Formononetin Ameliorates Cognitive Disorder via PGC-1α Pathway in Neuroinflammation Conditions in High-Fat Diet-Induced Mice

Author(s): Xinxin Fu, Tingting Qin, Jiayu Yu, Jie Jiao, Zhanqiang Ma, Qiang Fu, Xueyang Deng, Shiping Ma*.

Journal Name: CNS & Neurological Disorders - Drug Targets
(Formerly Current Drug Targets - CNS & Neurological Disorders)

Volume 18 , Issue 7 , 2019

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Graphical Abstract:


Abstract:

Background: Alzheimer’s disease is one of the most common neurodegenerative diseases in many modern societies. The core pathogenesis of Alzheimer’s disease includes the aggregation of hyperphosphorylated Tau and abnormal Amyloid-β generation. In addition, previous studies have shown that neuroinflammation is one of the pathogenesis of Alzheimer’s disease. Formononetin, an isoflavone compound extracted from Trifolium pratense L., has been found to have various properties including anti-obesity, anti-inflammation, and neuroprotective effects. But there are very few studies on the treatment of Alzheimer’s disease with Formononetin.

Objective: The present study focused on the protective activities of Formononetin on a high-fat dietinduced cognitive decline and explored the underlying mechanisms.

Methods: Mice were fed with HFD for 10 weeks and intragastric administrated daily with metformin (300 mg/kg) and Formononetin (20 and 40 mg/kg).

Results: We found that Formononetin (20, 40 mg/kg) significantly attenuated the learning and memory deficits companied by weight improvement and decreased the levels of blood glucose, total cholesterol and triglyceride in high-fat diet-induced mice. Meanwhile, we observed high-fat diet significantly caused the Tau hyperphosphorylation in the hippocampus of mice, whereas Formononetin reversed this effect. Additionally, Formononetin markedly reduced the levels of inflammation cytokines IL-1β and TNF-α in high-fat diet-induced mice. The mechanism study showed that Formononetin suppressed the pro-inflammatory NF-κB signaling and enhanced the anti-inflammatory Nrf-2/HO-1 signaling, which might be related to the regulation of PGC-1α in the hippocampus of high-fat diet -induced mice.

Conclusion: Taken together, our results showed that Formononetin could improve the cognitive function by inhibiting neuroinflammation, which is attributed to the regulation of PGC-1α pathway in HFD-induced mice.

Keywords: Alzheimer's disease, cognitive disorder, neuroinflammation, PGC-1α, formononetin, high-fat diet.

