Rosiglitazone Mitigates Dexamethasone-Induced Depression in Mice via Modulating Brain Glucose Metabolism and AMPK/mTOR Signaling Pathway

Author:

Alhaddad Aisha1,Radwan Asmaa2ORCID,Mohamed Noha A.3,Mehanna Eman T.4ORCID,Mostafa Yasser M.25,El-Sayed Norhan M.2ORCID,Fattah Shaimaa A.4

Affiliation:

1. Department of Pharmacology and Toxicology, College of Pharmacy, Taibah University, Al-Madinah Al-Munawwarah 30078, Saudi Arabia

2. Department of Pharmacology &Toxicology, Faculty of Pharmacy, Suez Canal University, Ismailia 41522, Egypt

3. Department of Forgery & Counterfeiting, Forensic Medicine, Ministry of Justice, Ismailia 41522, Egypt

4. Department of Biochemistry & Molecular Biology, Faculty of Pharmacy, Suez Canal University, Ismailia 41522, Egypt

5. Department of Pharmacology & Toxicology, Faculty of Pharmacy, Badr University in Cairo, Badr 11829, Egypt

Abstract

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.

Publisher

MDPI AG

Subject

General Biochemistry, Genetics and Molecular Biology,Medicine (miscellaneous)

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