Gardenia jasminoides J. Ellis extract GJ-4 attenuates hyperlipidemic vascular dementia in rats via regulating PPAR-γ-mediated microglial polarization

  • Hui Liu tate Key Laboratory of Bioactive Substrate and Function of Natural Medicine, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College
  • Caixia Zang tate Key Laboratory of Bioactive Substrate and Function of Natural Medicine, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College
  • Junmei Shang tate Key Laboratory of Bioactive Substrate and Function of Natural Medicine, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College
  • Zihong Zhang tate Key Laboratory of Bioactive Substrate and Function of Natural Medicine, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College
  • Lu Wang tate Key Laboratory of Bioactive Substrate and Function of Natural Medicine, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College
  • Hanyu Yang tate Key Laboratory of Bioactive Substrate and Function of Natural Medicine, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College
  • Chanjuan Sheng tate Key Laboratory of Bioactive Substrate and Function of Natural Medicine, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College
  • Fangyu Yuan tate Key Laboratory of Bioactive Substrate and Function of Natural Medicine, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College
  • Cheng Ju tate Key Laboratory of Bioactive Substrate and Function of Natural Medicine, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College
  • Fangyuan Li tate Key Laboratory of Bioactive Substrate and Function of Natural Medicine, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College
  • Yang Yu Jinan university
  • Xinsheng Yao Jinan university
  • Xiuqi Bao Chinese Academy of Medical Sciences and Peking Union Medical College,Institute of Materia Medica
  • Dan Zhang tate Key Laboratory of Bioactive Substrate and Function of Natural Medicine, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College
DOI: https://doi.org/10.29219/fnr.v66.8101
Keywords: GJ-4; Hyperlipemia; Vascular dementia; Microglial polarization; PPAR-γ

Abstract

Background: GJ-4 is extracted from Gardenia jasminoides J. Ellis (Fructus Gardenia) with crocin composition and has been demonstrated to improve memory deficits in several dementia models in our previous studies.

Objective: This study aimed to evaluate the effects of GJ-4 on hyperlipidemic vascular dementia (VD) and explore the underlying mechanisms.

Design: In the current study, we employed a chronic hyperlipidemic VD rat model by permanent bilateral common carotid arteries occlusion (2-VO) based on high-fat diet (HFD), which is an ideal model to mimic the clinical pathogenesis of human VD.

Results: Our results showed that GJ-4 could significantly reduce serum lipids level and improve cerebral blood flow in hyperlipidemic VD rats. Additionally, treatment with GJ-4 remarkedly ameliorated memory impairment and alleviated neuronal injury. Mechanistic investigation revealed that the neuroprotective effects of GJ-4 might be attributed to the inhibition of microglia-mediated neuro-inflammation via regulating the M1/M2 polarization. Our data further illustrated that GJ-4 could regulate the phenotype of microglia through activating the peroxisome proliferator-activated receptor-γ (PPAR-γ) and subsequently inhibited nuclear factor-κB (NF-κB) nuclear translocation and increased CCAAT/enhancer-binding protein β (C/EBPβ) expression.

Conclusion: Our results implied that GJ-4 might be a promising drug to improve VD through the regulation of microglial M1/M2 polarization and the subsequent inhibition of neuro-inflammation.

Downloads

Download data is not yet available.

References


  1. O’Brien JT, Thomas A. Vascular dementia. Lancet 2015; 386(10004): 1698–706. doi: 10.1016/S0140-6736(15)00463-8

  2. Venkat P, Chopp M, Chen J. Models and mechanisms of vascular dementia. Exp Neurol 2015; 272: 97–108. doi: 10.1016/j.expneurol.2015.05.006

  3. Kandasamy M, Anusuyadevi M, Aigner KM, Unger MS, Kniewallner KM, de Sousa DMB, et al. TGF-β signaling: a therapeutic target to reinstate regenerative plasticity in vascular dementia? Aging Disease 2020; 11(4): 828–50. doi: 10.14336/ad.2020.0222

  4. Sorrentino G, Migliaccio R, Bonavita V. Treatment of vascular dementia: the route of prevention. Eur Neurol 2008; 60(5): 217–23. doi: 10.1159/000151696

