Professor/Associated Dean Taipei Medical University Taipei City, Taiwan (Republic of China)
Introduction/Rationale: Neuroinflammation contributes to retinal degeneration by activating glia and recruiting peripheral myeloid cells. We examined whether the natural flavonoid isorhamnetin protects the retina by suppressing inflammatory responses in monocytes and microglia.
Methods: THP-1 monocytes were stimulated with tumor necrosis factor alpha (TNF-α), interleukin-1 beta (IL-1β), or lipopolysaccharide (LPS); BV-2 microglia with LPS. Matrix metalloproteinase 9 (MMP-9) activity (zymography) and expression, nitric oxide and inducible nitric oxide synthase (iNOS), and Src/AKT signaling were measured. ARPE-19 cells were exposed to sodium iodate or tert-butyl hydroperoxide for viability. In mice, sodium iodate induced macular degeneration-like injury, with outcomes including electroretinography, optical coherence tomography, pupillary light reflex, opsin and retinal pigment epithelium integrity, and retinal GFAP, MCP-1, MMP-9, and CD11b+ cell activation.
Results: Isorhamnetin suppressed MMP-9 gelatinolytic activity in cytokine- or LPS-stimulated THP-1 cells and reduced TNF-α/LPS-induced MMP-9 mRNA and protein. In BV-2 cells, isorhamnetin decreased LPS-induced nitric oxide release and iNOS expression. Mechanistically, isorhamnetin inhibited Src and AKT activation in THP-1 cells and AKT activation in BV-2 cells. Isorhamnetin had little effect on oxidant-induced ARPE-19 viability but consistently inhibited TNF-α-driven MMP-9 activity. In vivo, isorhamnetin preserved retinal function and thickness, restored chromatic pupillary responses, maintained opsin expression, protected the retinal pigment epithelium structure, reduced GFAP and MCP-1 levels, lowered MMP-9 levels/activity, and decreased the number and activation of CD11b+ immune cells.
Conclusion: Isorhamnetin protects against sodium iodate-induced retinal degeneration primarily through immune-modulatory and anti-inflammatory mechanisms, supporting its potential as a low-cost adjunct strategy for macular degeneration.
