Naunyn-Schmiedeberg's Archives of Pharmacology

, Volume 391, Issue 4, pp 407–422 | Cite as

Metformin potentiates cognitive and antidepressant effects of fluoxetine in rats exposed to chronic restraint stress and high fat diet: potential involvement of hippocampal c-Jun repression

  • Sara A. Khedr
  • Ahmed A. Elmelgy
  • Omnyah A. El-KharashiEmail author
  • Hadwa A. Abd-Alkhalek
  • Manal L. Louka
  • Hoda A. Sallam
  • Sawsan Aboul-Fotouh
Original Article


Several hypotheses link high fat diet (HFD) with the pathophysiology of depression and its response to antidepressants. This study aimed to determine the effect of metformin (MET) on the cognitive and antidepressant activity of fluoxetine (FLU) through its effect on c-Jun expression. Behavioral, cognitive function, biochemical, and histopathological studies were performed in non-HFD- and HFD-fed rats exposed to chronic restraint stress (CRS). Stressed group showed cognitive impairment, depressive-like symptoms, disturbed glucose homeostasis and lipid profile, reduced adiponectin level, brain-derived neurotrophic factor (BDNF) expression, and increased corticosterone and c-Jun. All these were aggravated by HFD. MET, FLU and their combination produced significant improvement in lipid profile with significant increase in adiponectin and BDNF expression. Corticosterone, body weight and insulin resistance showed significant decrease in the treated groups. Moreover, there was a significant decrease in hippocampal c Jun expression. There was a significant preferable effect toward the combination. Conclusion, MET may decrease the refractoriness to FLU and improves the cognition in individuals who are fed on HFD.


Depression c-Jun Metformin HFD Rat Fluoxetine 



adenosine monophosphate-activated protein kinase


blood-brain barrier


brain-derived neurotropic factor


body weight


central nervous system


chronic restraint stress




forced swim test




high-density lipoprotein


high fat diet


axis hypothalamic pituitary adrenal axis




insulin resistance


Jun N-terminal kinases


low-density lipoprotein


mitogen-activated protein kinase




open field test


oxidative stress


polymerase chain reaction


social interaction test


total cholesterol




tumor necrosis factor α


Authors’ information

Sara A. Khedr: Lecturer of Pharmacology, Faculty of Medicine, Ain Shams University.

Omnyah A. El-Kharashi: Assistant professor of Pharmacology, Faculty of Medicine, Ain Shams University.

Manal L. Louka: Assistant professor of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Ain Shams University.

Hadwa A. Abd-Alkhalek: Lecturer of Histology, Faculty of Medicine, Ain Shams University.

Sawsan Aboul-Fotouh: Professor of Pharmacology, Faculty of Medicine, Ain Shams University.

Ahmed A. Elmelgy: Professor of Pharmacology, Faculty of Medicine, Ain Shams University.

Hoda A. Sallam: Professor of Pharmacology, Faculty of Medicine, Ain Shams University.

Compliance with ethical standards

Ethics approval and consent to participate

The entire experimental protocol was approved by institutional ethical committee, and utmost care was taken during the experimental procedure, as well as at the time of sacrifice following the principles of the UK Animals (Scientific Procedures) Act, 1986 and associated guidelines, EU Directive 2010/63/EU for animal experiments.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.


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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Pharmacology, Faculty of MedicineAin Shams UniversityCairoEgypt
  2. 2.Department of Histology and Cell Biology, Faculty of MedicineAin Shams UniversityCairoEgypt
  3. 3.Department of Medical Biochemistry and Molecular Biology, Faculty of MedicineAin Shams UniversityCairoEgypt

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