Polygalacic Acid Attenuates Cognitive Impairment by Regulating Inflammation Through PPARγ/NF-κB Signaling Pathway

Overview

Journal CNS Neurosci Ther

Specialties Neurology
Pharmacology

Date 2024 Feb 29

PMID 38421141

Authors

Tan Zhao

Jianping Jia

Affiliations

Soon will be listed here.

Abstract

Aims: We aimed to explore the role and molecular mechanism of polygalacic acid (PA) extracted from traditional Chinese medicine Polygala tenuifolia in the treatment of Alzheimer's disease (AD).

Methods: The network pharmacology analysis was used to predict the potential targets and pathways of PA. Molecular docking was applied to analyze the combination between PA and core targets. Aβ42 oligomer-induced AD mice model and microglia were used to detect the effect of PA on the release of pro-inflammatory mediators and its further mechanism. In addition, a co-culture system of microglia and neuronal cells was constructed to assess the effect of PA on activating microglia-mediated neuronal apoptosis.

Results: We predict that PA might regulate inflammation by targeting PPARγ-mediated pathways by using network pharmacology. In vivo study, PA could attenuate cognitive deficits and inhibit the expression levels of inflammation-related factors. In vitro study, PA can also decrease the production of activated microglia-mediated inflammatory cytokines and reduce the apoptosis of N2a neuronal cells. PPARγ inhibitor GW9662 inversed the neuroprotective effect of PA. Both in vivo and in vitro studies showed PA might attenuate the inflammation through the PPARγ/NF-κB pathway.

Conclusions: PA is expected to provide a valuable candidate for new drug development for AD in the future.

Citing Articles

Pathogenesis and therapeutic applications of microglia receptors in Alzheimer's disease.

Fu J, Wang R, He J, Liu X, Wang X, Yao J Front Immunol. 2025; 16:1508023.

PMID: 40028337 PMC: 11867950. DOI: 10.3389/fimmu.2025.1508023.

Pioglitazone Modulates Microglia M1/M2 Polarization Through PPAR-γ Pathway and Exerts Neuroprotective Effects in Experimental Subarachnoid Hemorrhage.

Ding Y, Wang Y, Qi M, Zhang X, Wu D Mol Neurobiol. 2024; .

PMID: 39668302 DOI: 10.1007/s12035-024-04664-w.

A review of the botany, metabolites, pharmacology, toxicity, industrial applications, and processing of Polygalae Radix: the "key medicine for nourishing life".

Kuang H, Kong L, Hou A, Yang A, Jiang H Front Pharmacol. 2024; 15:1450733.

PMID: 39359244 PMC: 11445616. DOI: 10.3389/fphar.2024.1450733.

Role of Inflammation and the NF-κB Signaling Pathway in Hirschsprung's Disease.

Elkrewi E, Al Abdulqader A, Khasanov R, Maas-Omlor S, Boettcher M, Wessel L Biomolecules. 2024; 14(8).

PMID: 39199380 PMC: 11352745. DOI: 10.3390/biom14080992.

Polygalacic acid attenuates cognitive impairment by regulating inflammation through PPARγ/NF-κB signaling pathway.

Zhao T, Jia J CNS Neurosci Ther. 2024; 30(2):e14581.

PMID: 38421141 PMC: 10851321. DOI: 10.1111/cns.14581.

References

Vorhees C, Williams M . Morris water maze: procedures for assessing spatial and related forms of learning and memory. Nat Protoc. 2007; 1(2):848-58. PMC: 2895266. DOI: 10.1038/nprot.2006.116. View

Wang C, Zong S, Cui X, Wang X, Wu S, Wang L . The effects of microglia-associated neuroinflammation on Alzheimer's disease. Front Immunol. 2023; 14:1117172. PMC: 9992739. DOI: 10.3389/fimmu.2023.1117172. View

He Z, Li X, Han S, Ren B, Hu X, Li N . Bis(ethylmaltolato)oxidovanadium (IV) attenuates amyloid-beta-mediated neuroinflammation by inhibiting NF-κB signaling pathway via a PPARγ-dependent mechanism. Metallomics. 2021; 13(7). DOI: 10.1093/mtomcs/mfab036. View

Cheong M, Lee S, Yoo H, Jeong J, Kim G, Kim W . Anti-inflammatory effects of Polygala tenuifolia root through inhibition of NF-κB activation in lipopolysaccharide-induced BV2 microglial cells. J Ethnopharmacol. 2011; 137(3):1402-8. DOI: 10.1016/j.jep.2011.08.008. View

Leng F, Edison P . Neuroinflammation and microglial activation in Alzheimer disease: where do we go from here?. Nat Rev Neurol. 2020; 17(3):157-172. DOI: 10.1038/s41582-020-00435-y. View

