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.
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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
References
Aboul-Fotouh S (2013) Coenzyme Q10 displays antidepressant-like activity with reduction of hippocampal oxidative/nitrosative DNA damage in chronically stressed rats. Pharmacol Biochem Behav 104:105–112. https://doi.org/10.1016/j.pbb.2012.12.027
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
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):7809–17
Apaijai N, Pintana H, Chattipakorn et al (2012) Cardioprotective effects of metformin and vildagliptin in adult rats with insulin resistance induced by a high-fat diet. Endocrinology 153(8):3878–3885. https://doi.org/10.1210/en.2012-1262
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
Beilharz JE, Maniam J, Morris MJ (2014) Short exposure to a diet rich in both fat and sugar or sugar alone impairs place, but not object recognition memory in rats. Brain Behav Immun 37:134–141. https://doi.org/10.1016/j.bbi.2013.11.016
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
Beurel E, Song L, Jope RS (2011) Inhibition of glycogen synthase kinase-3 is necessary for the rapid antidepressant effect of ketamine in mice. Mol Psychiatry 16(11):1068–1070. https://doi.org/10.1038/mp.2011.47
Black PH, Garbutt LD (2002) Stress, inflammation and cardiovascular disease. J Psychosom Res 52(1):1–23. https://doi.org/10.1016/S0022-3999(01)00302-6
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 72:248–54
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
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
Brindley DN, McCann BS, Niaura R, Stoney CM, Suarez EC (1993) Stress and lipoprotein metabolism: modulators and mechanisms. Metabolism 42(9):3–15. https://doi.org/10.1016/0026-0495(93)90255-M
Brotto LA, Gorzalka BB, Barr AM (2001) Paradoxical effects of chronic corticosterone on forced swim behaviors in aged male and female rats. Eur J Pharmacol 424(3):203–209. https://doi.org/10.1016/S0014-2999(01)01148-7
Buchenauer T, Behrendt P, Bode FJ, Horn R, Brabant G, Stephan M, Nave H (2009) Diet-induced obesity alters behavior as well as serum levels of corticosterone in F344 rats. Physiol Behav 98(5):563–569. https://doi.org/10.1016/j.physbeh.2009.09.003
Buechler C, Wanninger J, Neumeier M (2011) Adiponectin, a key adipokine in obesity related liver diseases. World J Gastroenterol 17(23):2801–2811. https://doi.org/10.3748/wjg.v17.i23.2801
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 Press
Chung MM, Nicol CJ, Cheng YC, Lin KH, Chen YL, Pei D, Lin CH, Shih YN, Yen CH, Chen SJ, Huang RN, Chiang MC (2017) Metformin activation of AMPK suppresses AGE-induced inflammatory response in hNSCs. Exp Cell Res 352(1):75–83. https://doi.org/10.1016/j.yexcr.2017.01.017
Conrad CD (2006) What is the functional significance of chronic stress-induced CA3 dendritic retraction within the hippocampus? Behav Cogn Neurosci Rev 5(1):41–60. https://doi.org/10.1177/1534582306289043
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
Deng XQ, Chen L, Li NX (2007) The expression of Sirt1 in non alcoholic fatty liver disease induced by high fat diets in rats. Liver Int 15:708–715
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
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):879–884
Fasshauer M, Blüher M (2015) Adipokines in health and disease. Trends Pharmacol Sci 36(7):461–470. https://doi.org/10.1016/j.tips.2015.04.014
Freeman LR, Haley-Zitlin V, Rosenberger DS (2014) Damaging effects of a high-fat diet to the brain and cognition. Nutr Neurosci 17(6):241–251. https://doi.org/10.1179/1476830513Y.0000000092
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):499–502
Gad MZ, Ehssan NA, Ghiet MH, Wahman LF (2010) Pioglitazone versus metformin in two rat models of glucose intolerance and diabetes. Pak J Pharm Sci 23(3):305–312
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
Graham G, Punt J, Arora M (2011) Clinical pharmacokinetics of metformin. Clin Pharmacokinet 50(2):81–98. https://doi.org/10.2165/11534750-000000000-00000
Habib M, Shaker S, El-Gayar N (2015) The effects of antidepressants “fluoxetine and imipramine” on vascular abnormalities and toll like Receptor-4 expression in diabetic and non-diabetic rats exposed to chronic stress. PLoS One 10(3):1–25
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
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
Ismail ZMK, Morcos MA, Mohammad MDE, Aboulkhair AG (2014) Enhancement of neural stem cells after induction of depression in male albino rats (a histological & immunohistochemical study). Int J Stem Cells 7(2):70–78. https://doi.org/10.15283/ijsc.2014.7.2.70
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
Kleen JK, Sitomer MT, Killeen PR, Conrad CD (2006) Chronic stress impairs spatial memory and motivation for reward without disrupting motor ability and motivation to explore. Behav Neurosci 120(4):842–851. https://doi.org/10.1037/0735-7044.120.4.842
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
Kyrou I, Tsigos C (2009) Stress hormones: physiological stress and regulation of metabolism. Curr Opin Pharmacol 9(6):787–793. https://doi.org/10.1016/j.coph.2009.08.007
Labuzek K, Suchy D, Gabryel B (2010) Quantification of metformin by the HPLC method in brain regions, cerebrospinal fluid and plasma of rats treated with lipopolysaccharide. Pharmacol Rep 62(5):956–965. https://doi.org/10.1016/S1734-1140(10)70357-1
