PMID- 30668341 OWN - NLM STAT- MEDLINE DCOM- 20190521 LR - 20190521 IS - 1618-095X (Electronic) IS - 0944-7113 (Linking) VI - 56 DP - 2019 Mar 15 TI - The fungus-derived retinoprotectant theissenolactone C improves glaucoma-like injury mediated by MMP-9 inhibition. PG - 207-214 LID - S0944-7113(18)30558-0 [pii] LID - 10.1016/j.phymed.2018.11.002 [doi] AB - BACKGROUND: Elevated intraocular pressure (IOP) is a major risk factor for glaucoma that has been found to induce matrix metalloproteinase-9 (MMP-9) activation and result in eventual retinal dysfunction. Proinflammatory cytokines such as monocyte chemoattractant protein-1 (MCP-1) and interleukin-1beta (IL-1beta) were also found to be involved in disease progression by mediating MMP-9 production. We previously reported that fungal derivative theissenolactone C (LC53) could exert ocular protective effects by suppressing neuroinflammation in experimental uveitis. PURPOSE: The aim of this study was to investigate the retinoprotective effects of natural compound LC53 on the high IOP-induced ischemia/reperfusion (I/R)-injury model of glaucoma and its cellular mechanisms. METHODS: A high IOP-induced I/R-injury model was manipulated by normal saline injection into the anterior chamber of the rat eye. MCP-1-stimulated monocytes and IL-1beta-activated primary astrocytes were used to investigate the cellular mechanisms of LC53. Retinal function was evaluated with the scotopic threshold response (STR) and combined rod-cone response by electroretinography (ERG). As a positive control, rats were treated with memantine. MMP-9 gelatinolysis, mRNA expression and protein expression were analyzed by gelatin zymography, RT-PCR, and Western Blot, respectively. The phosphorylation levels of MAPKs and NF-kappaB p65 were tested by Western Blot. Additionally, the levels of inflammatory MCP-1 and IL-1beta were determined by ELISA. RESULTS: The present study revealed that LC53 preserved the retina functional deficiency assessed by scotopic threshold response (STR) and combined rod-cone response of ERG after high IOP-induced I/R injury. These retinal protective effects of LC53 were positively correlated with inhibitory activities in I/R injury-elicited ocular MMP-9 activation and expression. The increased level of MCP-1 was not affected, and the enhanced IL-1beta production was partially reduced by LC53 in the retina after I/R injury. According to cellular studies, LC53 significantly and concentration-dependently abrogated MMP-9 activation and expression in MCP-1-stimulated THP-1 monocytes. We found the inhibitory activities of LC53 were through the ERK- and NF-kappaB-dependent pathways. In addition, LC53 dramatically suppressed IL-1beta-induced MMP-9 activation and expression in primary astrocytes. The phosphorylation of 65-kD protein (p65) of NF-kappaB was substantially blocked by LC53 in IL-1beta-stimulated primary astrocytes. CONCLUSION: LC53 exerted a retinal protective effect through NF-kappaB inhibition and was highly potent against MMP-9 activities after high IOP-induced I/R injury, suggesting that LC53 would be a promising drug lead for glaucoma or related medical conditions attributed to retinal ischemia. CI - Copyright (c) 2018. Published by Elsevier GmbH. FAU - Lin, Fan-Li AU - Lin FL AD - 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. FAU - Cheng, Yu-Wen AU - Cheng YW AD - School of Pharmacy, College of Pharmacy, Taipei Medical University, 250 Wu-Hsing St. Taipei 110, Taiwan. FAU - Yu, Min AU - Yu M AD - 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. FAU - Ho, Jau-Der AU - Ho JD AD - Department of Ophthalmology, Taipei Medical University Hospital, 252 Wu-Hsing St. Taipei 110, Taiwan. FAU - Kuo, Yu-Cheng AU - Kuo YC AD - 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. FAU - Chiou, George C Y AU - Chiou GCY AD - Department of Neuroscience and Experimental Therapeutics, College of Medicine, Texas A&M Health Science Center, College Station, 8447 Riverside Pkwy, Bryan, TX 77807, USA. FAU - Chang, Hung-Ming AU - Chang HM AD - Department of Anatomy, School of Medicine, College of Medicine, Taipei Medical University, 250 Wu-Hsing St. Taipei 110, Taiwan. FAU - Lee, Tzong-Huei AU - Lee TH AD - Institute of Fisheries Science, National Taiwan University, No. 1, Sec. 4, Roosevelt Rd., Taipei 106, Taiwan. FAU - Hsiao, George AU - Hsiao G AD - 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; Ph.D. Program for the Clinical Drug Discovery from Botanical Herbs, College of Pharmacy, College of Pharmacy, Taipei Medical University, 250 Wu-Hsing St. Taipei 110, Taiwan. Electronic address: geohsiao@tmu.edu.tw. LA - eng PT - Journal Article DEP - 20181107 PL - Germany TA - Phytomedicine JT - Phytomedicine : international journal of phytotherapy and phytopharmacology JID - 9438794 RN - 0 (2,3,7,7a-tetrahydro-3-hydroxy-7-methyl-2-(prop-1-en-1-yl)-5H-furo(3,4-b)pyran-5-one) RN - 0 (Acetogenins) RN - 0 (Chemokine CCL2) RN - 0 (Cytokines) RN - 0 (Matrix Metalloproteinase Inhibitors) RN - 0 (NF-kappa B) RN - 0 (Transcription Factor RelA) RN - EC 3.4.24.35 (Matrix Metalloproteinase 9) SB - IM MH - Acetogenins/chemistry/isolation & purification/*pharmacology MH - Animals MH - Chemokine CCL2/metabolism MH - Cytokines/metabolism MH - Disease Models, Animal MH - Fungi/*chemistry MH - Glaucoma/*drug therapy MH - Intraocular Pressure MH - Male MH - Matrix Metalloproteinase 9/*metabolism MH - Matrix Metalloproteinase Inhibitors/*pharmacology MH - NF-kappa B/antagonists & inhibitors MH - Phosphorylation MH - Rats MH - Rats, Sprague-Dawley MH - Reperfusion Injury/*drug therapy MH - Retina/drug effects/metabolism MH - Transcription Factor RelA/metabolism OTO - NOTNLM OT - Glaucoma OT - Intraocular pressure OT - LC53 OT - Matrix metalloproteinase-9 OT - Monocyte chemoattractant protein-1 OT - NF-kappaB EDAT- 2019/01/23 06:00 MHDA- 2019/05/22 06:00 CRDT- 2019/01/23 06:00 PHST- 2018/06/27 00:00 [received] PHST- 2018/11/01 00:00 [revised] PHST- 2018/11/03 00:00 [accepted] PHST- 2019/01/23 06:00 [pubmed] PHST- 2019/05/22 06:00 [medline] PHST- 2019/01/23 06:00 [entrez] AID - S0944-7113(18)30558-0 [pii] AID - 10.1016/j.phymed.2018.11.002 [doi] PST - ppublish SO - Phytomedicine. 2019 Mar 15;56:207-214. doi: 10.1016/j.phymed.2018.11.002. Epub 2018 Nov 7.