[1]
Freeman LR, Haley-Zitlin V, Rosenberger DS, Granholm AC. Damaging effects of a high-fat diet to the brain and cognition: A review of proposed mechanisms. Nutr Neurosci 2014; 17(6): 241-51.
[http://dx.doi.org/10.1179/1476830513Y.0000000092] [PMID: 24192577]
[2]
Knight EM, Martins IV, Gümüsgöz S, Allan SM, Lawrence CB. High-fat diet-induced memory impairment in triple-transgenic Alzheimer’s Disease (3xTgAD) mice is independent of changes in amyloid and tau pathology. Neurobiol Aging 2014; 35(8): 1821-32.
[http://dx.doi.org/10.1016/j.neurobiolaging.2014.02.010] [PMID: 24630364]
[3]
Sanabria-Castro A, Alvarado-Echeverría I, Monge-Bonilla C. Molecular pathogenesis of Alzheimer’s disease: An update. Ann Neurosci 2017; 24(1): 46-54.
[http://dx.doi.org/10.1159/000464422] [PMID: 28588356]
[4]
Benilova I, Gallardo R, Ungureanu AA, et al. The Alzheimer disease protective mutation A2T modulates kinetic and thermodynamic properties of amyloid-β (Aβ) aggregation. J Biol Chem 2014; 289(45): 30977-89.
[http://dx.doi.org/10.1074/jbc.M114.599027] [PMID: 25253695]
[5]
Kinney JW, Bemiller SM, Murtishaw AS, Leisgang AM, Salazar AM, Lamb BT. Inflammation as a central mechanism in Alzheimer’s disease. Alzheimers Dement (N Y) 2018; 4: 575-90.
[http://dx.doi.org/10.1016/j.trci.2018.06.014] [PMID: 30406177]
[6]
Kumar A, Datusalia AK. Metabolic stress and inflammation: Implication in treatment for neurological disorders. CNS Neurol Disord Drug Targets 2018; 17(9): 642-3.
[http://dx.doi.org/10.2174/187152731709180926121555] [PMID: 30411678]
[7]
Hsing CH, Hung SK, Chen YC, et al. Histone deacetylase inhibitor trichostatin: A ameliorated endotoxin-induced neuroinflammation and cognitive dysfunction. Mediators Inflamm 2015; 2015163140
[http://dx.doi.org/10.1155/2015/163140] [PMID: 26273133]
[8]
Heneka MT, Carson MJ, El Khoury J, et al. Neuroinflammation in Alzheimer’s disease. Lancet Neurol 2015; 14(4): 388-405.
[http://dx.doi.org/10.1016/S1474-4422(15)70016-5] [PMID: 25792098]
[9]
White CS, Lawrence CB, Brough D, Rivers-Auty J. Inflammasomes as therapeutic targets for Alzheimer’s disease. Brain Pathol 2017; 27(2): 223-34.
[http://dx.doi.org/10.1111/bpa.12478] [PMID: 28009077]
[10]
Heneka MT, Kummer MP, Latz E. Innate immune activation in neurodegenerative disease. Nat Rev Immunol 2014; 14(7): 463-77.
[http://dx.doi.org/10.1038/nri3705] [PMID: 24962261]
[11]
Heneka MT. Inflammasome activation and innate immunity in Alzheimer’s disease. Brain Pathol 2017; 27(2): 220-2.
[http://dx.doi.org/10.1111/bpa.12483] [PMID: 28019679]
[12]
Heneka MT, Kummer MP, Stutz A, et al. NLRP3 is activated in Alzheimer’s disease and contributes to pathology in APP/PS1 mice. Nature 2013; 493(7434): 674-8.
[http://dx.doi.org/10.1038/nature11729] [PMID: 23254930]
[13]
Barron M, Gartlon J, Dawson LA, Atkinson PJ, Pardon MC. A state of delirium: Deciphering the effect of inflammation on tau pathology in Alzheimer’s disease. Exp Gerontol 2017; 94(8): 103-7.
[http://dx.doi.org/10.1016/j.exger.2016.12.006] [PMID: 27979768]
[14]
Bombassaro B, Ignacio-Souza LM, Nunez CE, et al. A20 deubiquitinase controls PGC-1α expression in the adipose tissue. Lipids Health Dis 2018; 17(1): 90.
[http://dx.doi.org/10.1186/s12944-018-0740-6] [PMID: 29678181]
[15]
Hu N, Ren J, Zhang Y. Mitochondrial aldehyde dehydrogenase obliterates insulin resistance-induced cardiac dysfunction through deacetylation of PGC-1α. Oncotarget 2016; 7(47): 76398-414.
[http://dx.doi.org/10.18632/oncotarget.11977] [PMID: 27634872]
[16]
Rodgers JT, Lerin C, Gerhart-Hines Z, Puigserver P. Metabolic adaptations through the PGC-1 alpha and SIRT1 pathways. FEBS Lett 2008; 582(1): 46-53.
[http://dx.doi.org/10.1016/j.febslet.2007.11.034] [PMID: 18036349]
[17]
Villena JA. New insights into PGC-1 coactivators: Redefining their role in the regulation of mitochondrial function and beyond. FEBS J 2015; 282(4): 647-72.
[http://dx.doi.org/10.1111/febs.13175] [PMID: 25495651]
