Neuroprotective Effect of Naturally Occurring RXR Agonists Isolated from Sophora Tonkinensis Gagnep. on Amyloid-β-induced Cytotoxicity in PC12 Cells

Overview

Journal J Nat Med

Publisher Springer

Date 2018 Nov 1

PMID 30377903

Citations 11

Authors

Wei Wang

Ken-Ichi Nakashima

Takao Hirai

Makoto Inoue

Affiliations

Soon will be listed here.

Abstract

Neuronal cell death induced by amyloid-β (Aβ) oligomers is implicated in neuronal degeneration and is a leading cause of Alzheimer's disease (AD). Therefore, to identify effective therapeutic agents for AD, we investigated the neuroprotective effects of two naturally occurring retinoid X receptor (RXR) agonists (SPF1 and SPF2), isolated from the root of Sophora tonkinensis Gagnep., on the Aβ-induced cytotoxicity against nerve growth factor-differentiated rat pheochromocytoma (PC12) cells. Pretreatment with SPFs significantly prevented Aβ-induced apoptosis in PC12 cells, similarly to the synthetic RXR agonist bexarotene. These effects were blocked by the RXR antagonist PA452. When the effects of SPFs were studied in the presence of the liver X receptor (LXR) agonist T0901317, the protective effects of SPFs were enhanced, suggesting that RXR/LXR heterodimers may play a key role in the neuroprotective effects of SPFs. SPFs and T0901317 induced ATP-binding cassette transporter 1 (ABCA1) protein expression in PC12 cells when administered alone or in combination. Intriguingly, a functional inhibitor of ABCA1 cyclosporine A negated the neuroprotective effects of SPFs or T0901317. Taken together, these results demonstrate that the RXR agonists SPF1 and SPF2 protect PC12 cells from Aβ-induced neurotoxicity in an RXR-dependent manner and that their effects are markedly enhanced by the LXR agonist T0901317, in part related to ABCA1 function. These results suggest a novel approach to the treatment or prevention of AD.

Citing Articles

New insights in lipid metabolism: potential therapeutic targets for the treatment of Alzheimer's disease.

Cao Y, Zhao L, Chen Z, Li S Front Neurosci. 2024; 18:1430465.

PMID: 39323915 PMC: 11422391. DOI: 10.3389/fnins.2024.1430465.

RXR nuclear receptor signaling modulates lipid metabolism and triggers lysosomal clearance of alpha-synuclein in neuronal models of synucleinopathy.

Tripathi A, Alnakhala H, Brontesi L, Selkoe D, Dettmer U Cell Mol Life Sci. 2024; 81(1):362.

PMID: 39162859 PMC: 11336128. DOI: 10.1007/s00018-024-05373-2.

Oligodendrocyte progenitor cells in Alzheimer's disease: from physiology to pathology.

Zou P, Wu C, Liu T, Duan R, Yang L Transl Neurodegener. 2023; 12(1):52.

PMID: 37964328 PMC: 10644503. DOI: 10.1186/s40035-023-00385-7.

Biological Activities and Secondary Metabolites from and Its Endophytic Fungi.

Liang J, Zhang P, Zhang W, Song D, Wei X, Yin X Molecules. 2022; 27(17).

PMID: 36080327 PMC: 9457587. DOI: 10.3390/molecules27175562.

Retinoid X Receptor: Cellular and Biochemical Roles of Nuclear Receptor with a Focus on Neuropathological Involvement.

Sharma S, Shen T, Chitranshi N, Gupta V, Basavarajappa D, Sarkar S Mol Neurobiol. 2022; 59(4):2027-2050.

PMID: 35015251 PMC: 9015987. DOI: 10.1007/s12035-021-02709-y.

References

Malm T, Mariani M, Donovan L, Neilson L, Landreth G . Activation of the nuclear receptor PPARδ is neuroprotective in a transgenic mouse model of Alzheimer's disease through inhibition of inflammation. J Neuroinflammation. 2015; 12:7. PMC: 4310027. DOI: 10.1186/s12974-014-0229-9. View

Nordestgaard L, Tybjaerg-Hansen A, Nordestgaard B, Frikke-Schmidt R . Loss-of-function mutation in ABCA1 and risk of Alzheimer's disease and cerebrovascular disease. Alzheimers Dement. 2015; 11(12):1430-1438. DOI: 10.1016/j.jalz.2015.04.006. View

Zameer A, Schulz P, Wang M, Sierks M . Single chain Fv antibodies against the 25-35 Abeta fragment inhibit aggregation and toxicity of Abeta42. Biochemistry. 2006; 45(38):11532-9. DOI: 10.1021/bi060601o. View

