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
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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.
KeywordsDepression c-Jun Metformin HFD Rat Fluoxetine
adenosine monophosphate-activated protein kinase
brain-derived neurotropic factor
central nervous system
chronic restraint stress
forced swim test
high fat diet
axis hypothalamic pituitary adrenal axis
Jun N-terminal kinases
mitogen-activated protein kinase
open field test
polymerase chain reaction
social interaction test
tumor necrosis factor α
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
The authors declare that they have no competing interests.
- Allard JS, Perez EJ, Fukui K, Carpenter P, Ingram DK, Cabo R (2016) Prolonged metformin treatment leads to reduced transcription of Nrf2 and neurotrophic factors without cognitive impairment in older C57BL/6J mice. Behav Brain Res 301:1–9. https://doi.org/10.1016/j.bbr.2015.12.012 CrossRefPubMedGoogle Scholar
- Anisman H, McIntyre DC (2002) Conceptual, spatial, and cue learning in the Morris water maze in fast or slow kindling rats: attention deficit comorbidity. J Neurosci. 22(17):7809–17Google Scholar
- Bayliss JA, Lemus MB, Santos VV, Deo M, Davies JS, Kemp BE, Elsworth JD, Andrews ZB (2016) Metformin prevents nigrostriatal dopamine degeneration independent of AMPK activation in dopamine neurons. PLoS One 11(7):e0159381. https://doi.org/10.1371/journal.pone.0159381 CrossRefPubMedPubMedCentralGoogle Scholar
- Benhaddou-Andaloussi A, Martineau L, Vuong T, Meddah B, Madiraju P, Settaf A, Haddad PS (2011) The in vivo antidiabetic activity of Nigella sativa is mediated through activation of the AMPK pathway and increased muscle Glut4 content. Evid Based Complement Alternat Med 2011:538671. https://doi.org/10.1155/2011/538671 CrossRefPubMedPubMedCentralGoogle Scholar
- Bradford MM (1976) A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 72:248–54Google Scholar
- Bravo JA, Díaz-Veliz G, Mora S, Ulloa JL, Berthoud VM, Morales P, Arancibia S, Fiedler JL (2009) Desipramine prevents stress-induced changes in depressive-like behavior and hippocampal markers of neuroprotection. Behav Pharmacol 20(3):273–285. https://doi.org/10.1097/FBP.0b013e32832c70d9 CrossRefPubMedGoogle Scholar
- Breum L, Bjerre U, Bak JF, Jacobsen S, Astrup A (1995) Long-term effects of fluoxetine on glycemic control in obese patients with non-insulin-dependent diabetes mellitus or glucose intolerance: influence on muscle glycogen synthase and insulin receptor kinase activity. Metabolism 44(12):1570–1576. https://doi.org/10.1016/0026-0495(95)90077-2 CrossRefPubMedGoogle Scholar
- Casteilla L, Pénicaud L, Cousin B et al (2008) Adipose tissue protocols. In: Kaiping Yang © (ed) Methods in molecular biology, 2nd edn, vol. 456: 23 Chapter 2. Humana PressGoogle Scholar
- David DJ, Samuels BA, Rainer Q, Wang JW, Marsteller D, Mendez I, Drew M, Craig DA, Guiard BP, Guilloux JP, Artymyshyn RP, Gardier AM, Gerald C, Antonijevic IA, Leonardo ED, Hen R (2009) Behavioral effects of fluoxetine in an animal model of anxiety/depression are mediated by both neurogenesis-dependent and independent mechanisms. Neuron 62(4):479–493. https://doi.org/10.1016/j.neuron.2009.04.017 CrossRefPubMedPubMedCentralGoogle Scholar
- Elgarf AS, Aboul-Fotouh S, Abd-Alkhalek HA et al (2014) Lipopolysaccharide repeated challenge followed by chronic mild stress protocol introduces a combined model of depression in rats: Reversibility by imipramine and pentoxifylline. Pharmacol Biochem Behav 126:152–162. https://doi.org/10.1016/j.pbb.2014.09.014 CrossRefPubMedGoogle Scholar
- Farhan M, Ikram H, Kanwal S et al (2014) Unpredictable chronic mild stress induced behavioral deficits: a comparative study in male and female rats. J Pharm 27(4):879–884Google Scholar
- Friedewald WT, Levy RI, Fredrickson DS (1972) Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem 18(6):499–502Google Scholar
- Ghadernezhad N, Khalaj L, Pazoki-Toroudi H, Mirmasoumi M, Ashabi G (2016) Metformin pretreatment enhanced learning and memory in cerebral forebrain ischemia: the role of the AMPK/BDNF/P70SK signaling pathway. Pharm Biol 54(10):2211–2219. https://doi.org/10.3109/13880209.2016.1150306 CrossRefPubMedGoogle Scholar
- Heyward FD, Walton RG, Carle MS, Coleman MA, Garvey WT, Sweatt JD (2012) Adult mice maintained on a high-fat diet exhibit object location memory deficits and reduced hippocampal SIRT1 gene expression. Neurobiol Learn Mem 98(1):25–32. https://doi.org/10.1016/j.nlm.2012.04.005 CrossRefPubMedPubMedCentralGoogle Scholar
- Isingrini E, Camus V, Le Guisquet AM, Pingaud M, Devers S, Belzung C (2010) Association between repeated unpredictable chronic mild stress (UCMS) procedures with a high fat diet: a model of fluoxetine resistance in mice. PLoS One 5(4):e10404. https://doi.org/10.1371/journal.pone.0010404 CrossRefPubMedPubMedCentralGoogle Scholar
