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Allicin ameliorates obesity comorbid depressive-like behaviors: involvement of the oxidative stress, mitochondrial function, autophagy, insulin resistance and NOX/Nrf2 imbalance in mice

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Abstract

The increased prevalence of obesity has been a major medical and public health problem in the past decades. In obese status, insulin resistance and sustained oxidative stress damage might give rise to behavioral deficits. The anti-obesity and anti-oxidant effects of allicin have been previously reported in peripheral tissues. In the present study, the functions and mechanisms of allicin involved in the prevention of high-fat diet (HFD)-induced depressive-like behaviors were investigated to better understand the pharmacological activities of allicin. Obese mice (five weeks of age) were treated with allicin (50, 100, and 200 mg/kg) by gavage for 15 weeks and behavioral test (sucrose preference, open field, and tail suspension) were performed. Furthermore, markers of oxidative stress, mitochondrial function, autophagy, and insulin resistance were measured in the hippocampal tissue. Finally, the levels of NADPH oxidase (NOX2, NOX4) and the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway were evaluated in the hippocampus. The body weight, metabolic disorders, and depressive-like behaviors in obese mice were ameliorated by allicin. The depressive-like behaviors presented in the obese mice were accompanied by remarkably excessive reactive oxygen species (ROS) production and oxidative stress, damaged mitochondrial function, imbalanced autophagy, and enhanced insulin resistance in the hippocampus. We found that allicin improved the above undesirable effects in the obese mice. Furthermore, allicin significantly decreased NOX2 and NOX4 levels and activated the Nrf2 pathway. Allicin attenuated depressive-like behaviors triggered by long-term HFD consumption by inhibiting ROS production and oxidative stress, improving mitochondrial function, regulating autophagy, and reducing insulin resistance in the hippocampus via optimization of NOX/Nrf2 imbalance.

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Abbreviations

HFD:

High fat diet

FER:

Food efficiency ratio

SPT:

Sucrose preference test

OFT:

Open field test

TST:

Tail suspension test

ROS:

Reactive oxygen species

MDA:

Malonaldehyde

SOD:

Superoxide dismutase

CAT:

Catalase

GSH:

Glutathione

GPx:

Glutathion peroxidase

ATG 5:

Autophagy-related protein 5

LC3B:

Microtubule-associated protein light chain 3B

Nrf2:

Nuclear factor erythroid 2-related factor 2

HO-1:

Heme oxygenase-1

NOX:

NADPH oxidase

References

  • Abdel-Daim MM et al (2017) Allicin ameliorates doxorubicin-induced cardiotoxicity in rats via suppression of oxidative stress, inflammation and apoptosis. Cancer Chemother Pharmacol 80(4):745–753

    Article  CAS  PubMed  Google Scholar 

  • Ali M et al (2000) Effect of allicin from garlic powder on serum lipids and blood pressure in rats fed with a high cholesterol diet. Prostaglandins Leukot Essent Fatty Acids 62(4):253–259

    Article  CAS  PubMed  Google Scholar 

  • Bedard K, Krause KH (2007) The NOX family of ROS-generating NADPH oxidases: physiology and pathophysiology. Physiol Rev 87(1):245–313

    Article  CAS  PubMed  Google Scholar 

  • Bhaskaran K et al (2014) Body-mass index and risk of 22 specific cancers: a population-based cohort study of 5.24 million UK adults. Lancet 384(9945):755–765

    Article  PubMed  PubMed Central  Google Scholar 

  • Bondia-Pons I, Ryan L, Martinez JA (2012) Oxidative stress and inflammation interactions in human obesity. J Physiol Biochem 68(4):701–711

    Article  CAS  PubMed  Google Scholar 

  • Bonnard C et al (2008) Mitochondrial dysfunction results from oxidative stress in the skeletal muscle of diet-induced insulin-resistant mice. J Clin Invest 118(2):789–800

