention. The similar results found that the expression of BMAL1, C-Cbl, BDNF and TrkB were also markedly decreased by MLT intervention, which is consistent with gene knockdown. Therefore, all data provided that CLOCK, SIRT1 and HDAC2 knockdown synergistic melatonin intervention decreased the concentration of GRα, while MLT intervention strengthened this effect, which might provide a molecular mechanism for treating CRH-induced IS.