[18]
Peng K, Yang L, Wang J, et al. The interaction of mitochondrial biogenesis and fission/fusion mediated by PGC-1α regulates rotenone-induced dopaminergic neurotoxicity. Mol Neurobiol 2017; 54(5): 3783-97.
[http://dx.doi.org/10.1007/s12035-016-9944-9] [PMID: 27271125]
[19]
Wu RM, Sun YY, Zhou TT, et al. Arctigenin enhances swimming endurance of sedentary rats partially by regulation of antioxidant pathways. Acta Pharmacol Sin 2014; 35(10): 1274-84.
[http://dx.doi.org/10.1038/aps.2014.70] [PMID: 25152028]
[20]
Kauppinen A, Suuronen T, Ojala J, Kaarniranta K, Salminen A. Antagonistic crosstalk between NF-κB and SIRT1 in the regulation of inflammation and metabolic disorders. Cell Signal 2013; 25(10): 1939-48.
[http://dx.doi.org/10.1016/j.cellsig.2013.06.007] [PMID: 23770291]
[21]
Wang R, Li JJ, Diao S, et al. Metabolic stress modulates Alzheimer’s β-secretase gene transcription via SIRT1-PPARγ-PGC-1 in neurons. Cell Metab 2013; 17(5): 685-94.
[http://dx.doi.org/10.1016/j.cmet.2013.03.016] [PMID: 23663737]
[22]
Gong B, Pan Y, Vempati P, et al. Nicotinamide riboside restores cognition through an upregulation of proliferator-activated receptor-γ coactivator 1α regulated β-secretase 1 degradation and mitochondrial gene expression in Alzheimer’s mouse models. Neurobiol Aging 2013; 34(6): 1581-8.
[http://dx.doi.org/10.1016/j.neurobiolaging.2012.12.005] [PMID: 23312803]
[23]
Morris EM, Jackman MR, Meers GM, et al. Reduced hepatic mitochondrial respiration following acute high-fat diet is prevented by PGC-1α overexpression. Am J Physiol Gastrointest Liver Physiol 2013; 305(11): G868-80.
[http://dx.doi.org/10.1152/ajpgi.00179.2013] [PMID: 24091599]
[24]
Morselli E, Fuente-Martin E, Finan B, et al. Hypothalamic PGC-1α protects against high-fat diet exposure by regulating ERα. Cell Rep 2014; 9(2): 633-45.
[http://dx.doi.org/10.1016/j.celrep.2014.09.025] [PMID: 25373903]
[25]
Qin W, Haroutunian V, Katsel P, et al. PGC-1alpha expression decreases in the Alzheimer disease brain as a function of dementia. Arch Neurol 2009; 66(3): 352-61.
[http://dx.doi.org/10.1001/archneurol.2008.588] [PMID: 19273754]
[26]
Yang X, Xu S, Qian Y, Xiao Q. Resveratrol regulates microglia M1/M2 polarization via PGC-1α in conditions of neuroinflammatory injury. Brain Behav Immun 2017; 64: 162-72.
[http://dx.doi.org/10.1016/j.bbi.2017.03.003] [PMID: 28268115]
[27]
Zhao D, Gu MY, Xu JL, Zhang LJ, Ryu SY, Yang HO. Anti-neuroinflammatory effects of 12-Dehydrogingerdione in LPS-activated microglia through inhibiting Akt/IKK/NF-κB pathway and activating Nrf-2/HO-1 pathway. Biomol Ther (Seoul) 2019; 27(1): 92-100.
[http://dx.doi.org/10.4062/biomolther.2018.104] [PMID: 30404129]
[28]
Li Z, Zeng G, Zheng X, et al. Neuroprotective effect of formononetin against TBI in rats via suppressing inflammatory reaction in cortical neurons. Biomed Pharmacother 2018; 106: 349-54.
[http://dx.doi.org/10.1016/j.biopha.2018.06.041] [PMID: 29966980]
[29]
Li Z, Wang Y, Zeng G, et al. Increased miR-155 and heme oxygenase-1 expression is involved in the protective effects of formononetin in traumatic brain injury in rats. Am J Transl Res 2017; 9(12): 5653-61.
[PMID: 29312517]
[30]
Jia WC, Liu G, Zhang CD, Zhang SP. Formononetin attenuates hydrogen peroxide (H2O2)-induced apoptosis and NF-κB activation in RGC-5 cells. Eur Rev Med Pharmacol Sci 2014; 18(15): 2191-7.
[PMID: 25070826]
[31]
Tian Z, Liu SB, Wang YC, Li XQ, Zheng LH, Zhao MG. Neuroprotective effects of formononetin against NMDA-induced apoptosis in cortical neurons. Phytother Res 2013; 27(12): 1770-5.
[http://dx.doi.org/10.1002/ptr.4928] [PMID: 23362211]
[32]
Fei HX, Zhang YB, Liu T, Zhang XJ, Wu SL. Neuroprotective effect of formononetin in ameliorating learning and memory impairment in mouse model of Alzheimer’s disease. Biosci Biotechnol Biochem 2018; 82(1): 57-64.
[http://dx.doi.org/10.1080/09168451.2017.1399788] [PMID: 29191087]
