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Possible role of rice bran extract in microglial modulation through PPAR-gamma receptors in alzheimer’s disease mice model

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Abstract

Alzheimer's Disease (AD), the most prevalent neurodegenerative disorder among elderly people, is ordinarily associated with progressive cognitive decline. Peroxisome proliferator-activated receptors-gamma (PPAR-γ) agonists can be targeted as a beneficial therapeutic strategy against AD. In the present study, we aimed to investigate the preventive and therapeutic effects of rice bran extract (RBE) as a possible PPAR-γ agonist on the microglial phenotype modulation in AD in mice compared to the effects of pioglitazone. This study included 64 adult male Swiss Albino mice divided into 8 groups, each group comprised 8 mice; control group, RBE group, lipopolysaccharide-induced neurodegeneration (a) (LPSa) group, (LPSb) group, RBE-preventive group (RBE + LPSa), pioglitazone-preventive group (PG + LPSa), RBE-treated group (RBE + LPSb), and pioglitazone-treated group (PG + LPSb). Cognitive functions were assessed by Y-maze and Morris water maze tests. The expression of PPAR-γ, CD45, arginase1, CD36, and CD163 genes was assessed by real time qPCR and the estimation of NF-kβ protein level was done by Western blot technique. Moreover, the assessment of Aβ42 and P-tau levels was performed by ELISA. Histopathological examination of brain tissues was performed for all the studied groups. Our results showed that RBE and pioglitazone could modulate microglial phenotype from M1 to M2 where they significantly decreased the expression of NF-κβ and the pro-inflammatory microglial marker (CD45) in parallel with increasing the expression of the anti-inflammatory microglial and phagocytic markers (arginase1, CD163, and CD36). In addition, RBE and pioglitazone significantly increased PPAR-γ expression and reduced Aβ42 deposition as well as p-tau protein levels. In conclusion, our study identified the possible role of PPAR-γ agonistic activity of RBE as a preventive and therapeutic agent in the treatment of the neuro-inflammation associated with AD.

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Data availability

All data generated or analyzed during this study are included in this published article (and its supplementary information files).

References

  • Aboulhoda BE, Rashed LA, Ahmed H, Obaya EM, Ibrahim W, Alkafass M A, Abd El‐Aal SA, ShamsEldeen AM (2021): Hydrogen sulfide and mesenchymal stem cells‐extracted microvesicles attenuate LPS‐induced Alzheimer's disease. J Cellular Physiol https://doi.org/10.1002/jcp.30283

  • Aghamohammadzadeh R, Unwin RD, Greenstein AS et al (2015) Effects of obesity on perivascular adipose tissue vasorelaxant function: nitric oxide, inflammation and elevated systemic blood pressure. J Vasc Res 52:299–305

    Article  CAS  Google Scholar 

  • Arai K, Matsuki N, Ikegaya Y et al (2001) Deterioration of spatial learning performances in lipopolysaccharide-treated mice. Jpn J Pharmacol 87:195–201

    Article  CAS  Google Scholar 

  • Bhatia HS, Baron J, Hagl S et al (2016) Rice bran derivatives alleviate microglia activation: Possible involvement of MAPK pathway. J Neuroinflammation 13:148

    Article  Google Scholar 

  • Bromley-Brits K, Deng Y, Song W (2011) Morris Water Maze Test for Learning and Memory Deficits in Alzheimer’s Disease Model Mice. J Vis Exp 53:2920

    Google Scholar 

  • Castellani RJ, Plascencia-Villa G, Perry G (2019) The amyloid cascade and Alzheimer’s disease therapeutics: Theory versus observation. Lab Investig 7:958–970

    Article  Google Scholar 

  • Chan YH (2003) Biostatistics102: Quantitative Data – Parametric & Non-parametric Tests. Singapore Med J 44(8):391–396

    CAS  PubMed  Google Scholar 

  • Cheng H, Shang Y, Jiang L et al (2015) The peroxisome proliferators activated receptor-gamma agonists as therapeutics for the treatment of Alzheimer’s disease and mild-to-moderate Alzheimer’s disease: a meta-analysis. Int J Neurosci 126:299–307

    Article  Google Scholar 

  • Chin KY, Tay SS (2018) A Review on the Relationship between Tocotrienol and Alzheimer Disease. Nutrients 10:881

