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PP-57

Gentisyl alcohol attenuates glaucomatous retinal damage by suppressing

retinal glial crosstalk-induced neuroinflammation via the STAT3 and NF-κB

pathway

1,4
3
3
Cheng-Yan Jiang, #,1,4 Tzong-Huei Lee, Shu-Jung Huang, Yi-Chien Liu, Yan-Cheng
1
Shan, Y u -Wen Cheng,* ,4,5 George Hsiao* ,1,2,4

1 Department of Pharmacology, School of Medicine, College of Medicine, Taipei Medical
University, Taipei 110, Taiwan
2 Graduate Institute of Medical Sciences, School of Medicine, College of Medicine, Taipei
Medical University, Taipei 110, Taiwan
3 Institute of Fisheries Science, National Taiwan University, Taipei, Taiwan
4 Ph.D. Program in Drug Discovery and Development Industry, College of Pharmacy, Taipei
Medical University, Taipei 110, Taiwan
5 Department of Pharmaceutical Sciences, School of Pharmacy, College of Pharmacy, Taipei
Medical University, Taipei 110, Taiwan
* Email: geohsiao@tmu.edu.tw

Abstract
Glaucoma is a neurodegenerative disease leading to irreversible blindness, characterized by
the loss of retinal ganglion cells (RGCs) and optic nerve degeneration. While elevated
intraocular pressure is a major risk factor, accumulating evidence highlights the pivotal role of
neuroinflammation driven by retinal glial overactivation. In particular, crosstalk between
microglia and Müller cells exacerbates RGC injury. This study investigated whether gentisyl
alcohol, a marine fungal extract, could protect retinal neurons by suppressing glial-mediated
inflammatory signaling. In vitro, gentisyl alcohol showed no cytotoxicity toward BV-2 and
rMC-1 cells, but dose-dependently reduced the release of NO, TNF-α, and IL-6 from LPS-
stimulated BV-2 cells, and lowered inflammatory mediator production in rMC-1 cells exposed
to BV-2–conditioned medium. gentisyl alcohol also downregulated iNOS and COX-2 protein
expression in both cell types. Pathway analysis revealed that LPS induced IKKε upregulation
and STAT3/NF-κB activation in BV-2 cells, enhancing pro-inflammatory factor release. These
mediators promoted rMC-1 activation via a positive feedback loop, amplifying
neuroinflammation, which was effectively suppressed by gentisyl alcohol. In vivo, a normal-
tension glaucoma model was induced by NMDA injection. Electroretinography showed that
gentisyl alcohol -treated mice retained a-, b-, and PhNR-waves responses 7 days after NMDA
insult. Immunohistochemistry confirmed that gentisyl alcohol inhibited microglial and Müller
cell activation and proliferation, while reducing RGC loss. Collectively, these results
demonstrate that gentisyl alcohol attenuates neuroinflammation by modulating glial crosstalk,
thereby protecting RGCs from degeneration and showing therapeutic potential for glaucoma.

Keywords: Glaucoma; Retinal glial cells; Glial crosstalk; Neuroinflammation; Gentisyl alcohol