  5. Appleton JP, Scutt P, Sprigg N, Bath PM. Hypercholesterolaemia and vascular dementia. Clin Sci (Lond) 2017; 131(14): 1561–78. doi: 10.1042/CS20160382

  6. Reitz C, Tang MX, Luchsinger J, Mayeux R. Relation of plasma lipids to Alzheimer disease and vascular dementia. Arch Neurol 2004; 61(5): 705–14. doi: 10.1001/archneur.61.5.705

  7. Toscano R, Millan-Linares MC, Lemus-Conejo A, Claro C, Sanchez-Margalet V, Montserrat-de la Paz S. Postprandial triglyceride-rich lipoproteins promote M1/M2 microglia polarization in a fatty-acid-dependent manner. J Nutr Biochem 2020; 75: 108248. doi: 10.1016/j.jnutbio.2019.108248

  8. Ye Y, Zhu W, Wang XR, Yang JW, Xiao LY, Liu Y, et al. Mechanisms of acupuncture on vascular dementia-A review of animal studies. Neurochem Int 2017; 107: 204–10. doi: 10.1016/j.neuint.2016.12.001

  9. Stranahan AM, Norman ED, Lee K, Cutler RG, Telljohann RS, Egan JM, et al. Diet-induced insulin resistance impairs hippocampal synaptic plasticity and cognition in middle-aged rats. Hippocampus 2008; 18(11): 1085–8. doi: 10.1002/hipo.20470

  10. Orihuela R, McPherson CA, Harry GJ. Microglial M1/M2 polarization and metabolic states. Br J Pharmacol 2016; 173(4): 649–65. doi: 10.1111/bph.13139

  11. David S, Kroner A. Repertoire of microglial and macrophage responses after spinal cord injury. Nat Rev Neurosci 2011; 12(7): 388–99. doi: 10.1038/nrn3053

  12. Gaire BP, Bae YJ, Choi JW. S1P1 regulates M1/M2 polarization toward brain injury after transient focal cerebral ischemia. Biomol Ther (Seoul) 2019;6(11):522–9. doi: 10.4062/biomolther.2019.005

  13. Saijo K, Glass CK. Microglial cell origin and phenotypes in health and disease. Nat Rev Immunol 2011; 11(11): 775–87. doi: 10.1038/nri3086

  14. Tang Y, Le W. Differential roles of M1 and M2 microglia in neurodegenerative diseases. Mol Neurobiol 2016; 53(2): 1181–94. doi: 10.1007/s12035-014-9070-5

  15. Culman J, Zhao Y, Gohlke P, Herdegen T. PPAR-gamma: therapeutic target for ischemic stroke. Trends Pharmacol Sci 2007; 28(5): 244–9. doi: 10.1016/j.tips.2007.03.004

  16. Feng X, Weng D, Zhou F, Owen YD, Qin H, Zhao J, et al. Activation of PPARγ by a natural flavonoid modulator, apigenin ameliorates obesity-related inflammation via regulation of macrophage polarization. EBioMedicine 2016; 9: 61–76. doi: 10.1016/j.ebiom.2016.06.017

  17. Sharma B, Singh N. Behavioral and biochemical investigations to explore pharmacological potential of PPAR-gamma agonists in vascular dementia of diabetic rats. Pharmacol Biochem Behav 2011; 100(2): 320–9. doi: 10.1016/j.pbb.2011.08.020

  18. Lue LF, Kuo YM, Beach T, Walker DG. Microglia activation and anti-inflammatory regulation in Alzheimer’s disease. Mol Neurobiol 2010; 41(2–3): 115–28. doi: 10.1007/s12035-010-8106-8

  19. Pan J, Jin JL, Ge HM, Yin KL, Chen X, Han LJ, et al. Malibatol A regulates microglia M1/M2 polarization in experimental stroke in a PPARγ-dependent manner. J Neuroinflammation 2015; 12: 51. doi: 10.1186/s12974-015-0270-3

  20. Sain H, Sharma B, Jaggi AS, Singh N. Pharmacological investigations on potential of peroxisome proliferator-activated receptor-gamma agonists in hyperhomocysteinemia-induced vascular dementia in rats. Neuroscience 2011; 192: 322–33. doi: 10.1016/j.neuroscience.2011.07.002

