2. Academic Validation
  3. A novel HDAC8 inhibitor H7E exerts retinoprotective effects against glaucomatous injury via ameliorating aberrant Müller glia activation and oxidative stress

A novel HDAC8 inhibitor H7E exerts retinoprotective effects against glaucomatous injury via ameliorating aberrant Müller glia activation and oxidative stress

  • Biomed Pharmacother. 2024 May:174:116538. doi: 10.1016/j.biopha.2024.116538.
Liang-Huan Wu 1,  Yu-Wen Cheng 2,  Fan-Li Lin 3,  Kai-Cheng Hsu 4,  Mong-Heng Wang 5,  Jing-Lun Yen 6,  Tsung-Jen Wang 7,  Tony Eight Lin 8,  Yi-Chien Liu 9,  Wei-Jan Huang 10,  George Hsiao 11
Affiliations

Affiliations

  • 1 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.
  • 2 Ph.D. Program in Drug Discovery and Development Industry, College of Pharmacy, Taipei Medical University, 250 Wu-Hsing St., Taipei 110, Taiwan; Department of Pharmaceutical Sciences, School of Pharmacy, College of Pharmacy, Taipei Medical University, 250 Wu-Hsing St., Taipei 110, Taiwan. Electronic address: ywcheng@tmu.edu.tw.
  • 3 Department of Pharmacology, School of Medicine, Kaohsiung Medical University, 100 Shih-Chuan 1st Rd., Kaohsiung 807, Taiwan. Electronic address: fllin@kmu.edu.tw.
  • 4 Ph.D. Program in Drug Discovery and Development Industry, College of Pharmacy, Taipei Medical University, 250 Wu-Hsing St., Taipei 110, Taiwan; Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, 301 Yuantong Rd., New Taipei 235, Taiwan. Electronic address: piki@tmu.edu.tw.
  • 5 Independent Scholar, 3466 Rhodes Hill Drive, Martinez, GA 30907, USA. Electronic address: monghengwang12345@gmail.com.
  • 6 Graduate Institute of Medical Sciences and Department of Pharmacology, School of Medicine, College of Medicine, Taipei Medical University, 250 Wu-Hsing St., Taipei 110, Taiwan. Electronic address: m120102039@tmu.edu.tw.
  • 7 Department of Ophthalmology, Taipei Medical University Hospital, 252 Wu-Hsing St., Taipei 110, Taiwan; Department of Ophthalmology, School of Medicine, College of Medicine, Taipei Medical University, 250 Wu-Hsing St., Taipei 110, Taiwan. Electronic address: tjw@h.tmu.edu.tw.
  • 8 Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, 301 Yuantong Rd., New Taipei 235, Taiwan. Electronic address: tonyelin@tmu.edu.tw.
  • 9 Ph.D. Program in Drug Discovery and Development Industry, College of Pharmacy, Taipei Medical University, 250 Wu-Hsing St., Taipei 110, Taiwan. Electronic address: d343112003@tmu.edu.tw.
  • 10 Ph.D. Program in Drug Discovery and Development Industry, College of Pharmacy, Taipei Medical University, 250 Wu-Hsing St., Taipei 110, Taiwan; Department of Pharmaceutical Sciences, School of Pharmacy, College of Pharmacy, Taipei Medical University, 250 Wu-Hsing St., Taipei 110, Taiwan. Electronic address: wjhuang@tmu.edu.tw.
  • 11 Ph.D. Program in Drug Discovery and Development Industry, College of Pharmacy, Taipei Medical University, 250 Wu-Hsing St., Taipei 110, Taiwan; Graduate Institute of Medical Sciences and Department of Pharmacology, School of Medicine, College of Medicine, Taipei Medical University, 250 Wu-Hsing St., Taipei 110, Taiwan; Department of Ophthalmology, School of Medicine, College of Medicine, Taipei Medical University, 250 Wu-Hsing St., Taipei 110, Taiwan. Electronic address: geohsiao@tmu.edu.tw.
PMID: 38579401 DOI: 10.1016/j.biopha.2024.116538
Abstract

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.

Keywords

Glaucoma; Glutamate; HDAC8 inhibitor; NMDA; Retinal Müller glia; S100B.

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