Nobiletin and Eriodictyol Suppress Release of IL-1β, CXCL8, IL-6, and MMP-9 from LPS, SARS-CoV-2 Spike Protein, and Ochratoxin A-Stimulated Human Microglia.

Neuroinflammation is involved in various neurological and neurodegenerative disorders in which the activation of microglia is one of the key factors. In this study, we examined the anti-inflammatory effects of the flavonoids nobiletin (5,6,7,8,3',4'-hexamethoxyflavone) and eriodictyol (3',4',5,7-tetraxydroxyflavanone) on human microglia cell line activation stimulated by either lipopolysaccharide (LPS), severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) full-length Spike protein (FL-Spike), or the mycotoxin ochratoxin A (OTA). Human microglia were preincubated with the flavonoids (10, 50, and 100 µM) for 2 h, following which, they were stimulated for 24 h. The inflammatory mediators interleukin-1 beta (IL-1β), chemokine (C-X-C motif) ligand 8 (CXCL8), IL-6, and matrix metalloproteinase-9 (MMP-9) were quantified in the cell culture supernatant by enzyme-linked immunosorbent assay (ELISA). Both nobiletin and eriodictyol significantly inhibited the LPS, FL-Spike, and OTA-stimulated release of IL-1β, CXCL8, IL-6, and MMP-9 at 50 and 100 µM, while, in most cases, nobiletin was also effective at 10 µM, with the most pronounced reductions at 100 µM. These findings suggest that both nobiletin and eriodictyol are potent inhibitors of the pathogen-stimulated microglial release of inflammatory mediators, highlighting their potential for therapeutic application in neuroinflammatory diseases, such as long COVID.