  21. Cai W, Yang T, Liu H, Han L, Zhang K, Hu X, et al. Peroxisome proliferator-activated receptor γ (PPARγ): a master gatekeeper in CNS injury and repair. Prog Neurobiol 2018; 163–4: 27–58. doi: 10.1016/j.pneurobio.2017.10.002

  22. Higashino S, Sasaki Y, Giddings JC, Hyodo K, Sakata SF, Matsuda K, et al. Crocetin, a carotenoid from Gardenia jasminoides Ellis, protects against hypertension and cerebral thrombogenesis in stroke-prone spontaneously hypertensive rats. Phytother Res 2014; 28(9): 1315–9. doi: 10.1002/ptr.5130

  23. Chen L, Li M, Yang Z, Tao W, Wang P, Tian X, et al. Gardenia jasminoides Ellis: ethnopharmacology, phytochemistry, and pharmacological and industrial applications of an important traditional Chinese medicine. J Ethnopharmacol 2020; 257: 112829. doi: 10.1016/j.jep.2020.112829

  24. Zhang H, Xue W, Wu R, Gong T, Tao W, Zhou X, et al. Rapid antidepressant activity of ethanol extract of Gardenia jasminoides Ellis is associated with upregulation of BDNF expression in the hippocampus. Evid Based Complement Alternat Med 2015; 2015: 761238. doi: 10.1155/2015/761238

  25. Zhang H, Lai Q, Li Y, Liu Y, Yang M. Learning and memory improvement and neuroprotection of Gardenia jasminoides (Fructus gardenia) extract on ischemic brain injury rats. J Ethnopharmacol 2017; 196: 225–35. doi: 10.1016/j.jep.2016.11.042

  26. Zhao C, Zhang H, Li H, Lv C, Liu X, Li Z, et al. Geniposide ameliorates cognitive deficits by attenuating the cholinergic defect and amyloidosis in middle-aged Alzheimer model mice. Neuropharmacology 2017; 116: 18–29. doi: 10.1016/j.neuropharm.2016.12.002

  27. Pang Q, Zhang W, Li C, Li H, Zhang Y, Li L, et al. Antidementia effects, metabolic profiles and pharmacokinetics of GJ-4, a crocin-rich botanical candidate from Gardeniae fructus. Food Funct 2020; 11(10): 8825–36. doi: 10.1039/d0fo01678k

  28. Zang CX, Bao XQ, Li L, Yang HY, Wang L, Yu Y, et al. The protective effects of Gardenia jasminoides (Fructus Gardenia) on amyloid-β-induced mouse cognitive impairment and neurotoxicity. Am J Chin Med 2018; 46(2): 389–405. doi: 10.1142/s0192415x18500192

  29. Liu H, Zhang Z, Zang C, Wang L, Yang H, Sheng C, et al. GJ-4 ameliorates memory impairment in focal cerebral ischemia/reperfusion of rats via inhibiting JAK2/STAT1-mediated neuroinflammation. J Ethnopharmacol 2021; 267: 113491. doi: 10.1016/j.jep.2020.113491

  30. Ni Y, Li L, Zhang W, Lu D, Zang C, Zhang D, et al. Discovery and LC-MS characterization of new crocins in gardeniae fructus and their neuroprotective potential. J Agric Food Chem 2017; 65(14): 2936–46. doi: 10.1021/acs.jafc.6b03866

  31. Liu JM, Wu PF, Rao J, Zhou J, Shen ZC, Luo H, et al. ST09, a novel thioester derivative of tacrine, alleviates cognitive deficits and enhances glucose metabolism in vascular dementia rats. CNS Neurosci Ther 2016; 22(3): 220–9. doi: 10.1111/cns.12495

  32. Du SQ, Wang XR, Zhu W, Ye Y, Yang JW, Ma SM, et al. Acupuncture inhibits TXNIP-associated oxidative stress and inflammation to attenuate cognitive impairment in vascular dementia rats. CNS Neurosci Ther 2018; 24(1): 39–46. doi: 10.1111/cns.12773