[33]
Gautam J, Khedgikar V, Kushwaha P, et al. Formononetin, an isoflavone, activates AMP-activated protein kinase/β-catenin signalling to inhibit adipogenesis and rescues C57BL/6 mice from high-fat diet-induced obesity and bone loss. Br J Nutr 2017; 117(5): 645-61.
[http://dx.doi.org/10.1017/S0007114517000149] [PMID: 28367764]
[34]
Wang J, Wang L, Zhou J, Qin A, Chen Z. The protective effect of formononetin on cognitive impairment in streptozotocin (STZ)-induced diabetic mice. Biomed Pharmacother 2018; 106: 1250-7.
[http://dx.doi.org/10.1016/j.biopha.2018.07.063] [PMID: 30119194]
[35]
Markowicz-Piasecka M, Sikora J, Szydłowska A, Skupień A, Mikiciuk-Olasik E, Huttunen KM. Metformin - A future therapy for neurodegenerative diseases: Theme: drug discovery, development and delivery in Alzheimer's disease guest editor: Davide Brambilla. Pharm Res 2017; 34(12): 2614-7.
[36]
Vorhees CV, Williams MT. Morris water maze: Procedures for assessing spatial and related forms of learning and memory. Nat Protoc 2006; 1(2): 848-58.
[http://dx.doi.org/10.1038/nprot.2006.116]
[37]
Vossel KA, Xu JC, Fomenko V, et al. Tau reduction prevents Aβ-induced axonal transport deficits by blocking activation of GSK3β. J Cell Biol 2015; 209(3): 419-33.
[http://dx.doi.org/10.1083/jcb.201407065] [PMID: 25963821]
[38]
Parada E, Egea J, Buendia I, et al. The microglial α7-acetylcholine nicotinic receptor is a key element in promoting neuroprotection by inducing heme oxygenase-1 via nuclear factor erythroid-2-related factor 2. Antioxid Redox Signal 2013; 19(11): 1135-48.
[http://dx.doi.org/10.1089/ars.2012.4671] [PMID: 23311871]
[39]
Morris MC, Evans DA, Bienias JL, et al. Dietary fats and the risk of incident Alzheimer disease. Arch Neurol 2003; 60(2): 194-200.
[http://dx.doi.org/10.1001/archneur.60.2.194] [PMID: 12580703]
[40]
Parrott MD, Greenwood CE. Dietary influences on cognitive function with aging: From high-fat diets to healthful eating. Ann N Y Acad Sci 2007; 1114: 389-97.
[http://dx.doi.org/10.1196/annals.1396.028] [PMID: 17986600]
[41]
Baranowski BJ, Bott KN, MacPherson REK. Evaluation of neuropathological effects of a high-fat high-sucrose diet in middle-aged male C57BL6/J mice. Physiol Rep 2018; 6(11)e13729
[http://dx.doi.org/10.14814/phy2.13729] [PMID: 29890051]
[42]
Anstey KJ, Cherbuin N, Budge M, Young J. Body mass index in midlife and late-life as a risk factor for dementia: A meta-analysis of prospective studies. Obes Rev 2011; 12(5): e426-37.
[http://dx.doi.org/10.1111/j.1467-789X.2010.00825.x] [PMID: 21348917]
[43]
Zhang L, Du J, Yano N, et al. Sodium butyrate protects against high fat diet-induced cardiac dysfunction and metabolic disorders in type II diabetic mice. J Cell Biochem 2017; 118(8): 2395-408.
[http://dx.doi.org/10.1002/jcb.25902] [PMID: 28109123]
[44]
Johnson LA, Zuloaga KL, Kugelman TL, et al. Amelioration of metabolic syndrome-associated cognitive impairments in mice via a reduction in dietary fat content or infusion of non-diabetic plasma. EBioMedicine 2015; 3: 26-42.
[http://dx.doi.org/10.1016/j.ebiom.2015.12.008] [PMID: 26870815]
[45]
Maesako M, Uemura K, Kubota M, et al. Exercise is more effective than diet control in preventing high fat diet-induced β-amyloid deposition and memory deficit in amyloid precursor protein transgenic mice. J Biol Chem 2012; 287(27): 23024-33.
[http://dx.doi.org/10.1074/jbc.M112.367011] [PMID: 22563077]
[46]
Killion EA, Reeves AR, El Azzouny MA, et al. A role for long-chain acyl-CoA synthetase-4 (ACSL4) in diet-induced phospholipid remodeling and obesity-associated adipocyte dysfunction. Mol Metab 2018; 9: 43-56.
[http://dx.doi.org/10.1016/j.molmet.2018.01.012] [PMID: 29398618]
[47]
Wang Q, Yuan J, Yu Z, et al. FGF21 attenuates high-fat diet-induced cognitive impairment via metabolic regulation and anti-inflammation of obese mice. Mol Neurobiol 2018; 55(6): 4702-17.
