Professor Taipei Medical University Taipei City, Taiwan (Republic of China)
Introduction/Rationale: Neuroinflammation is a critical contributor to ocular inflammatory diseases and sepsis-associated encephalopathy. STAT3 and NF-κB are key signaling regulators in immune cells and microglia. Dehydrocurvularin (DC), a natural metabolite isolated from the marine fungus Curvularia intermedia Km0855, exhibits anti-inflammatory activity; however, its effects on neuroinflammation and ocular inflammation remain unclear.
Methods: The anti-inflammatory effects of DC were examined in LPS-stimulated human monocytic THP-1 cells and murine BV-2 microglial cells. MMP-9 gelatinolytic activity was assessed by zymography, and inflammatory signaling pathways were analyzed by Western blotting and RT-PCR. Intracellular ROS, nitric oxide production, and inflammatory protein expression were evaluated. In vivo efficacy was assessed using an endotoxin-induced uveitis (EIU) model and a sepsis-associated encephalopathy model induced by intracranial LPS injection. Retinal function was evaluated by electroretinography (ERG).
Results: DC significantly suppressed LPS-induced MMP-9 gelatinolytic activity and reduced MMP-9 protein and mRNA expression in THP-1 cells. DC attenuated phosphorylation of STAT3, NF-κB p65, and ERK, and decreased surface TLR4 expression. In BV-2 microglial cells, DC reduced LPS-induced ROS production, nitric oxide release, and iNOS and COX-2 expression, accompanied by inhibition of STAT3 and p65 activation. In vivo, DC pretreatment alleviated retinal inflammation and restored ERG a- and b-wave amplitudes in the EIU model. DC also reduced MMP-9 activity and iNOS and COX-2 expression in striatal tissues in the sepsis-associated encephalopathy model.
Conclusion: Dehydrocurvularin exerts potent anti-inflammatory and neuroprotective effects through inhibition of STAT3- and NF-κB–mediated signaling pathways, highlighting its potential as a marine-derived therapeutic agent for ocular and sepsis-associated neuroinflammatory disorders.