- Jiang T, Yu JT, Zhu XC, Wang HF, Tan MS, Cao L, Zhang QQ, Gao L, Shi JQ, Zhang YD, Tan L (2014) Acute metformin preconditioning confers neuroprotection against focal cerebral ischaemia by pre-activation of AMPK-dependent autophagy. Br J Pharmacol 171(13):3146–3157. https://doi.org/10.1111/bph.12655 CrossRefPubMedPubMedCentralGoogle Scholar
- Kuo LE, Czarnecka M, Kitlinska JB, Tilan JU, Kvetnanský R, Zukowska Z (2008) Chronic stress, combined with a high-fat/high-sugar diet, shifts sympathetic signaling toward neuropeptide Y and leads to obesity and the metabolic syndrome. Ann N Y Acad Sci 1148(1):232–237. https://doi.org/10.1196/annals.1410.035 CrossRefPubMedPubMedCentralGoogle Scholar
- Li N, Liu Q, Li XJ et al (2015) TCM formula Xiaoyaosan decoction improves depressive-like behaviors in rats with type 2 diabetes. Evid Based Complement Alternat Med 10:415243Google Scholar
- Lubin FD, Roth TL, Sweatt JD (2008) Epigenetic Regulation Of Bdnf Gene Transcription In The Consolidation Of Fear Memory. J Neurosci. 28(42):10576–10586Google Scholar
- Machado DG, Cunha MP, Neis VB, Balen GO, Colla A, Grando J, Brocardo PS, Bettio LEB, Capra JC, Rodrigues ALS (2012) Fluoxetine reverses depressive-like behaviors and increases hippocampal acetylcholinesterase activity induced by olfactory bulbectomy. Pharmacol Biochem Behav 103(2):220–229. https://doi.org/10.1016/j.pbb.2012.08.024 CrossRefPubMedGoogle Scholar
- Magni LR, Purgato M, Gastaldon C et al (2013) Fluoxetine versus other types of pharmacotherapy for depression. Cochrane Database Syst Rev (7):CD004185. https://doi.org/10.1002/14651858.CD004185.pub3
- Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC (1985) Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 28(7):412–419. https://doi.org/10.1007/BF00280883 CrossRefPubMedGoogle Scholar
- Paget GE, Barnes JM (1964) Toxicity tests in evaluation of drug activities pharmacometries. In: Laurence DR, Bacharach AL (eds). Academic Press, London and New YorkGoogle Scholar
- Patil SP, Jain PD, Ghumatkar PJ, Tambe R, Sathaye S (2014) Neuroprotective effect of metformin in MPTP-induced Parkinson’s disease in mice. Neuroscience 277:747–754. https://doi.org/10.1016/j.neuroscience.2014.07.046 CrossRefPubMedGoogle Scholar
- Pinnock SB, Blake AM, Platt NJ, Herbert J (2010) The roles of BDNF, pCREB and Wnt3a in the latent period preceding activation of progenitor cell mitosis in the adult dentate gyrus by fluoxetine. PLoS One 5(10):e13652. https://doi.org/10.1371/journal.pone.0013652 CrossRefPubMedPubMedCentralGoogle Scholar
- Sambrook J, Fritsch EF, Maniatis T (1989) Molecular cloning, vol 18, 3rd edn. Cold Spring Harbor: Cold Spring Harbor Laboratory, pp 42–59Google Scholar
- Souza-Mello V, Gregório BM, Cardoso-de-Le- mos FS et al (2010) Comparative effects of telmisartan, sitagliptin and metformin alone or in combination on obesity, insulin resistance, and liver and pancreas remodelling in C57BL/6 mice fed on a very high-fat diet. Clin Sci 119(6):239–250. https://doi.org/10.1042/CS20100061 CrossRefPubMedGoogle Scholar
- Steiner CA, Janez A, Jensterle M (2007) Impact of treatment with rosiglitazone or metformin on biomarkers for insulin resistance and metabolic syndrome in patients with polycystic ovary syndrome. J Diabetes Sci Technol 1(2):211–217. https://doi.org/10.1177/193229680700100212 CrossRefPubMedPubMedCentralGoogle Scholar
- Ullah I, Ullah N, Naseer MI et al (2012) Neuro-protection with metformin and thymoquinone against ethanol-induced apoptotic neuro-degeneration in prenatal rat cortical neurons. BMC Neurosci 13:11Google Scholar
- Yoo DY, Kim W, Nam SM, Yoo KY, Lee CH, Choi JH, Won MH, Hwang IK, Yoon YS (2011) Reduced cell proliferation and neuroblast differentiation in the dentate gyrus of high fat diet-fed mice are ameliorated by metformin and glimepiride treatment. Neurochem Res 36(12):2401–2408. https://doi.org/10.1007/s11064-011-0566-3 CrossRefPubMedGoogle Scholar
- Zemdegs J, Quesseveur G, Jarriault D et al (2016) High fat diet-induced metabolic disorders impairs serotonergic function and anxiety-like behaviors in mice. Brit J Pharmacol 173(13):2095–2110Google Scholar
- Zhang D, Guo M, Zhang W et al (2011) Adiponectin stimulates proliferation of adult hippocampal neural stem/progenitor cells through activation of p38 mitogen-activated protein kinase (p38MAPK)/glycogen synthase kinase 3β (GSK-3β)/β-catenin signaling cascade. J Biol Chem 286(52):44913–44920. https://doi.org/10.1074/jbc.M111.310052 CrossRefPubMedPubMedCentralGoogle Scholar
- Zhang R, Zhoua J, Li M et al (2014) Ameliorating effect and potential mechanism of Rehmannia glutinosa oligosaccharides on the impaired glucose metabolism in chronic stress rats fed with high-fat diet. Phytomedicine 21(5):607–614. https://doi.org/10.1016/j.phymed.2013.11.008 CrossRefPubMedGoogle Scholar