    Article  Google Scholar 

  • Chinetti-Gbaguidi G, Baron M, Bouhlel MA et al (2011) Human atherosclerotic plaque alternative macrophages display low cholesterol handling but high phagocytosis because of distinct activities of the PPARgamma and LXRalpha pathways. Circ Res 108:985–995

    Article  CAS  Google Scholar 

  • Choi JY, Kim JY, Park J et al (2017) M2 Phenotype Microglia-derived Cytokine Stimulates Proliferation and Neuronal Differentiation of Endogenous Stem Cells in Ischemic Brain. Exp Neurobiol 26:33

    Article  Google Scholar 

  • Collins SC, Wagner C, Gagliardi L, Kretz PF, Fischer MC, Kessler P, Kannan M, Yalcin B (2018) A method for parasagittal sectioning for neuroanatomical quantification of brain structures in the adult mouse. Current protocols in mouse biology 8(3):e48

    Article  Google Scholar 

  • Colonna M, Butovsky O (2017) Microglia function in the central nervous system during health and neurodegeneration. Annu Rev Immunol 35:441–468

    Article  CAS  Google Scholar 

  • Colton CA, Wilcock DM (2010) Assessing activation states in microglia. CNS Neurol. Disord. Drug Targets 9: 174–191

  • Croasdell A, Duffney PF, Kim N et al (2016) PPARγ and the Innate Immune System Mediate the Resolution of Inflammation. PPAR Res., 549691

  • Crous-Bou M, Minguillón C, Gramunt N et al (2017) Alzheimer’s disease prevention: from risk factors to early intervention. Alzheimers Res Ther 9:71

    Article  Google Scholar 

  • Escribano L, Sim´on AM, Gimeno E et al (2010) Rosiglitazone rescues memory impairment in Alzheimer’s transgenic mice: mechanisms involving a reduced amyloid and tau pathology. Neuropsychopharmacology 35:1593–1604

    Article  CAS  Google Scholar 

  • Garman RH (2011) Histology of the Central Nervous System. Toxicol Pathol 39(1):22–35

    Article  Google Scholar 

  • Govindarajulu M, Pinkyn PD, Bloemer J et al (2018) Signaling mechanisms of selective PPAR gamma modulators in Alzheimer's disease PPAR Res.; 2010675

  • Hidaka N, Suemaru K, Takechi K et al (2011) Inhibitory effects of valproate on impairment of Y-maze alternation behavior induced by repeated electroconvulsive seizures and c-Fos protein levels in rat brains. Acta Med Okayama 65(4):269–277

    CAS  PubMed  Google Scholar 

  • Kettenmann H, Kirchhoff F, Verkhratsky A (2013) Microglia: new roles for the synaptic stripper. Neuron 77:10–18

    Article  CAS  Google Scholar 

  • Landreth G, Jiang Q, Mandrekar S et al (2008) PPARγ Agonists as Therapeutics for the Treatment of Alzheimer`s Disease. The Journal of the American Society for Experimental NeuroTherapeutics 5:481–489

    Article  CAS  Google Scholar 

  • Lee JW, Lee YK, Yuk DY et al (2008) Neuro-inflammation induced by lipopolysaccharide causes cognitive impairment through enhancement of beta-amyloid generation. J Neuroinflammation 5:37

    Article  Google Scholar 

  • Liu D, Zeng BX, Shang Y (2006) Decreased expression of peroxisome proliferator-activated receptor gamma in endotoxin-induced acute lung injury. Physiol Res 55:291–299

    CAS  PubMed  Google Scholar 

  • Mandrekar-Colucci S, Landreth GE (2010) Microglia and inflammation in Alzheimer’s disease. CNS Neurol Disord Drug Targets 9:156–167

    Article  CAS  Google Scholar 

  • Masliah E, Mallory M, Hansen L et al (1991) Immunoreactivity of CD45, a protein phosphotyrosine phosphatase, in Alzheimer’s disease. Acta Neuropathol 83:12–20

    Article  CAS  Google Scholar 

  • Mostafa AO, Abdel-Kader RM, Heikal OA (2018) Enhancement of cognitive functions by rice bran extract in a neuroinflammatory mouse model via regulation of PPARγ. Journal of Functional Foods 48:314–321