    CAS  PubMed  PubMed Central  Google Scholar 

  • Cao L et al (2009) Autophagy is upregulated in rats with status epilepticus and partly inhibited by vitamin E. Biochem Biophys Res Commun 379(4):949–953

    Article  CAS  PubMed  Google Scholar 

  • Chandran R et al (2017) A combination antioxidant therapy to inhibit NOX2 and activate Nrf2 decreases secondary brain damage and improves functional recovery after traumatic brain injury. J Cereb Blood Flow Metab:271678X17738701

  • Chauhan NB (2003) Anti-amyloidogenic effect of Allium sativum in Alzheimer's transgenic model Tg2576. J Herb Pharmacother 3(1):95–107

    Article  CAS  PubMed  Google Scholar 

  • Chen W et al (2014) Neuroprotective effect of allicin against traumatic brain injury via Akt/endothelial nitric oxide synthase pathway-mediated anti-inflammatory and anti-oxidative activities. Neurochem Int 68:28–37

    Article  CAS  PubMed  Google Scholar 

  • Chung LY (2006) The antioxidant properties of garlic compounds: allyl cysteine, alliin, allicin, and allyl disulfide. J Med Food 9(2):205–213

    Article  CAS  PubMed  Google Scholar 

  • Dai Y et al (2018) Isoquercetin attenuates oxidative stress and neuronal apoptosis after ischemia/reperfusion injury via Nrf2-mediated inhibition of the NOX4/ROS/NF-kappaB pathway. Chem Biol Interact 284:32–40

    Article  CAS  PubMed  Google Scholar 

  • Daiber A et al (2017) Crosstalk of mitochondria with NADPH oxidase via reactive oxygen and nitrogen species signalling and its role for vascular function. Br J Pharmacol 174(12):1670–1689

    Article  CAS  PubMed  Google Scholar 

  • Deng ZF et al (2019) miR-214-3p targets beta-catenin to regulate depressive-like behaviors induced by chronic social defeat stress in mice. Cereb Cortex 29(4):1509–1519

    Article  PubMed  Google Scholar 

  • Dong C, Sanchez LE, Price RA (2004) Relationship of obesity to depression: a family-based study. Int J Obes Relat Metab Disord 28(6):790–795

    Article  CAS  PubMed  Google Scholar 

  • Dong M et al (2014) Aged black garlic extract inhibits HT29 colon cancer cell growth via the PI3K/Akt signaling pathway. Biomed Rep 2(2):250–254

    Article  PubMed  PubMed Central  Google Scholar 

  • Fernandez-Sanchez A et al (2011) Inflammation, oxidative stress, and obesity. Int J Mol Sci 12(5):3117–3132

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Freeman LR et al (2013) Obesity increases cerebrocortical reactive oxygen species and impairs brain function. Free Radic Biol Med 56:226–233

    Article  CAS  PubMed  Google Scholar 

  • Furukawa S et al (2004) Increased oxidative stress in obesity and its impact on metabolic syndrome. J Clin Invest 114(12):1752–1761

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gan L, Johnson JA (2014) Oxidative damage and the Nrf2-ARE pathway in neurodegenerative diseases. Biochim Biophys Acta 1842(8):1208–1218

    Article  CAS  PubMed  Google Scholar 

  • Gao HM, Zhou H, Hong JS (2012) NADPH oxidases: novel therapeutic targets for neurodegenerative diseases. Trends Pharmacol Sci 33(6):295–303

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gassen NC et al (2015) FKBP5/FKBP51 enhances autophagy to synergize with antidepressant action. Autophagy 11(3):578–580

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Grillo CA et al (2019, pii: S0014-4886(18)30693-9) Insulin resistance and hippocampal dysfunction: disentangling peripheral and brain causes from consequences. Exp Neurol 318:71–77

    Article  CAS  PubMed  Google Scholar 

  • Hernandez-Aguilera A et al (2013) Mitochondrial dysfunction: a basic mechanism in inflammation- related non-communicable diseases and therapeutic opportunities. Mediat Inflamm 2013:135698