Levitan RD, Davis C, Kaplan AS, Arenovich T, Phillips DIW, Ravindran AV (2012) Obesity comorbidity in unipolar major depressive disorder: refining the core phenotype. J Clin Psychiatry 73(08):1119–1124. https://doi.org/10.4088/JCP.11m07394
Li J, Deng J, Sheng W, Zuo Z (2012) Metformin attenuates Alzheimer’s disease-like neuropathology in obese, leptin-resistant mice. Pharmacol Biochem Behav 101(4):564–574. https://doi.org/10.1016/j.pbb.2012.03.002
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 10:415243
Liu J, Guoa M, Zhanga D et al (2012) Adiponectin is a critical in determining susceptibility to depressive behaviors and has antidepressant like effect. Proc Natl Acad Sci U S A 109(30):12248–12253. https://doi.org/10.1073/pnas.1202835109
Lubin FD, Roth TL, Sweatt JD (2008) Epigenetic Regulation Of Bdnf Gene Transcription In The Consolidation Of Fear Memory. J Neurosci. 28(42):10576–10586
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
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
Malberg JE, Eisch AJ, Nestler EJ, Duman RS (2000) Chronic antidepressant treatment increases neurogenesis in adult rat hippocampus. J Neurosci 20(24):9104–9110
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
Paget GE, Barnes JM (1964) Toxicity tests in evaluation of drug activities pharmacometries. In: Laurence DR, Bacharach AL (eds). Academic Press, London and New York
Park HR, Park M, Choi J, Park KY, Chung HY, Lee J (2010) A high-fat diet impairs neurogenesis: involvement of lipid peroxidation and brain-derived neurotrophic factor. Neurosci Lett 482(3):235–239. https://doi.org/10.1016/j.neulet.2010.07.046
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
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
Pintana H, Apaijai N, Pratchayasakul W (2012) Effects of metformin on learning and memory behaviors and brain mitochondrial functions in high fat diet induced insulin resistant rats. Life Sci 91(11-12):409–414. https://doi.org/10.1016/j.lfs.2012.08.017
Rajput RM (2012) Feed consumption and weight gaining behavior of zucker fatty (fa/fa) rats with single and in combination treatment of clonidine and metformin. Int J Basic Clin Pharmacol 1(2):102–110. https://doi.org/10.5455/2319-2003.ijbcp001312
Sambrook J, Fritsch EF, Maniatis T (1989) Molecular cloning, vol 18, 3rd edn. Cold Spring Harbor: Cold Spring Harbor Laboratory, pp 42–59
Shin NR, Lee JC, Lee HY, Kim MS, Whon TW, Lee MS, Bae JW (2014) An increase in the Akkermansia spp. population induced by metformin treatment improves glucose homeostasis in diet-induced obese mice. Gut 63(5):727–735. https://doi.org/10.1136/gutjnl-2012-303839
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
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
Stranahan AM, Norman ED, Lee K, Cutler RG, Telljohann RS, Egan JM, Mattson MP (2008) Diet-induced insulin resistance impairs hippocampal synaptic plasticity and cognition in middle-aged rats. Hippocampus 18(11):1085–1088. https://doi.org/10.1002/hipo.20470
Tõnisaar M, Mällo T, Eller M (2008) Rat behaviour after chronic variable stress and partial lesioning of 5-HT-ergic neurotransmission: effects of citalopram. Prog Neuro-Psychopharmacol Biol Psychiatry 32(1):164–177. https://doi.org/10.1016/j.pnpbp.2007.08.001
Tonissaar M, Philips MA, Eller M, Harro J (2004) Sociability trait and serotonin metabolism in the rat social interaction test. Neurosci Lett 367(3):309–312. https://doi.org/10.1016/j.neulet.2004.06.023
Tu FY, Tsai YS, Wang WL et al (2011) Overweight worsens apoptosis, neuroinflammation and blood-brain barrier damage after hypoxic ischemia in neonatal brain through JNK hyperactivation. J Neuroinflammation 8(1):40. https://doi.org/10.1186/1742-2094-8-40
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 13:11
Umukoro S, Omorogbe O, Modupe O et al (2015) Jobelyn®, a sorghum-based nutritional supplement attenuates unpredictable chronic mild stress-induced memory deficits in mice. J Behav Brain Sci 5(13):586–597. https://doi.org/10.4236/jbbs.2015.513056
Vaderav R, Velichety S, Madabhushi C et al (2014) Neuroprotective effect of rosuvastatin on ca1 & ca3 regions of hippocampus in high fat diet and stress induced rats. Int J Neurol Brain Disord 1(1):1–5. https://doi.org/10.15436/2377-1348.14.006
Wang X, Wu H, Lakdawala VS, Hu F, Hanson ND, Miller AH (2005) Inhibition of Jun N-terminal kinase (JNK) enhances glucocorticoid receptor-mediated function in mouse hippocampal HT22 cells. Neuropsychopharmacology 30(2):242–249. https://doi.org/10.1038/sj.npp.1300606
Wang HN, Wang YR, Liu GQ et al (2008) Inhibition of hepatic interleukin-18 production by rosiglitazone in a rat model of nonalcoholic fatty liver disease. World J Gastroenterol 47:7240–7246
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
Zafir A, Banu N (2007) Antioxidant potential of fluoxetine in comparison to Curcuma longa in restraint-stressed rats. Eur J Pharmacol 572(1):23–31. https://doi.org/10.1016/j.ejphar.2007.05.062
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):2095–2110
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
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
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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.
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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.
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Khedr, S.A., Elmelgy, A.A., El-Kharashi, O.A. et al. 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. Naunyn-Schmiedeberg's Arch Pharmacol 391, 407–422 (2018). https://doi.org/10.1007/s00210-018-1466-8
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DOI: https://doi.org/10.1007/s00210-018-1466-8