Major depressive disorder (MDD) is a common, complex disease with poorly understood pathogenesis. Disruption of glucose metabolism is implicated in the pathogenesis of depression. AMP-activated protein kinase (AMPK) has been shown to regulate the activity of several kinases, including pAKT, p38MAPK, and mTOR, which are important signaling pathways in the treatment of depression. This study tested the hypothesis that rosiglitazone (RGZ) has an antidepressant impact on dexamethasone (DEXA)-induced depression by analyzing the function of the pAKT/p38MAPK/mTOR pathway and NGF through regulation of AMPK. MDD-like pathology was induced by subcutaneous administration of DEXA (20 mg/kg) for 21 days in all groups except in the normal control group, which received saline. To investigate the possible mechanism of RGZ, the protein expression of pAMPK, pAKT, p38MAPK, and 4EBP1 as well as the levels of hexokinase, pyruvate kinase, and NGF were assessed in prefrontal cortex and hippocampal samples. The activities of pAMPK and NGF increased after treatment with RGZ. The administration of RGZ also decreased the activity of mTOR as well as downregulating the downstream signaling pathways pAKT, p38MAPK, and 4EBP1. Here, we show that RGZ exerts a potent inhibitory effect on the pAKT/p38MAPK/mTOR/4EBP1 pathway and causes activation of NGF in brain cells. This study has provided sufficient evidence of the potential for RGZ to ameliorate DEXA-induced depression. A new insight has been introduced into the critical role of NGF activation in brain cells in depression. These results suggest that RGZ is a promising antidepressant for the treatment of MDD.

Major depressive disorder (MDD) is one of the most popular diseases affecting an enormous population of worldwide. MDD is considered a complex mental disorder with unknown clear etiology. It becomes the most common neuropsychiatric disorder. MDD affects a person’s life efficiency. Many data support that the excess administration of glucocorticoids may lead lot of behavioral, biochemical, functional and morphological characteristics of depression. The disturbance in glucose metabolism involves depression pathogenesis. The concentration of glucose and glycogen in the frontal cortex and hippocampus increases during depression. The marked increase in the concentration of carbohydrates and glucose transporters is evidence of animal exposure to stress. Mammalian targets of rapamycin (mTOR) signaling pathways are involved in the pathogenesis of depression. This signaling is impaired in the frontal cortex and hippocampus of an animal with MDD. It was demonstrated that mTOR is activated by its phosphorylation at serine 2448 and promoting two downstream molecules. It was reported that the mTOR system is involved in antidepressant mechanisms. This review discusses the role of brain glucose and mTOR pathways involved in controlling major depressive disorder in addition to the different therapeutic approaches for the treatment of depression.