    Article  CAS  Google Scholar 

  • Hosseini A, Hosseinzadeh H (2015) A review on the effects of Allium sativum (garlic) in metabolic syndrome. J Endocrinol Investig 38(11):1147–1157

    Article  CAS  Google Scholar 

  • Jia J, Le W (2015) Molecular network of neuronal autophagy in the pathophysiology and treatment of depression. Neurosci Bull 31(4):427–434

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jiang P et al (2017) Salvianolic acid B protects against lipopolysaccharide-induced behavioral deficits and neuroinflammatory response: involvement of autophagy and NLRP3 inflammasome. J Neuroinflammation 14(1):239

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jiang B et al (2018) Hippocampal salt-inducible kinase 2 plays a role in depression via the CREB-regulated transcription coactivator 1-cyclic AMP response element binding-brain-derived neurotrophic factor pathway. Biol Psychiatry 85(8):650–666

  • Kan C et al (2013) A systematic review and meta-analysis of the association between depression and insulin resistance. Diabetes Care 36(2):480–489

    Article  PubMed  PubMed Central  Google Scholar 

  • Kanth V, Rajani PUMR, Raju TN (2008) Attenuation of streptozotocin-induced oxidative stress in hepatic and intestinal tissues of wistar rat by methanolic-garlic extract. Acta Diabetol 45(4):243–251

    Article  Google Scholar 

  • Keller CW, Lunemann JD (2017) Autophagy and autophagy-related proteins in CNS autoimmunity. Front Immunol 8:165

    PubMed  PubMed Central  Google Scholar 

  • Kern L et al (2018) Obesity-induced TNFα and IL-6 signaling: the missing link between obesity and inflammation-driven liver and colorectal cancers. Cancers (Basel) 11(1):pii: E24

    Article  Google Scholar 

  • Kim I et al (2013) Beneficial effects of Allium sativum L. stem extract on lipid metabolism and antioxidant status in obese mice fed a high-fat diet. J Sci Food Agric 93(11):2749–2757

    Article  CAS  PubMed  Google Scholar 

  • Knight JA (2011) Diseases and disorders associated with excess body weight. Ann Clin Lab Sci 41(2):107–121

    PubMed  Google Scholar 

  • Kroller-Schon S et al (2014) Molecular mechanisms of the crosstalk between mitochondria and NADPH oxidase through reactive oxygen species-studies in white blood cells and in animal models. Antioxid Redox Signal 20(2):247–266

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kwon H, Pessin JE (2013) Adipokines mediate inflammation and insulin resistance. Front Endocrinol (Lausanne) 4:71

    Article  Google Scholar 

  • Lee J, Giordano S, Zhang J (2012) Autophagy, mitochondria and oxidative stress: cross-talk and redox signalling. Biochem J 441(2):523–540

    Article  CAS  PubMed  Google Scholar 

  • Levitan RD et al (2012) Obesity comorbidity in unipolar major depressive disorder: refining the core phenotype. J Clin Psychiatry 73(8):1119–1124

    Article  PubMed  Google Scholar 

  • Li S et al (2009) Adiponectin levels and risk of type 2 diabetes: a systematic review and meta-analysis. JAMA. 302(2):179–188

    Article  CAS  PubMed  Google Scholar 

  • Li XH et al (2012) Allicin ameliorates cognitive deficits ageing-induced learning and memory deficits through enhancing of Nrf2 antioxidant signaling pathways. Neurosci Lett 514(1):46–50

    Article  CAS  PubMed  Google Scholar 

  • Li L et al (2015) ROS and Autophagy: interactions and molecular regulatory mechanisms. Cell Mol Neurobiol 35(5):615–621

    Article  CAS  PubMed  Google Scholar 

  • Liang E et al (2018) The BET/BRD inhibitor JQ1 attenuates diabetes-induced cognitive impairment in rats by targeting Nox4-Nrf2 redox imbalance. Biochem Biophys Res Commun 495(1):204–211