[http://dx.doi.org/10.1007/s12035-017-0663-7] [PMID: 28712011]
[48]
Martinelli I, Tomassoni D, Moruzzi M, Traini E, Amenta F, Tayebati SK. Obesity and metabolic syndrome affect the cholinergic transmission and cognitive functions. CNS Neurol Disord Drug Targets 2017; 16(6): 664-76.
[http://dx.doi.org/10.2174/1871527316666170428123853] [PMID: 28462694]
[49]
Arshad N, Lin TS, Yahaya MF. Metabolic syndrome and its effect on the brain: Possible mechanism. CNS Neurol Disord Drug Targets 2018; 17(8): 595-603.
[http://dx.doi.org/10.2174/1871527317666180724143258] [PMID: 30047340]
[50]
Andersen C, Schjoldager JG, Tortzen CG, et al. 2-heptyl-formononetin increases cholesterol and induces hepatic steatosis in mice. BioMed Res Int 2013; 20132013926942
[http://dx.doi.org/10.1155/2013/926942] [PMID: 23738334]
[51]
Tseng HH, Vong CT, Leung GPH, et al. Calycosin and formononetin induce endothelium-dependent vasodilation by the activation of large-conductance Ca2+-activated K+ channels (BKCa). Evid Based Complement Alternat Med 2016; 20165272531
[http://dx.doi.org/10.1155/2016/5272531] [PMID: 27994632]
[52]
Millan MJ, Agid Y, Brüne M, et al. Cognitive dysfunction in psychiatric disorders: Characteristics, causes and the quest for improved therapy. Nat Rev Drug Discov 2012; 11(2): 141-68.
[http://dx.doi.org/10.1038/nrd3628] [PMID: 22293568]
[53]
Kempuraj D, Thangavel R, Selvakumar GP, et al. Brain and peripheral atypical inflammatory mediators potentiate neuroinflammation and neurodegeneration. Front Cell Neurosci 2017; 11: 216.
[http://dx.doi.org/10.3389/fncel.2017.00216] [PMID: 28790893]
[54]
Nazem A, Sankowski R, Bacher M, Al-Abed Y. Rodent models of neuroinflammation for Alzheimer’s disease. J Neuroinflammation 2015; 12: 74.
[http://dx.doi.org/10.1186/s12974-015-0291-y] [PMID: 25890375]
[55]
Zhang Y, Chen C, Jiang Y, Wang S, Wu X, Wang K. PPARγ coactivator-1α (PGC-1α) protects neuroblastoma cells against amyloid-beta (Aβ) induced cell death and neuroinflammation via NF-κB pathway. BMC Neurosci 2017; 18(1): 69.
[http://dx.doi.org/10.1186/s12868-017-0387-7] [PMID: 28946859]
[56]
Syapin PJ. Regulation of haeme oxygenase-1 for treatment of neuroinflammation and brain disorders. Br J Pharmacol 2008; 155(5): 623-40.
[http://dx.doi.org/10.1038/bjp.2008.342] [PMID: 18794892]
[57]
Cuadrado A, Martín-Moldes Z, Ye J, Lastres-Becker I. Transcription factors NRF2 and NF-κB are coordinated effectors of the Rho family, GTP-binding protein RAC1 during inflammation. J Biol Chem 2014; 289(22): 15244-58.
[http://dx.doi.org/10.1074/jbc.M113.540633] [PMID: 24759106]
[58]
Liang D, Huang A, Jin Y, et al. Protective effects of exogenous NaHS against sepsis-induced myocardial mitochondrial injury by enhancing the PGC-1α/NRF2 pathway and mitochondrial biosynthesis in mice. Am J Transl Res 2018; 10(5): 1422-30.
[PMID: 29887956]
[59]
Choi HI, Kim HJ, Park JS, et al. PGC-1α attenuates hydrogen peroxide-induced apoptotic cell death by upregulating Nrf-2 via GSK3β inactivation mediated by activated p38 in HK-2 Cells. Sci Rep 2017; 7(1): 4319.
[http://dx.doi.org/10.1038/s41598-017-04593-w] [PMID: 28659586]
[60]
Cuyàs E, Verdura S, Llorach-Parés L, et al. Metformin is a direct SIRT1-activating compound: Computational modeling and experimental validation. Front Endocrinol (Lausanne) 2018; 9: 657.
[http://dx.doi.org/10.3389/fendo.2018.00657] [PMID: 30459716]
[61]
Hwang JS, Kang ES, Han SG, et al. Formononetin inhibits lipopolysaccharide-induced release of high mobility group box 1 by upregulating SIRT1 in a PPARδ-dependent manner. PeerJ 2018; 6e4208
[62]
Oza MJ, Kulkarni YA. Formononetin Treatment in type 2 diabetic rats reduces insulin resistance and hyperglycemia. Front Pharmacol 2018; 9: 739.


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VOLUME: 18
ISSUE: 7
Year: 2019
Page: [566 - 577]
Pages: 12
DOI: 10.2174/1871527318666190807160137
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