Bexarotene modulates retinoid-X-receptor expression and is protective against neurotoxic endoplasmic reticulum stress response and apoptotic pathway activation
Open accessAbstract
Retinoid X-receptors (RXRs) are members of the ligand-dependent transcription factor family of nuclear receptors that have gained recent research focus as potential targets for neurodegenerative disorders. Bexarotene is an RXR pharmacological agonist that is shown to be neuroprotective through its effects in promoting amyloid beta (Aβ) uptake by the glial cells in the brain. This study aimed to evaluate the dose-dependent effects of bexarotene on RXR expression in SH-SY5Y neuroblastoma cells and validate the drug effects in the brain in vivo. The protein expression studies were carried out using a combination of various drug treatment paradigms followed by expression analysis using Western blotting and immunofluorescence. Our study demonstrated that bexarotene promoted the expression of RXR α, β and γ isoforms at optimal concentrations in the cells and in the mice brain. Interestingly, a decreased RXR expression was identified in Alzheimer's disease mouse model and in the cells that were treated with Aβ. Bexarotene treatment not only rescued the RXR expression loss caused by Aβ treatment (p < 0.05) but also protected the cells against Aβ-induced ER stress (p < 0.05) and pro-apoptotic BAD protein activation (p < 0.05). In contrast, higher concentrations of bexarotene upregulated the ER stress proteins and led to BAD activation. Our study revealed that these downstream neurotoxic effects of high drug concentrations could be prevented by pharmacological targeting of the TrkB rec…
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RXRα expression is downregulated in AD model mice.
“RXRα expression is downregulated in AD model mice (58)”
From Nuclear SphK2/S1P signaling is a key regulator of ApoE production and Aβ uptake in astrocytes (2024) · cites this paper as [58]
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Nuclear SphK2/S1P signaling is a key regulator of ApoE production and Aβ uptake in astrocytes
Komai, M., Noda, Y., Ikeda, A., Kaneshiro, N., Kamikubo, Y., Sakurai, T., Uehara, T., & Takasugi, N. (2024) · Journal of Lipid Research · doi:10.1016/j.jlr.2024.100510 · Cited by 13 · see citing works
- Authors
- Dheer, Y., Chitranshi, N., Gupta, V., Abbasi, M., Mirzaei, M., You, Y., Chung, R., Graham, S. L., & Gupta, V.
- Affiliations
- Macquarie University (AU)
- Edith Cowan University (AU)
- The University of Sydney (AU)
- Corresponding author
- Dheer, Yogita
- ORCID
- Venue
- Molecular Neurobiology
- Published
- 2018-04-10
- Volume
- 55
- Issue
- 12
- Pages
- 9043-9056
- ISSN
- 0893-7648 (ISSN-L)
- 1559-1182
- OpenAlex
- W2796577521
- Cited by
- 63
- References
- 12
- Citations by year
- 2026: 1 · 2025: 5 · 2024: 11 · 2023: 6 · 2022: 6 · 2021: 10 · 2020: 10 · 2019: 11 · 2018: 2 · 2013: 1
- FWCI
- 5.65
- Type
- journal article
- Language
- en
- Open access
- green
- figshare.com
- Licence
- Locations
- Molecular Neurobiology (publishedVersion)
- PubMed (publishedVersion)
- Edith Cowan University Research Online (Edith Cowan University) (submittedVersion)
- Own your potential (DEAKIN) (submittedVersion)
- Figshare (submittedVersion, cc-by)
- Funders
- National Health and Medical Research Council (1084767)
- The Ophthalmic Research Institute of Australia (9201400700)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Endoplasmic Reticulum Stress and Disease
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pharmacological Receptor Mechanisms and Effects
- Keywords
- bexarotene, retinoid X receptor, Alzheimer's disease, amyloid-beta, endoplasmic reticulum stress, apoptosis, BAD protein, TrkB signaling, 7,8-dihydroxyflavone, neuroprotection, SH-SY5Y cells
- MeSH terms
- Neuroprotection, Bexarotene, Alzheimer Disease, Animals, Cell Survival, Disease Models, Animal, Humans, Male, Mice, Inbred C57BL, Up-Regulation, Amyloid beta-Peptides, Apoptosis, Neurotoxicity Syndromes, Receptor, trkB, Cell Line, Tumor, Retinoid X Receptors, bcl-Associated Death Protein, Endoplasmic Reticulum Stress
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