    Article  CAS  Google Scholar 

  • Necela BM, Su W, Thompson EA (2008) Toll-like receptor 4 mediates cross-talk between peroxisome proliferator activated receptor gamma and nuclear factor-kappa B in macrophages. Immunology 125:344–358

    Article  CAS  Google Scholar 

  • Nunez J (2008) Morris Water Maze Experiment. J Vis Exp (19)

  • Pathan AR, Viswanad B, Sonkusare SK et al (2006) Chronic administration of pioglitazone attenuates intracerebroventricular streptozotocin induced-memory impairment in rats. Life Sci.;2;79(23):2209–16

  • Qureshi A, Sami S, Salser W et al (2002) Dose-dependent suppression of serum cholesterol by tocotrienol-rich fraction (TRF25) of rice bran in hypercholesterolemic humans. Atherosclerosis 161:199–207

    Article  CAS  Google Scholar 

  • Wang L, Waltenberger B, Pferschy-Wenzig E et al (2014) Natural product agonists of peroxisome proliferator-activated receptor gamma (PPARγ): a review. Biochem Pharmacol 92:73–89

    Article  CAS  Google Scholar 

  • Wilcock DM, Gordon MN, Ugen KE et al (2001) Number of Abeta inoculations in APP+PS1 transgenic mice influences antibody titers, microglial activation, and congophilic plaque levels. DNA Cell Biol 20:731–736

    Article  CAS  Google Scholar 

  • Yamanaka M, Ishikawa T, Griep A et al (2012) PPARγ/RXRA-induced and CD36-mediated microglial amyloid-β phagocytosis results in cognitive improvement in amyloid precursor protein/presenilin 1mice. J Neurosci 32:17321–17331

    Article  CAS  Google Scholar 

  • Zhang W, Wang G, Zhou S (2018) Protective Effects of Isoliquiritigenin on LPS-Induced Acute Lung Injury by Activating PPAR-γ. Inflammation 41(4):1290–1296

    Article  CAS  Google Scholar 

Download references

Funding

Many thanks and appreciation to the Integrated Pharmaceutical Alliance funded by the Academy of Scientific research and Technology for supporting this work.

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Authors and Affiliations

  1. The Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Cairo University, Cairo, Egypt

    Shimaa Saad El-Din, Sahar Abd Elwahab, Laila Rashed, Salwa Fayez & Zeinab A. Nour

  2. The Department of Anatomy and Embryology, Faculty of Medicine, Cairo University, Cairo, Egypt

    Basma Emad Aboulhoda

  3. The Department of Narcotics, Ergogenics and Poisons, National Research Centre, Giza, Egypt

    Ola Ahmed Heikal & Asmaa Fathi Galal

Authors
  1. Shimaa Saad El-Din
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  2. Sahar Abd Elwahab
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  3. Laila Rashed
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  4. Salwa Fayez
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  5. Basma Emad Aboulhoda
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  6. Ola Ahmed Heikal
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  7. Asmaa Fathi Galal
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  8. Zeinab A. Nour
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Contributions

SS: contributed in writing the manuscript, analyzed and interpreted data, reviewed the article before submission and corresponded with the journal; SA: Participated in construction of the design of this research, performed the biochemical and molecular tests and contributed in writing the manuscript; LR: performed the western blot technique, performed molecular tests and supervised the final work; SF: supervised the course of the work and critically reviewed the manuscript; BE: performed the histopathological and histomorphological studies of mice brain tissues and participated in writing the manuscript; OA: constructing the hypothesis of this research, designed the animal models, performed behavioral tests, performed HPLC analysis of RBE; AF: contributed in performing behavioral tests and HPLC analysis; ZA: contributed in writing the manuscript, participated in performing molecular tests, reviewed the article before submission; All authors read and approved the final manuscript.

Corresponding author

Correspondence to Shimaa Saad El-Din.

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Ethical approval

All animal procedures were performed with the approval of the Ethics Committee of Cairo University Institutional Animal Care and Use Committee (IACUC) and according to its standards.

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All authors declare no conflict of interest.

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El-Din, S.S., Abd Elwahab, S., Rashed, L. et al. Possible role of rice bran extract in microglial modulation through PPAR-gamma receptors in alzheimer’s disease mice model. Metab Brain Dis 36, 1903–1915 (2021). https://doi.org/10.1007/s11011-021-00741-4

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