The fungus-derived retinoprotectant theissenolactone C improves glaucoma-like injury mediated by MMP-9 inhibition
| Autor: | Fan Li Lin, George Hsiao, Yu Wen Cheng, Yu Cheng Kuo, Tzong-Huei Lee, Jau Der Ho, George C.Y. Chiou, Hung Ming Chang, Min Yu |
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| Rok vydání: | 2019 |
| Předmět: |
Male
MAPK/ERK pathway Acetogenins genetic structures Pharmaceutical Science Matrix Metalloproteinase Inhibitors Pharmacology Retina Proinflammatory cytokine Rats Sprague-Dawley 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Western blot Drug Discovery medicine Animals Phosphorylation Chemokine CCL2 Intraocular Pressure Neuroinflammation 030304 developmental biology 0303 health sciences medicine.diagnostic_test Fungi NF-kappa B Transcription Factor RelA Glaucoma Retinal eye diseases Rats Disease Models Animal medicine.anatomical_structure Matrix Metalloproteinase 9 Complementary and alternative medicine chemistry Reperfusion Injury 030220 oncology & carcinogenesis Cytokines Molecular Medicine sense organs Erg Electroretinography |
| Zdroj: | Phytomedicine. 56:207-214 |
| ISSN: | 0944-7113 |
| DOI: | 10.1016/j.phymed.2018.11.002 |
| Popis: | 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-1β (IL-1β) 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-1β-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-κB p65 were tested by Western Blot. Additionally, the levels of inflammatory MCP-1 and IL-1β 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-1β 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-κB-dependent pathways. In addition, LC53 dramatically suppressed IL-1β-induced MMP-9 activation and expression in primary astrocytes. The phosphorylation of 65-kD protein (p65) of NF-κB was substantially blocked by LC53 in IL-1β-stimulated primary astrocytes. Conclusion LC53 exerted a retinal protective effect through NF-κB 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. |
| Databáze: | OpenAIRE |
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