  • Liang S, Ping Z, Ge J (2017) Coenzyme Q10 regulates Antioxidative stress and autophagy in acute myocardial ischemia-reperfusion injury. Oxidative Med Cell Longev 2017:9863181

    Google Scholar 

  • Lucca G et al (2009) Increased oxidative stress in submitochondrial particles into the brain of rats submitted to the chronic mild stress paradigm. J Psychiatr Res 43(9):864–869

    Article  Google Scholar 

  • Ma W et al (2014) Mitochondrial dysfunction and oxidative damage in the brain of diet-induced obese rats but not in diet-resistant rats. Life Sci 110(2):53–60

    Article  CAS  PubMed  Google Scholar 

  • Ma MW et al (2017) NADPH oxidase in brain injury and neurodegenerative disorders. Mol Neurodegener 12(1):7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Maes M et al (2011a) A review on the oxidative and nitrosative stress (O&NS) pathways in major depression and their possible contribution to the (neuro)degenerative processes in that illness. Prog Neuro-Psychopharmacol Biol Psychiatry 35(3):676–692

    Article  CAS  Google Scholar 

  • Maes M et al (2011b) IgM-mediated autoimmune responses directed against multiple neoepitopes in depression: new pathways that underpin the inflammatory and neuroprogressive pathophysiology. J Affect Disord 135(1–3):414–418

    Article  CAS  PubMed  Google Scholar 

  • Mandviwala T, Khalid U, Deswal A (2016) Obesity and cardiovascular disease: a risk factor or a risk marker. Curr Atheroscler Rep 18(5):21

    Article  CAS  PubMed  Google Scholar 

  • Mansur RB, Brietzke E, McIntyre RS (2015) Is there a "metabolic-mood syndrome"? A review of the relationship between obesity and mood disorders. Neurosci Biobehav Rev 52:89–104

    Article  PubMed  Google Scholar 

  • Matsuda M, Shimomura I (2013) Increased oxidative stress in obesity: implications for metabolic syndrome, diabetes, hypertension, dyslipidemia, atherosclerosis, and cancer. Obes Res Clin Pract 7(5):e330–e341

    Article  PubMed  Google Scholar 

  • McIntyre RS et al (2007) Should depressive syndromes be reclassified as "metabolic syndrome type II"? Ann Clin Psychiatry 19(4):257–264

    Article  PubMed  Google Scholar 

  • Nakamura T, Cho DH, Lipton SA (2012) Redox regulation of protein misfolding, mitochondrial dysfunction, synaptic damage, and cell death in neurodegenerative diseases. Exp Neurol 238(1):12–21

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Natoli R et al (2018) Obesity-induced metabolic disturbance drives oxidative stress and complement activation in the retinal environment. Mol Vis 24:201–217

    CAS  PubMed  PubMed Central  Google Scholar 

  • Ng F et al (2008) Oxidative stress in psychiatric disorders: evidence base and therapeutic implications. Int J Neuropsychopharmacol 11(6):851–876

    Article  CAS  PubMed  Google Scholar 

  • Pipatpiboon N et al (2012) PPARgamma agonist improves neuronal insulin receptor function in hippocampus and brain mitochondria function in rats with insulin resistance induced by long term high- fat diets. Endocrinology 153(1):329–338

    Article  CAS  Google Scholar 

  • Saltiel AR, Olefsky JM (2017) Inflammatory mechanisms linking obesity and metabolic disease. J Clin Invest 127(1):1–4

    Article  PubMed  PubMed Central  Google Scholar 

  • Seo JS et al (2012) NADPH oxidase mediates depressive behavior induced by chronic stress in mice. J Neurosci 32(28):9690–9699

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sheela GC (1992) Antidiabetic effects of S-allyl cystine sulphoxide isolated from garlic Allium sativum Linn. Indian J Exp Biol 30(6):523–526

