Hyperoside mitigates photoreceptor degeneration in part by targeting cGAS and suppressing DNA-induced microglial activation.

Publisher: BioMed Central Country of Publication: England NLM ID: 101610673 Publication Model: Electronic Cited Medium: Internet ISSN: 2051-5960 (Electronic) Linking ISSN: 20515960 NLM ISO Abbreviation: Acta Neuropathol Commun Subsets: MEDLINE

Original Publication: London : BioMed Central, [2013]-

Microglia*/drug effects ; Microglia*/metabolism ; Microglia*/pathology ; Nucleotidyltransferases*/drug effects ; Nucleotidyltransferases*/metabolism ; Quercetin*/pharmacology ; Quercetin*/analogs & derivatives ; Retinal Degeneration*/pathology ; Retinal Degeneration*/metabolism ; Retinal Degeneration*/drug therapy ; Retinal Degeneration*/prevention & control; Animals ; Mice ; Cell Line ; DNA/metabolism ; Mice, Inbred C57BL ; Photoreceptor Cells, Vertebrate/drug effects ; Photoreceptor Cells, Vertebrate/pathology ; Photoreceptor Cells, Vertebrate/metabolism

Activated microglia play an important role in driving photoreceptor degeneration-associated neuroinflammation in the retina. Controlling pro-inflammatory activation of microglia holds promise for mitigating the progression of photoreceptor degeneration. Our previous study has demonstrated that pre-light damage treatment of hyperoside, a naturally occurring flavonol glycoside with antioxidant and anti-inflammatory activities, prevents photooxidative stress-induced photoreceptor degeneration and neuroinflammatory responses in the retina. However, the direct impact of hyperoside on microglia-mediated neuroinflammation during photoreceptor degeneration remains unknown. Upon verifying the anti-inflammatory effects of hyperoside in LPS-stimulated BV-2 cells, our results here further demonstrated that post-light damage hyperoside treatment mitigated the loss of photoreceptors and attenuated the functional decline of the retina. Meanwhile, post-light damage hyperoside treatment lowered neuroinflammatory responses and dampened microglial activation in the illuminated retinas. With respect to microglial activation, hyperoside mitigated the pro-inflammatory responses in DNA-stimulated BV-2 cells and lowered DNA-stimulated production of 2'3'-cGAMP in BV-2 cells. Moreover, hyperoside was shown to directly interact with cGAS and suppress the enzymatic activity of cGAS in a cell-free system. In conclusion, the current study suggests for the first time that the DNA sensor cGAS is a direct target of hyperoside. Hyperoside is effective at mitigating DNA-stimulated cGAS-mediated pro-inflammatory activation of microglia, which likely contributes to the therapeutic effects of hyperoside at curtailing neuroinflammation and alleviating neuroinflammation-instigated photoreceptor degeneration.
(© 2024. The Author(s).)

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82274264 National Natural Science Foundation of China

Keywords: Hyperoside; Microglia activation; Neuroinflammation; Photoreceptor degeneration; cGAS

EC 2.7.7.- (cGAS protein, mouse)
9007-49-2 (DNA)
8O1CR18L82 (hyperoside)
EC 2.7.7.- (Nucleotidyltransferases)
9IKM0I5T1E (Quercetin)

Date Created: 20240516 Date Completed: 20240517 Latest Revision: 20240815

20240815

PMC11097432

10.1186/s40478-024-01793-0

38755736