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Abstract #117976 Published in IGR 24-4
A novel HDAC8 inhibitor H7E exerts retinoprotective effects against glaucomatous injury via ameliorating aberrant Müller glia activation and oxidative stress
Wu LH; Cheng YW; Lin FL; Hsu KC; Wang MH; Yen JL; Wang TJ; Lin TE; Liu YC; Huang WJ; Hsiao GBiomedicine & pharmacotherapy = Biomédecine & pharmacothérapie 2024; 174: 116538
Glaucoma is considered a neurodegenerative disease characterized by progressive visual field defects that may lead to blindness. Although controlling intraocular pressure (IOP) is the mainstay of glaucoma treatment, some glaucoma patients have unmet needs due to unclear pathogenic mechanisms. Recently, there has been growing evidence that neuroinflammation is a potential target for the development of novel antiglaucoma agents. In this study, we investigated the protective effects and cellular mechanisms of H7E, a novel small molecule inhibits HDAC8, using in vitro and in vivo glaucoma-like models. Importantly, H7E mitigated extracellular MMP-9 activity and MCP-1 levels in glutamate- or S100B-stimulated reactive Müller glia. In addition, H7E inhibited the upregulation of inflammation- and proliferation-related signaling pathways, particularly the ERK and JNK MAPK pathways. Under conditions of oxidative damage, H7E prevents retinal cell death and reduces extracellular glutamate released from stressed Müller glia. In a mouse model of NMDA-induced retinal degeneration, H7E alleviated functional and structural defects within the inner retina as assessed by electroretinography and optical coherence tomography. Our results demonstrated that the newly identified compound H7E protects against glaucoma damage by specifically targeting HDAC8 activity in the retina. This protective effect is attributed to the inhibition of Müller glial activation and the prevention of retinal cell death caused by oxidative stress.
Ph.D. Program in Drug Discovery and Development Industry, College of Pharmacy, Taipei Medical University, 250 Wu-Hsing St., Taipei 110, Taiwan. Electronic address: d343109003@tmu.edu.tw.
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