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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

Abstract

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.

Keywords

Depression c-Jun Metformin HFD Rat Fluoxetine 

Abbreviations

AMPK

adenosine monophosphate-activated protein kinase

BBB

blood-brain barrier

BDNF

brain-derived neurotropic factor

BW

body weight

CNS

central nervous system

CRS

chronic restraint stress

FLU

fluoxetine

FST

forced swim test

H&E

hematoxylin-eosin

HDL

high-density lipoprotein

HFD

high fat diet

HPA

axis hypothalamic pituitary adrenal axis

IL-1

interleukin-1

IR

insulin resistance

JNKs

Jun N-terminal kinases

LDL

low-density lipoprotein

MAPK

mitogen-activated protein kinase

MET

metformin

OFT

open field test

OS

oxidative stress

PCR

polymerase chain reaction

SIT

social interaction test

TC

total cholesterol

TGs

triglycerides

TNFα

tumor necrosis factor α

Notes

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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