Lenhard J, Lancaster M, Paulik M, Weiel J, Binz J, Sundseth S . The RXR agonist LG100268 causes hepatomegaly, improves glycaemic control and decreases cardiovascular risk and cachexia in diabetic mice suffering from pancreatic beta-cell dysfunction. Diabetologia. 1999; 42(5):545-54. DOI: 10.1007/s001250051193. View

Gschwind M, Huber G . Apoptotic cell death induced by beta-amyloid 1-42 peptide is cell type dependent. J Neurochem. 1995; 65(1):292-300. DOI: 10.1046/j.1471-4159.1995.65010292.x. View

Herrup K . The case for rejecting the amyloid cascade hypothesis. Nat Neurosci. 2015; 18(6):794-9. DOI: 10.1038/nn.4017. View

Moutinho M, Landreth G . Therapeutic potential of nuclear receptor agonists in Alzheimer's disease. J Lipid Res. 2017; 58(10):1937-1949. PMC: 5625128. DOI: 10.1194/jlr.R075556. View

Jarosz-Griffiths H, Noble E, Rushworth J, Hooper N . Amyloid-β Receptors: The Good, the Bad, and the Prion Protein. J Biol Chem. 2016; 291(7):3174-83. PMC: 4751366. DOI: 10.1074/jbc.R115.702704. View

Carty M, Bowie A . Evaluating the role of Toll-like receptors in diseases of the central nervous system. Biochem Pharmacol. 2011; 81(7):825-37. DOI: 10.1016/j.bcp.2011.01.003. View

10.

Mounier A, Georgiev D, Nam K, Fitz N, Castranio E, Wolfe C . Bexarotene-Activated Retinoid X Receptors Regulate Neuronal Differentiation and Dendritic Complexity. J Neurosci. 2015; 35(34):11862-76. PMC: 4549399. DOI: 10.1523/JNEUROSCI.1001-15.2015. View

11.

Liu S, Ogilvie K, Klausing K, Lawson M, Jolley D, Li D . Mechanism of selective retinoid X receptor agonist-induced hypothyroidism in the rat. Endocrinology. 2002; 143(8):2880-5. DOI: 10.1210/endo.143.8.8930. View

12.

Du K, Liu M, Zhong X, Yao W, Xiao Q, Wen Q . Epigallocatechin Gallate Reduces Amyloid β-Induced Neurotoxicity via Inhibiting Endoplasmic Reticulum Stress-Mediated Apoptosis. Mol Nutr Food Res. 2018; 62(8):e1700890. DOI: 10.1002/mnfr.201700890. View

13.

Kubo T, Nishimura S, Kumagae Y, Kaneko I . In vivo conversion of racemized beta-amyloid ([D-Ser 26]A beta 1-40) to truncated and toxic fragments ([D-Ser 26]A beta 25-35/40) and fragment presence in the brains of Alzheimer's patients. J Neurosci Res. 2002; 70(3):474-83. DOI: 10.1002/jnr.10391. View

14.

Mullard A . Alzheimer amyloid hypothesis lives on. Nat Rev Drug Discov. 2016; 16(1):3-5. DOI: 10.1038/nrd.2016.281. View

15.

Sturchler E, Galichet A, Weibel M, Leclerc E, Heizmann C . Site-specific blockade of RAGE-Vd prevents amyloid-beta oligomer neurotoxicity. J Neurosci. 2008; 28(20):5149-58. PMC: 6670634. DOI: 10.1523/JNEUROSCI.4878-07.2008. View

16.

Lefebvre P, Benomar Y, Staels B . Retinoid X receptors: common heterodimerization partners with distinct functions. Trends Endocrinol Metab. 2010; 21(11):676-83. DOI: 10.1016/j.tem.2010.06.009. View

17.

Pinaire J, Reifel-Miller A . Therapeutic potential of retinoid x receptor modulators for the treatment of the metabolic syndrome. PPAR Res. 2007; 2007:94156. PMC: 1852898. DOI: 10.1155/2007/94156. View

18.

Mariani M, Malm T, Lamb R, Jay T, Neilson L, Casali B . Neuronally-directed effects of RXR activation in a mouse model of Alzheimer's disease. Sci Rep. 2017; 7:42270. PMC: 5311933. DOI: 10.1038/srep42270. View

19.

Zheng S, Yang H, Chen Z, Zheng C, Lei C, Lei B . Activation of liver X receptor protects inner retinal damage induced by N-methyl-D-aspartate. Invest Ophthalmol Vis Sci. 2015; 56(2):1168-80. DOI: 10.1167/iovs.14-15612. View

20.

Chen Q, Liang B, Wang Z, Cheng X, Huang Y, Liu Y . Influence of four polymorphisms in ABCA1 and PTGS2 genes on risk of Alzheimer's disease: a meta-analysis. Neurol Sci. 2016; 37(8):1209-20. DOI: 10.1007/s10072-016-2579-9. View