  33. Tuzcu Z, Orhan C, Sahin N, Juturu V, Sahin K. Cinnamon polyphenol extract inhibits hyperlipidemia and inflammation by modulation of transcription factors in high-fat diet-fed rats. Oxid Med Cell Longev 2017; 2017: 1583098. doi: 10.1155/2017/1583098

  34. Sun MK. Potential therapeutics for vascular cognitive impairment and dementia. Curr Neuropharmacol 2018; 16(7): 1036–44. doi: 10.2174/1570159x15666171016164734

  35. Dai SJ, Zhang JY, Bao YT, Zhou XJ, Lin LN, Fu YB, et al. Intracerebroventricular injection of Aβ(1-42) combined with two-vessel occlusion accelerate Alzheimer’s disease development in rats. Pathol Res Pract 2018; 214(10): 1583–95. doi: 10.1016/j.prp.2018.07.020

  36. Serra D, Almeida LM, Dinis TC. Anti-inflammatory protection afforded by cyanidin-3-glucoside and resveratrol in human intestinal cells via Nrf2 and PPAR-γ: comparison with 5-aminosalicylic acid. Chem Biol Interact 2016; 260: 102–9. doi: 10.1016/j.cbi.2016.11.003

  37. Bouhlel MA, Derudas B, Rigamonti E, Dièvart R, Brozek J, Haulon S, et al. PPARgamma activation primes human monocytes into alternative M2 macrophages with anti-inflammatory properties. Cell Metab 2007; 6(2): 137–43. doi: 10.1016/j.cmet.2007.06.010

  38. Villapol S. Roles of peroxisome proliferator-activated receptor gamma on brain and peripheral inflammation. Cell Mol Neurobiol 2018; 38(1): 121–32. doi: 10.1007/s10571-017-0554-5

  39. Huang M, Li Y, Wu K, Yan W, Tian T, Wang Y, et al. Paraquat modulates microglia M1/M2 polarization via activation of TLR4-mediated NF-κB signaling pathway. Chem Biol Interact 2019; 310: 108743. doi: 10.1016/j.cbi.2019.108743

  40. Shi H, Wang XL, Quan HF, Yan L, Pei XY, Wang R, et al. Effects of betaine on LPS-stimulated activation of microglial M1/M2 phenotypes by suppressing TLR4/NF-κB pathways in N9 cells. Molecules 2019;1(21):367 doi: 10.3390/molecules24020367

  41. Arranz A, Doxaki C, Vergadi E, Martinez de la Torre Y, Vaporidi K, Lagoudaki ED, et al. Akt1 and Akt2 protein kinases differentially contribute to macrophage polarization. Proc Natl Acad Sci U S A 2012; 109(24): 9517–22. doi: 10.1073/pnas.1119038109

  42. Zhong XM, Ren XC, Lou YL, Chen MJ, Li GZ, Gong XY, et al. Effects of in-vitro cultured calculus bovis on learning and memory impairments of hyperlipemia vascular dementia rats. J Ethnopharmacol 2016; 192: 390–7. doi: 10.1016/j.jep.2016.09.014

  43. Yang X, Xu S, Qian Y, Xiao Q. Resveratrol regulates microglia M1/M2 polarization via PGC-1alpha in conditions of neuroinflammatory injury. Brain Behav Immun 2017; 64: 162–72. doi: 10.1016/j.bbi.2017.03.003

  44. Hase Y, Horsburgh K, Ihara M, Kalaria RN. White matter degeneration in vascular and other ageing-related dementias. J Neurochem 2018; 144(5): 617–33. doi: 10.1111/jnc.14271

  45. Subhramanyam CS, Wang C, Hu Q, Dheen ST. Microglia-mediated neuroinflammation in neurodegenerative diseases. Semin Cell Dev Biol 2019; 94: 112–20. doi: 10.1016/j.semcdb.2019.05.004

  46. Du L, Zhang Y, Chen Y, Zhu J, Yang Y, Zhang HL. Role of microglia in neurological disorders and their potentials as a therapeutic target. Mol Neurobiol 2017; 54(10): 7567–84. doi: 10.1007/s12035-016-0245-0

  47. Gaire BP, Song MR, Choi JW. Sphingosine 1-phosphate receptor subtype 3 (S1P3) contributes to brain injury after transient focal cerebral ischemia via modulating microglial activation and their M1 polarization. J Neuroinflammation 2018; 15(1): 284. doi: 10.1186/s12974-018-1323-1

