Chryxanthone A, an extracted substance from endophytic fungal Aspergillus versicolor, produces anti-oxidant neuroprotection possibly via the action on mTOR/CREB axis.

Background: Neurons are susceptible to oxidative stress due to the elevated reactive oxygen species (ROS) production and the limited antioxidant defense mechanisms. Therefore, it is possible to treat oxidative stress-related neurological disorders via the inhibition of oxidative stress. Chryxanthone A is an extracted substance derived from the endophytic fungal Aspergillus versicolor, with an atypical dihydropyran ring. However, it is unknown whether and how chryxanthone A could produce anti-oxidant protection.

Purposes: The activity and mechanisms underlying the anti-oxidant protection of chryxanthone A were explored in the study.

Study Design And Methods: HT22 neuronal cells were used to evaluate the anti-oxidant protection of chryxanthone A. Comprehensive bioinformatic methods, including RNA-seq analysis, transcription factor prediction, CMap prediction and molecular docking analysis, were utilized to explore the molecular mechanisms how chryxanthone A prevented oxidative stress, which was confirmed by Western blotting analysis.

Results: Chryxanthone A concentration-dependently prevented HO-induced cell death and increase in intracellular ROS in HT22 cells. Results from RNA-seq and bioinformatic analysis indicated that chryxanthone A might act on mTOR/CREB axis, possibly via binding to the Val2227 site within ATP binding pocket of mTOR. The action of chryxanthone A on HO-induced alteration of mTOR/CREB axis were further confirmed in HT22 cells.

Conclusion: These results suggested that chryxanthone A produced anti-oxidant protection via the action on mTOR/CREB axis, providing a support that chryxanthone A might be developed as a novel drug candidate for the treatment of oxidative stress-related disorders.