Calsolaro V, Edison P . Neuroinflammation in Alzheimer's disease: Current evidence and future directions. Alzheimers Dement. 2016; 12(6):719-32. DOI: 10.1016/j.jalz.2016.02.010. View

Shin J, Cheong Y, Koo Y, Kim S, Noh C, Son Y . α-Asarone Ameliorates Memory Deficit in Lipopolysaccharide-Treated Mice via Suppression of Pro-Inflammatory Cytokines and Microglial Activation. Biomol Ther (Seoul). 2014; 22(1):17-26. PMC: 3936426. DOI: 10.4062/biomolther.2013.102. View

Hou Y, Mortimer L, Chadee K . Entamoeba histolytica cysteine proteinase 5 binds integrin on colonic cells and stimulates NFkappaB-mediated pro-inflammatory responses. J Biol Chem. 2010; 285(46):35497-504. PMC: 2975174. DOI: 10.1074/jbc.M109.066035. View

Ghosh S, Wu M, Shaftel S, Kyrkanides S, LaFerla F, Olschowka J . Sustained interleukin-1β overexpression exacerbates tau pathology despite reduced amyloid burden in an Alzheimer's mouse model. J Neurosci. 2013; 33(11):5053-64. PMC: 3637949. DOI: 10.1523/JNEUROSCI.4361-12.2013. View

10.

Qi S, Xin Y, Guo Y, Diao Y, Kou X, Luo L . Ampelopsin reduces endotoxic inflammation via repressing ROS-mediated activation of PI3K/Akt/NF-κB signaling pathways. Int Immunopharmacol. 2011; 12(1):278-87. DOI: 10.1016/j.intimp.2011.12.001. View

11.

Zolezzi J, Inestrosa N . Peroxisome proliferator-activated receptors and Alzheimer's disease: hitting the blood-brain barrier. Mol Neurobiol. 2013; 48(3):438-51. DOI: 10.1007/s12035-013-8435-5. View

12.

Dhouafli Z, Cuanalo-Contreras K, Hayouni E, Mays C, Soto C, Moreno-Gonzalez I . Inhibition of protein misfolding and aggregation by natural phenolic compounds. Cell Mol Life Sci. 2018; 75(19):3521-3538. PMC: 11105286. DOI: 10.1007/s00018-018-2872-2. View

13.

Tao P, Xu W, Gu S, Shi H, Wang Q, Xu Y . Traditional Chinese medicine promotes the control and treatment of dementia. Front Pharmacol. 2022; 13:1015966. PMC: 9592982. DOI: 10.3389/fphar.2022.1015966. View

14.

Akama K, Van Eldik L . Beta-amyloid stimulation of inducible nitric-oxide synthase in astrocytes is interleukin-1beta- and tumor necrosis factor-alpha (TNFalpha)-dependent, and involves a TNFalpha receptor-associated factor- and NFkappaB-inducing kinase-dependent.... J Biol Chem. 2000; 275(11):7918-24. DOI: 10.1074/jbc.275.11.7918. View

15.

Perneczky R, Jessen F, Grimmer T, Levin J, Floel A, Peters O . Anti-amyloid antibody therapies in Alzheimer's disease. Brain. 2023; 146(3):842-849. DOI: 10.1093/brain/awad005. View

16.

Jin M, Lee D, Um Y, Lee J, Park C, Jetter R . Isolation and characterization of an oxidosqualene cyclase gene encoding a β-amyrin synthase involved in Polygala tenuifolia Willd. saponin biosynthesis. Plant Cell Rep. 2014; 33(3):511-9. DOI: 10.1007/s00299-013-1554-7. View

17.

. Global, regional, and national burden of Alzheimer's disease and other dementias, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurol. 2018; 18(1):88-106. PMC: 6291454. DOI: 10.1016/S1474-4422(18)30403-4. View

18.

Pascual G, Fong A, Ogawa S, Gamliel A, Li A, Perissi V . A SUMOylation-dependent pathway mediates transrepression of inflammatory response genes by PPAR-gamma. Nature. 2005; 437(7059):759-63. PMC: 1464798. DOI: 10.1038/nature03988. View

19.

Schmid S, Jungwirth B, Gehlert V, Blobner M, Schneider G, Kratzer S . Intracerebroventricular injection of beta-amyloid in mice is associated with long-term cognitive impairment in the modified hole-board test. Behav Brain Res. 2017; 324:15-20. DOI: 10.1016/j.bbr.2017.02.007. View

20.

Xu S, Guan Q, Wang C, Wei X, Chen X, Zheng B . Rosiglitazone prevents the memory deficits induced by amyloid-beta oligomers via inhibition of inflammatory responses. Neurosci Lett. 2014; 578:7-11. DOI: 10.1016/j.neulet.2014.06.010. View