  48. Hu X, Leak RK, Shi Y, Suenaga J, Gao Y, Zheng P, et al. Microglial and macrophage polarization-new prospects for brain repair. Nat Rev Neurol 2015; 11(1): 56–64. doi: 10.1038/nrneurol.2014.207

  49. Du Y, Luo M, Du Y, Xu M, Yao Q, Wang K, et al. Liquiritigenin decreases Aβ levels and ameliorates cognitive decline by regulating microglia M1/M2 transformation in AD mice. Neurotox Res 2021;4:349–58. doi: 10.1007/s12640-020-00284-z

  50. Luo XQ, Li A, Yang X, Xiao X, Hu R, Wang TW, et al. Paeoniflorin exerts neuroprotective effects by modulating the M1/M2 subset polarization of microglia/macrophages in the hippocampal CA1 region of vascular dementia rats via cannabinoid receptor 2. Chin Med 2018; 13: 14. doi: 10.1186/s13020-018-0173-1

  51. Geloso MC, Corvino V, Marchese E, Serrano A, Michetti F, D’Ambrosi N. The dual role of microglia in ALS: mechanisms and therapeutic approaches. Front Aging Neurosci 2017; 9: 242. doi: 10.3389/fnagi.2017.00242

  52. Mrak RE, Landreth GE. PPARgamma, neuroinflammation, and disease. J Neuroinflammation 2004; 1(1): 5. doi: 10.1186/1742-2094-1-5

  53. Luo Y, Yin W, Signore AP, Zhang F, Hong Z, Wang S, et al. Neuroprotection against focal ischemic brain injury by the peroxisome proliferator-activated receptor-gamma agonist rosiglitazone. J Neurochem 2006; 97(2): 435–48. doi: 10.1111/j.1471-4159.2006.03758.x

  54. Zuhayra M, Zhao Y, von Forstner C, Henze E, Gohlke P, Culman J, et al. Activation of cerebral peroxisome proliferator-activated receptors γ (PPARγ) reduces neuronal damage in the substantia nigra after transient focal cerebral ischaemia in the rat. Neuropathol Appl Neurobiol 2011; 37(7): 738–52. doi: 10.1111/j.1365-2990.2011.01169.x

  55. Khan MA, Alam Q, Haque A, Ashafaq M, Khan MJ, Ashraf GM, et al. Current progress on peroxisome proliferator-activated receptor gamma agonist as an emerging therapeutic approach for the treatment of alzheimer’s disease: an update. Curr Neuropharmacol 2019; 17(3): 232–46. doi: 10.2174/1570159x16666180828100002

  56. Pena-Altamira E, Prati F, Massenzio F, Virgili M, Contestabile A, Bolognesi ML, et al. Changing paradigm to target microglia in neurodegenerative diseases: from anti-inflammatory strategy to active immunomodulation. Expert Opin Ther Targets 2016; 20(5): 627–40. doi: 10.1517/14728222.2016.1121237

  57. Yunna C, Mengru H, Lei W, Weidong C. Macrophage M1/M2 polarization. Eur J Pharmacol 2020; 877: 173090. doi: 10.1016/j.ejphar.2020.173090

Published
2022-07-19
How to Cite
Liu H., Zang C., Shang J., Zhang Z., Wang L., Yang H., Sheng C., Yuan F., Ju C., Li F., Yu Y., Yao X., Bao X., & Zhang D. (2022). <em>Gardenia jasminoides</em&gt; J. Ellis extract GJ-4 attenuates hyperlipidemic vascular dementia in rats via regulating PPAR-γ-mediated microglial polarization. Food & Nutrition Research, 66. https://doi.org/10.29219/fnr.v66.8101
Issue
Vol 66 (2022)
Section
Original Articles
Creative Commons License

This work is licensed under a Creative Commons Attribution 4.0 International License.

Authors retain copyright of their work, with first publication rights granted to SNF Swedish Nutrition Foundation. Read the full Copyright- and Licensing Statement.

 

 

Crossref
Scopus
Google Scholar
Europe PMC