    CAS  PubMed  Google Scholar 

  • Sheela CG, Kumud K, Augusti KT (1995) Anti-diabetic effects of onion and garlic sulfoxide amino acids in rats. Planta Med 61(4):356–357

    Article  CAS  PubMed  Google Scholar 

  • Stolarczyk E (2017) Adipose tissue inflammation in obesity: a metabolic or immune response? Curr Opin Pharmacol 37:35–40

    Article  CAS  Google Scholar 

  • Vogelzangs N et al (2011) Metabolic depression: a chronic depressive subtype? Findings from the InCHIANTI study of older persons. J Clin Psychiatry 72(5):598–604

    Article  PubMed  PubMed Central  Google Scholar 

  • Xin X et al (2013) Pentamethylquercetin ameliorates fibrosis in diabetic Goto-Kakizaki rat kidneys and mesangial cells with suppression of TGF-β/Smads signaling. Eur J Pharmacol 713(1–3):6–15

    Article  CAS  PubMed  Google Scholar 

  • Xu Y et al (2014) Novel therapeutic targets in depression and anxiety: antioxidants as a candidate treatment. Curr Neuropharmacol 12(2):108–119

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yamada N et al (2011) Impaired CNS leptin action is implicated in depression associated with obesity. Endocrinology 152(7):2634–2643

    Article  CAS  PubMed  Google Scholar 

  • Yin Y et al (2017) ER stress and impaired autophagy flux in neuronal degeneration and brain injury. Ageing Res Rev 34:3–14

    Article  CAS  PubMed  Google Scholar 

  • Zafir A, Banu N (2009) Modulation of in vivo oxidative status by exogenous corticosterone and restraint stress in rats. Stress 12(2):167–177

    Article  CAS  PubMed  Google Scholar 

  • Zhao G et al (2009) Depression and anxiety among US adults: associations with body mass index. Int J Obes 33(2):257–266

    Article  CAS  Google Scholar 

  • Zhao Z et al (2017) Rosiglitazone exerts an anti-depressive effect in unpredictable chronic mild- stress-induced depressive mice by maintaining essential neuron autophagy and inhibiting excessive astrocytic apoptosis. Front Mol Neurosci 10:293

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zong J et al (2018) The antidepressant effects of rosiglitazone on rats with depression induced by neuropathic pain. Life Sci 203:315–322

    Article  CAS  PubMed  Google Scholar 

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Financial support

National Natural Science Foundation of China, the grant number are 81470387 and 81500230.

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Authors and Affiliations

  1. Department of Central Experimental Laboratory, The First College of Clinical Medical Science, China Three Gorges University & Yichang Central People’s Hospital, Yichang, 443000, China

    Wenqi Gao, Wei Wang, Jing Zhang, Jun Hu & Jian Yang

  2. Institute of Maternal and Child Health, Wuhan Children’s Hospital (Wuhan Maternal and Child Healthcare Hospital), Tongji Medical College, Huazhong University&Technology, Wuhan, Hubei, China

    Wenqi Gao

  3. Department of Nuclear medicine, The First College of Clinical Medical Science, China Three Gorges University & Yichang Central People’s Hospital, Yichang, 443000, China

    Pengyi Deng

  4. Department of Pharmacy, The First College of Clinical Medical Science, China Three Gorges University & Yichang Central People’s Hospital, Yichang, 443000, China

    Zhifang Deng

  5. Department of Pharmacy, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science & Technology, Wuhan, Hubei, China

    Zhifang Deng

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  1. Wenqi Gao
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  2. Wei Wang
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  3. Jing Zhang
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Correspondence to Jian Yang or Zhifang Deng.

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Gao, W., Wang, W., Zhang, J. et al. Allicin ameliorates obesity comorbid depressive-like behaviors: involvement of the oxidative stress, mitochondrial function, autophagy, insulin resistance and NOX/Nrf2 imbalance in mice. Metab Brain Dis 34, 1267–1280 (2019). https://doi.org/10.1007/s11011-019-00443-y

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